AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

The respiratory system serves a dual purpose: delivering oxygen to the pulmonary capillary bed from the environment and eliminating carbon dioxide from the blood stream by removing it from the pulmonary capillary bed. Metabolic production of carbon dioxide occurs rapidly. Thus, a failure of ventilation promptly increases the partial pressure of carbon dioxide measured by arterial blood gas analysis (PaCO₂).

Alveolar hypoventilation is defined as insufficient ventilation leading to an increase in PaCO₂ (ie, hypercapnia). Alveolar hypoventilation is caused by several disorders that are collectively referred as hypoventilation syndromes. Alveolar hypoventilation also is a cause of hypoxemia. Thus, patients who hypoventilate may develop clinically significant hypoxemia. 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. The specific hypoventilation syndromes that are discussed in this article include central alveolar hypoventilation, obesity hypoventilation syndrome, chest wall deformities, neuromuscular disorders, and chronic obstructive pulmonary disease (COPD). 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 the rapid eye movement (REM) stage of sleep, which further exacerbates hypoventilation secondary to insufficient respiratory effort.

Hypoventilation may be caused by depression of the central respiratory drive. In patients with primary alveolar hypoventilation (the Ondine curse), the cause of hypoventilation and hypercapnia is not known. Patients with primary alveolar hypoventilation have normal alveolar-arterial oxygen gradients and are able to voluntarily hyperventilate and normalize their PaCO₂. 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 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. However, no specific body mass index is associated with the development of OHS. A recent article investigated the association of obstructive sleep apnea (OSA) to OHS in a cohort of 34 patients. In most of the cases (23 of the 26 patients) OSA was also present. The patients with both OSA and OHS had worst gas exchange abnormalities and more severe pulmonary hypertension when compared with the patients with OSA only. However, OHS is an autonomous disease. Three of the patients with OHS had no associated OSA (Kessler, 2001).

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

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 saturations may precede the onset of daytime hypoventilation and gas exchange abnormalities.

Hypoventilation is not uncommon in patients with severe COPD. Alveolar hypoventilation in COPD usually does not occur unless the forced expiratory volume in one second (FEV_1.0) is less than 1 L or 35% 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.

Pathophysiology

Control of ventilation

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 both 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 (H₂CO₃). The lungs excrete the volatile fraction via ventilation; therefore, acid accumulation does not occur. The 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 and by neural impulses from lung stretch receptors and impulses from the cerebral cortex. Failure of any of these mechanisms results in a state of hypoventilation and hypercapnia.

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 follows: 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, PaCO₂ increases as the VA decreases and is referred to as alveolar hypoventilation. 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, dead-space gas volume-to-tidal gas volume [VD/VT] ratio) occurs. Physiologic dead space occurs when an increase in ventilation occurs to poorly perfused alveoli. An increase in physiologic dead space results in 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 following 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

As mentioned previously, 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

Present from birth, this rare syndrome, congenital central hypoventilation syndrome (CCHS), is defined as the failure of automatic control of breathing. 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. The diagnosis is established after excluding other pulmonary, cardiac, metabolic, or neurologic cause 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 obesity hypoventilation syndrome 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 obesity hypoventilation syndrome 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.

These patients 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 obesity hypoventilation syndrome when compared with patients who are obese who do not have hypoventilation. Obesity increases the work of breathing because of reduced 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.

Despite the above-mentioned physiologic abnormalities, the most important factor in the development of hypoventilation in obesity hypoventilation syndrome 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, with the most severe deformity of the spine.

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 what is expected solely from the underlying respiratory muscle weakness, and these patients are likely to also have 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 a lessening in respiratory centers 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 a FEV_1.0 of less than 1 L or 35% 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.

Frequency

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 14 million people in the United States. Kyphoscoliosis is the chest wall deformity most commonly associated with hypoventilation.

The prevalence of hypoventilation was studied in 54 stable hypercapnic COPD patients without concomitant sleep apnea or morbid obesity. Of these, 43% had sleep-related hypoventilation, which was more severe in rapid eye movement sleep.

Mortality/Morbidity

• The morbidity and mortality rates of patients with hypoventilation syndromes depend on the specific etiology of the hypoventilation.
• The morbidity and mortality rates of each of the above-mentioned disorders are increased secondary to the presence of respiratory failure and alveolar hypoventilation.
• Studies reported several decades ago showed significant increase in mortality in patients with obesity hypoventilation syndrome. This increased mortality is likely secondary to an increased risk of arrhythmias and cardiovascular complications. Miller reported an in-hospital mortality rate of 70% in a small cohort of hospitalized patients in 1974. This mortality rate is likely lower today due to improvements in treatment of sleep apnea and hypoventilation related to sleep apnea and improvements in the treatment of cardiovascular disease.

Sex

• Primary alveolar hypoventilation occurs more commonly in male patients than female patients.
• COPD occurs more commonly in men than in women; however, because of increased smoking in women, the incidence is increasing in females.
• Obesity hypoventilation syndrome also occurs more commonly in men because they have more upper-body obesity than women with similar body mass indices.

Age

• 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.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

The clinical manifestations of hypoventilation syndromes usually are nonspecific, and in most cases, they are secondary to the underlying clinical diagnosis.

• Manifestations vary depending on the severity of hypoventilation, the rate of development of hypercapnia, and the degree of compensation for respiratory acidosis that may be present.
• During the early stages of hypoventilation with mild-to-moderate hypercapnia, patients usually are asymptomatic or have only minimal symptoms.
• • Patients may be anxious and complain of dyspnea with exertion.
  • As the degree of hypoventilation progresses, patients develop dyspnea at rest. Some patients may have disturbed sleep and daytime hypersomnolence.
  • As the hypoventilation progresses, more patients develop increased hypercapnia and hypoxemia. Therefore, they may have clinical manifestations of hypoxemia, such as cyanosis, and they also may have signs related to their hypercapnia.
  • As the hypoventilation progresses, the PaCO₂ increases; anxiety may progress to delirium; and patients become progressively more confused, somnolent, and obtunded. This condition occasionally is referred to as carbon dioxide narcosis.
  • Patients may develop asterixis, myoclonus, and seizures in severe hypercapnia.
  • Papilledema may be seen in some individuals secondary to increased intracranial pressure related to cerebral vasodilation.
  • Conjunctival and superficial facial blood vessel dilation also may be noted.
  • Patients with respiratory muscle weakness usually display generalized weakness secondary to their underlying neuromuscular disorder. Respiratory muscle weakness also may lead to impaired cough and recurrent lower respiratory tract infections.
  • With advanced disease, patients may develop respiratory failure and require ventilatory support.
• Patients with central alveolar hypoventilation usually have no respiratory complaints. They may have symptoms of sleep disturbances and daytime hypersomnolence.
• • In some patients, the diagnosis of central alveolar hypoventilation is made only after the development of respiratory failure.
  • Frequently, patients with obesity hypoventilation syndrome have associated obstructive sleep apnea (OSA) and complain of daytime hypersomnolence. This combination is known as pickwickian syndrome. Patients with obesity hypoventilation also may have pulmonary hypertension and chronic right heart failure (cor pulmonale), with secondary peripheral edema in advanced disease.
  • Patients with COPD and hypoventilation usually have severe disease and complain of significant dyspnea. They also may have peripheral edema secondary to pulmonary hypertension with cor pulmonale.

Physical

• In patients with alveolar hypoventilation, the findings upon physical examination usually are nonspecific and are related to the underlying illness.
• Upon thoracic examination, patients with obstructive lung disease have diffuse wheezing, hyperinflation (barrel chest), diffusely decreased breath sounds, hyperresonance upon percussion, and prolonged expiration.
• • Coarse crackles beginning with inspiration may be heard, and wheezes frequently are heard upon forced and unforced expiration.
  • Cyanosis may be noted if accompanying hypoxia is present. Clubbing may be present.
• The patient's mental status may be depressed with severe elevations of PaCO₂. Patients may have asterixis and papilledema upon examination, and conjunctival and superficial facial blood vessels may be dilated.
• Patients with central alveolar hypoventilation, COPD, and obesity hypoventilation syndrome may show evidence of pulmonary hypertension from examination findings. These findings include a narrowly split and loud pulmonary component (P2) of the second heart sound, a large a-wave component in the jugular venous pulse, a left parasternal (right ventricular) heave, and an S4 of right ventricular origin. A diastolic murmur indicative of pulmonic valve regurgitation may be auscultated.
• Patients with advanced disease develop signs of right ventricular failure (cor pulmonale) and may have elevated jugular venous pressure with a prominent V wave, lower-extremity edema, and hepatomegaly upon physical examination. A pulsatile liver develops if tricuspid regurgitation is severe. Ascites may occur but is unusual. The systolic murmur of tricuspid valve regurgitation may be present.

Causes

Hypoventilation may be secondary to several mechanisms, including central respiratory drive depression, neuromuscular disorders, chest wall abnormalities, obesity hypoventilation, and COPD.

• Chronic obstructive pulmonary disease
• • Emphysema
  • Chronic bronchitis
• Neuromuscular disorders
• • Amyotrophic lateral sclerosis
  • Muscular dystrophy
  • 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
  • Primary alveolar hypoventilation
• Obesity hypoventilation syndrome

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

The differential diagnosis for hypoventilation syndromes is broad, and all the potential diagnoses listed in Causes and the above listed differentials should be considered. A thorough history, physical examination, and laboratory evaluation should be helpful in limiting the differential diagnosis.

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Serum chemistries
• • The most common finding in chronic hypoventilation after chemistry analysis is the presence of a compensatory increase in the serum bicarbonate (HCO₃) concentration secondary to respiratory acidosis.
  • Patients also occasionally may have hypercalcemia and hyperkalemia
• CBC count
• • Many patients with chronic hypoventilation also are hypoxemic.
  • These patients also may have secondary polycythemia, and a CBC count may reveal an elevated hematocrit level.
• Thyroid function studies
• • Hypothyroidism is a potential cause of obesity. Obesity can contribute to hypoventilation and OSA.
  • Thyroid function should be evaluated in all patients with alveolar hypoventilation who are suspected of having central etiology or OSA.

Imaging Studies

• Chest radiograph
• • Perform a chest radiograph to rule out pulmonary disease as a cause of hypoventilation.
  • Findings on chest radiographs that may help determine the etiology of hypoventilation syndromes include hyperinflation of lung volumes, diaphragm flattening, and elevation of the diaphragms. Hyperinflation of lung volumes and diaphragm flattening occur secondary to severe obstructive airway disease. Elevation of the hemidiaphragms may be related to diaphragm weakness or paralysis or atelectasis.
  • Evidence of bony thoracic abnormalities such as kyphoscoliosis also may be present.
  • With complicating pulmonary hypertension, the hilar vascular shadows are prominent secondary to pulmonary artery enlargement, and the cardiac silhouette may become prominent secondary to right ventricular enlargement.
• Chest computed tomography scan
• • CT scan of the chest may be performed for the same reasons as the chest radiograph.
  • It is more sensitive for detecting disease and may reveal abnormalities not seen on the chest radiograph. CT scan is more sensitive in detecting emphysema, diaphragm abnormalities, and skeletal thoracic abnormalities.
• Brain computed tomography scan
• • Perform imaging of the brain if a central cause of hypoventilation is suspected.
  • Specific etiologies that may be diagnosed by brain CT scan include cerebrovascular accident, central nervous system tumor, and central nervous system trauma. Pay particular attention to the brainstem for lesions in the pons and medulla.
• Magnetic resonance imaging of the brain
• • If a central cause of hypoventilation is suspected and the initial brain CT scan is negative or inconclusive, consider an MRI of the brain.
  • MRI may disclose abnormalities that are not seen on CT scan. Pay particular attention to the brainstem, as with the CT scan mentioned above.
• Fluoroscopy: The fluoroscopic "sniff test" (in which paradoxical elevation of the paralyzed diaphragm is seen during inspiratory effort against a closed glottis) can confirm chest radiographic findings regarding unilateral diaphragmatic paralysis. This test is less useful in the diagnosis of bilateral diaphragmatic paralysis.
• Echocardiography
• • Echocardiography is indicated to evaluate patients with hypoventilation syndromes for evidence of pulmonary hypertension and right ventricular enlargement. It also is useful to determine the presence of other potential complicating factors such as left ventricular dysfunction and valvular dysfunction.
  • On 2-dimensional echocardiography, patients with pulmonary artery hypertension have increased thickness of the right ventricle. As pulmonary hypertension becomes severe, a paradoxical bulging of the interventricular septum into the left ventricle occurs during systole. Later, the right ventricle dilates, becomes hypokinetic, and the septum develops diastolic flattening.
  • Doppler echocardiography is the most reliable method of estimating pulmonary artery pressure (PAP). Patients with pulmonary artery hypertension may have functional tricuspid valve regurgitation. The maximum tricuspid regurgitant (TR) jet velocity is recorded, and the PAP is calculated using a modified Bernoulli equation: PAP systolic = (4 X TR jet velocity squared) + RAP. RAP is right atrial pressure estimated from the size of the inferior vena cava (IVC) and respiratory variation in flow in the IVC.

Other Tests

• Pulmonary function tests
• • These measurements are required for the diagnosis of obstructive lung disease and assessment of the severity of disease.
  • FEV₁ is the most commonly used index of airflow obstruction. The ratio of FEV₁ to forced vital capacity is reduced in airflow obstruction and is the diagnostic variable.
  • Lung volume measurements may document an increase in total lung capacity, functional residual capacity, and residual volume in obstructive pulmonary disease.
  • Measurement of maximal inspiratory and expiratory pressures may be useful in screening for respiratory muscle weakness.
• Electromyography and nerve conduction velocity
• • An electromyogram (EMG) and nerve conduction velocity study are useful in diagnosing neuromuscular disorders such as myasthenia gravis, Guillain-Barré syndrome, and amyotrophic lateral sclerosis that may be the cause of ventilatory muscle weakness.
  • These studies may reveal a neuropathic or myopathic pattern, depending on the etiology.
• Measurement of transdiaphragmatic pressure
• • This study is useful in documenting respiratory muscle weakness. This test is performed by placing an esophageal catheter with an esophageal balloon and a gastric balloon. The difference between the pressures measured at the 2 balloons is the transdiaphragmatic pressure.
  • Patients with diaphragmatic dysfunction and paralysis have a decrease in transdiaphragmatic pressures.
• Polysomnography
• • A large percentage of patients with obesity hypoventilation syndrome have OSA. Polysomnography is used to diagnose sleep-related disorders, including OSA, central apneas, and other causes of sleep disruption such as periodic limb movements. Polysomnography involves monitoring of multiple physiologic variables to include respiratory effort, airflow, oxygen saturation, sleep stages, body position, limb movements, and electrocardiography.
  • Sleep stages and arousals are monitored by electroencephalogram to determine brain wave activity, electrooculogram (EOG) to determine eye movement, and submental EMG to detect muscle tone. The EOG and EMG facilitate the determination of the REM sleep stage, which is associated with decreased muscle tone and increased frequency of obstructive apneas. Respiratory effort is recorded using devices to measure abdominal and chest wall movement. These devices include strain gauges, impedance devices, EMG bands, and an esophageal balloon with respiratory inductive plethysmography.
  • From the collected data, sleep stage distribution, arousals, apneas, and hypopneas can be quantitated. Central and obstructive apneas can be differentiated. The apnea index and apnea-plus-hypopnea index (AHI) can be calculated by dividing the total number of apneas or apneas plus hypopneas by the total sleep time. The AHI also is known as the respiratory disturbance index. An AHI is considered abnormal at 5 per hour, and an AHI of 5-15 represents mild OSA.
• Arterial blood gas
• • Alveolar hypoventilation can be documented by the presence of hypercapnia or an elevated PaCO₂ (>45 mm Hg). The PaO₂ should be evaluated because hypoxemia may be present and frequently is associated with alveolar hypoventilation.
  • HCO₃ and pH should be evaluated to determine the presence of acute or chronic acidosis and the degree of compensation.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

The treatment of hypoventilation primarily is directed at correcting the underlying disorder. Use caution when correcting chronic hypercapnia. Rapid correction of the hypercapnia can alkalinize the cerebrospinal fluid, which may cause seizures, and can induce a metabolic alkalosis placing the patient at risk for cardiac dysrhythmias. Infusion of sodium HCO₃ is not indicated for chronic hypoventilation syndromes.

• Bronchodilators such as beta-agonists (eg, albuterol, salmeterol), anticholinergic agents (eg, ipratropium bromide), and methylxanthines (eg, theophylline) are helpful in treating patients with obstructive lung disease and severe bronchospasm. Additionally, theophylline may improve diaphragm muscle contractility and stimulate the respiratory center.
• Treatment also is aimed at assisting ventilation. Therapies that may be beneficial are endotracheal intubation with mechanical ventilation and noninvasive ventilatory techniques such as bilevel positive-pressure ventilation. Ventilatory assistance may be required in patients for the following indications:
  • Symptoms of nocturnal hypoventilation such as daytime hypersomnolence, morning headaches, fatigue, nightmares, and enuresis
  • Dyspnea at rest
  • Hypoventilation that causes pulmonary hypertension and cor pulmonale
  • Nocturnal hypoxia (arterial oxygen saturation <88%) despite supplemental oxygen
• A series of 54 study patients (18 women) diagnosed with OHS showed that, at the end of the follow-up period (mean = 50 mo), PaO₂ had increased by 24 mm Hg and PaCO₂ had decreased by 17 mm Hg from baseline. Noninvasive ventilation therapy improved subjective sleepiness and dyspnea decreased in most of the patients. (Llano, 2005).
• Noninvasive ventilation utilizing nocturnal positive-pressure ventilation (PPV) is widely accepted as the ventilatory mode of choice in patients with chronic respiratory failure related to COPD, neuromuscular disease, thoracic deformities, and idiopathic hypoventilation. Nocturnal PPV may obviate the need for tracheotomy and has improved many patient-oriented outcomes. Bilevel positive-pressure ventilation is the preferred method of noninvasive ventilation.
  • Based on the available literature, the indications for noninvasive PPV for nocturnal hypoventilation syndromes have been formulated. Patients considered for this therapy should have the following: a disease known to cause hypoventilation; symptoms and signs of hypoventilation present; failure to respond to first-line therapies in mild cases of hypoventilation (ie, treatment of primary underlying disease with bronchodilators, respiratory stimulants, weight loss, supplemental oxygen, or CPAP); or moderate-to-severe hypoventilation.
  • Nocturnal PPV is indicated for use in patients with neuromuscular disorders who exhibit morning headache, daytime hypersomnolence, sleep difficulties, or cognitive dysfunction.
  • In the absence of symptoms, nocturnal PPV is recommended when the partial pressure of alveolar carbon dioxide (PaCO₂) is higher than 45 mm Hg or when the partial pressure of arterial oxygen (PaO₂) is less than 60 mm Hg on a morning blood gas measurement.
• Consideration for intubation and invasive mechanical ventilation should be undertaken if attempts at noninvasive ventilation fail to benefit the patient.
• Drugs aimed at reversing the effects of certain sedative drugs also may be helpful in the event of an overdose. Naloxone (Narcan) may be used to reverse the effects of narcotics, and flumazenil (Romazicon) may be used to reverse the effects of benzodiazepines.
• Because many patients with hypercapnia also are hypoxemic during the day, oxygen therapy may be indicated.
• • Oxygen therapy is indicated to prevent the sequelae of long-standing hypoxemia. Patients with COPD who meet the criteria for oxygen therapy have a decreased mortality when treated with oxygen. Oxygen therapy also has been shown to reduce pulmonary hypertension. Oxygen use alone is an inadequate therapy for OHS.
  • Use oxygen therapy with caution because it may worsen hypercapnia in some situations. In patients with COPD, the presence of worsening hypercapnia following oxygen therapy is a consequence of ventilation-perfusion mismatching rather than reduced ventilatory drive secondary to reduction in hypoxia. Hypercapnia is best avoided by titration of oxygen delivery to maintain oxygen saturations in the range of 90-94% and a PaO₂ between 60 and 65 mm Hg.
• Respiratory stimulants have been used but have limited efficacy in alveolar hypoventilation.
  • Medroxyprogesterone increases the central respiratory drive, and it has been shown to be effective in obesity hypoventilation syndrome. Medroxyprogesterone also has been shown to stimulate ventilation in patients with COPD and alveolar hypoventilation. Initial studies documenting a reduction in hypercapnia with treatment with medroxyprogesterone were performed in the 1960s. Recent studies also have documented a decrease in hypercapnia in patients with obesity hypoventilation syndrome and COPD with associated hypercapnia while receiving total daily doses of 60 mg of medroxyprogesterone in divided doses 2-3 times per day. However, it does not improve apnea frequency or symptoms of sleepiness. Limited data exist regarding adverse effects and outcomes of long-term use. Many experts do not currently recommend progesterone therapy.
  • Acetazolamide is a diuretic that inhibits carbonic anhydrase, increases HCO₃ excretion, and causes metabolic acidosis. The metabolic acidosis subsequently stimulates ventilation. However, this medication must be used with caution. If the patient's respiratory system can not compensate for the metabolic acidosis it induces, the patient may suffer hyperkalemia and, potentially, a cardiac dysrhythmia.
  • Theophylline increases diaphragm muscle strength and stimulates the central ventilatory drive.
• Weight loss should be encouraged in patients with obesity hypoventilation syndrome. Diet regulation and exercise are prudent recommendations, and supervised weight loss programs should be offered to these patients. Unfortunately, many of these patients have numerous comorbidities that prevent them from performing an adequate level of exercise to facilitate significant weight loss. Bariatric surgical procedures such as gastric bypass procedures should be offered to patients who are appropriate surgical candidates and are willing to accept the risk of the surgical procedure.

Surgical Care

• Bariatric surgical techniques may be appropriate for some patients with obesity hypoventilation syndrome. The numerous surgical options available today and can be grouped into 2 categories based on their weight loss mechanism. Gastric restrictive procedures include vertical banded gastroplasty (VBG), adjustable gastric banding (AGB), and Roux-en-Y gastric bypass (RYGB). The procedures causing malabsorption include biliopancreatic diversion (BPD) and biliopancreatic diversion with duodenal switch (BPD-DS). All of the procedures have been successful in improving the comorbidities associated with obesity. The most commonly performed procedure is RYGB because it has the best short- and long-term results for safety, efficacy, and durability, and it has been shown to be superior to AGB. RYBG is generally performed laparoscopically. All the procedures require long-term dietary compliance and careful nutritional follow-up.
• The National Institutes of Health consensus statement addresses the issue of surgical treatment for obesity and obesity with associated comorbid conditions. According to these guidelines, patients with a body mass index greater than 35 kg/m² and an obesity-related comorbid condition (including obesity hypoventilation syndrome) or patients with a body mass index greater than 40 kg/m² are recommended for surgical treatment.
• Some patients with thoracic deformities such as kyphoscoliosis may be candidates for corrective surgical procedures if they are acceptable candidates for thoracic surgery.
• Diaphragm pacing in appropriate patients with primary alveolar hypoventilation may allow for a more normal lifestyle. This requires surgical placement of an electrode onto the phrenic nerve, which is connected to a subcutaneous receiver. An external battery-operated transmitter and antenna are placed on the skin over the receiver. This phrenic nerve is stimulated by the electric current thereby resulting in a diaphragmatic contraction. The transmitter settings may be adjusted for respiratory rate and to give enough tidal volume to allow for adequate oxygenation and ventilation. Unfortunately, phrenic nerve stimulation results in irreversible injury to the nerve. Thus, over time, pacing of the phrenic nerve becomes ineffective.
• More recently, direct pacing of the diaphragm in patients with phrenic nerve paralysis has been of interest. Studies are ongoing to determine the utility of this treatment modality.

Consultations

• Consider consultation with experts in certain medical specialties for assistance with evaluation and management of hypoventilation syndromes. The patient's history, physical examination findings, and available laboratory studies should guide the selection of consultation. Specialists who should be considered include the following:
• • Pulmonary medicine specialist
  • Neurologist
  • Physical and rehabilitation medicine specialist

Diet

Weight loss is an ideal treatment in OHS and will improve the abnormal physiology and restore normal day time gas exchange. Even a modest weight loss of 10 kg will improve minute ventilation and normalize daytime PaCO₂. In concomitant OSA, weight loss has been shown to decrease the number of sleep-disordered breathing events (apneas and hypopneas) and severity of hypoxemia.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Several drugs may be used to treat hypoventilation syndromes. Most produce the desired effect by stimulating the central respiratory drive, by reversing the effects of other medications that can depress central respiratory drive, and by inducing bronchial dilatation.

Drug Category: Bronchodilators

Act to decrease the muscle tone in both small and large airways in the lungs, thereby increasing ventilation. Include beta adrenergic, methylxanthines, and anticholinergic agonists.

Drug Category: Opioid antagonists

Opioid abuse, toxicity, and overdose are potential etiologies of hypoventilation. Opioid antagonists can be used to reverse the effects of opiates and to improve ventilation.

Drug Category: Benzodiazepine antagonists

Used in reversing the CNS-depressant effects of benzodiazepine overdose. Ability to reverse the benzodiazepine-induced respiratory depression is less predictable.

Drug Category: Carbonic anhydrase inhibitors

Inhibit the enzyme carbonic anhydrase, which, in turn, increases HCO₃ excretion and causes metabolic acidosis. The metabolic acidosis subsequently stimulates ventilation.

Drug Category: Progestins

Progestins stimulate central respiratory drive and may be beneficial in patients with hypoventilation.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• Intensive care unit admission
• • If hypoventilation is severe and leads to respiratory failure, admission to an intensive care unit (ICU) may be required.
  • ICU admission allows for more specialized nursing and respiratory care.
  • Criteria for admission to the ICU are confusion, lethargy, respiratory muscle fatigue, worsening hypoxemia, hypercapnia, and respiratory acidosis with a pH of less than 7.3.
  • All patients requiring immediate tracheal intubation and mechanical ventilation also require ICU admission.
  • Most acute care facilities require that all patients being treated with noninvasive ventilation also be admitted to the ICU.

Further Outpatient Care

• Home oxygen therapy
• • In the outpatient setting, continue oxygen therapy in patients who meet the specific criteria for long-term oxygen therapy.
  • The specific criteria for long-term oxygen therapy include a PaO₂ less than 55 mm Hg, a PaO₂ less than 59 mm Hg with evidence of polycythemia, or cor pulmonale.
  • Re-evaluate patients in 1-3 months after initiating therapy because some patients may improve and may not require long-term oxygen.
  • Again, use oxygen therapy with caution in patients with alveolar hypoventilation because some of these patients may experience worsening of hypercapnia.
• Noninvasive ventilation
• • Noninvasive mechanical ventilation can be continued in the outpatient setting.
  • Bilevel positive-pressure ventilation can be used long-term to treat patients with hypoventilation syndromes.
  • Furthermore, patients with hypoventilation syndromes improve with nocturnal noninvasive mechanical ventilation only. Clinical studies have shown improvements in hypercapnia and hypoxia after treatment with nocturnal noninvasive mechanical ventilation in patients with COPD with associated hypoventilation, neuromuscular disorders, obesity hypoventilation syndrome, and kyphoscoliosis.

Deterrence/Prevention

• Alcohol and many illicit substances are known respiratory depressants. Their use in patients with hypoventilation syndromes may lead to coma and death.

Prognosis

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

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Failure to correctly diagnose the cause of hypoventilation is a concern. Patients with hypoventilation should be thoroughly evaluated for an etiology. Many of the potential causes of hypoventilation are treatable. Efforts should be made to determine a diagnosis early in the course of the illness in order to facilitate prompt treatment and prevention of potential morbidity and mortality.
• A diagnosis of lung disease should not be assumed because other organ system dysfunction may be the primary cause of hypoventilation.
• Central and peripheral neurologic disorders and muscular disorders should be considered.
• The effects of sedating drugs such as narcotics and benzodiazepines in causing or worsening hypoventilation should always be considered. In patients without an obvious source of hypoventilation, a drug screen should be performed.
• Efforts should be taken to use oxygen therapy cautiously in patients with COPD and hypoventilation because higher fractions of inspired oxygen can worsen hypoventilation.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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Article Last Updated: Jun 29, 2006