Disorders of Ventilation

Hypoventilation

Definition and Etiology

Alveolar hypoventilation exists by definition when arterial PCO2 (PaCO2) increases above the normal range of 37–43 mmHg, but in clinically important hypoventilation syndromes PaCO2 is generally in the range of 50–80 mmHg. Hypoventilation disorders can be acute or chronic. This chapter deals with chronic hypoventilation syndromes. The acute disorders, which represent life-threatening emergencies, are discussed in Chap. 262.

Chronic hypoventilation can result from numerous disease entities (Table 258-1), but in all cases the underlying mechanism involves a defect in either the metabolic respiratory control system, the respiratory neuromuscular system, or the ventilatory apparatus. Disorders associated with impaired respiratory drive, defects in the respiratory neuromuscular system, some chest wall disorders such as obesity, and upper airway obstruction produce an increase in PaCO2, despite normal lungs, because of a reduction in overall minute volume of ventilation and hence in alveolar ventilation. In contrast, most disorders of the chest wall and disorders of the lower airways and lungs may produce an increase in PaCO2, despite a normal or even increased minute volume of ventilation, because of severe ventilation-perfusion mismatching that results in net alveolar hypoventilation.

Table 258-1 Chronic Hypoventilation Syndromes



Mechanism Site of Defect Disorder
Impaired respiratory drive Peripheral and central chemoreceptors Carotid body dysfunction, trauma

Prolonged hypoxia

Metabolic alkalosis

Brainstem respiratory neurons Bulbar poliomyelitis, encephalitis

Brainstem infarction, hemorrhage, trauma

Brainstem demyelination, degeneration

Chronic drug administration

Hypothyroidism

Primary alveolar hypoventilation syndrome

Defective respiratory neuromuscular system Spinal cord and peripheral nerves High cervical trauma

Poliomyelitis

Motor neuron disease

Peripheral neuropathy

Respiratory muscles Myasthenia gravis

Muscular dystrophy

Chronic myopathy

Impaired ventilatory apparatus Chest wall Kyphoscoliosis

Fibrothorax

Thoracoplasty

Ankylosing spondylitis

Obesity hypoventilation

Airways and lungs Laryngeal and tracheal stenosis

Obstructive sleep apnea

Cystic fibrosis

Chronic obstructive pulmonary disease




Source: From EA Phillipson, AS Slutsky in JF Murray, JA Nadel (eds), Textbook of Respiratory Medicine, 3d ed. Philadelphia, Saunders, 2000; with permission.


Several hypoventilation syndromes involve combined disturbances in two elements of the respiratory system. For example, patients with chronic obstructive pulmonary disease may hypoventilate not simply because of impaired ventilatory mechanics but also because of a reduced central respiratory drive, which can be inherent or secondary to a coexisting metabolic alkalosis (related to diuretic and steroid therapy).

Physiologic and Clinical Features

Regardless of cause, the hallmark of all alveolar hypoventilation syndromes is an increase in alveolar PCO2 (PACO2) and therefore in PaCO2 (Fig. 258-1). The resulting respiratory acidosis eventually leads to a compensatory increase in plasma HCO3– concentration and a decrease in Cl– concentration. The increase in PACO2 produces an obligatory decrease in PAO2, resulting in hypoxemia. If severe, the hypoxemia manifests clinically as cyanosis and can stimulate erythropoiesis and induce secondary polycythemia. The combination of chronic hypoxemia and hypercapnia may also induce pulmonary vasoconstriction, leading eventually to pulmonary hypertension, right ventricular hypertrophy, and congestive heart failure. The disturbances in arterial blood gases are typically magnified during sleep because of a further reduction in central respiratory drive. The resulting increased nocturnal hypercapnia may cause cerebral vasodilation leading to morning headache; sleep quality may also be severely impaired, resulting in morning fatigue, daytime somnolence, mental confusion, and intellectual impairment. Other clinical features associated with hypoventilation syndromes are related to the specific underlying disease (Table 258-1).

Figure 258-1




Physiologic and clinical features of alveolar hypoventilation. Hb, hemoglobin; PaCO2, arterial PCO2; PaO2, arterial PO2. [After EA Phillipson, AS Slutsky, in JF Murray, JA Nadel (eds), Textbook of Respiratory Medicine, 3d ed. Philadelphia, Saunders, 2000.]



Diagnosis

Investigation of the patient with chronic hypoventilation involves several laboratory tests that will usually localize the disorder to either the metabolic respiratory control system, the neuromuscular system, or the ventilatory apparatus (Fig. 258-2). Defects in the control system impair responses to chemical stimuli, including ventilatory, occlusion pressure, and diaphragmatic electromyographic (EMG) responses. During sleep, hypoventilation is usually more marked, and central apneas and hypopneas are common. However, because the behavioral respiratory control system (which is anatomically distinct from the metabolic control system), the neuromuscular system, and the ventilatory apparatus are intact, such patients can usually hyperventilate voluntarily, generate normal inspiratory and expiratory muscle pressures (PImax, PEmax, respectively) against an occluded airway, generate normal lung volumes and flow rates on routine spirometry, and have normal respiratory system resistance and compliance and a normal alveolar-arterial PO2[(A–a)PO2] difference.

Figure 258-2




Pattern of laboratory test results in alveolar hypoventilation syndromes, based on the site of defect. Ventil, ventilation; P.1, mouth pressure generated after 0.1 s of inspiration against an occluded airway; EMGdi, diaphragmatic EMG; PImax, PEmax, maximum inspiratory or expiratory pressure that can be generated against an occluded airway; (A–a)PO2, alveolar-arterial PO2 difference; N, normal. Defects in the metabolic control system impair central respiratory drive in response to chemical stimuli (CO2 or hypoxia); therefore responses of EMGdi, P.1, and minute volume of ventilation are reduced and hypoventilation during sleep is aggravated. In contrast, tests of voluntary respiratory control, muscle strength, lung mechanics, and gas exchange [(A–a)PO2] are normal. Defects in the respiratory neuromuscular system impair muscle strength; therefore all tests dependent on muscular activity (voluntary or in response to metabolic stimuli) are abnormal, but lung resistance, lung compliance, and gas exchange are normal. Defects in the ventilatory apparatus usually impair gas exchange. Because resistance and compliance are also impaired, all tests dependent on ventilation (whether voluntary or in response to chemical stimuli) are abnormal; in contrast, tests of muscle activity or strength that do not involve airflow (i.e., P.1, EMGdi, PImax, PEmax) are normal. (After Phillipson and Duffin.)



Patients with defects in the respiratory neuromuscular system also have impaired responses to chemical stimuli but in addition are unable to hyperventilate voluntarily or to generate normal static respiratory muscle pressures, lung volumes, and flow rates. However, at least in the early stages of the disease, the resistance and compliance of the respiratory system and the alveolar-arterial oxygen difference are normal.

In contrast to patients with disorders of the respiratory control or neuromuscular systems, patients with disorders of the chest wall, lungs, and airways typically demonstrate abnormalities of respiratory system resistance and compliance and have a widened (A–a)PO2. Because of the impaired mechanics of breathing, routine spirometric tests are abnormal, as is the ventilatory response to chemical stimuli. However, because the neuromuscular system is intact, tests that are independent of resistance and compliance are usually normal, including tests of respiratory muscle strength and respiratory control that do not involve airflow.

Hypoventilation: Treatment

The management of chronic hypoventilation must be individualized to the patient's particular disorder, circumstances, and needs and should include measures directed toward the underlying disease. Coexistent metabolic alkalosis should be corrected, including elevations of HCO3– that are inappropriately high for the degree of chronic hypercapnia. Administration of supplemental oxygen is effective in attenuating hypoxemia, polycythemia, and pulmonary hypertension but can aggravate CO2 retention and the associated neurologic symptoms. For this reason, supplemental oxygen must be prescribed judiciously and the results monitored carefully. Pharmacologic agents that stimulate respiration, such as progesterone and methylxanthines, are of benefit in some patients, but results are generally disappointing.

Most patients with chronic hypoventilation related to impairment of respiratory drive or neuromuscular disease eventually require mechanical ventilatory assistance for effective management. When hypoventilation is severe, treatment may be required on a 24-h basis, but in most patients ventilatory assistance only during sleep produces dramatic improvement in clinical features and daytime arterial blood gases. In patients with reduced respiratory drive but intact respiratory lower motor neurons, phrenic nerves, and respiratory muscles, diaphragmatic pacing through an implanted phrenic electrode can be very effective. However, for patients with defects in the respiratory nerves and muscles, electrophrenic pacing is contraindicated. Such patients can usually be managed effectively with either intermittent negative-pressure ventilation in a cuirass or intermittent positive-pressure ventilation delivered through a tracheostomy or nose mask. For patients who require ventilatory assistance only during sleep, positive-pressure ventilation through a nose mask is the preferred method because it obviates a tracheostomy and avoids the problem of upper airway occlusion that can arise in a negative-pressure ventilator. Hypoventilation related to restrictive disorders of the chest wall (Table 258-1) can also be managed effectively with nocturnal intermittent positive-pressure ventilation through a nose mask or tracheostomy.

Hypoventilation Syndromes

Primary Alveolar Hypoventilation

Primary alveolar hypoventilation (PAH) is a disorder of unknown cause characterized by chronic hypercapnia and hypoxemia in the absence of identifiable neuromuscular disease or mechanical ventilatory impairment. The disorder is thought to arise from a defect in the metabolic respiratory control system, but few neuropathologic studies have been reported in such patients. Studies in animals suggest an important role for genetic factors in the pathogenesis of hypoventilation, and familial cases in humans have been described. Isolated PAH is relatively rare, and although it occurs in all age groups, the majority of reported cases in adults have been in males ages 20–50 years. The disorder typically develops insidiously and often first comes to attention when severe respiratory depression follows administration of standard doses of sedatives or anesthetics. As the degree of hypoventilation increases, patients typically develop lethargy, fatigue, daytime somnolence, disturbed sleep, and morning headaches; eventually cyanosis, polycythemia, pulmonary hypertension, and congestive heart failure occur (Fig. 258-1). Despite severe arterial blood gas derangements, dyspnea is uncommon, presumably because of impaired chemoreception and ventilatory drive. If left untreated, PAH is usually progressive over a period of months to years and ultimately fatal.

The key diagnostic finding in PAH is a chronic respiratory acidosis in the absence of respiratory muscle weakness or impaired ventilatory mechanics (Fig. 258-2). Because patients can hyperventilate voluntarily and reduce PaCO2 to normal or even hypocapnic levels, hypercapnia may not be demonstrable in a single arterial blood sample, but the presence of an elevated plasma HCO3– level should draw attention to the underlying chronic disturbance. Despite normal ventilatory mechanics and respiratory muscle strength, ventilatory responses to chemical stimuli are reduced or absent (Fig. 258-2), and breath-holding time may be markedly prolonged without any sensation of dyspnea.

Patients with PAH maintain rhythmic respiration when awake, although the level of ventilation is below normal. However, during sleep, when breathing is critically dependent on the metabolic control system, there is typically a further deterioration in ventilation, with frequent episodes of central hypopnea or apnea.

PAH must be distinguished from other central hypoventilation syndromes that are secondary to underlying neurologic disease of the brainstem or chemoreceptors (Table 258-1). This distinction requires a careful neurologic investigation for evidence of brainstem or autonomic disturbances. Unrecognized respiratory neuromuscular disorders, particularly those that produce diaphragmatic weakness, are often misdiagnosed as PAH. However, such disorders can usually be suspected on clinical grounds (see below) and can be confirmed by the finding of reduced voluntary hyperventilation, as well as PImax and PEmax.

Patients with PAH must be cautioned against the use of sedative medications, which may readily induce acute respiratory failure. Some patients respond favorably to respiratory stimulant medications and to supplemental oxygen. However, the majority eventually require mechanical ventilatory assistance. Excellent long-term benefits can be achieved with diaphragmatic pacing by electrophrenic stimulation or with negative- or positive-pressure mechanical ventilation. The administration of such treatment only during sleep is sufficient in most patients.

Respiratory Neuromuscular Disorders

Several primary disorders of the spinal cord, peripheral respiratory nerves, and respiratory muscles produce a chronic hypoventilation syndrome (Table 258-1). Hypoventilation usually develops gradually over a period of months to years and often first comes to attention when a relatively trivial increase in mechanical ventilatory load (such as mild airways obstruction) produces severe respiratory failure. In some of the disorders (such as motor neuron disease, myasthenia gravis, and muscular dystrophy), involvement of the respiratory nerves or muscles is usually a later feature of a more widespread disease. In other disorders, respiratory involvement can be an early or even isolated feature, and hence the underlying problem is often not suspected. Included in this category are the postpolio syndrome (a form of chronic respiratory insufficiency that develops 20–30 years following recovery from poliomyelitis), the myopathy associated with adult acid maltase deficiency, and idiopathic diaphragmatic paralysis.

Generally, respiratory neuromuscular disorders do not result in chronic hypoventilation unless there is significant weakness of the diaphragm. Distinguishing features of bilateral diaphragmatic weakness include orthopnea, paradoxical movement of the abdomen in the supine posture, and paradoxical diaphragmatic movement under fluoroscopy. However, the absence of these features does not exclude diaphragmatic weakness. Important laboratory features are a fall in forced vital capacity in the supine, compared to the upright, posture; a rapid deterioration of ventilation during a maximum voluntary ventilation maneuver; and reduced PImax and PEmax (Fig. 258-2). More sophisticated investigations reveal reduced or absent transdiaphragmatic pressures, calculated from simultaneous measurement of esophageal and gastric pressures; reduced diaphragmatic EMG responses (recorded from an esophageal electrode) to transcutaneous phrenic nerve stimulation; and marked hypopnea and arterial oxygen desaturation during rapid eye movement sleep, when there is normally a physiologic inhibition of all nondiaphragmatic respiratory muscles and breathing becomes critically dependent on diaphragmatic activity.

The management of chronic alveolar hypoventilation due to respiratory neuromuscular disease involves treatment of the underlying disorder, where feasible, and mechanical ventilatory assistance as described for the PAH syndrome. However, electrophrenic diaphragmatic pacing is contraindicated in these disorders, except for high cervical spinal cord lesions in which the phrenic lower motor neurons and nerves are intact.

Obesity-Hypoventilation Syndrome

Massive obesity represents a mechanical load to the respiratory system because the added weight on the rib cage and abdomen serves to reduce the compliance of the chest wall. As a result, the functional residual capacity (i.e., end-expiratory lung volume) is reduced, particularly in the recumbent posture. An important consequence of breathing at a low lung volume is that some airways, particularly those in the lung bases, may be closed throughout part or even all of each tidal breath, resulting in underventilation of the lung bases and widening of the (A–a)PO2. Nevertheless, in the majority of obese individuals, central respiratory drive is increased sufficiently to maintain a normal PaCO2. However, a small proportion of obese patients develop chronic hypercapnia, hypoxemia, and eventually polycythemia, pulmonary hypertension, and right-sided heart failure. Studies in mice demonstrate that genetically obese mice lacking circulating leptin also develop chronic hypoventilation that can be reversed by leptin infusions. In humans with obesity-hypoventilation syndrome, serum leptin levels are elevated, suggesting that leptin resistance may play a role in the pathogenesis of the disorder.

In many patients, obstructive sleep apnea (Chap. 259) is a prominent feature, and even in those patients without sleep apnea, sleep-induced hypoventilation is an important element of the disorder and contributes to its progression. Most patients demonstrate a decrease in central respiratory drive, which may be inherent or acquired, and many have mild to moderate degrees of airflow obstruction, usually related to smoking. Based on these considerations, several therapeutic measures can be of considerable benefit, including weight loss, cessation of smoking, elimination of obstructive sleep apnea, and enhancement of respiratory drive by medications such as progesterone.

Hyperventilation and Its Syndromes

Definition and Etiology

Alveolar hyperventilation exists when PaCO2 decreases below the normal range of 37–43 mmHg. Hyperventilation is not synonymous with hyperpnea, which refers to an increased minute volume of ventilation without reference to PaCO2. Although hyperventilation is frequently associated with dyspnea, patients who are hyperventilating do not necessarily complain of shortness of breath; and conversely, patients with dyspnea need not be hyperventilating.

Numerous disease entities can be associated with alveolar hyperventilation (Table 258-2), but in all cases the underlying mechanism involves an increase in respiratory drive that is mediated through either the behavioral or the metabolic respiratory control systems (Fig. 258-3). Thus, hypoxemia drives ventilation by stimulating the peripheral chemoreceptors, and several pulmonary disorders and congestive heart failure drive ventilation by stimulating afferent vagal receptors in the lungs and airways. Low cardiac output and hypotension stimulate the peripheral chemoreceptors and inhibit the baroreceptors, both of which increase ventilation. Metabolic acidosis, a potent respiratory stimulant, excites both the peripheral and central chemoreceptors and increases the sensitivity of the peripheral chemoreceptors to coexistent hypoxemia. Hepatic failure can also produce hyperventilation, presumably as a result of metabolic stimuli acting on the peripheral and central chemoreceptors.

Table 258-2 Hyperventilation Syndromes



1. Hypoxemia
a. High altitude
b. Pulmonary disease
c. Cardiac shunts
2. Pulmonary disorders
a. Pneumonia
b. Interstitial pneumonitis, fibrosis, edema
c. Pulmonary emboli, vascular disease
d. Bronchial asthma
e. Pneumothorax
f. Chest wall disorders
3. Cardiovascular disorders
a. Congestive heart failure
b. Hypotension
4. Metabolic disorders
a. Acidosis (diabetic, renal, lactic)
b. Hepatic failure
5. Neurologic and psychogenic disorders
a. Psychogenic or anxiety hyperventilation
b. Central nervous system infection, tumors
6. Drug-induced
a. Salicylates
b. Methylxanthine derivatives
c. -Adrenergic agonists
d. Progesterone
7. Miscellaneous
a. Fever, sepsis
b. Pain
c. Pregnancy



Figure 258-3




Schematic diagram of the mechanisms involved in alveolar hyperventilation. [From EA Phillipson, AS Slutsky, in JF Murray, JA Nadel (eds), Textbook of Respiratory Medicine, 3d ed. Philadelphia, Saunders, 2000.]



Several neurologic and psychological disorders are thought to drive ventilation through the behavioral respiratory control system. Included in this category are psychogenic or anxiety hyperventilation and severe cerebrovascular insufficiency, which may interfere with the inhibitory influence normally exerted by cortical structures on the brainstem respiratory neurons. Rarely, disorders of the midbrain and hypothalamus induce hyperventilation, and it is conceivable that fever and sepsis also cause hyperventilation through effects on these structures. Several drugs cause hyperventilation by stimulating the central or peripheral chemoreceptors or by direct action on the brainstem respiratory neurons. Chronic hyperventilation is a normal feature of pregnancy and results from the effects of progesterone and other hormones acting on the respiratory neurons.

Physiologic and Clinical Features

Because hyperventilation is associated with increased respiratory drive, muscle effort, and minute volume of ventilation, the most frequent symptom associated with hyperventilation is dyspnea. However, there is considerable discrepancy between the degree of hyperventilation, as measured by PaCO2, and the degree of associated dyspnea. From a physiologic standpoint, hyperventilation is beneficial in patients who are hypoxemic, because the alveolar hypocapnia is associated with an increase in alveolar and arterial PO2. Conversely, hyperventilation can also be detrimental. In particular, the alkalemia associated with hypocapnia may produce neurologic symptoms, including dizziness, visual impairment, syncope, and seizure activity (secondary to cerebral vasoconstriction); paresthesia, carpopedal spasm, and tetany (secondary to decreased free serum calcium); and muscle weakness (secondary to hypophosphatemia). It may also be associated with panic attacks, and severe alkalemia can induce cardiac arrhythmias and evidence of myocardial ischemia. Patients with a primary respiratory alkalosis are also prone to periodic breathing and central sleep apnea (Chap. 259).

Diagnosis

In most patients with a hyperventilation syndrome, the cause is readily apparent on the basis of history, physical examination, and knowledge of coexisting medical disorders (Table 258-2). In patients in whom the cause is not clinically apparent, investigation begins with arterial blood gas analysis, which establishes the presence of alveolar hyperventilation (decreased PaCO2) and its severity. Equally important is the arterial pH, which generally allows the disorder to be classified as either a primary respiratory alkalosis (elevated pH) or a primary metabolic acidosis (decreased pH). Also of importance is the PaO2 and calculation of the (A–a)PO2, since a widened alveolar-arterial oxygen difference suggests a pulmonary disorder as the underlying cause. The finding of a reduced plasma HCO3– level establishes the chronic nature of the disorder and points toward an organic cause. Measurements of ventilation and arterial or transcutaneous PCO2 during sleep are very useful in suspected psychogenic hyperventilation, since such patients do not maintain the hyperventilation during sleep.

The disorders that most frequently give rise to unexplained hyperventilation are pulmonary vascular disease (particularly chronic or recurrent thromboembolism) and psychogenic or anxiety hyperventilation. Hyperventilation due to pulmonary vascular disease is associated with exertional dyspnea, a widened (A–a)PO2 and maintenance of hyperventilation during exercise. In contrast, patients with psychogenic hyperventilation typically complain of dyspnea at rest, but not during mild exercise, and of the need to sigh frequently. They are also more likely to complain of dizziness, sweating, palpitations, and paresthesia. During mild to moderate exercise, their hyperventilation tends to disappear and (A–a)PO2 is normal, but heart rate and cardiac output may be increased relative to metabolic rate.

Hyperventilation: Treatment

Mild alveolar hyperventilation is usually of relatively minor clinical consequence and therefore is generally managed by appropriate treatment of the underlying cause. In the few patients in whom alkalemia is thought to be inducing significant cerebral vasoconstriction, paresthesia, tetany, or cardiac disturbances, acute inhalation of a low concentration of CO2 can be very beneficial. For patients with disabling psychogenic hyperventilation, careful explanation of the basis of their symptoms can be reassuring and is often sufficient. Others have benefited from -adrenergic antagonists or an exercise program. Specific treatment for anxiety may also be indicated.