Hypo Ventilation

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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 Usually life-threatening emergencies Discussed in Acute Respiratory Distress Syndrome link

o Chronic hypoventilation syndromes (focus of this topic) are characterized by: Impaired respiratory drive Defective respiratory neuromuscular system 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 Control of respiratory drive is perturbed by disorders of brainstem

neurons or chemoreceptors (central or peripheral). o Respiratory neuromuscular system

Control of respiratory muscles is impaired because of disorders of spinal or peripheral nerves or the respiratory muscles themselves.


o Ventilatory apparatus 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 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:

Postpolio syndrome: a form of chronic respiratory insufficiency that develops 20–30 years after recovery from poliomyelitis

Myopathy associated with adult acid maltase deficiency Idiopathic diaphragmatic paralysis

o A later feature of disorders, such as: Motor neuron disease Myasthenia gravis Muscular dystrophy

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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: Mild to moderate degree of airflow obstruction Decrease in central respiratory drive Obstructive sleep apnea

Differential Diagnosis

• Impaired respiratory drive (metabolic respiratory control system) o Peripheral and central chemoreceptors

Carotid body dysfunction, trauma Prolonged hypoxia Metabolic alkalosis

o Brainstem respiratory neurons Primary alveolar hypoventilation syndrome Bulbar poliomyelitis, encephalitis Brainstem infarction, hemorrhage, trauma Brainstem demyelination, degeneration Long-term drug administration

• Defective respiratory neuromuscular system o Spinal cord and peripheral nerves

High cervical trauma Poliomyelitis Motor neuron disease (see Amyotrophic Lateral Sclerosis) Peripheral neuropathy

o Respiratory muscles Myasthenia gravis Muscular dystrophy Chronic myopathy

• Impaired ventilatory apparatus o Chest wall

Kyphoscoliosis Fibrothorax Thoracoplasty Ankylosing spondylitis Obesity hypoventilation syndrome

o Airways and lungs Laryngeal and tracheal stenosis Obstructive sleep apnea Cystic fibrosis 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:

Mouth pressure generated after 0.1 second of inspiration against an occluded airway

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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

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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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: Hyperinflation of lung volumes and diaphragm flattening: usually seen

in severe obstructive airway disease Diaphragm elevation: seen in pneumothorax, diaphragm paralysis, or

atelectasis

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Evidence of bony thoracic abnormalities, such as kyphoscoliosis o Pulmonary hypertension

Findings suggestive of pulmonary artery enlargement 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:

Stroke 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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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: Intermittent negative-pressure ventilation in a cuirass or 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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o As condition progresses, most patients require additional treatment with: Diaphragmatic pacing or 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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• 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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Hypo Ventilation

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