eMedicine Specialties > Pulmonology > Sleep-Related Disorders

Hypoventilation Syndromes

Jazeela Fayyaz, DO, Senior Fellow, Department of Pulmonology, Lenox Hill Hospital
Klaus-Dieter Lessnau, MD, FCCP, Clinical Associate Professor of Medicine, New York University School of Medicine; Medical Director, Pulmonary Physiology Laboratory; Director of Research in Pulmonary Medicine, Department of Medicine, Section of Pulmonary Medicine, Lenox Hill Hospital

Updated: Sep 18, 2009

Introduction

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. Congenital central hypoventilation syndrome (CCHS), previously known as Ondine curse, generally presents in newborns and, in 90% of the cases, is caused by a polyalanine repeat expansion mutation in the PHOX2B gene. Patients heterozygous for PHOX2B may have milder forms of disease and live into adulthood.¹ Ventilation in CCHS patients is more stable during rapid eye movement (REM) sleep compared with non-REM sleep.² Ventilatory responses to hypercapnia and hypoxia are absent or diminished in these patients. CCHS may occur in association with Hirschsprung disease; additionally, CCHS patients are at increased risk of neuroblastoma and ganglioneuroma.¹

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. OHS is defined as a combination of obesity, body mass index greater than or equal to 30 kg/m² with awake chronic hypercapnia (PaCO₂ >45 mm Hg) and sleep-disordered breathing. Other disorders that may cause hypoventilation should be ruled out first. Approximately 90% of patients with OHS also have obstructive sleep apnea (OSA).³ Unlike in CCHS, in OHS hypoventilation is worse in REM sleep compared with non-REM sleep.

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 desaturations 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 (FEV₁) 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 (H₂ CO₃). 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.

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. 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 REM sleep.

Currently, the prevalence of OHS ranges from 10-20%.⁵ Data from the US Centers of Disease Control and Prevention (CDC) show that one third of the adult US population is obese. With an increase in the obesity rate, the prevalence of OHS will likely continue to increase.⁶

Kyphoscoliosis is the chest wall deformity most commonly associated with hypoventilation.

Mortality/Morbidity

• The morbidity and mortality rates of 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 with only OSA. 
• OHS patients have higher rates of ICU admission compared with patients with similar levels of obesity without hypoventilation.³
• The morbidity and mortality rates of each of the above-mentioned 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 reported several decades ago showed significant increase in mortality in patients with OHS. 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 1974.⁷ 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.
• OHS also occurs more commonly in males, with a 2:1 male-to-female ratio.³

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.
• Most patients with OHS are older than 50 years.⁸

Clinical

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.
  • Patients with OHS typically report symptoms of OSA, such as daytime hypersomnolence, fatigue, loud snoring, nocturnal choking, and morning headaches. They may also have pulmonary hypertension and chronic right-sided 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 disorders⁹
  • 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
• Obesity hypoventilation syndrome

Differential Diagnoses

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

Laboratory 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 obstructive sleep apnea (OSA).
  • Thyroid function should be evaluated in all patients with alveolar hypoventilation who are suspected of having central etiology or OSA.

Imaging Studies

• Chest radiography
  • 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 scanning
  • 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 scanning
  • 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 testing
  • 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.
• Electrocardiography
  • An ECG may show signs of right heart strain, right ventricular hypertrophy, and right atrial enlargement.³
• Electromyography and nerve conduction velocity
  • Electromyography (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
  • Polysomnography should be performed in all patients with obesity hypoventilation syndrome (OHS) because the majority of patients also have OSA. Polysomnography involves monitoring of multiple physiologic variables to include respiratory effort, airflow, oxygen saturation, sleep stages, body position, limb movements, and ECG.
  • 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.
  • Also see the clinical guideline summary from the American Sleep Disorders Association, Practice parameters for the indications for polysomnography and related procedures: an update for 2005.¹⁰  
• Arterial blood gas analysis
  • 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

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
• Noninvasive ventilation using nocturnal positive-pressure ventilation (PPV) is widely accepted as the ventilatory mode of choice in patients with chronic respiratory failure related to chronic obstructive pulmonary disease (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 greater 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.¹¹
  • Daytime ventilation should be used when these patients have PaCO₂ greater than 50 mm Hg or oxygen saturation of less than 92%.⁹
  • Studies in obesity hypoventilation syndrome (OHS) patients have shown that 1 year of treatment with nocturnal PPV improves blood gas values.¹²
  • Nocturnal hypoventilation acts by improving nocturnal hypoventilation and improving carbon dioxide responsiveness.¹¹
  • See the related clinical guideline summary from the American Academy of Sleep Medicine, Practice parameters for the use of continuous and bilevel positive airway pressure devices to treat adult patients with sleep-related breathing disorders.¹³
  • Also see Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease, a clinical guideline summary from the Global Initiative for Chronic Obstructive Lung Disease (GOLD).¹⁴
• 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 obesity hypoventilation syndrome (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.
  • Approximately half the patients with OHS require oxygen therapy in addition to nocturnal PPV.³
  • Patients with neuromuscular disease should not be given oxygen therapy without ventilatory support.
• 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 OHS. 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.¹⁵ More recent studies also have documented a decrease in hypercapnia in patients with OHS and COPD with associated hypercapnia while receiving total daily doses of 60 mg of medroxyprogesterone in divided doses 2-3 times per day.¹⁶ However, it does not improve apnea frequency or symptoms of sleepiness. In addition, the risk of venous thromboembolism is increased with progestational agents.⁶ 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 cannot 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 OHS. 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 who are willing to accept the risk of the surgical procedure. OHS is associated with a higher operative mortality.³

Surgical Care

• The numerous surgical options available today 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.¹⁷
• 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.¹⁸
• 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.¹⁹

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.²⁰ 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 improves the abnormal physiology and restores normal daytime gas exchange. Even a modest weight loss of 10 kg improves minute ventilation and normalizes daytime PaCO₂. In concomitant obstructive sleep apnea (OSA), weight loss has been shown to decrease the number of sleep-disordered breathing events (apneas and hypopneas) and severity of hypoxemia.

Medication

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.

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.

Albuterol (Proventil, Ventolin)

Beta-agonist for reversal of bronchospasm.
Relaxes bronchial smooth muscle by its action on beta2-receptors, with little effect on cardiac muscle contractility.

Dosing

Adult

2-4 mg/dose PO divided tid/qid; not to exceed 32 mg/d
MDI: 1-2 puffs q4-6h; not to exceed 12 puffs/d
Nebulizer: Dilute 0.5 mL (2.5 mg) of 0.5% inhalation solution in 1-2.5 mL of NS; administer 2.5-5 mg q4-6h, diluted in 2-5 mL NS or water via nebulizer

Pediatric

<2 years: Not established
2-5 years: 0.1-0.2 mg/kg/dose PO divided tid; not to exceed 12 mg/d
5-12 years: 2 mg/dose PO divided tid/qid; not to exceed 24 mg/d
>12 years: Administer as in adults
MDI
<12 years: 1-2 puffs qid with tube spacer
>12 years: Administer as in adults
Nebulizer
<5 years: Dilute 0.25-0.5 mL (1.25-2.5 mg) of 0.5% inhalation solution in 1-2.5 mL of NS and administer q4-6h in equally divided doses
>5 years: Administer as in adults

Interactions

Beta-adrenergic blockers antagonize effects; inhaled ipratropium may increase duration of bronchodilatation; cardiovascular effects may increase with MAOIs, inhaled anesthetics, TCAs, and sympathomimetic agents

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in hyperthyroidism, diabetes mellitus, and cardiovascular disorders

Metaproterenol (Alupent, Metaprel)

Beta2-adrenergic agonist that relaxes bronchial smooth muscle with little effect on heart rate.

Dosing

Adult

0.3 mL of 5% solution diluted in 2.5 mL of 0.45% or 0.9% NS, nebulized over 5-15 min q4h

Pediatric

0.1-0.2 mL of 5% solution diluted in 3 mL of 0.45% or 0.9% NS, over 5-15 min q4h

Interactions

Decreases effect of beta-receptor blockers; increases toxicity of MAOIs, TCAs, and sympathomimetics

Contraindications

Documented hypersensitivity; arrhythmia associated with tachycardia

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in hypertension, cardiovascular disease, congestive heart failure, hyperthyroidism, diabetes, and seizures; not recommended for breastfeeding mothers; adverse reactions include tachycardia, headache, nervousness, dizziness, tremor, gastrointestinal upset, hypertension, paradoxical bronchospasm, and cough

Ipratropium (Atrovent)

Anticholinergic bronchodilator chemically related to atropine.

Dosing

Adult

MDI: 2-4 puffs q4-6h
Nebulizer: 250 mcg diluted with 2.5 mL NS q4-6h

Pediatric

MDI: 1-2 puffs tid; not to exceed 6 puffs/d
Nebulizer: 250 mcg tid

Interactions

Drugs with anticholinergic properties (eg, dronabinol) may increase toxicity; albuterol may increase effects

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in narrow-angle glaucoma, prostatic hypertrophy, or bladder neck obstruction

Theophylline (Theo-Dur, Slo-bid, Theo-24, Aminophyllin, Theolair)

Potentiates exogenous catecholamines, stimulates endogenous catecholamine release, and stimulates diaphragmatic muscular relaxation, which, in turn, stimulates bronchodilation. Popularity has decreased because of narrow therapeutic range and frequent toxicity.
Therapeutic range is 10-20 mg/dL, but bronchodilation may require near-toxic (>20 mg/dL) levels. Clinical efficacy is controversial, especially in acute setting.

Dosing

Adult

Initial: 10 mg/kg/d PO divided q8-12h; IV loading dose is 5.6 mg/kg (based on aminophylline) IV over 20 min, followed by maintenance infusion of 0.1-1.1 mg/kg/h
Maintenance: 10 mg/kg/d PO qd or divided bid; adjust dose in 25% increments to maintain serum theophylline level of 5-15 mcg/mL; not to exceed 800 mg/d

Pediatric

<6 weeks: Not established
6 weeks to 6 months: 0.5 mg/kg/h loading dose IV in first 12 h (based on aminophylline), followed by maintenance infusion of 12 mg/kg/d thereafter; may administer continuous infusion by dividing total daily dose by 24 h
6 months to 1 year: 0.6-0.7 mg/kg/h loading dose IV in first 12 h, followed by maintenance infusion of 15 mg/kg/d; may administer as continuous infusion, as above
>1 year: Administer as in adults

Interactions

Aminoglutethimide, barbiturates, carbamazepine, ketoconazole, loop diuretics, charcoal, hydantoins, phenobarbital, phenytoin, rifampin, isoniazid, and sympathomimetics may decrease effects; effects may increase with allopurinol, beta-blockers, ciprofloxacin, corticosteroids, disulfiram, quinolones, thyroid hormones, ephedrine, carbamazepine, cimetidine, erythromycin, macrolides, propranolol, and interferons

Contraindications

Documented hypersensitivity; uncontrolled arrhythmias; peptic ulcers; hyperthyroidism; uncontrolled seizure disorders

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in peptic ulcer disease, hypertension, tachyarrhythmias, hyperthyroidism, and compromised cardiac function; not to inject IV solution >25 mg/min; patients diagnosed with pulmonary edema or liver dysfunction are at greater risk of toxicity because of reduced drug clearance

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.

Naloxone (Narcan)

Pure opioid antagonist. Prevents or reverses opioid effects (eg, hypotension, respiratory depression, sedation), possibly by displacing opiates from their receptors. Used to reverse opioid intoxication.

Dosing

Adult

0.4-2 mg IV/IM/SC q2-3min prn; use increments of 0.1-0.2 mg in patients dependent on opioids; may need to repeat dose q20-60min; if no response after administering 10 mg, question diagnosis

Pediatric

0.1 mg/kg IV/IM/SC, repeat q2-3min prn

Interactions

Decreases analgesic effects of narcotics

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in cardiovascular disease; may precipitate withdrawal symptoms in patients who are opioid dependent

Benzodiazepine antagonists

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

Flumazenil (Romazicon)

Reverses effects of benzodiazepines in an overdose by selectively antagonizing GABA/benzodiazepine receptor complex. If patient who is overdosed has not responded after 5 min of administering a cumulative dose of 5 mg, cause of sedation is not likely due to benzodiazepines. Short acting, with a half-life of 0.7-1.3 h. However, because most benzodiazepines have longer half-lives, multiple doses should be administered to avoid relapse into sedative state.

Dosing

Adult

0.2 mg IV over 30 seconds initially; repeat at 1-min intervals with 0.5 mg over 30 seconds until satisfactory response attained or 3 mg administered; may require additional titration to a total 5 mg

Pediatric

0.01 mg/kg IV over 15 seconds initially; repeat at 1-min intervals with 0.005-0.01 mg/kg; not to exceed 0.2 mg/dose

Interactions

Caution in cases of mixed-drug overdose; toxic effects due to other drugs taken in overdose (eg, tricyclic antidepressants) may occur with reversal of benzodiazepine effects

Contraindications

Documented hypersensitivity; serious cyclic antidepressant overdosage; patients taking a benzodiazepine for control of potentially life-threatening condition (eg, intracranial pressure, status epilepticus)

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Monitor for resedation (at least 2 h); respiratory depression, seizures, or other benzodiazepine residual effects; caution in drug or alcohol dependence, head injury, hepatic disease, and panic disorder; patients on benzodiazepines for prolonged periods may experience seizures

Carbonic anhydrase inhibitors

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

Acetazolamide (Diamox)

Improves symptomatic periodic breathing and hypoxia.

Dosing

Adult

250 mg PO qd/qid or 500 mg SR cap PO bid; 250 mg IV q8-12h

Pediatric

8-30 mg/kg/d PO or 300-900 mg/m²/d PO divided q8h; alternatively, 20-40 mg/kg/d PO divided q6h; not to exceed 1 g/d

Interactions

Can decrease therapeutic levels of lithium and alter excretion of drugs (eg, amphetamines, quinidine, phenobarbital, salicylates) by alkalinizing urine

Contraindications

Documented hypersensitivity; hepatic disease; severe renal disease; adrenocortical insufficiency; severe pulmonary obstruction

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Patients with impaired hepatic function may go into coma; may cause substantial increase in blood glucose in some patients with diabetes

Progestins

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

Medroxyprogesterone acetate (Provera)

Increases central respiratory drive and stimulates ventilation. May increase upper airway muscular tone.
For treatment of hypoventilation, higher doses than usual of medroxyprogesterone acetate required to induce significant reductions in hypercapnia.

Dosing

Adult

60 mg PO divided bid/tid

Pediatric

Not recommended

Interactions

May decrease effects of aminoglutethimide

Contraindications

Documented hypersensitivity; cerebral apoplexy, undiagnosed vaginal bleeding, thrombophlebitis, and liver dysfunction

Precautions

Pregnancy

X - Contraindicated; benefit does not outweigh risk

Precautions

Caution in asthma, depression, renal or cardiac dysfunction, or thromboembolic disorders

Follow-up

Further Inpatient Care

• Intensive care unit admission
  • If hypoventilation is severe and leads to respiratory failure, admission to an 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 chronic obstructive pulmonary disease (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.²¹

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

Medicolegal 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.

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Keywords

hypoventilation syndrome, primary alveolar hypoventilation, alveolar ventilation, VA, obesity hypoventilation syndrome, OHS, chronic obstructive pulmonary disease with hypercapnia, hypercapnia, chronic obstructive pulmonary disease, COPD, chronic lung disease, hypoxemia, hypoxia, respiratory system, respiratory failure, obstructive sleep apnea, sleep apnea, OSA, chest wall deformities, respiratory insufficiency, myasthenia gravis, amyotrophic lateral sclerosis, Guillain-Barre syndrome, Guillain-Barré syndrome, muscular dystrophy, kyphoscoliosis, dyspnea, central respiratory drive depression, pickwickian syndrome

Contributor Information and Disclosures

Author

Jazeela Fayyaz, DO, Senior Fellow, Department of Pulmonology, Lenox Hill Hospital
Jazeela Fayyaz, DO is a member of the following medical societies: American College of Physicians and American Thoracic Society
Disclosure: Nothing to disclose.

Coauthor(s)

Klaus-Dieter Lessnau, MD, FCCP, Clinical Associate Professor of Medicine, New York University School of Medicine; Medical Director, Pulmonary Physiology Laboratory; Director of Research in Pulmonary Medicine, Department of Medicine, Section of Pulmonary Medicine, Lenox Hill Hospital
Klaus-Dieter Lessnau, MD, FCCP is a member of the following medical societies: American College of Chest Physicians, American College of Physicians, American Medical Association, American Society for Artificial Internal Organs, American Thoracic Society, Physicians for Social Responsibility, and Society of Critical Care Medicine
Disclosure: sepracor Ownership interest None

Medical Editor

Ryland P Byrd Jr, MD, Professor, Department of Internal Medicine, Division of Pulmonary Medicine and Critical Care Medicine, James H Quillen College of Medicine, East Tennessee State University; Chief of Pulmonary Medicine, Medical Director of Respiratory Therapy, Intensive Care Unit, Program Director of Pulmonary Diseases and Critical Care Medicine Fellowship, James H Quillen Veterans Affairs Medical Center
Ryland P Byrd Jr, MD is a member of the following medical societies: American College of Chest Physicians, American Thoracic Society, and Southern Medical Association
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Om Prakash Sharma, MD, FRCP, FCCP, DTM&H, Professor, Department of Medicine, Division of Pulmonary and Critical Care Medicine, University of Southern California Keck School of Medicine
Om Prakash Sharma, MD, FRCP, FCCP, DTM&H is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American College of Chest Physicians, American College of Physicians, American Federation for Medical Research, American Osler Society, American Thoracic Society, New York Academy of Medicine, and Royal Society of Medicine
Disclosure: Keck School of Medicine, USC None None

CME Editor

Timothy D Rice, MD, Associate Professor, Departments of Internal Medicine and Pediatrics and Adolescent Medicine, Saint Louis University School of Medicine
Timothy D Rice, MD is a member of the following medical societies: American Academy of Pediatrics and American College of Physicians
Disclosure: Nothing to disclose.

Chief Editor

Zab Mosenifar, MD, Director, Division of Pulmonary and Critical Care Medicine, Director, Women's Guild Pulmonary Disease Institute, Executive Vice Chair, Department of Medicine, Cedars Sinai Medical Center; Professor of Medicine, David Geffen School of Medicine at UCLA
Zab Mosenifar, MD is a member of the following medical societies: American College of Chest Physicians, American College of Physicians, American Federation for Medical Research, and American Thoracic Society
Disclosure: Nothing to disclose.

The authors and editors of eMedicine gratefully acknowledge the contributions of previous authors, Jackie A. Hayes, MD, FCCP, and Sat Sharma, MD, FRCPC, FACP, FCCP, DABSM, to the development and writing of this article.

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