Hypoventilation

(See also Harrison’s Principles of Internal Medicine, 17th Edition, Chapter 33)

Definition

• Alveolar hypoventilation exists when arterial partial pressure of carbon dioxide

(PaCO2) increases above the upper limit of normal (i.e., 43 mmHg).
• In clinically important hypoventilation syndromes, PaCO2 exceeds 50 mmHg.
• Hypoventilation disorders can be acute or chronic.
o Acute disorders
ƒ Usually life-threatening emergencies
ƒ Discussed in Acute Respiratory Distress Syndrome link
o Chronic hypoventilation syndromes (focus of this topic) are characterized by:
ƒ Impaired respiratory drive
ƒ Defective respiratory neuromuscular system
ƒ Impaired ventilatory apparatus

Epidemiology

• Prevalence
o Varies depending on the underlying cause of hypoventilation
o Primary alveolar hypoventilation is relatively rare.
• Age
o Overall prevalence of hypoventilation increases with age
o Primary alveolar hypoventilation occurs more commonly in early adulthood.
• Sex
o Occurs more frequently in men than women

Mechanism

• The physiologic hallmark of all alveolar hypoventilation syndromes is:

o Increase in alveolar PCO2 and therefore in arterial PCO2
o Respiratory acidosis
o Compensatory increase in plasma bicarbonate concentration and a decrease
in chloride concentration
o Increase in alveolar PCO2 produces an obligatory decrease in alveolar partial
pressure of oxygen (PO2), resulting in hypoxemia.
• Alveolar hypoventilation is due to a defect in ≥1 respiratory systems.
o Metabolic respiratory control system
ƒ Control of respiratory drive is perturbed by disorders of brainstem
neurons or chemoreceptors (central or peripheral).
o Respiratory neuromuscular system
ƒ Control of respiratory muscles is impaired because of disorders
of spinal or peripheral nerves or the respiratory muscles
themselves.

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2 Hypoventilation

o Ventilatory apparatus
ƒ Ventilation is impaired because of mechanical changes to the chest
wall, airways, or lungs.
o See Differential Diagnosis for a list of disorders corresponding to these
defective mechanisms.

Symptoms & Signs

General

• Cyanosis secondary to severe hypoxemia

• Impairment of sleep due to nocturnal hypercapnia
o Morning fatigue, daytime somnolence, mental confusion, and intellectual
impairment
• Other clinical features associated with hypoventilation syndromes are related to the
specific underlying disease.

Primary alveolar hypoventilation

• Characterized by chronic hypercapnia and hypoxemia in the absence of identifiable

neuromuscular disease or mechanical ventilatory impairment
• Typically develops insidiously
o Patients typically develop lethargy, fatigue, daytime somnolence, disturbed
sleep, and morning headaches.
o Dyspnea is uncommon.
o Often first comes to attention when severe respiratory depression follows
administration of standard doses of sedatives or anesthetics
• Eventually cyanosis, polycythemia, pulmonary hypertension, and congestive heart
failure occur.

Respiratory neuromuscular disorders

• Hypoventilation usually develops gradually over months to years.

o Generally does not develop unless there is significant weakness of the
diaphragm
ƒ Distinguishing features of bilateral diaphragmatic weakness include
orthopnea and paradoxical movement of the abdomen in the supine
posture.
o May come to attention when a relatively trivial increase in mechanical
ventilatory load (e.g., viral bronchitis with airways obstruction) produces
severe respiratory failure
• Involvement of respiratory nerves or muscles
o An early feature of such diseases as:
ƒ Postpolio syndrome: a form of chronic respiratory insufficiency that
develops 20–30 years after recovery from poliomyelitis
ƒ Myopathy associated with adult acid maltase deficiency
ƒ Idiopathic diaphragmatic paralysis
o A later feature of disorders, such as:
ƒ Motor neuron disease
ƒ Myasthenia gravis
ƒ Muscular dystrophy

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Hypoventilation 3

Obesity hypoventilation syndrome

• Morbid obesity can lead to reduced functional residual capacity (i.e., end-expiratory
lung volume), particularly in the recumbent posture.
o May be accompanied by:
ƒ Mild to moderate degree of airflow obstruction
ƒ Decrease in central respiratory drive
ƒ Obstructive sleep apnea

Differential Diagnosis

• Impaired respiratory drive (metabolic respiratory control system)

o Peripheral and central chemoreceptors
ƒ Carotid body dysfunction, trauma
ƒ Prolonged hypoxia
ƒ Metabolic alkalosis
o Brainstem respiratory neurons
ƒ Primary alveolar hypoventilation syndrome
ƒ Bulbar poliomyelitis, encephalitis
ƒ Brainstem infarction, hemorrhage, trauma
ƒ Brainstem demyelination, degeneration
ƒ Long-term drug administration
• Defective respiratory neuromuscular system
o Spinal cord and peripheral nerves
ƒ High cervical trauma
ƒ Poliomyelitis
ƒ Motor neuron disease (see Amyotrophic Lateral Sclerosis)
ƒ Peripheral neuropathy
o Respiratory muscles
ƒ Myasthenia gravis
ƒ Muscular dystrophy
ƒ Chronic myopathy
• Impaired ventilatory apparatus
o Chest wall
ƒ Kyphoscoliosis
ƒ Fibrothorax
ƒ Thoracoplasty
ƒ Ankylosing spondylitis
ƒ Obesity hypoventilation syndrome
o Airways and lungs
ƒ Laryngeal and tracheal stenosis
ƒ Obstructive sleep apnea
ƒ Cystic fibrosis
ƒ Chronic obstructive pulmonary disease

Diagnostic Approach

• Diagnosis of hypoventilation is based on:

o History and physical examination
o Arterial blood gas analysis that shows elevated PaCO2 (>43 mmHg)
• Localizing chronic hypoventilation may require additional diagnostic tests, such as:
o Pulmonary function tests with:
ƒ Mouth pressure generated after 0.1 second of inspiration against an
occluded airway

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4 Hypoventilation

ƒ Maximum inspiratory or expiratory pressure that can be generated

against an occluded airway (PImax and PEmax)
o Sleep studies
o Diaphragmatic electromyography (EMG)
o Alveolar–arterial PO2 difference
• See Figure 1 for details.
• Metabolic control system impairment
o Central respiratory drive is impaired in response to chemical stimuli (carbon
dioxide or hypoxia).
o Diaphragmatic EMG activity, mouth pressure, and minute volume of
ventilation are reduced.
o Hypoventilation during sleep is aggravated.
o Tests of voluntary respiratory control, muscle strength, lung mechanics, and
gas exchange are normal.
• Respiratory neuromuscular system impairment
o All tests dependent on muscular activity (voluntary or in response to
metabolic stimuli) are abnormal.
o Lung resistance, lung compliance, and gas exchange are normal.
• Ventilatory apparatus impairments
o Gas exchange is usually impaired.
o Because resistance and compliance are also impaired, all tests dependent on
ventilation (whether voluntary or in response to chemical stimuli) are
abnormal.
o Tests of muscle activity or strength that do not involve airflow (i.e., mouth
pressure, diaphragmatic EMG) are normal.
• Primary alveolar hypoventilation
o Key diagnostic finding is chronic respiratory acidosis in the absence of
respiratory muscle weakness or impaired ventilatory mechanics.
o Must be distinguished from other central hypoventilation syndromes that are
secondary to underlying neurologic disease of the brainstem or
chemoreceptors
ƒ Requires a careful neurologic investigation for evidence of brainstem or
autonomic disturbances
• Unrecognized respiratory neuromuscular disorders
o Often misdiagnosed as primary alveolar hypoventilation, particularly those
that produce diaphragmatic weakness
o Can usually be suspected on clinical grounds and confirmed by the finding of
reduced voluntary hyperventilation, as well as PImax and PEmax
o Hypercapnia may not be demonstrable in a single arterial blood sample, but
the presence of an elevated plasma bicarbonate level should draw attention to
the underlying chronic disturbance.

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Hypoventilation 5

Figure 1: 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 nspiration
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 Slutsky.)

Laboratory Tests

• Arterial blood gas

o PaCO2 > 43 mmHg by definition (more typically >50 mmHg)
o PaO2 is often reduced.
o pH: normal or slightly reduced in compensated respiratory acidosis; more
reduced in the setting of acute decompensation
• Serum chemistry
o Compensatory increase in the serum bicarbonate concentration secondary to
respiratory acidosis
o Hypercalcemia and hyperkalemia may also be present.
• Complete blood count
o May have elevated hematocrit due to chronic hypoxemia
• Thyroid function studies
o Because hypothyroidism may exacerbate hypoventilation, thyroid tests may
be indicated in patients with a suspected central cause of hypoventilation.

Imaging

• Chest radiography
o Findings on chest radiography that may help determine the cause of
hypoventilation syndromes include:
ƒ Hyperinflation of lung volumes and diaphragm flattening: usually seen
in severe obstructive airway disease
ƒ Diaphragm elevation: seen in pneumothorax, diaphragm paralysis, or
atelectasis
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6 Hypoventilation

ƒ Evidence of bony thoracic abnormalities, such as kyphoscoliosis

o Pulmonary hypertension
ƒ Findings suggestive of pulmonary artery enlargement
ƒ Cardiomegaly secondary to right ventricular enlargement
• Chest CT
o May be useful in detection of suspected chest or skeletal cause
• Brain CT
o If a central cause of hypoventilation is suspected, particularly brainstem
lesions in the pons and medulla
o Specific causes that may be diagnosed include:
ƒ Stroke
ƒ Central nervous system tumor or trauma
• Brain MRI
o If a central cause of hypoventilation is suspected and the initial brain CT is
negative or inconclusive
• Fluoroscopy
o Fluoroscopic sniff test: The diaphragm is visualized with fluoroscopy as the
patient quickly inspires.
o Paradoxical elevation of the diaphragm is seen with inspiration in patients
with unilateral diaphragmatic paralysis.
• Echocardiography and Doppler flow study
o May demonstrate pulmonary hypertension and right ventricular enlargement

Diagnostic Procedures

• EMG
o Response to transcutaneous phrenic nerve stimulation recorded from an
esophageal electrode
o Used to diagnose neuromuscular disorders and defects in the metabolic
respiratory control system
o May reveal a neuropathic or myopathic pattern, depending on the etiology
• Pulmonary function tests
o Useful to diagnose obstructive lung disease and assessment of its severity
o Measurement of maximal inspiratory and expiratory pressures may be useful
in screening for respiratory muscle weakness.
• Measurement of transdiaphragmatic pressure
o Useful in documenting respiratory muscle and diaphragm weakness
• Polysomnography
o PaCO 2 tends to increase progressively during the night, particularly during
REM sleep, in patients with a defect in respiratory control or neuromuscular
function.
o Periods of apnea not accompanied by respiratory effort may also be seen.

Treatment Approach

• Management is based on the underlying disorder.

• Therapies include:
o Correction of metabolic alkalosis, if present
o Supplemental oxygen
o Respiratory stimulants
o Diaphragmatic pacing
o Mechanical ventilation
o Some patients with thoracic deformities, such as kyphoscoliosis, may be
candidates for corrective thoracic surgical procedures.

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Hypoventilation 7

Specific Treatments

Supplemental oxygen

• Effective in attenuating hypoxemia, polycythemia, and pulmonary hypertension

• However, can aggravate carbon dioxide retention and associated neurologic
symptoms
• Must be prescribed judiciously and the results monitored carefully
o Aim to keep PaO2 between 60 and 65 mm Hg.

Respiratory stimulants

• May be of benefit in some patients with central causes of hypoventilation and obesity
hypoventilation syndrome
• Medroxyprogesterone
o Agent most commonly used
o Dosage: 10–20 mg PO tid
• Other agents
o Theophylline: stimulates central drive and increases strength of diaphragm
contraction
o Acetazolamide: causes excretion of bicarbonate leading to metabolic acidosis,
which stimulates ventilation

Mechanical ventilatory assistance

• Eventually required in most patients with chronic hypoventilation related to

impairment of respiratory drive or neuromuscular disease
• Ventilatory assistance only during sleep
o Usually managed by positive-pressure ventilation through a nose mask
o Produces dramatic improvement in clinical features and daytime arterial blood
gases
• Continuous ventilation
o When hypoventilation is severe, treatment may be required on a 24-hour
basis.
o Managed by:
ƒ Intermittent negative-pressure ventilation in a cuirass or
ƒ Intermittent positive-pressure ventilation delivered through a
tracheostomy or nose mask

Diaphragmatic pacing

• Delivered by electrophrenic stimulation

• Effective in patients with reduced respiratory drive but intact respiratory lower motor
neurons, phrenic nerves, and respiratory muscles
• Contraindicated in patients with defects in the respiratory nerves and muscles
o Except for high cervical spinal cord lesions in which the phrenic lower motor
neurons and nerves are intact

Treatment of specific diseases

• Primary alveolar hypoventilation

o Supplemental oxygen
o Respiratory stimulants

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8 Hypoventilation

o As condition progresses, most patients require additional treatment with:

ƒ Diaphragmatic pacing or
ƒ Mechanical ventilation
• Neuromuscular disorder
o Treatment of underlying condition, if possible
o Mechanical ventilatory assistance at night (often through nasal mask) or the
entire day (typically through tracheostomy)
o Diaphragmatic pacing may be an alternative for patients with high cervical
spinal cord lesions.
• Obesity hypoventilation syndrome
o Weight loss, including consideration of bariatric surgery
o Smoking cessation
o Respiratory stimulants
o Nocturnal mask ventilation, if required
o See Obesity for more details.
• See also:
o Chronic Obstructive Lung Disease
o Sleep Apnea

Monitoring

• Monitor for progression of disease, response to therapy, and complications.

• If hypoventilation is severe and leads to respiratory failure, admission to an intensive
care unit may be required.

Complications

• Pulmonary hypertension
• Cor pulmonale
• Polycythemia

Prognosis

• The prognosis of patients with hypoventilation syndromes is variable and depends on

the underlying cause of hypoventilation and the severity of the underlying illness.
• Primary alveolar hypoventilation is usually progressive over months to years and
ultimately fatal.

Prevention

• Smoking cessation
• Weight loss in obese patients

ICD-9-CM

• 786.09 Other dyspnea and respiratory abnormalities (includes hypoventilation)

See Also

• Chronic Obstructive Lung disease

• Obesity
• Pulmonary Arterial Hypertension, Secondary

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Hypoventilation 9

• Pulmonary Function Tests

• Sleep Apnea

Internet Sites

• Professionals
o Central Hypoventilation Syndrome, Congenital
National Organization for Rare Disorders
o Hypoventilation
ClinicalTrials.gov
• Patients
o Obesity hypoventilation syndrome (OHS)
MedlinePlus Medical Encyclopedia
o Primary alveolar hypoventilation
MedlinePlus Medical Encyclopedia

General Bibliography

• O'donnell CP et al: Leptin prevents respiratory depression in obesity. Am J Respir Crit

Care Med 159:1477, 1999 [PMID:10228114]
• Olson AL, Zwillich C: The obesity hypoventilation syndrome. Am J Med
118:948, 2005 [PMID:16164877]
• Phillipson EA, Slutsky AS: Hypoventilation and hyperventilation syndromes, in
Textbook of Respiratory Medicine, 3d ed, JF Murray, JA Nadel (eds). Philadelphia,
Saunders, 2000, pp 2139–2152
• Phipps PR et al: Association of serum leptin with hypoventilation in human obesity.
Thorax 57:75, 2002 [PMID:11809994]
• Tankersley CG et al: Genetic control of differential baseline breathing pattern. J Appl
Physiol 82:874, 1997 [PMID:9074977]

PEARLS

• Charles Dickens provided the classical description of the syndrome of hypoventilation

associated with extreme obesity in his novel The Pickwick Papers; hence, it is termed
Pickwickian syndrome.
o The fat boy, Joe, exhibited daytime somnolence and cyanosis.
o The syndrome also includes muscular twitching, secondary polycythemia, and
right ventricular hypertrophy and failure.

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