Hypoventilation Syndromes

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

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.

Specific hypoventilation syndromes discussed in this article include the following:

• Central alveolar hypoventilation
• Obesity-hypoventilation syndrome (OHS)
• Chest-wall deformities
• Neuromuscular disorders
• Chronic obstructive pulmonary disease (COPD)

Central alveolar hypoventilation

The termn 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 (CVAs), 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 (body mass index [BMI] ≥30 kg/m²) with awake chronic hypercapnia (PaCO₂ >45 mm Hg). In children, obesity is defined as a BMI greater than or equal to the 95th percentile of the BMI for age as shown on growth charts of boys and girls aged 2-19 years; BMI percentiles are used instead of absolute BMI because the amount of body fat changes with age and differs in boys and girls.

Other disorders that may cause hypoventilation should be ruled out first. Approximately 90% of patients with OHS also have obstructive sleep apnea (OSA). ^{[2, 3]}  Hypoventilation is worse during rapid-eye-movement (REM) sleep than during non-REM sleep.

Chest-wall deformities

Chest-wall deformities (eg, kyphoscoliosis, fibrothorax, and deformities occurring post thoracoplasty) 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 1 L 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 (V_A) 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, along with 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 (H₂CO₃). The lungs excrete the volatile fraction via ventilation. Consequently, acid accumulation does not occur. In normal circumatances, PaCO₂ is tightly maintained in a range of 39-41 mm Hg.

Ventilation is influenced and regulated by chemoreceptors for PaCO₂, partial pressure of oxygen in arterial blood (PaO₂), and hydrogen ion concentration (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 oxygen desaturation deteriorate during sleep secondary to a decrease 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.

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 relation between ventilation and PaCO₂ can be expressed as follows:

• PaCO₂ = (k × VCO₂)/V_A

where VCO₂ is metabolic production of carbon dioxide (ie, venous carbon dioxide production), k is a constant, and V_A is alveolar ventilation. Therefore, in alveolar hypoventilation, PaCO₂ increases as V_A decreases. Because the alveolus is a limited space, an increase in PaCO₂ leads to a decrease in oxygen, with resultant hypoxemia.

V_A also can be reduced when an increase in physiologic dead-space ratio (ie, the ratio of dead-space gas volume [V_D] to tidal gas volume [V_T]; V_D/V_T) 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 (V/Q) mismatch, which, in the classic presentation, occurs in patients with COPD.

The effect of physiologic dead space on alveolar hypoventilation can be expressed as follows:

• PaCO₂ = (k × VCO₂)/[V_E × (1 – V_D/V_T)]

where V_E (ie, expired volume) is the total expired ventilation and 1 – V_D/V_T is 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 cannot centrally integrate chemoreceptor signals, though 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; sometimes known as Ondine's curse) is defined as the failure of automatic control of breathing. It generally presents in newborns, and in 90% of the cases, it is caused by a polyalanine repeat expansion mutation (PARM) in the gene PHOX2B. Among individuals with PARMs, those with longer expansions generally have more severe CCHS phenotypes. ^[4] Patients heterozygous for PHOX2B may have milder forms of the disease and live into adulthood. ^[5]   

In addition to PARMs, there is a wide spectrum of variant PHOX2B genes that are also associated with CCHS. These variants, termed nonpolyalanine repeat mutations (NPARMs), cause the remaining 10% of CCHS cases. Some NPARMs are associated with Hirschsprung disease and malignant neural crest tumors. ^[4]  

These patients have absent or minimal ventilatory response to hypercapnia and hypoxemia during sleep and wakefulness. Because they 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 REM sleep than in non-REM sleep. ^[6]

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.

Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation syndrome

Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD) syndrome is a rare, life-threatening neurocristopathy with a presentation that overlaps with CCHS, though no genetic etiology has been found.

ROHHAD syndrome presents with rapid-onset obesity over a 3- to 12-month period between the ages of 1.5 and 7 years. It continues to progress over several months, and the patient develops hypothalamic dysfunction, hypoventilation, autonomic dysfunction (including impaired bowel motility), and tumors of neural crest origin. The hypoventilation can become severe and can lead to cardiorespiratory arrest in previously healthy children if not identified and treated early. ^{[7, 8]}  

Obesity-hypoventilation syndrome

Typically, patients with OHS are obese (BMI ≥30 kg/m²) with chronic alveolar hypoventilation leading to daytime hypercapnia (PaCO₂ ≥45 mm Hg) and sleep-disordered breathing (SDB).  Approximately 90% of patients with OHS also have OSA; the remaining cases have nonobstructive sleep hypoventilation. ^[3]

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. ^[9]

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 OHS. Pulmonary compliance is lower in patients with OHS than in patients who are obese but 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. ^[10]

The aforementioned physiologic abnormalities notwithstanding, 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 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 decrease in V_T. Alveolar V_D is unchanged, but the V_D/V_T ratio is increased because of the reduction in V_T.

The chest-wall abnormality that most commonly causes hypoventilation is kyphoscoliosis. It is associated with a decrease in vital capacity and expiratory reserve volume, whereas 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

In patients with neuromuscular disorders, vital capacity and expiratory reserve volume are reduced secondary to respiratory-muscle weakness. The residual volume is maintained.

The reduction in vital capacity is greater than would be expected solely on the basis of the underlying respiratory-muscle weakness, and these patients are likely to also have significant reductions in lung and chest-wall compliance, which further reduce vital capacity. These reductions in compliance may be secondary to atelectasis and reduced tissue elasticity. In addition, the V_D/V_T ratio is increased because of the reduction in V_T, 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 low sensitivity of the respiratory centers. Nocturnal mechanical ventilation improves nocturnal hypoventilation and daytime arterial blood gas (ABG) measurements in these patients.

Chronic obstructive pulmonary 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 V_T and a rapid, shallow breathing pattern, which leads to an increased V_D/V_T ratio. Patients also may have abnormal diaphragm function secondary to muscular fatigue and muscular mechanical disadvantage from hyperinflation.

The respiratory system serves two purposes: 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 (see Pathophysiology), including the following:

• COPD
• Neuromuscular disorders ^[11] - 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
• OHS
• Carotid body resection and/or injury
• Myxedema (severe hypothyroidism)

US statistics

The frequency of hypoventilation syndromes varies with the underlying cause of hypoventilation. The most common of these disorders is COPD, 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.

The prevalence of OHS is in the range of 10-20%. ^[12] Data from the US Centers of Disease Control and Prevention (CDC) have shown that prevalence of obesity continues to grow.  As of 2020, approximately 42% of US adults were obese (BMI ≥30 kg/m²) and more than 9% were severely obese (BMI ≥of 40 kg/m²). ^[13]  As many as 20% of US children aged between 2 and 19 years may be obese (BMI ≥95th percentile for age and sex). ^{[14, 15]}  The increasing prevalence of obesity has led to a corresponding rise in the occurrence of OHS among all age groups. ^[3]  

CCHS has an estimated incidence of 1 in 200,000 live births; however, there is evidence to suggest that the disorder may be underdiagnosed.

Age- and sex-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. ^[16]  CCHS has mostly been identified in neonates, but with advances in molecular testing, milder phenotypes have been diagnosed in older children, adolescents, and adults. ^[17]

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]

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

Morbidity and mortality in 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 who have only OSA. OHS patients have higher rates of intensive care unit (ICU) admission than patients with similar levels of obesity but without hypoventilation. ^[2]

The morbidity and mortality of each of these 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 from several decades ago reported significantly increased mortality in patients with OHS. This increased mortality is likely secondary to an increased risk of arrhythmias and cardiovascular complications.