2201 Disorders of Ventilation CHAPTER 296

TABLE 295-1 The Three Compartments of the Mediastinum

ANTERIOR COMPARTMENT MIDDLE COMPARTMENT POSTERIOR COMPARTMENT

Anatomical boundaries Manubrium and sternum anteriorly,

pericardium, aorta, and brachiocephalic

vessels posteriorly

Anterior mediastinum anteriorly, posterior mediastinum

posteriorly

Pericardium and trachea anteriorly;

vertebral column posteriorly

Contents Thymus gland, anterior mediastinal

lymph nodes, internal mammary

arteries, and veins

Pericardium, heart, ascending and transverse

arch of aorta, superior and inferior vena cavae,

brachiocephalic arteries and veins, phrenic nerves,

trachea, and main bronchi and their contiguous lymph

nodes, pulmonary arteries, and veins

Descending thoracic aorta, esophagus,

thoracic duct, azygos and hemiazygos

veins, sympathetic chains, and the

posterior group of mediastinal lymph

nodes

Common abnormalities Thymoma, lymphomas, teratomatous

neoplasms, thyroid masses, parathyroid

masses, mesenchymal tumors, giant

lymph node hyperplasia, hernia through

foramen of Morgagni

Metastatic lymph node enlargement, granulomatous

lymph node enlargement, pleuropericardial cysts,

bronchogenic cysts, masses of vascular origin

Neurogenic tumors, meningocele,

meningomyelocele, gastroenteric cysts,

esophageal diverticula, hernia through

foramen of Bochdalek, extramedullary

hematopoiesis

esophageal rupture are acutely ill with chest pain and dyspnea due to

the mediastinal infection. The esophageal rupture can occur spontaneously or as a complication of esophagoscopy or the insertion of a

Blakemore tube. Appropriate treatment consists of exploration of the

mediastinum with primary repair of the esophageal tear and drainage

of the pleural space and the mediastinum.

The incidence of mediastinitis after median sternotomy is 0.4–5.0%.

Patients most commonly present with wound drainage. Other presentations include sepsis and a widened mediastinum. The diagnosis

usually is established with mediastinal needle aspiration. Treatment

includes immediate drainage, debridement, and parenteral antibiotic

therapy, but the mortality rate still exceeds 20%.

■ CHRONIC MEDIASTINITIS

The spectrum of chronic mediastinitis ranges from granulomatous

inflammation of the lymph nodes in the mediastinum to fibrosing

mediastinitis. Most cases are due to histoplasmosis or tuberculosis, but

sarcoidosis, silicosis, and other fungal diseases are at times causative.

Patients with granulomatous mediastinitis are usually asymptomatic.

Those with fibrosing mediastinitis usually have signs of compression of

a mediastinal structure such as the superior vena cava or large airways,

phrenic or recurrent laryngeal nerve paralysis, or obstruction of the

pulmonary artery or proximal pulmonary veins. If veins or arteries are

involved, the placement of stents has relieved the symptoms in many

patients.

■ PNEUMOMEDIASTINUM

In this condition, there is gas in the interstices of the mediastinum.

The three main causes are (1) alveolar rupture with dissection of air

into the mediastinum; (2) perforation or rupture of the esophagus,

trachea, or main bronchi; and (3) dissection of air from the neck or

the abdomen into the mediastinum. Typically, there is severe substernal chest pain with or without radiation into the neck and arms. The

physical examination usually reveals subcutaneous emphysema in the

suprasternal notch and Hamman’s sign, which is a crunching or clicking noise synchronous with the heartbeat and is best heard in the left

lateral decubitus position. The diagnosis is confirmed with the chest

radiograph. Usually no treatment is required, but the mediastinal air

will be absorbed faster if the patient inspires high concentrations of

oxygen. If mediastinal structures are compressed, the compression can

be relieved with needle aspiration.

■ FURTHER READING

Carter BW et al: ITMIG classification of mediastinal compartments

and multidisciplinary approach to mediastinal masses. Radiographics

37:413, 2017.

Ponamgi SP et al: Catheter-based intervention for pulmonary vein

stenosis due to fibrosing mediastinitis: The Mayo Clinic experience.

Int J Cardiol Heart Vasc 8:103, 2015.

DEFINITION AND PHYSIOLOGY

In health, the arterial level of carbon dioxide (Paco2

) is maintained

between 37 and 43 mmHg at sea level. All disorders of ventilation result

in abnormal measurements of Paco2

. This chapter reviews chronic

ventilatory disorders.

The continuous production of carbon dioxide (CO2

) by cellular

metabolism necessitates its efficient elimination by the respiratory system. The relationship between CO2

 production and Paco2

 is described

by the equation: Paco2

 = (k) (V.

co2

)/V.

A, where V.

co2

 represents the

carbon dioxide production, k is a constant, and V.

A is fresh gas alveolar

ventilation (Chap. 285). V.

A can be calculated as minute ventilation ×

(1 – Vd/Vt), where the dead space fraction Vd/Vt represents the portion of a tidal breath that remains within the conducting airways at

the conclusion of inspiration and so does not contribute to alveolar

ventilation. As such, all disturbances of Paco2

 must reflect altered CO2

production, minute ventilation, or dead space fraction.

Diseases that alter (V.

co2

) are often acute (e.g., sepsis, burns, or

pyrexia), and their contribution to ventilatory abnormalities and/or

respiratory failure is reviewed elsewhere. Chronic ventilatory disorders

typically involve inappropriate levels of minute ventilation or increased

dead space fraction. Characterization of these disorders requires a

review of the normal respiratory cycle.

The spontaneous cycle of inspiration and expiration is automatically

generated in the brainstem. Two groups of neurons located within

the medulla are particularly important: the dorsal respiratory group

(DRG) and the ventral respiratory column (VRC). These neurons have

widespread projections including the descending projections into the

contralateral spinal cord where they perform many functions. They

initiate activity in the phrenic nerve/diaphragm, project to the upper

airway muscle groups and spinal respiratory neurons, and innervate

the intercostal and abdominal muscles that participate in normal

respiration. The DRG acts as the initial integration site for many of

the afferent nerves relaying information about Pao2

, Paco2

, pH, and

blood pressure from the carotid and aortic chemoreceptors and baroreceptors to the central nervous system (CNS). In addition, the vagus

nerve relays information from stretch receptors and juxtapulmonarycapillary receptors in the lung parenchyma and chest wall to the DRG.

The respiratory rhythm is generated within the VRC as well as the

more rostrally located parafacial respiratory group (pFRG), which is

particularly important for the generation of active expiration. One particularly important area within the VRC is the so-called pre-Bötzinger

complex. This area is responsible for the generation of various forms

296 Disorders of Ventilation

John F. McConville, Julian Solway,

Babak Mokhlesi

2202 PART 7 Disorders of the Respiratory System

FIGURE 296-1 Examples of balance between respiratory system strength and load.

A. Excess respiratory muscle strength in health. B. Load greater than strength.

C. Increased drive with acceptable strength.

Excess respiratory muscle strength in health

Strength

Chest wall

elastic

loads

Adequate neural

transmission to motor

units

Respiratory

muscle strength Load Lung resistive

loads

Lung elastic

loads

Respiratory

A drive

Load > Strength

Load Strength

Impaired neuromuscular

transmission

Amyotrophic lateral sclerosis

Myasthenia gravis

Phrenic nerve injury

Spinal cord lesion

Muscle

weakness

Myopathy

Malnutrition

Fatigue

Sleep-disordered

breathing

Upper airway

obstruction

Intermittent hypoxemia

Chest wall disease

Kyphoscoliosis

Obesity

Abdominal distention (ascites)

Diminished drive

Sleep-disordered breathing

Narcotic/sedative use

Brainstem stroke

Hypothyroidism

1º Alveolar hypoventilation

Lung disease

Interstitial lung disease

Airflow obstruction

Atelectasis

Pulmonary embolus

B

Increased drive with acceptable strength

Load Strength

Increased drive

Numerous initiating and

sustaining factors (see text)

No chest wall

disease

Normal neural

transmission

No lung disease Normal respiratory

C muscle strength

the strength of the respiratory muscles readily accomplishes this, and

normal respiration continues indefinitely. Reduction in respiratory

drive or neuromuscular competence or substantial increase in respiratory load can diminish minute ventilation, resulting in hypercapnia

(Fig. 296-1B). Alternatively, if normal respiratory muscle strength is

coupled with excessive respiratory drive, then alveolar hyperventilation

ensues and leads to hypocapnia (Fig. 296-1C).

HYPOVENTILATION

■ CLINICAL FEATURES

Diseases that reduce minute ventilation or increase dead space fall

into four major categories: parenchymal lung and chest wall disease,

sleep-disordered breathing, neuromuscular disease, and respiratory

drive disorders (Fig. 296-1B). The clinical manifestations of hypoventilation syndromes are nonspecific (Table 296-1) and vary depending on

the severity of hypoventilation, the rate at which hypercapnia develops,

the degree of compensation for respiratory acidosis, and the underlying

disorder. Patients with parenchymal lung or chest wall disease typically

present with shortness of breath and diminished exercise tolerance.

Episodes of increased dyspnea and sputum production are hallmarks

of obstructive lung diseases such as chronic obstructive pulmonary disease (COPD), whereas progressive dyspnea and cough are common in

interstitial lung diseases. Excessive daytime somnolence, poor-quality

sleep, and snoring are common among patients with sleep-disordered

breathing. Sleep disturbance and orthopnea are also described in

neuromuscular disorders. As neuromuscular weakness progresses, the

respiratory muscles, including the diaphragm, are placed at a mechanical disadvantage in the supine position due to the upward movement

of the abdominal contents. New-onset orthopnea is frequently a sign

of reduced respiratory muscle force generation. More commonly, however, extremity weakness or bulbar symptoms develop prior to sleep

disturbance in neuromuscular diseases such as amyotrophic lateral

sclerosis (ALS) or muscular dystrophy. Patients with respiratory drive

disorders do not have symptoms distinguishable from other causes of

chronic hypoventilation.

The clinical course of patients with chronic hypoventilation from

neuromuscular or chest wall disease follows a characteristic sequence:

an asymptomatic stage where daytime Pao2

 and Paco2

 are normal

followed by nocturnal hypoventilation, initially during rapid eye movement (REM) sleep and later in non-REM sleep. Finally, if vital capacity

drops further, daytime hypercapnia develops. Symptoms can develop at

any point along this time course and often depend on the pace of respiratory muscle functional decline. Regardless of cause, the hallmark of

all alveolar hypoventilation syndromes is an increase in alveolar Pco2

(PAco2

) and therefore in Paco2

. The resulting respiratory acidosis

eventually leads to a compensatory increase in plasma bicarbonate concentration. The increase in Paco2

 results in an obligatory decrease in

PAo2

, often resulting in hypoxemia. If severe, the hypoxemia manifests

clinically as cyanosis and can stimulate erythropoiesis and thus induce

secondary erythrocytosis. The combination of chronic hypoxemia and

hypercapnia may also induce pulmonary vasoconstriction, leading

eventually to pulmonary hypertension, right ventricular hypertrophy,

and right heart failure.

■ DIAGNOSIS

Elevated serum bicarbonate (i.e., total serum CO2

, which equals calculated bicarbonate plus dissolved CO2

) in the absence of volume depletion is suggestive of hypoventilation. However, it is important to point

TABLE 296-1 Signs and Symptoms of Hypoventilation

Dyspnea during activities of daily living

Orthopnea in diseases affecting diaphragm function

Poor-quality sleep

Daytime hypersomnolence

Early morning headaches

Anxiety

Impaired cough in neuromuscular diseases

of inspiratory activity, and lesioning of the pre-Bötzinger complex

leads to the complete cessation of breathing. The neural output of

these medullary respiratory networks can be voluntarily suppressed

or augmented by input from higher brain centers and the autonomic

nervous system. During normal sleep, there is an attenuated response

to hypercapnia and hypoxemia, resulting in mild nocturnal hypoventilation that corrects upon awakening.

Once neural input has been delivered to the respiratory pump

muscles, normal gas exchange requires an adequate amount of respiratory muscle strength to overcome the elastic and resistive loads of

the respiratory system (Fig. 296-1A) (also see Chap. 285). In health,

2203 Disorders of Ventilation CHAPTER 296

out that a serum bicarbonate level <27 mmol/L in the setting of normal

renal function makes the diagnosis of hypoventilation very unlikely.

By contrast, a serum bicarbonate level ≥27 mmol/L should trigger clinicians to measure Paco2

 as a confirmatory diagnostic test. Therefore,

serum bicarbonate can be used as a sensitive test to rule out hypercapnia, not to rule it in. An arterial blood gas demonstrating elevated

Paco2

 with a normal pH confirms chronic alveolar hypoventilation.

The subsequent evaluation to identify an etiology should initially focus

on whether the patient has lung disease or chest wall abnormalities.

Physical examination, imaging studies (chest x-ray and/or CT scan),

and pulmonary function tests are sufficient to identify most lung/

chest wall disorders leading to hypercapnia. If these evaluations are

unrevealing, the clinician should screen for obesity hypoventilation

syndrome (OHS), the most frequent sleep disorder leading to chronic

hypoventilation, which is typically accompanied by obstructive sleep

apnea (OSA). Several screening tools have been developed to identify

patients at risk for OSA. The Berlin Questionnaire has been validated

in a primary care setting and identifies patients likely to have OSA.

The Epworth Sleepiness Scale (ESS) measures daytime sleepiness, with

a score of ≥10 identifying individuals who warrant additional investigation; however, it is not a useful test to screen for sleep-disordered

breathing. Owing to its ease of use, the STOP-Bang questionnaire has

become a popular tool to screen for OSA and has been validated in

various outpatient settings. The STOP-Bang survey has been used in

preoperative anesthesia clinics to identify patients at risk of having

OSA. In this population, it has 93% sensitivity and 90% negative predictive value. Additionally, the STOP-Bang questionnaire has been

validated as a screening tool for OSA in sleep and surgical clinics. The

probability of moderate and severe OSA steadily increases with higher

STOP-Bang scores.

If the ventilatory apparatus (lung, airways, chest wall) is not responsible for chronic hypercapnia, then the focus should shift to respiratory

drive and neuromuscular disorders. There is an attenuated increase

in minute ventilation in response to elevated CO2

 and/or low O2

 in

respiratory drive disorders. These diseases are difficult to diagnose

and should be suspected when patients with hypercapnia are found

to have normal respiratory muscle strength, normal pulmonary function, and normal alveolar-arterial Po2

 difference. Hypoventilation is

more marked during sleep in patients with respiratory drive defects,

and polysomnography often reveals central apneas, hypopneas, or

hypoventilation. Brain imaging (CT scan or MRI) can sometimes

identify structural abnormalities in the pons or medulla that result in

hypoventilation. Chronic narcotic use or significant hypothyroidism

can depress the central respiratory drive and lead to chronic hypercapnia as well.

Respiratory muscle weakness has to be profound before lung volumes are compromised and hypercapnia develops. Typically, physical

examination reveals decreased strength in major muscle groups prior

to the development of hypercapnia. Measurement of maximum inspiratory and expiratory pressures or forced vital capacity (FVC) can be

used to monitor for respiratory muscle involvement in diseases with

progressive muscle weakness. These patients also have increased risk

for sleep-disordered breathing, including hypopneas, central and

obstructive apneas, and hypoxemia. Nighttime oximetry and capnometry during polysomnography are helpful in better characterizing sleep

disturbances in this patient population.

TREATMENT

Hypoventilation

Nocturnal noninvasive positive-pressure ventilation (NIPPV) has

been used successfully in the treatment of hypoventilation and

apneas, both central and obstructive, in patients with neuromuscular and chest wall disorders. Nocturnal NIPPV has been shown

to improve daytime hypercapnia, prolong survival, and improve

health-related quality of life when daytime hypercapnia is documented. ALS guidelines recommend consideration of nocturnal NIPPV if symptoms of hypoventilation exist and one of the

following criteria is present: Paco2

 ≥45 mmHg; nocturnal oximetry demonstrates oxygen saturation ≤88% for 5 consecutive min;

maximal inspiratory pressure <60 cmH2

O; or sniff nasal pressure

<40 cmH2

O and FVC <50% predicted. However, at present, there is

inconclusive evidence to support preemptive nocturnal NIPPV use

in all patients with neuromuscular and chest wall disorders who

demonstrate nocturnal but not daytime hypercapnia. Nevertheless,

at some point, the institution of full-time ventilatory support with

either pressure or volume-preset modes is required in progressive

neuromuscular disorders. There is less evidence to direct the timing

of this decision, but ventilatory failure requiring mechanical ventilation and chest infections related to ineffective cough are frequent

triggers for the institution of full-time ventilatory support.

Treatment of chronic hypoventilation from lung or neuromuscular diseases should be directed at the underlying disorder.

Pharmacologic agents that stimulate respiration, such as medroxyprogesterone and acetazolamide, have been poorly studied in

chronic hypoventilation and should not replace treatment of the

underlying disease process. Regardless of the cause, excessive metabolic alkalosis should be corrected, as serum bicarbonate levels

elevated out of proportion for the degree of chronic respiratory

acidosis can result in additional hypoventilation. When indicated,

administration of supplemental oxygen is effective in attenuating

hypoxemia, polycythemia, and pulmonary hypertension. However,

in some patients, supplemental oxygen, even at low concentrations,

can worsen hypercapnia.

Phrenic nerve or diaphragm pacing is a potential therapy for

patients with hypoventilation from high cervical spinal cord lesions

or respiratory drive disorders. Prior to surgical implantation,

patients should have nerve conduction studies to ensure normal

bilateral phrenic nerve function. Small case series suggest that

effective diaphragmatic pacing can improve quality of life in these

patients.

HYPOVENTILATION SYNDROMES

■ OBESITY HYPOVENTILATION SYNDROME

The diagnosis of OHS requires the following: body mass index (BMI)

≥30 kg/m2

; chronic daytime alveolar hypoventilation, defined as Paco2

≥45 mmHg at sea level in the absence of other known causes of hypercapnia; and evidence of sleep-disordered breathing. In almost 90% of

cases, the sleep-disordered breathing is in the form of OSA, with close

to 70% exhibiting severe OSA. Several international studies in different

populations confirm that the overall prevalence of OSA syndrome,

defined by an apnea-hypopnea index ≥5 and daytime sleepiness, is

~14% in men and 5% in women aged 30–70 years in the United States.

Thus, the population at risk for the development of OHS continues to

rise as the worldwide obesity epidemic persists. Although no population-based prevalence studies of OHS have been performed, some

estimates suggest it may be as high as 0.4% of the U.S. adult population

(or 1 in 263 adults).

Some, but not all, studies suggest that severe obesity (BMI >40 kg/

m2

) and severe OSA (AHI >30 events per h) are risk factors for the

development of OHS. The pathogenesis of hypoventilation in these

patients is the result of multiple physiologic variables and conditions

including OSA, increased work of breathing, respiratory muscle

impairment relative to the increased load because of excess adiposity,

ventilation-perfusion mismatching, and depressed central ventilatory

responsiveness to hypoxemia and hypercapnia. These defects in central

respiratory drive often improve with treatment of sleep-disordered

breathing with CPAP or NIPPV without any significant change in body

weight, which suggests that decreased ventilatory responsiveness is a

consequence rather than a primary cause of OHS. The treatment of

OHS is similar to that for OSA: weight reduction and positive airway

pressure therapy during sleep with either continuous positive airway

pressure (CPAP) or NIPPV. There is evidence that substantial weight

loss (i.e., 20–25% of actual body weight) alone normalizes Paco2

in patients with OHS. Unfortunately, achieving and sustaining this

2204 PART 7 Disorders of the Respiratory System

degree of weight loss without bariatric surgery are very challenging for

most patients. Treatment with CPAP or NIPPV should not be delayed

while the patient attempts to lose weight. CPAP improves daytime

hypercapnia and hypoxemia in more than half of patients with OHS

and concomitant severe OSA. Bilevel positive airway pressure without

a backup rate (bilevel PAP spontaneous mode) should be reserved

for patients not able to tolerate high levels of CPAP support or when

obstructive respiratory events persist despite reaching the maximum

CPAP pressure of 20 cmH2

O. NIPPV in the form of bilevel PAP with a

backup rate (bilevel PAP ST or spontaneous timed) or volume-assured

pressure support modes should be strongly considered if hypercapnia

persists after several weeks of CPAP therapy with objectively proven

adherence. Patients with OHS and no evidence of significant OSA are

typically started on bilevel PAP ST or volume-assured pressure support

modes, as are patients presenting with acute decompensated OHS.

Finally, comorbid conditions that impair ventilation, such as COPD,

should be aggressively treated in conjunction with coexisting OHS.

■ CENTRAL HYPOVENTILATION SYNDROME

This syndrome can present later in life or in the neonatal period, when

it is often called Ondine’s curse or congenital central hypoventilation

syndrome (CCHS). Abnormalities in the gene encoding PHOX2b, a

transcription factor with a role in neuronal development, have been

implicated in the pathogenesis of CCHS. Regardless of the age of onset,

these patients have absent respiratory response to hypoxia or hypercapnia, mildly elevated Paco2

 while awake, and markedly elevated

Paco2

 during non-REM sleep. Interestingly, these patients are able to

augment their ventilation and “normalize” Paco2

 during exercise and

during REM sleep. These patients typically require NIPPV or mechanical ventilation as therapy and should be considered for phrenic nerve

or diaphragmatic pacing at centers with experience performing these

procedures.

HYPERVENTILATION

■ CLINICAL FEATURES

Hyperventilation is defined as ventilation in excess of metabolic

requirements (CO2

 production) leading to a reduction in Paco2

.

The physiology of patients with chronic hyperventilation is poorly

understood, and there is no typical clinical presentation. Symptoms

can include dyspnea, paresthesias, tetany, headache, dizziness, visual

disturbances, and atypical chest pain. Because symptoms can be so

diverse, patients with chronic hyperventilation present to a variety of

health care providers, including internists, neurologists, psychologists,

psychiatrists, and pulmonologists.

It is helpful to think of hyperventilation as having initiating and sustaining factors. Some investigators believe that an initial event leads to

increased alveolar ventilation and a drop in Paco2

 to ~20 mmHg. The

ensuing onset of chest pain, breathlessness, paresthesia, or altered consciousness can be alarming. The resultant increase in minute volume

to relieve these acute symptoms only serves to exacerbate symptoms

that are often misattributed by the patient and health care workers to

cardiopulmonary disorders. An unrevealing evaluation for causes of

these symptoms often results in patients being anxious and fearful of

additional attacks. It is important to note that anxiety disorders and

panic attacks are not synonymous with hyperventilation. Anxiety

disorders can be both an initiating and sustaining factor in the pathogenesis of chronic hyperventilation, but these are not necessary for the

development of chronic hypocapnia.

■ DIAGNOSIS

Respiratory symptoms associated with acute hyperventilation can be

the initial manifestation of systemic illnesses such as diabetic ketoacidosis. Causes of acute hyperventilation need to be excluded before a

diagnosis of chronic hyperventilation is considered. Arterial blood gas

sampling that demonstrates a compensated respiratory alkalosis with a

near normal pH, low Paco2

, and low calculated bicarbonate is necessary to confirm chronic hyperventilation. Other causes of respiratory

alkalosis, such as mild asthma, need to be diagnosed and treated before

chronic hyperventilation can be considered. A high index of suspicion

is required as increased minute ventilation can be difficult to detect on

physical examination. Once chronic hyperventilation is established, a

sustained 10% increase in alveolar ventilation is enough to perpetuate

hypocapnia. This increase can be accomplished with subtle changes in

the respiratory pattern, such as occasional sigh breaths or yawning 2–3

times per min.

TREATMENT

Hyperventilation

There are few well-controlled treatment studies of chronic hyperventilation owing to its diverse features and the lack of a universally

accepted diagnostic process. Clinicians often spend considerable

time identifying initiating factors, excluding alternative diagnoses, and discussing the patient’s concerns and fears. In some

patients, reassurance and frank discussion about hyperventilation

can be liberating. Identifying and eliminating habits that perpetuate

hypocapnia, such as frequent yawning or sigh breathing, can be

helpful. Some evidence suggests that breathing exercises and diaphragmatic retraining may be beneficial for some patients. The evidence for using medications to treat hyperventilation is scant. Beta

blockers may be helpful in patients with sympathetically mediated

symptoms such as palpitations and tremors.

■ FURTHER READING

Anderson PM et al: EFNS guidelines on the clinical management of

amyotrophic lateral sclerosis (MALS)–revised report of the EFNS

task force. Eur J Neurol 19:360, 2012.

Benditt JO: Pathophysiology of neuromuscular respiratory diseases.

Clin Chest Med 39:297, 2018.

Chung F et al: STOP-Bang questionnaire: A practical approach to

screen for obstructive sleep apnea. Chest 149:631, 2016.

Douglas IS: Acute-on-chronic respiratory failure, in Principles of

Critical Care, 4th ed. JB Hall, GS Schmidt, JP Kress (eds). New York,

McGraw-Hill, 2015, pp 482–495.

Gardner WN: The pathophysiology of hyperventilation disorders.

Chest 109:516, 1996.

Masa JF et al: Long-term clinical effectiveness of continuous positive

airway pressure therapy versus non-invasive ventilation therapy

in patients with obesity hypoventilation syndrome: A multicentre,

open-label, randomised controlled trial. Lancet 393:1721, 2019.

Masa JF et al: Obesity hypoventilation syndrome. Eur Respir Rev

28:180097, 2019.

Obstructive sleep apnea (OSA) and central sleep apnea (CSA) are both

classified as sleep-related breathing disorders. OSA and CSA share

some risk factors and physiologic bases but also have unique features.

Each disorder is associated with impaired ventilation during sleep and

disruption of sleep, and each diagnosis requires careful elicitation of

the patient’s history, physical examination, and physiologic testing.

OSA, the more common disorder, causes daytime sleepiness and

impaired daily function. It is a cause of hypertension and is strongly

associated with cardiovascular disease in adults and behavioral problems in children. CSA is less common and may occur alone or in combination with OSA. It can occur as a primary condition, as a response

297 Sleep Apnea

Andrew Wellman, Daniel J. Gottlieb,

Susan Redline

2205 Sleep Apnea CHAPTER 297

Individuals with a small pharyngeal lumen require relatively high

levels of neuromuscular activation to maintain patency during wakefulness and thus are predisposed to airway collapse following the

normal sleep-related reduction in pharyngeal muscle activity during

sleep. The airway lumen may be narrowed by enlargement of soft tissue

structures (tongue, palate, and uvula) due to fat deposition, increased

lymphoid tissue, or genetic variation. Craniofacial factors such as mandibular retroposition or micrognathia, reflecting genetic variation or

developmental influences, also can reduce lumen dimensions. In addition, lung volumes influence the caudal traction on the pharynx and

consequently the stiffness of the pharyngeal wall. Accordingly, low lung

volume in the recumbent position, which is particularly pronounced in

the obese, contributes to collapse (less caudal traction). A high degree

of nasal resistance (e.g., due to nasal septal deviation or polyps) can

contribute to airway collapse by reducing intraluminal pressure downstream in the pharynx. High-level nasal resistance also may trigger

mouth opening during sleep, which breaks the seal between the tongue

and the palate and allows the tongue to fall posteriorly and occlude the

airway.

Pharyngeal muscle activation is integrally linked to ventilatory

drive. Thus, factors related to ventilatory control, particularly ventilatory sensitivity, arousal threshold, and neuromuscular responses to carbon dioxide (CO2

), contribute to the pathogenesis of OSA. A buildup

in CO2

 during sleep activates both the diaphragm and the pharyngeal

muscles. Pharyngeal activation stiffens the upper airway and can

counteract inspiratory suction pressure and maintain airway patency

to an extent that depends on the anatomic predisposition to collapse.

However, pharyngeal collapse can occur when the ventilatory control

system is overly sensitive to CO2

, with resultant wide fluctuations in

ventilation, ventilatory drive, and upper airway stiffness. Moreover,

increasing levels of CO2

 during sleep result in central nervous system

arousal, causing the individual to move from a deeper to a lighter level

of sleep or to awaken. A low arousal threshold (i.e., awakening to a

low level of CO2

 or ventilatory drive) can preempt the CO2

-mediated

process of pharyngeal muscle compensation and prevent airway stabilization. A high arousal threshold, conversely, may prevent appropriate

termination of apneas, prolonging apnea duration and exacerbating

oxyhemoglobin desaturation. Finally, any impairment in the ability

of the muscles to compensate during sleep can contribute to collapse

of the pharynx. The relative contributions of risk factors vary among

individuals. Approaches to the measurement of these factors in clinical

settings, with consequent enhancement of “personalized” therapeutic

interventions, are being actively investigated.

Risk Factors and Prevalence The major risk factors for OSA

are obesity, male sex, and older age. Additional risk factors include

mandibular retrognathia and micrognathia, a positive family history of

OSA, sedentary lifestyle, genetic syndromes that reduce upper airway

patency (e.g., Down syndrome, Treacher-Collins syndrome), adenotonsillar hypertrophy (especially in children), menopause (in women), and

various endocrine syndromes (e.g., acromegaly, hypothyroidism).

Approximately 40–60% of cases of OSA are attributable to excess

weight. Obesity predisposes to OSA through the narrowing effects of

upper airway fat on the pharyngeal lumen. Obesity also reduces chest

wall compliance and decreases lung volumes, resulting in a loss of

caudal traction on upper airway structures. Obese individuals are at

a fourfold or greater risk for OSA than their normal-weight counterparts. A 10% weight gain is associated with a >30% increase in AHI.

Even modest weight loss or weight gain can influence the risk and

severity of OSA. However, the absence of obesity does not exclude this

diagnosis.

The prevalence of OSA is twofold higher among men than among

women. Factors that predispose men to OSA include android pattern

of obesity (resulting in upper-airway and abdominal fat deposition)

and relatively greater pharyngeal length, which increases collapsibility. Premenopausal women are relatively protected from OSA by the

influence of sex hormones on ventilatory drive. The decline in sex

difference in older age reflects an increased OSA prevalence in women

after menopause. The pathogenesis and presentation of OSA also differ

Palate

Tongue

Epiglottis

Lateral

pharyngeal

walls

FIGURE 297-1 The structures causing airway collapse in obstructive sleep apnea

include the palate, the tongue, and/or the epiglottis. In addition, collapse can also

occur due to the lateral pharyngeal walls.

to high altitude, or secondary to a medical condition (such as heart

failure) or medication (such as opioids). Patients with CSA often report

frequent awakenings and daytime fatigue and are at increased risk for

heart failure and atrial fibrillation.

■ OBSTRUCTIVE SLEEP APNEA/HYPOPNEA

SYNDROME

Definition OSA is defined on the basis of nocturnal and daytime

symptoms as well as sleep study findings. Diagnosis requires the patient

to have (1) either symptoms of nocturnal breathing disturbances (snoring, snorting, gasping, or breathing pauses during sleep) or daytime

sleepiness or fatigue that occurs despite sufficient opportunity to sleep

and is unexplained by other medical problems; and (2) five or more

episodes of obstructive apnea or hypopnea per hour of sleep (the

apnea-hypopnea index [AHI], calculated as the number of episodes

divided by the number of hours of sleep) documented during a sleep

study. OSA also may be diagnosed in the absence of symptoms if the

AHI is ≥15 episodes/h. Each episode of apnea or hypopnea represents a

reduction in breathing for at least 10 s and commonly results in a ≥3%

drop in oxygen saturation or a brain cortical arousal. OSA severity can

be characterized by the frequency of breathing disturbances (AHI), the

amount of oxyhemoglobin desaturation with respiratory events, the

duration of apneas and hypopneas, the degree of sleep fragmentation,

and the level of reported daytime sleepiness or functional impairment.

Pathophysiology During inspiration, intraluminal pharyngeal

pressure becomes increasingly negative, creating a “suctioning” force.

Because the pharyngeal airway has no fixed bone or cartilage, airway

patency is dependent on the stabilizing influence of the pharyngeal

dilator muscles. Although these muscles are continuously activated

during wakefulness, neuromuscular output declines with sleep onset.

In patients with a collapsible airway, the reduction in neuromuscular

output results in transient episodes of pharyngeal collapse (manifesting as an “apnea”) or near collapse (manifesting as a “hypopnea”). The

episodes of collapse are typically terminated when ventilatory reflexes

are activated and cause arousal, thus stimulating an increase in neuromuscular activity and opening of the airway. The airway may collapse

at different sites, such as the soft palate (most common), tongue base,

lateral pharyngeal walls, and/or epiglottis (Fig. 297-1). OSA may be

most severe during rapid eye movement (REM) sleep, when neuromuscular output to the skeletal muscles is particularly low, and in the

supine position due to gravitational forces.

2206 PART 7 Disorders of the Respiratory System

in men and women: compared to men, women have a lower arousal

threshold and less neuromuscular collapsibility. Women tend to have

shorter duration of apneas and apneas that occur predominantly in

REM sleep. Failure to recognize these differences can contribute to

underrecognition of OSA in women.

Variations in craniofacial morphology that reduce the size of the

posterior airway space increase OSA risk. The contribution of skeletal

structural features to OSA is most evident in nonobese patients. Identification of features such as retrognathia can influence therapeutic

decision-making.

OSA has a strong genetic basis, as evidenced by its significant familial aggregation and heritability. For a first-degree relative of a patient

with OSA, the odds of having OSA is approximately twofold higher

than that of someone without an affected relative. Several genetic

variants have been associated with prevalence of OSA or with related

traits, such as the frequency of apneas and hypopneas, the duration of

respiratory events, and degree of overnight levels of hypoxemia.

OSA prevalence varies with age, from 5 to 15% among middle-aged

adults to >20% among elderly individuals, although in a majority of

affected adults, the disorder is undiagnosed. There is a peak due to

lymphoid hypertrophy among children between the ages of 3 and

8 years; with airway growth and lymphoid tissue regression during later

childhood, prevalence declines. Then, as obesity prevalence increases

in adolescence and adulthood, OSA prevalence again increases.

The prevalence of OSA is especially high among patients with

certain medical conditions, including diabetes mellitus, hypertension, and atrial fibrillation. Individuals of East Asian ancestry appear

to be at increased risk of OSA at relatively low levels of body mass

index, reflecting the greater influence of craniofacial risk factors. In

the United States, African Americans, especially children and young

adults, are at higher risk for OSA than their white counterparts.

Course of the Disorder The precise onset of OSA is usually hard

to identify. A person may snore for many years, often beginning in

childhood, before OSA is identified. Weight gain may precipitate an

increase in symptoms, which in turn may lead the patient to pursue an

evaluation. OSA may become less severe with weight loss, particularly

after bariatric surgery. In adults, there is a gradual increase in AHI with

age, although marked increases and decreases in the AHI are uncommon unless accompanied by weight change.

APPROACH TO THE PATIENT

Obstructive Sleep Apnea/Hypopnea Syndrome

An evaluation for OSA should be considered in patients with symptoms of OSA and one or more risk factors. Screening also should

be considered in patients who report symptoms consistent with

OSA and who are at high risk for OSA-related morbidities, such as

hypertension, diabetes mellitus, and cardiac and cerebrovascular

diseases.

SYMPTOMS AND HISTORY

When possible, a sleep history should be obtained with assistance

from a bed partner or household member. Snoring is the most

common complaint; however, its absence does not exclude the diagnosis, as pharyngeal collapse may occur without tissue vibration.

Gasping or snorting during sleep may also be reported, reflecting

termination of individual apneas with abrupt airway opening. Dyspnea is unusual, and its absence generally distinguishes OSA from

paroxysmal nocturnal dyspnea, nocturnal asthma, and acid reflux

with laryngospasm. Patients also may describe frequent awakening

or sleep disruption, which is more common among women and

older adults. The most common daytime symptom is excessive

daytime sleepiness, identified by a history of difficulty maintaining

alertness or involuntary periods of dozing. However, many women

preferentially report fatigue rather than sleepiness. Other symptoms

include a dry mouth, nocturnal heartburn, diaphoresis of the chest

and neck, nocturia, morning headaches, trouble concentrating,

irritability, and mood disturbances. Insomnia, which is common in

the general population, may coexist with OSA. Although difficulty

falling sleep is rarely caused by OSA, awakening at apnea termination may cause difficulty maintaining sleep, a symptom more

likely to be reported by women than by men, and often responds

to treatment of OSA. Several questionnaires that evaluate snoring

frequency, self-reported apneas, and daytime sleepiness can facilitate OSA screening. The predictive ability of a questionnaire can be

enhanced by a consideration of whether the patient is male or has

risk factors such as obesity or hypertension.

PHYSICAL FINDINGS

Physical findings often reflect the etiologic factors for the disorder

as well as comorbid conditions, particularly vascular disease. On

examination, patients may exhibit hypertension and regional (central) obesity, as indicated by a large waist and neck circumference.

The oropharynx may reveal a small orifice with crowding due to an

enlarged tongue, a low-lying soft palate with a bulky uvula, large

tonsils, a high-arched palate, or micro-/retrognathia. Since nasal

resistance can increase the propensity to pharyngeal collapse, the

nasal cavity should be inspected for polyps, septal deviation, allergic

rhinitis, and other signs of obstruction. Because patients with heart

failure are at increased risk for both OSA and CSA, a careful cardiac

examination should be conducted to detect possible left- or rightsided cardiac dysfunction. Evidence of cor pulmonale suggests a

comorbid cardiopulmonary condition; OSA alone is not thought

to cause right-heart failure. A neurologic evaluation is needed to

evaluate for conditions such as neuromuscular and cerebrovascular

diseases, which increase OSA risk.

LABORATORY FINDINGS

Diagnostic Findings Since symptoms and signs do not accurately

predict the severity of sleep-related breathing disturbances, specific

diagnosis and categorization of OSA severity requires objective

measurement of breathing during sleep. The gold standard for diagnosis of OSA is an overnight polysomnogram (PSG). A negative

in-laboratory PSG usually rules out OSA. However, false-negative

studies can result from night-to-night variation in OSA severity,

particularly if there was insufficient REM sleep or less supine sleep

during testing than is typical for the patient. Home sleep tests that

record only respiratory and cardiac channels are commonly used

as a cost-effective means for diagnosing OSA. However, a home

study may yield a false-negative result if sleep time is not accurately

estimated or in individuals experiencing hypopneas with arousals

rather than oxyhemoglobin desaturation. Therefore, if there is a

high prior probability of OSA, a negative home study should be

followed by PSG.

The key physiologic information collected during a sleep study

for OSA assessment includes measurement of breathing (changes

in airflow, respiratory excursion), oxygenation (hemoglobin oxygen saturation), body position, and cardiac rhythm. In addition,

PSGs and some home sleep studies measure sleep continuity and

sleep stages (by electroencephalography, chin electromyography,

electro-oculography, and actigraphy), leg movements, and snoring

intensity. This information is used to quantify the frequency and

subtypes of abnormal respiratory events during sleep as well as

associated changes in oxygen hemoglobin saturation, arousals, and

sleep stage distributions. Tables 297-1 and 297-2 define the respiratory events scored and the severity guidelines employed during a

sleep study. Fig. 297-2 shows examples of sleep-related respiratory

events. A typical sleep study report provides quantitative data such

as the AHI (number of apneas plus hypopneas per hour of sleep)

and the profile of oxygen saturation over the night (mean, nadir,

time at low levels). Reports may also include the respiratory disturbance index, which includes the number of respiratory effort–

related arousals in addition to the AHI. In-laboratory PSG also

quantifies sleep latency (time from “lights off ” to first sleep onset),

the frequency of periodic limb movements during sleep, sleep

2207 Sleep Apnea CHAPTER 297

TABLE 297-1 Respiratory Event Definitions

• Apnea: Cessation of airflow for ≥10 s during sleep, accompanied by:

• Persistent respiratory effort (obstructive apneas, Fig. 297-2A), or

• Absence of respiratory effort (central apneas, Fig. 297-2B)

• Hypopnea: A ≥30% reduction in airflow for at least 10 s during sleep that is

accompanied by either a ≥3% desaturation or an arousal (Fig. 297-2C)

• Respiratory effort–related arousal (RERA): Partial obstruction that does not

meet the criteria for hypopnea but provides evidence of increasing inspiratory

effort (usually through pleural pressure monitoring) punctuated by an arousal

(Fig. 297-2D)

• Flow-limited breath: A partially obstructed breath, typically within a hypopnea

or RERA, identified by a flattened or “scooped-out” inspiratory flow shape

(Fig. 297-3)

TABLE 297-2 Obstructive Sleep Apnea/Hypopnea Syndrome

(OSAHS): Quantification and Severity Scale

• Apnea-hypopnea index (AHI)a

: Number of apneas plus hypopneas per hour of

sleep

• Respiratory disturbance index (RDI): Number of apneas plus hypopneas plus

RERAs per hour of sleep

• Mild OSAHS: AHI of 5–14 events/h

• Moderate OSAHS: AHI of 15–29 events/h

• Severe OSAHS: AHI of ≥30 events/h

a

Each level of AHI can be further quantified by level of sleepiness and associated

hypoxemia.

Abbreviation: RERAs, respiratory effort–related arousals.

efficiency (percentage of time asleep relative to time in bed), arousal

index (number of cortical arousals per hour of sleep), and time in

each sleep stage. These metrics can further characterize the severity

of OSA, which is associated with an increased arousal index, low

sleep efficiency, and a reduction of time in deep (stage N3) and

REM sleep and increase in light (stage N1) sleep. The detection of

autonomic responses to apneas and hypopneas, such as surges in

blood pressure, changes in heart rate, and abnormalities in cardiac

rhythm, also provides relevant information on OSA severity.

Other Laboratory Findings Various imaging studies, including

cephalometric radiography, upper airway MRI and CT, and fiberoptic endoscopy, can be used to identify anatomic risk factors for

OSA. While these may be useful for planning surgical interventions,

they are not indicated in the routine evaluation of OSA. Cardiac

testing may yield evidence of impaired systolic or diastolic ventricular function or abnormal cardiac structure. Overnight blood

pressure monitoring often displays a “nondipping” pattern (absence

of the typical 10% fall of blood pressure during sleep compared

to wakefulness). Arterial blood gas measurements made during

wakefulness are usually normal. Waking hypoxemia or hypercarbia

suggests coexisting cardiopulmonary disease or hypoventilation

syndromes. Patients with severe nocturnal hypoxemia may have

elevated hemoglobin values. A multiple sleep latency test or a maintenance of wakefulness test can be useful in quantifying sleepiness

and helping to distinguish OSA from narcolepsy.

EKG

snore

t. flow

chest

abdomen

SaO2

EEG

EOG

chin

n. p. flow

snore

chest

abdomen

SaO2

EEG

EOG

chin

flow

Hypnogram

Stage

snore

flow

position

chest

abdomen

SaO2

EEG

A

C

EKG

snore

t. flow

chest

abdomen

SaO2

EEG

EOG

chin

n. p. flow

Legs

B

D

Ar

FIGURE 297-2 Obstructive apnea. A. There are 30 s of no airflow, as shown in the nasal pressure (n. p. flow) and thermistor-measured flow (t. flow). Note the presence of

chest-abdomen paradox, indicating respiratory effort against an occluded airway. B. Central apnea in a patient with Cheyne-Stokes respiration due to congestive heart

failure. The flat chest-abdomen tracings indicate the absence of inspiratory effort during the central apneas. C. Hypopnea. Partial obstruction of the pharyngeal airway can

limit ventilation, leading to desaturation (a mild decrease in this patient, from 93 to 90%) and arousal. D. Respiratory effort–related arousal (RERA). Minimal flow reduction

terminated by an arousal (Ar) without desaturation constitutes a RERA. EEG, electroencephalogram; EOG, electro-oculogram; EKG, electrocardiogram.

2208 PART 7 Disorders of the Respiratory System

Normal Flow limitation

FIGURE 297-3 Example of flow limitation. The inspiratory flow pattern in a patent

airway is rounded and peaks in the middle. In contrast, a partially obstructed airway

exhibits an early peak followed by mid-inspiratory flattening, yielding a scooped-out

appearance.

Health Consequences and Comorbidities OSA is the most

common medical cause of daytime sleepiness and negatively influences

quality of life. It is also strongly associated with cardiac, cerebrovascular, and metabolic disorders and with premature death. This broad

range of health effects is attributable to the impact of sleep fragmentation, cortical arousal, and intermittent hypoxemia and hypercapnia

on vascular, cardiac, metabolic, and neurologic functions. OSA-related

respiratory events stimulate sympathetic overactivity, leading to acute

blood pressure surges during sleep and nocturnal as well as daytime

hypertension. OSA-related hypoxemia also stimulates release of acutephase proteins and reactive oxygen species that exacerbate insulin

resistance and lipolysis and cause an augmented prothrombotic and

proinflammatory state. Inspiratory effort against an occluded airway

causes large intrathoracic negative pressure swings, altering cardiac

preload and afterload and resulting in cardiac remodeling and reduced

cardiac function. Hypoxemia and sympathetic-parasympathetic imbalance also may cause electrical remodeling of the heart and myocyte

injury.

HYPERTENSION OSA can raise blood pressure to prehypertensive and

hypertensive ranges, increase the prevalence of a nondipping overnight

blood pressure pattern, and increase the risk of uncontrolled and resistant hypertension. Elevations in blood pressure are due to augmented

sympathetic nervous system activation as well as alterations in the

renin-angiotensin-aldosterone system and fluid balance. Treatment of

OSA with nocturnal continuous positive airway pressure (CPAP) has

been shown to reduce 24-h ambulatory blood pressure. Although the

overall impact of CPAP on blood pressure levels is relatively modest

(averaging 2–4 mmHg), larger improvements are observed among

patients who have a high AHI, report daytime sleepiness, or have resistant hypertension.

CARDIOVASCULAR, CEREBROVASCULAR, AND METABOLIC DISEASES

Among the most serious health consequences of OSA may be its impact

on cardiac and metabolic functions. Strong epidemiologic evidence

indicates that OSA significantly increases the risk of coronary artery disease, heart failure with and without reduced ejection fraction, atrial and

ventricular arrhythmias, atherosclerosis and coronary artery disease,

stroke, and diabetes. Treatment of OSA has been shown to reduce several markers of cardiovascular risk and improve insulin resistance and,

in uncontrolled studies, is associated with a decreased recurrence rate of

atrial fibrillation. Recent randomized clinical trials, however, have failed

to demonstrate that OSA treatment with CPAP reduces cardiac event

rates or prolongs survival. These outcomes may reflect exclusion from

these trials of patients with excessive sleepiness, as there is evidence

that sleepy patients may have the greatest OSA-related cardiovascular

risk. Limited adherence to treatment among trial participants or the

widespread use of other effective secondary prevention measures, such

as beta blockade, antiplatelet agents, and lipid-lowering therapy, may

also limit the impact of CPAP on cardiovascular risk.

SLEEPINESS More than 50% of patients with moderate to severe OSA

report daytime sleepiness. Patients with OSA symptoms have a twofold

increased risk of occupational accidents. Individuals with elevated

AHIs are involved in motor vehicle crashes approximately two to

three times as often as persons with normal AHIs. Randomized controlled trials have shown that treatment of OSA with CPAP alleviates

sleepiness as measured by either questionnaire or objective testing in

patients with both mild and more severe disease. However, the degree

of improvement varies widely. Residual sleepiness may be due to several factors, including suboptimal treatment adherence, insufficient

sleep time, other sleep disorders, or prior hypoxic-mediated damage

in brain areas involved in alertness. Moreover, visceral adipose tissue,

which is present in higher amounts in patients with OSA, releases somnogenic cytokines that may contribute to sleepiness. Thus, even after

treatment, it is important to assess and monitor patients for residual

sleepiness and to optimize treatment adherence, improve sleep patterns, and identify other disorders that may contribute to sleepiness.

Careful and supervised use of alerting agents may be appropriate as

adjunctive treatment in patients in whom sleepiness does not respond

to CPAP alone.

QUALITY OF LIFE AND MOOD Reductions in health-related quality

of life are common in patients with OSA, with the largest decrements

observed in scales that measure physical functioning and energy levels.

Work-related productivity also has been shown to improve in patients

with moderate to severe OSA treated with CPAP. Numerous studies,

including a large-scale trial of minimally symptomatic patients, have

shown that treatment with CPAP can improve these patient-reported

outcomes. Depressive symptoms, in particular somatic symptoms

(irritability, fatigue, lack of energy), are commonly reported in OSA

and improve with CPAP.

TREATMENT

Obstructive Sleep Apnea

A comprehensive approach to the management of OSA is needed

to reduce risk factors and comorbidities. The clinician should

seek to identify and address lifestyle and behavioral factors as well

as comorbidities that may be exacerbating OSA. As appropriate,

treatment should aim to reduce weight; optimize sleep duration

(7–9 h); regulate sleep schedules (with similar bedtimes and wake

times across the week); encourage the patient to avoid sleeping in

the supine position; treat nasal allergies; increase physical activity; eliminate alcohol ingestion (which impairs pharyngeal muscle

activity) within 3 h of bedtime; and minimize use of opiate medications. Sedative hypnotic medications have inconsistent effects

on OSA but should be avoided in most patients with moderate to

severe OSA. Patients should be counseled to avoid drowsy driving.

CPAP is the standard medical therapy with the highest level

of evidence for efficacy. Delivered through a nasal or nasal-oral

mask, CPAP works as a mechanical splint to hold the airway open,

thus maintaining airway patency during sleep. An overnight CPAP

titration study can determine the optimal pressure setting that

reduces the number of apneas/hypopneas during sleep, improves

gas exchange, and reduces arousals; however, the use of “autotitrating” CPAP devices used in home settings has eliminated the

need for titration sleep studies in many patients. Rates of adherence

to CPAP treatment are highly variable (average, 50–80%) and may

be improved with support by a skilled health care team who can

address side effects, help the patient “problem solve,” and provide

motivational education (Table 297-3). Despite the limitations of

TABLE 297-3 Side Effects of Continuous Positive Airway Pressure

(CPAP) and Their Treatments

SIDE EFFECT TREATMENT

Nasal congestion Provide heated humidification, administer

saline/steroid nasal sprays

Claustrophobia Change mask interface (e.g., to nasal prongs),

promote habituation (i.e., practice breathing on

CPAP while awake)

Difficulty exhaling Temporarily reduce pressure, provide bilevel

positive airway pressure

Bruised nasal ridge Change mask interface, provide protective

padding

Aerophagia Administer antacids

2209 Lung Transplantation CHAPTER 298

CPAP, controlled studies have demonstrated its beneficial effect on

alertness, mood, quality of life, work-related productivity, blood

pressure, and insulin sensitivity. Uncontrolled studies also indicate

a favorable effect on cardiovascular outcomes, cardiac ejection fraction, atrial fibrillation recurrence, and mortality risk.

Oral appliances for OSA work by advancing the mandible, thus

opening the airway by repositioning the lower jaw and pulling the

tongue forward. These devices generally work better when customized for patient use; maximal adaptation can take several weeks.

Efficacy studies show that these devices can reduce the AHI by

≥50% in two-thirds of individuals, although these data are based

largely on patients with mild OSA. Some patients with moderate

or severe OSA respond to oral appliances as well, although no consistent predictors of success have been identified in these groups,

and thus, follow-up sleep testing is recommended. Side effects of

oral appliances include temporomandibular joint pain and tooth

movement; thus, they require that the patient have adequate dental

and periodontal structures. Oral appliances are most often used for

treating patients with mild/moderate OSA or patients who do not

tolerate CPAP. However, as some patients are more adherent to oral

appliances than to CPAP, these devices are under investigation for

treatment of more severe disease.

Upper airway surgery for OSA is less efficacious than CPAP and

is mostly reserved for the treatment of patients who snore, have

mild OSA, or cannot tolerate CPAP. Uvulopalatopharyngoplasty

(removal of the uvula and the margin of the soft palate) is the most

commonly performed surgery for OSA and, although results vary

greatly, is generally less successful than treatment with oral appliances. Upper airway surgery is less effective in severe OSA and in

obese patients. Success rates may be higher for multilevel surgery

(involving more than one site/structure) performed by an experienced surgeon, but the selection of patients is an important factor

and relies on careful targeting of culprit areas for surgical resection.

Bariatric surgery is an option for obese patients with OSA and can

improve not only OSA but also other obesity-associated health

conditions. Other procedures that can decrease snoring but have

minimal effects on OSA include injection of a hardening agent to

the soft palate (resulting in stiffening), radiofrequency ablation,

laser-assisted uvulopalatoplasty, and palatal implants.

Upper airway neurostimulation is a recently tested alternative

treatment for OSA. Unilateral stimulation of the hypoglossal nerve

through a surgically implanted device was shown to significantly

decrease the AHI and improve a number of patient-reported outcomes, such as sleepiness and quality of life, for a duration of at least

5 years after treatment in carefully selected patients. This therapy

is reserved for patients who cannot tolerate or fail CPAP therapy.

Current inclusion criteria are moderate to severe OSA (AHI 15–65),

BMI <32 kg/m2

, and absence of complete concentric collapse at the

level of the velum documented by awake and drug-induced endoscopy (a predictor of response to surgery). Additional research is

underway to further evaluate longer-term effectiveness and potential utility of this treatment in other patient groups.

Supplemental oxygen can improve oxygen saturation, but there is

little evidence that it improves OSA symptoms or the AHI in unselected patients. There is conflicting evidence regarding the effect of

supplemental oxygen on blood pressure in patients with OSA.

CENTRAL SLEEP APNEA

CSA, which is less common than OSA, may occur in isolation or,

more often, in combination with obstructive events in the form of

“mixed” apneas. CSA is often caused by an increased sensitivity to

Pco2

, which leads to an unstable breathing pattern that manifests

as hyperventilation alternating with apnea. A prolonged circulation

delay between the pulmonary capillaries and carotid chemoreceptors is also a contributing cause; thus, individuals with congestive heart failure are at risk for CSA. With prolonged circulation

delay, there is a crescendo-decrescendo breathing pattern known as

Cheyne-Stokes breathing (Fig. 297–2B). Other risk factors for CSA

include opioid medications (which appear to have a dose-dependent

effect on CSA) and hypoxia (e.g., breathing at high altitude). In

some individuals, CPAP—particularly at high pressures—seems to

induce central apnea; this condition is referred to as complex sleep

apnea or treatment-emergent central sleep apnea. Rarely, CSA may

be caused by blunted chemosensitivity due to congenital disorders

(congenital central hypoventilation syndrome) or acquired factors.

CSA is an independent risk factor for the development of both

heart failure and atrial fibrillation, possibly related to elevations in

sympathetic nervous system activity that accompany this disorder;

alternatively, CSA may be an early marker of subclinical myocardial

dysfunction. Patients with CSA may report symptoms of frequent

awakenings as well as daytime fatigue. Treatment of CSA is difficult

and depends on the underlying cause. Limited data suggest that

supplemental oxygen can reduce the frequency of central apneas,

particularly in patients with hypoxemia, and ongoing clinical trials are further evaluating supplemental oxygen for use in patients

with heart failure and CSA. Cheyne-Stokes breathing is treated by

optimizing therapy for heart failure. At this time, there is no good

evidence that CPAP, including adaptive servoventilation (a form

of ventilatory support that attempts to regularize the breathing

pattern), improves health outcomes in patients with Cheyne-Stokes

breathing without OSA, and in fact, it may be detrimental in those

with heart failure associated with reduced ejection fraction.

■ FURTHER READING

Berry R, Wagner M: Sleep Medicine Pearls, 3rd ed. Philadelphia,

Elsevier, 2015.

Gottlieb DJ, Punjabi NM: Diagnosis and management of obstructive

sleep apnea. A review. JAMA 323:1389, 2020.

Javaheri S et al: Sleep apnea: Types, mechanisms, and clinical cardiovascular consequences. J Am Coll Cardiol 769:841, 2017.

Kapur VK et al: Clinical Practice Guideline for Diagnostic Testing

for Adult Obstructive Sleep Apnea: An American Academy of Sleep

Medicine clinical practice guideline. J Clin Sleep Med 13:479, 2017.

Marklund M et al: Update on oral appliance therapy. Eur Respir Rev

28:190083, 2019.

■ END-STAGE LUNG DISEASE AND INDICATIONS

FOR LUNG TRANSPLANTATION

For the purpose of lung allocation score (LAS) prioritization for organ

allocation, the United Network for Organ Sharing (UNOS) divides

advanced lung disease diagnoses into four categories: (A) obstructive

lung disease (including non-cystic fibrosis-related bronchiectasis and

obliterative bronchiolitis), (B) pulmonary vascular disease, (C) cystic

fibrosis, and (D) restrictive lung disease. Historically, obstructive lung

disease was the most common indication for transplantation, but since

the implementation of the LAS system, idiopathic pulmonary fibrosis (IPF), the most common restrictive lung disease, has become an

increasingly frequent indication for transplantation. Prior to the era of

antifibrotic therapy, the average life expectancy from the time of diagnosis of IPF was 3–5 years, making patients with this disease the cohort

to experience most clearly a survival benefit from lung transplantation.

As a result, the LAS system prioritizes patients with IPF. Similarly,

patients who experience secondary effects of their lung disease, including pulmonary hypertension, right heart dysfunction, and hypercarbia,

are prioritized for allocation and should be considered for referral for

transplant evaluation irrespective of other markers of disease severity.

298 Lung Transplantation

Hilary J. Goldberg, Hari R. Mallidi