Hypoventilation Syndromes

Alveolar hypoventilation is caused by several disorders that are collectively referred as hypoventilation syndromes. Alveolar hypoventilation is defined as insufficient ventilation leading to hypercapnia, which is an increase in the partial pressure of carbon dioxide as measured by arterial blood gas analysis (PaCO₂). ^[1] (See Etiology.)

Patients who hypoventilate may develop clinically significant hypoxemia, and the presence of hypoxemia along with hypercapnia aggravates the clinical manifestations seen with hypoventilation syndromes. Alveolar hypoventilation may be acute or chronic and may be caused by several mechanisms. (See Etiology and Presentation.)

The specific hypoventilation syndromes discussed in this article include the following (See Etiology, Presentation, Workup, Treatment, and Medication):

• Central alveolar hypoventilation

• Obesity-hypoventilation syndrome (OHS)

• Chest wall deformities

• Neuromuscular disorders

• Chronic obstructive pulmonary disease (COPD)

Central alveolar hypoventilation

The phrase "central alveolar hypoventilation" is used to describe patients with alveolar hypoventilation secondary to an underlying neurologic disease. Causes of central alveolar hypoventilation include drugs and central nervous system (CNS) diseases such as cerebrovascular accidents, trauma, and neoplasms.

Obesity-hypoventilation syndrome

OHS is another well-known cause of hypoventilation. Abnormal central ventilatory drive and obesity contribute to the development of OHS. OHS is defined as a combination of obesity and a body mass index greater than or equal to 30kg/m² with awake chronic hypercapnia (PaCO₂ >45 mm Hg). Other disorders that may cause hypoventilation should be ruled out first. Approximately 90% of patients with OHS also have obstructive sleep apnea (OSA). ^[2] Hypoventilation is worse during rapid eye movement (REM) sleep than during non-REM sleep.

Chest wall deformities

Chest wall deformities such as kyphoscoliosis, fibrothorax, and those occurring postthoracoplasty are associated with alveolar hypoventilation leading to respiratory insufficiency and respiratory failure.

Neuromuscular disorders

Neuromuscular diseases that can cause alveolar hypoventilation include myasthenia gravis, amyotrophic lateral sclerosis, Guillain-Barré syndrome, and muscular dystrophy. Patients with neuromuscular disorders have rapid, shallow breathing secondary to severe muscle weakness or abnormal motor neuron function.

The central respiratory drive is maintained in patients with neuromuscular disorders. Thus, hypoventilation is secondary to respiratory muscle weakness. Patients with neuromuscular disorders have nocturnal desaturations that are most prevalent in the REM stage of sleep. The degree of nocturnal desaturation is correlated with the degree of diaphragm dysfunction. The nocturnal desaturations may precede the onset of daytime hypoventilation and gas exchange abnormalities.

Chronic obstructive pulmonary disease

Hypoventilation is not uncommon in patients with severe COPD. Alveolar hypoventilation in COPD usually does not occur unless the forced expiratory volume in 1 second (FEV₁) is less than 1L or 30% of the predicted value. However, many patients with severe airflow obstruction do not develop hypoventilation. Therefore, other factors, such as abnormal control of ventilation, genetic predisposition, and respiratory muscle weakness, are likely to contribute.

Respiratory physiology

The respiratory control system tightly regulates ventilation. Alveolar ventilation (VA) is under the control of the central respiratory centers, which are located in the ventral aspects of the pons and medulla. The control of ventilation has metabolic and voluntary neural components. The metabolic component is spontaneous and receives chemical and neural stimuli from the chest wall and lung parenchyma and receives chemical stimuli from the blood levels of carbon dioxide and oxygen.

Metabolism rapidly generates a large quantity of volatile acid (carbon dioxide) and nonvolatile acid in the body. The metabolism of fats and carbohydrates leads to the formation of a large amount of carbon dioxide, which combines with water to form carbonic acid (H₂ CO₃). The lungs excrete the volatile fraction via ventilation. Therefore, acid accumulation does not occur. PaCO₂ is tightly maintained in a range of 39-41 mm Hg in normal states.

Ventilation is influenced and regulated by chemoreceptors for PaCO₂, PaO₂, and pH, located in the brainstem; by neural impulses from lung stretch receptors; and by impulses from the cerebral cortex. Failure of any of these mechanisms results in a state of hypoventilation and hypercapnia.

Hypoventilation and sleep

Hypoventilation and oxygen desaturation deteriorate during sleep secondary to a decrement in ventilatory response to hypoxia and increased PaCO₂. In addition, diminished muscle tone develops during REM sleep, which further exacerbates hypoventilation secondary to insufficient respiratory effort.

The respiratory system serves a dual purpose: delivering oxygen to the pulmonary capillary bed from the environment and eliminating carbon dioxide from the bloodstream by removing it from the pulmonary capillary bed. Metabolic production of carbon dioxide occurs rapidly. Thus, a failure of ventilation promptly increases PaCO₂.

Hypoventilation may be secondary to several mechanisms, including central respiratory drive depression, neuromuscular disorders, chest wall abnormalities, obesity hypoventilation, and COPD. The specific causes can be summarized as follows:

• COPD

• Neuromuscular disorders ^[3] - Amyotrophic lateral sclerosis, muscular dystrophies (Duchenne and Becker dystrophies), diaphragm paralysis, Guillain-Barré syndrome, myasthenia gravis

• Chest wall deformities - Kyphoscoliosis, fibrothorax, thoracoplasty

• Central respiratory drive depression - Drugs (narcotics, benzodiazepines, barbiturates), neurologic disorders (encephalitis, brainstem disease, trauma, poliomyelitis, multiple sclerosis), primary alveolar hypoventilation

• Obesity-hypoventilation syndrome (OHS)

• Carotid body resection and/or injury

• Myxedema (severe hypothyroidism)

Gas exchange abnormalities

The alveoli are perfused by venous blood flow from the pulmonary capillary bed and participate in gas exchange. This gas exchange includes delivery of oxygen to the capillary bed and elimination of carbon dioxide from the bloodstream. The continued removal of carbon dioxide from the blood is dependent on adequate ventilation.

The relationship between ventilation and PaCO₂ can be expressed as PaCO₂ = (k)(VCO₂)/VA, in which VCO₂ is the metabolic production of carbon dioxide (ie, venous carbon dioxide production), k is a constant, and VA is alveolar ventilation. Therefore, in alveolar hypoventilation, PaCO₂ increases as the VA decreases. Because the alveolus is a limited space, an increase in PaCO₂ leads to a decrease in oxygen, with resultant hypoxemia.

VA also can be reduced when an increase in physiologic dead-space ratio (ie, the dead-space gas volume-to-tidal gas volume [VD/VT] ratio) occurs. Physiologic dead space occurs when an increase in ventilation to poorly perfused alveoli occurs. An increase in physiologic dead space results in a ventilation-perfusion mismatch, which, in classic presentation, occurs in patients with COPD.

The effect of physiologic dead space on alveolar hypoventilation can be expressed in the equation PaCO₂ = (k)(VCO₂)/VE(1 - VD/VT), in which VE (ie, expired volume) is the total expired ventilation and 1 - VD/VT measures the portion of ventilation directly involved in gas exchange. An increase in the physiologic dead space without an augmentation in ventilation leads to alveolar hypoventilation and an increased PaCO₂.

Primary and central alveolar hypoventilation

Patients with primary alveolar hypoventilation can voluntarily hyperventilate and normalize their PaCO₂. These patients are unable to centrally integrate chemoreceptor signals, although the peripheral chemoreceptors appear to function normally.

Congenital central hypoventilation syndrome

Hypoventilation may be caused by depression of the central respiratory drive. Congenital central hypoventilation syndrome (CCHS), previously known as Ondine curse, is defined as the failure of automatic control of breathing. It generally presents in newborns and, in 90% of the cases, is caused by a polyalanine repeat expansion mutation in the PHOX2B gene. Patients heterozygous for PHOX2B may have milder forms of the disease and live into adulthood. ^[4]

CCHS may occur in association with Hirschsprung disease. In addition, patients with CCHS are at increased risk for neuroblastoma and ganglioneuroma. ^[4]

These patients have absent or minimal ventilatory response to hypercapnia and hypoxemia during sleep and wakefulness. Since these individuals do not develop respiratory distress when challenged with hypercapnia or hypoxia, progressive hypercapnia and hypoxemia occurs during sleep. Ventilation in CCHS patients is more stable during rapid eye movement (REM) sleep than in non-REM sleep. ^[5]

The diagnosis is established after excluding another cause, either pulmonary, cardiac, metabolic, or neurologic, for central hypoventilation. Patients with CCHS require lifelong ventilatory support during sleep, and some may require 24-hour ventilatory support.

Obesity-hypoventilation syndrome

Patients with OHS have a higher incidence of restrictive ventilatory defects when compared with patients who are obese but do not hypoventilate. Studies have shown that patients with OHS have total lung capacities that are 20% lower and maximal voluntary ventilation that is 40% lower than patients who are obese who do not have hypoventilation. ^[6]

Patients with OHS demonstrate an excessive work of breathing and an increase in carbon dioxide production. Inspiratory muscle strength and resting tidal volumes also are reported to be decreased in patients with obesity hypoventilation. Pulmonary compliance is lower in patients with OHS when compared with patients who are obese who do not have hypoventilation.

Obesity increases the work of breathing because of reductions in chest wall compliance and respiratory muscle strength. An excessive demand on the respiratory muscles leads to the perception of increased breathing effort and could unmask other associated respiratory and heart diseases.

Leptin deficiency or leptin resistance may also contribute to OHS, by reducing ventilatory responsiveness and leading to carbon dioxide retention. ^[7]

Despite the above-mentioned physiologic abnormalities, the most important factor in the development of hypoventilation in OHS is likely a defect in the central respiratory control system. These patients have been shown to have a decreased responsiveness to carbon dioxide rebreathing, hypoxia, or both.

Chest wall deformities

In patients with chest wall deformities, hypoventilation develops secondary to decreased chest wall compliance, with a resultant decreased tidal volume. Alveolar dead space is unchanged, but the VD/VT ratio is increased due to the reduced tidal volume.

The most common chest wall abnormality to cause hypoventilation is kyphoscoliosis. It is associated with a decrease in vital capacity and expiratory reserve volume, while the residual volume is only moderately reduced. These patients usually are asymptomatic until the late stages of disease, when the most severe deformity of the spine has occurred.

Neuromuscular disorders

Patients with neuromuscular disorders have a reduced vital capacity and expiratory reserve volume secondary to respiratory muscle weakness. The residual volume is maintained.

The reduction in vital capacity is greater than that which would be expected solely from the underlying respiratory muscle weakness, and these patients are likely to also have a significant reduction in lung and chest wall compliance, which further reduces vital capacity. The reduction in lung and chest wall compliance may be secondary to atelectasis and reduced tissue elasticity. In addition, the VD/VT ratio is increased due to the reduced tidal volume, and this further contributes to hypoventilation.

During sleep, ventilation decreases because of a lessening in respiratory center function. During REM sleep, atonia worsens, thus leading to more severe hypoventilation, particularly when diaphragmatic function is impaired. The effects of atonia are amplified by a low sensitivity of the respiratory centers. Nocturnal mechanical ventilation improves nocturnal hypoventilation and daytime arterial blood gases in these patients.

Chronic obstructive lung disease

Hypoventilation in patients with COPD is secondary to multiple mechanisms. As mentioned previously, these patients usually have severe obstruction, with an FEV₁ of less than 1 L or 30% of the predicted value.

Patients with COPD who hypoventilate have a decreased chemical responsiveness to hypoxia and hypercapnia. This decreased chemical responsiveness also is observed in relatives of these patients who do not have COPD, leading researchers to believe that a genetic predisposition to alveolar hypoventilation exists.

These patients have a reduced tidal volume and a rapid, shallow breathing pattern, which leads to an increased VD/VT ratio. Patients also may have abnormal diaphragm function secondary to muscular fatigue and muscular mechanical disadvantage from hyperinflation.

Occurrence in the United States

The frequency of hypoventilation syndromes varies with the underlying cause of hypoventilation. The most common of these disorders is chronic obstructive lung disease, which affects more than 15 million people in the United States.

When the prevalence of hypoventilation was studied in 54 stable, hypercapnic COPD patients without concomitant sleep apnea or morbid obesity, it was found that 43% had sleep-related hypoventilation, which was more severe in REM sleep.

Currently, the prevalence of OHS ranges from 10-20%. ^[8] Data from the US Centers of Disease Control and Prevention (CDC) show that one third of the adult US population is obese. With an increase in the obesity rate, the prevalence of OHS will likely continue to increase. ^[9]

Sex-related demographics

Primary alveolar hypoventilation occurs more commonly in male patients than in female patients. COPD also occurs more commonly in men than in women; however, because of increased smoking in women, the incidence is increasing in females. OHS is another condition that occurs more commonly in males, with a 2:1 male-to-female ratio. ^[2]

Age-related demographics

Most patients with hypoventilation syndromes are older. COPD and obesity increase in prevalence with age. Primary alveolar hypoventilation occurs more commonly in early adulthood, but it also occasionally is diagnosed in infancy. Most patients with OHS are older than 50 years. ^[10]

The prognosis of patients with hypoventilation syndromes is variable, being dependent on the underlying cause of hypoventilation and the severity of the underlying illness.

The morbidity and mortality rates of patients with hypoventilation syndromes depend on the specific etiology of the hypoventilation. Pulmonary hypertension is more common and more severe in patients with OHS than in those with only obstructive sleep apnea (OSA).

OHS patients have higher rates of ICU admission compared with patients with similar levels of obesity without hypoventilation. ^[2]

The morbidity and mortality rates of each of the above-mentioned disorders are increased secondary to the presence of respiratory failure and alveolar hypoventilation.

Some of the consequences of hypoventilation, such as cor pulmonale and pulmonary hypertension, may be irreversible.

Studies reported several decades ago showed significant increase in mortality in patients with OHS. This increased mortality is likely secondary to an increased risk of arrhythmias and cardiovascular complications.