Approach

Clinical suspicion is central to diagnosing hypoventilation syndromes. Many of these disorders commonly present with, or develop, alveolar hypoventilation. It is with this knowledge that clinicians should first question and then confirm whether the patient's signs and symptoms can be explained by the diagnosis of alveolar hypoventilation.

Disease states that have been associated with the hypoventilation syndromes include:[1]

  • Obesity hypoventilation syndrome (OHS)

  • Restrictive thoracic disorders, such as patients with chest wall deformities (e.g., kyphoscoliosis, fibrothorax, or thoracoplasty)

  • Neuromuscular disorders, particularly Duchenne muscular dystrophy and other types of muscular dystrophies and spinal muscular atrophies

  • Central sleep apnea syndromes, such as idiopathic central sleep apnea, and Cheyne-Stokes respiration (CSR)

  • Congenital central alveolar hypoventilation, which is a rare disorder

  • Obstructive airway disease (in particular, COPD).

This topic focuses on OHS, restrictive thoracic disorders, Cheyne-Stokes respiration, and COPD.

See Central sleep apnea, Obstructive sleep apnea, and Muscular dystrophies.

History

Many of the symptoms secondary to the disorder causing hypoventilation are nonspecific and of limited value. In the early stages of the disorder, the patient may be totally asymptomatic. However, as the syndrome progresses, dyspnea on exertion followed by dyspnea at rest is the most common symptom encountered by patients with hypoventilation. Disturbed sleep and daytime hypersomnolence resulting from nocturnal hypoventilation may progress and be associated with symptoms of morning headaches and fatigue. If a disorder causes respiratory muscle weakness, impaired cough and repeated lower respiratory tract infections may also complicate the patient's course. In addition, careful history-taking can allow one to determine the rate of progression of the underlying disorder, in order to initiate appropriate therapeutic interventions.

Congenital central alveolar hypoventilation typically presents in newborns, with symptomatic and asymptomatic children surviving to adulthood.[25][26][27] In patients with neuromuscular disease, sleep-disordered breathing, including nocturnal alveolar hypoventilation, presents in childhood.[16][28] Patients with obesity hypoventilation are usually middle-aged.[23] Patients with COPD and those with CSR are usually in the age range of 40 to 60 years, but this can be variable. In patients with OHS, there is a 2:1 male-to-female ratio.[23]

Physical examination

The value of the physical exam is not only in characterizing the cause of hypoventilation (e.g., chest wall deformity, obesity [BMI ≥30 kg/m²], severe COPD) but also in detailing the severity of the complications that result from it (e.g., the presence of cor pulmonale). While a precipitating event such as a respiratory tract infection can trigger acute respiratory failure at any time, most patients' physical exam reflects the more usual, gradual progressive development of alveolar hypoventilation over months or years. As a result of diurnal CO₂ retention and associated hypoxemia, patients may demonstrate signs of cor pulmonale, including an increased pulmonic component of the second heart sound (P2), and lower-extremity edema. An increased P2 can be seen with most causes of hypoventilation syndrome.[16][23][28] Patients with OHS have a BMI ≥30 kg/m², with an increasing prevalence with increasing BMI.[23] Lower-extremity edema and right-sided third heart sound (S3 gallop) are evident with most causes of hypoventilation syndrome.[16][23][28]

Other conditions, such as CSR, may present with physical findings suggestive of left-sided congestive heart failure (CHF), such as an S3 gallop, and inspiratory crackles on examination of the lungs. A left-sided fourth heart sound (S4 gallop) can be seen in patients with CSR due to CHF.

Confirmatory investigations

An arterial blood gas analysis is required in all patients to document the presence of an elevated CO₂ and confirm the diagnosis. It is the definitive test used to confirm the diagnosis of alveolar hypoventilation and to document the extent of associated hypoxemia.[29] If hypoventilation becomes more severe, hypercapnia or hypoxemia becomes more evident, and respiratory failure may ensue, requiring ventilatory support.

Pulmonary function tests, including spirometry, measurement of lung volumes, and measurements of respiratory muscle strength, give important clues as to the cause and severity of the disease underlying the hypoventilation. In patients with neuromuscular disease, sleep-disordered breathing is evident when the FVC declines to <65% of predicted.[30] In patients with OHS, the restrictive pattern is accompanied by a decrease in the expiratory reserve volume.[31] Respiratory muscle strength is known to be decreased in patients with restrictive thoracic disorders, which correlates with the development of sleep-disordered breathing.[16] It is also decreased in patients with OHS due to a combination of abnormal respiratory mechanics and weak respiratory muscles.[32]

Because many of the disorders associated with the hypoventilation syndrome initially demonstrate more significant hypoxemia during sleep (particularly REM sleep) an overnight polysomnogram is often indicated. In addition, many disorders have associated obstructive and central sleep-disordered breathing events that would require appropriate treatment if recognized. A polysomnogram is indicated in patients with chest wall abnormalities and neuromuscular disease to identify patients who would benefit from nocturnal ventilation.[33][34][35][36][37] It identifies associated obstructive sleep apnea (OSA) in patients with OHS.[2] In addition, it may identify patients with OHS prior to developing awake elevations in PaCO₂.[38] In CHF with a left ventricular ejection fraction <45% and disturbed sleep, a polysomnogram identifies CSR.[5][6][7][8] A polysomnogram is used in patients with COPD who have suspected overlap syndrome (associated OSA), but use to identify REM-associated hypoventilation is undefined.

An echocardiogram may be performed to evaluate for cor pulmonale and/or the presence of left-sided CHF. It documents the development of pulmonary hypertension in patients with OHS, neuromuscular disease, and COPD. In patients with CSR, an echocardiogram documents the severity of left ventricular dysfunction.[3]​​[5][6][7][8][39]

A chest x-ray should be performed to exclude other causes for hypoxemia.

Other investigations

While an elevation of serum bicarbonate, as well as a low oxygen saturation on pulse oximetry, may suggest the presence of alveolar hypoventilation, they are not recommended as diagnostic tests. Measurement of serum bicarbonate may be used to screen for the presence of alveolar hypoventilation, but does not confirm the diagnosis.[2][40] Pulse oximetry suggests the presence of alveolar hypoventilation, but does not confirm the diagnosis and should not be used to decide when to measure PaCO₂.[40]

In the right clinical setting, other laboratory tests may be indicated. In patients with hypercapnia who demonstrate signs of hypothyroidism, measurement of thyroid-stimulating hormone levels may be indicated. Measurement of hematocrit is indicated in all patients with suspected or documented daytime and/or nocturnal hypoxemia. If there is a clinical suspicion for congenital central alveolar hypoventilation, mutations in the paired-like homeobox 2B (PHOX2B) gene should be evaluated, as mutations are noted in up to 91% of these patients.[24]​ Patients with PHOX2B mutations exhibit respiratory-related cortical activity on electroencephalograms at rest.[41]

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