Chapter 25: Management of Sleep-Related Breathing Disorders

Introduction

The three major types of sleep-related breathing disorders are obstructive sleep apnea syndrome (OSAS), central sleep apnea syndrome, and sleep-related hypoventilation hypoxemic syndromes. Of these, OSAS is the most common type of sleep-related breathing disorder and is characterized by repetitive episodes of complete apnea or partial hypopnea caused by upper airway obstruction. Episodes last at least 10 seconds, occur during sleep, are usually associated with decreased S_ao₂%, and are terminated by brief arousals. OSAS is associated not only with neurocognitive dysfunction but also with increased cardiovascular morbidity and mortality.

Epidemiology of OSAS

OSAS is relatively common, with a prevalence of 4% in men and 2% in women when defined by an apnea-hypopnea index (AHI) ≥5 events/h plus a complaint of excessive daytime sleepiness. Features predisposing to OSAS include male sex, age, obesity, menopausal state, race, craniofacial abnormalities with decreased orohypopharyngeal space, endocrine disorders, and certain congenital disorders (Table 25.1).

The high male-to-female prevalence ratio for OSAS of 2:1 is attributed to the protective effect of female sex hormones predominant in premenopausal women; the prevalence of OSAS in women triples after menopause and is reduced to premenopausal levels with hormone replacement therapy. Meanwhile, increased body mass index (BMI) is the major risk factor for OSAS in adults (Chap. 12). There appears to be a linear relationship between BMI and OSAS severity: Each 10% increase in body weight results in a 30% increase in AHI. On the other hand, adenotonsillar hypertrophy is the major cause of OSAS in children. For patients who are not overweight or obese, certain craniofacial features (eg, retrognathia, long uvula) can predispose to OSAS. Increased nasal resistance from rhinitis or a deviated nasal septum can worsen airway collapse due to the greater inspiratory effort required to breathe through such nasal passages. Asians may be at a higher risk for OSAS due to crowding of the posterior oropharynx and a steep thyromental plane. Smoking causes nasal and oropharyngeal mucosal edema that can aggravate upper airway obstruction. Hormonal abnormalities may alter craniofacial skeletal and soft tissue structure, thereby promoting oropharyngeal crowding, as seen in the macroglossia of hypothyroidism and acromegaly. Up to 50% of patients with Down syndrome suffer from OSAS due to multiple risk factors. These can include midfacial and mandibular hypoplasia, small upper airways with superficially positioned tonsils and relative tonsillar and adenoidal encroachment, generalized hypotonia, and an increased prevalence of obesity and hypothyroidism.

Pathophysiology of OSAS

OSAS occurs due to dynamic upper airway closure or narrowing. These may be secondary to excessive pharyngeal tissue volume from obesity, adenotonsillar hypertrophy, craniofacial anatomy, and can accompany attenuated tone of the pharyngeal dilating muscles during sleep (Fig. 25.1).

Adverse Health Effects of OSAS

Left untreated, OSAS is associated with neurocognitive impairment, cardiovascular dysfunction, endocrine abnormalities, and mortality (Table 25.2). In prospective cohort studies, moderate-to-severe OSAS has been associated with an increased incidence in systemic hypertension and diabetes mellitus, as well as an increased risk of overall mortality. The Sleep Heart Health Study, based upon a large cross-sectional population, showed a significant increase in the prevalence of congestive heart failure in middle-aged individuals with moderate-to-severe OSAS. Neurocognitive dysfunction in OSAS is a consequence of poor sleep efficiency and reduced slow wave and rapid eye movement sleep that are caused by frequent nocturnal awakenings from disordered-breathing events. Neurocognitive dysfunction can manifest as hypersomnolence, decreased vigilance, impaired short-term memory, depression, and increased risk of motor vehicle accidents. Meanwhile, the surges in hypoxemia, hypercapnia, and circulating catecholamines associated with OSAS are now implicated in development of both hypertension and increased insulin resistance.

Diagnosis of OSAS

The diagnosis of OSAS requires the presence of its clinical features (snoring, witnessed apneas, excessive daytime sleepiness, etc), and a polysomnogram showing a respiratory disturbance index (RDI) of ≥5 scoreable respiratory events (obstructive apneas, hypopneas, and respiratory-related arousals) per hour of sleep (Fig. 25.2 and Tables 25.3 and 25.4). In the absence of clinical features or cardiovascular comorbidities, an RDI ≥15 scoreable respiratory events per hour of sleep is required to make the diagnosis. Obstructive apneas correspond to episodes of complete upper airway obstruction (Fig. 25.2), while obstructive hypopneas are episodes of partial upper airway obstruction (Fig. 25.3). Respiratory effort-related arousals (RERAs) are "mini-awakenings," or shifts in electroencephalographic waveforms. These RERAs result from progressively increasing inspiratory efforts (ie, negative intrathoracic pressures) by the patient in an attempt to overcome high upper airway resistance. These arousals are preceded by blunting of the nasal pressure airflow waveform normally associated with increasing respiratory efforts, and are best detected by measuring intrathoracic pressures using esophageal manometry (see Fig. 4.6). RERAs do not meet the criteria for a decrease in S_ao₂% (of ≥3%-4%) nor the airflow reduction criteria (≥50%) that signify obstructive hypopneas.

Therapeutic Approaches to OSAS

Weight loss for obese patients has been shown to decrease the AHI and improve nocturnal S_ao₂% in patients with OSAS. Compared to controls, OSA patients have been found to have higher serum [leptin], a peptide hormone which regulates appetite and metabolism. These higher [leptin] levels in OSA patients may indicate resistance to its anorexigenic effect, making weight loss more difficult to achieve.

Continuous positive airway pressure (CPAP) provides a mechanical air stent to the upper airways and is the mainstay for treating OSAS in adults. CPAP is demonstrated to have multisystemic effects, notably ameliorating the neurocognitive deficits, cardiovascular dysfunction, and endocrinologic abnormalities (Fig. 25.3, Table 25.5). The optimal CPAP level is that pressure (in cm H₂O) determined to be effective in abolishing apneas, hypopneas, RERAs, and snoring during a therapeutic CPAP trial.

Positional obstructive sleep apnea is said to occur in those patients whose supine AHI is twice their lateral decubitus AHI, and in whom the lateral decubitus AHI < 10 events/h. In such patients, relatively simple positional adjustments to promote sleeping in the lateral decubitus position can decrease their overall nightly AHI and respiratory-related arousal index, and ameliorate their excessive daytime sleepiness.

Oral appliances are dental devices designed to advance the mandible, thereby increasing the orohypopharyngeal space. Oral appliances have been demonstrated to moderately decrease the AHI in patients with mild-to-moderate OSA and, to a lesser extent, their systemic blood pressure if they are hypertensive.

Tonsillectomy and adenoidectomy is the treatment of choice for children with OSAS and adenotonsillar hypertrophy (Clinical Correlation 25.1). Uvulopalatopharyngoplasty (UPPP) is the most commonly performed surgical procedure for adult patients with OSAS, and involves the surgical removal of the tonsils and redundant soft palate and tonsillar pillars. UPPP has been found to have an overall success rate of 40% when defined as reducing the severity of patients' OSA by at least 50%. Other surgical procedures for OSAS may help correct specific anatomic abnormalities responsible for causing upper airway obstruction (Table 25.6).

Definitions

Central sleep apnea (CSA) is a condition characterized by recurrent cessation of respiration during sleep, with the observed apnea having no associated ventilatory effort (Fig. 25.4). A CSA may be due to idiopathic/primary disorders, or be caused by medical and neurological conditions, drugs, or ascent to high altitude (Table 25.7).

Cheyne-Stokes respiration (CSR) is a subtype of CSA in which a breathing pattern consists of hypopneas alternating with hyperpneas. During such episodes, the patient's V_T gradually waxes and wanes in a crescendo-decrescendo pattern (Fig. 25.5).

Epidemiology of Central Sleep Apnea Syndromes

Primary CSA is a rare idiopathic subtype of CSA diagnosed after ruling out other secondary causes of CSA or CSR, and it typically affects middle-age to elderly individuals. CSA due to Cheyne-Stokes respiration occurs in subjects 60 years and older with congestive heart failure, cerebrovascular disease, and renal insufficiency, with a male predominance. High-altitude periodic breathing occurs more commonly in men who recently ascended to high altitude (≥4,000 m). The increased prevalence of both CSR and high-altitude periodic breathing in men compared to women is attributed not only to their higher prevalence of cardiovascular disease and outdoor activity participation but also to greater ventilatory chemoresponsiveness in men. Long-acting opioids (eg, methadone, time-released morphine, and hydrocodone) taken for at least 2 months are the most common drugs associated with CSA.

Pathophysiology of CSAS

A high ventilatory chemoresponsiveness to P_aco₂ is believed to be the underlying predisposing factor for the development of CSA and CSR. In CSA patients with such increased ventilatory chemoresponsiveness, sleep-related rises in P_aco₂ stimulate an exaggerated ventilatory response, resulting in subsequent decrements of the P_aco₂ to below the patient's apneic threshold. This exaggerated hyperpnea for a given disturbance (apnea or hypopnea with resulting ↑P_aco₂ and/or ↓P_ao₂), or high loop gain, is considered most likely to produce these sustained oscillations in the system leading to periodic breathing or CSR (Fig. 25.6).

In patients with CSR due to congestive heart failure, the circulatory delay time, measured from the termination of the central apnea to the nadir of S_ao₂%, is inversely related to Q̇. The prolonged circulatory delays in patients with heart failure reflect the longer time required for oxygenated blood to travel from the pulmonary veins and left ventricle to a pulse oximeter probe attached to the finger or ear because of their cardiac pump failure. Heart transplantation has been demonstrated to reduce circulatory delay time in patients with congestive heart failure and CSA-CSR. However, their high ventilatory chemoresponsiveness and dysregulated control of breathing seem to persist post-transplantation in this cohort.

Diagnosis of CSAS

A diagnosis of CSAS requires clinical features (excessive daytime sleepiness, frequent arousals and awakenings, insomnia complaints, or awakenings due to dyspnea), plus a polysomnogram showing a central apnea index of ≥5 scoreable events per hour of sleep. A central apnea is a respiratory event characterized by cessation of airflow lasting at least 10 seconds that is unaccompanied by respiratory effort. The diagnosis of CSR is confirmed by a polysomnogram showing at least 10 central apneas and hypopneas per hour of sleep, occurring in a crescendo-decrescendo pattern of V_T accompanied by frequent arousals from sleep and derangement of sleep structure.

Therapeutic Approaches to CSAS

Most published clinical trials for CSAS focus on the treatment of CSA-CSR that is due to congestive heart failure. Optimizing treatment of such patients with congestive heart failure (eg, antihypertensives/vasodilators, diuretics, and inotropes, coronary revascularization, etc) is the first step in treating their CSA-CSR. Supplemental O₂ therapy increases body O₂ reserves and blunts hypoxemic respiratory drive, thereby reducing central apneas and periodic breathing pattern and enhancing quality of life in patients with CSR due to CHF. Acetazolamide, a carbonic anhydrase inhibitor, induces a mild metabolic acidosis that stimulates respiration by increasing the difference between the subject's prevailing P_aco₂ and their apneic P_aco₂ threshold. Acetazolamide improves central sleep apnea, nocturnal oxygenation, and related daytime symptoms. Theophylline, a phosphodiesterase inhibitor, has excitatory effects on breathing, enhances ventilation, reduces respiratory disturbances, and increases nocturnal oxygenation. However, theophylline also nearly doubles circulating renin levels in CHF patients. As for OSA patients, the use of CPAP has been shown to improve left ventricular ejection fraction, mitral regurgitant fraction, atrial natriuretic peptide level, and ventilation efficiency in patients with CSA-CSR due to CHF. However, a large, randomized controlled trial conducted in Canada found that CPAP did not affect overall survival in all patients with CSA-CSR due to CHF, except in those whose central apneas are suppressed soon after CPAP initiation.

Variable or bilevel positive airway pressure (BiPAP) ventilation, in which the positive airway pressure applied is higher during inspiration than during expiration, appears to be as effective as CPAP in improving respiratory disturbances, nocturnal oxygenation, and sleep architecture in patients with CSR due to CHF (Chap. 30). Adaptive support servo-ventilation (ASV) suppresses CSA and/or CSR in CHF patients and improves their sleep quality better than CPAP or O₂ supplementation. Use of ASV automatically adjusts the positive inspiratory P_AW according to the patient's fluctuating V_t pattern. In patients with symptomatic sinus bradycardia, the use of atrial overdrive pacing significantly reduced central apneas in one study, presumably by increasing Q̇ via an increase in heart rate. Low-flow supplemental CO₂ raises the patient's P_aco₂ above their apnea threshold and has been demonstrated to improve CSA and CSR in patients with CHF. However, such CO₂ supplementation is ineffective in reducing arousals and is associated with sympathetic activation that may be detrimental in CHF.

Descending just 500-1,000 m of elevation can ameliorate most high altitude clinical syndromes, including acute mountain sickness, high-altitude periodic breathing, and high-altitude pulmonary edema (Chap. 13). At altitude, nocturnal O₂ enrichment of the ambient air to an effective F_Io₂ = 0.25 can ameliorate the central apneas and periodic breathing and improve both sleep quality and daytime function. As mentioned above, theophylline and acetazolamide both normalize sleep disordered breathing at high altitude. Temazepam, a benzodiazepine receptor agonist, reduces periodic breathing at high altitude by consolidating sleep. However, its use has been associated with a small decrease in nocturnal S_ao₂%. Zolpidem, a non-benzodiazepine receptor agonist, improves sleep quality without affecting respiration at high altitude.

In patients with known or suspected drug-related CSA, the discontinuation of long-acting opioid medications, their substitution with non-narcotic medications, or reduction of the narcotic dose may each help ameliorate periodic breathing.

Definition

Complex sleep apnea syndrome (CompSAS) is a form of sleep apnea specifically identified by the persistence or emergence of central apneas or hypopneas upon exposure of a patient to CPAP when any obstructive events have disappeared.

Epidemiology of CompSAS

The reported estimate of the prevalence of CompSAS among sleep apnea patients in the United States is 16%, although it is derived from a relatively small clinical cohort study. A larger study of >1,200 Japanese patients with all forms of sleep apnea syndromes revealed a CompSAS prevalence of 5%. There appears to be an overwhelming male predominance in CompSAS, approaching 80%-90% across racial and national borders.

Pathophysiology of CompSAS

The pathophysiology of this disorder involves the combination of an anatomically narrow and excessively collapsible airway with a highly sensitive hypocapnia-induced apneic threshold. Baseline polysomnography in CompSAS patients typically demonstrates OSAS, and features predominantly obstructive respiratory events (apnea, hypopneas, and respiratory-effort related arousals). With administration of CPAP to eliminate upper airway obstruction, however, the dysregulated central control of ventilation is unmasked, causing the emergence of central apneas and a Cheyne-Stokes breathing pattern. The lowering by CPAP of P_aco₂ below the patient's apneic threshold likely precipitates the central apneas in those CompSAS patients with highly sensitive hypocapnia-induced ventilatory control system. Meanwhile, excessive CPAP that increases intrathoracic pressures and hyperinflation may also trigger central apneas via the Hering-Breuer reflex (Chap. 11).

Diagnosis of CompSAS

In a patient presenting with clinical features of a sleep apnea syndrome, the diagnosis of CompSAS is based upon an initial baseline polysomnogram that demonstrates predominately obstructive respiratory events occurring at least five times per hour. Then a subsequent therapeutic CPAP trial should demonstrate the resolution of obstructive respiratory events and the emergence of prominent or disruptive central apneas (again ≥5/h) and/or a Cheyne-Stokes respiratory pattern.

Treatment of CompSAS

As mentioned above, the use of adaptive support servo-ventilation (ASV) appears to be superior to other PAP therapies in controlling the respiratory disturbances in CompSAS. Several promising therapies, including positive airway pressure with gas modulation using a low F_Ico₂ (PAPGAM), artificially enhanced dead space, and prescription of acetazolamide, all aim to stabilize chemoreceptor control of respiration by inducing metabolic acidosis or raising P_aco₂ above a patient's apneic threshold.

Definition

Sleep-related hypoventilation/hypoxemic syndrome (SRH) is a group of breathing disorders characterized by decreased V̇_A from various causes that exclude OSA, all of which decrease S_ao₂% and increase P_aco₂ during sleep. Most authors divide SRH into two categories based on their underlying etiologies. These include primary or idiopathic disorders, namely the sleep-related non-obstructive alveolar hypoventilation syndrome, and congenital central alveolar hypoventilation syndrome (CCAHS). CCAHS is also known as Ondine's curse, from the German folktale of Ondine, a water nymph who cursed her unfaithful husband to cease breathing should he ever fall asleep again. Other cases of SRH develop secondarily to an underlying pulmonary, neuromuscular, or skeletal abnormality (Table 25.8).

Epidemiology of SRH

The demographics of patients with secondary SRH parallel those of the underlying causative medical conditions. The primary SRH syndromes occur very rarely, with only 160-180 confirmed cases of CCAHS having been reported worldwide. CCAHS affects newborns and infants, and is associated with other congenital abnormalities including Hirschsprung disease, autonomic dysfunction, neural tumors, swallowing dysfunctions, and ocular abnormalities. CCAHS usually occurs sporadically but some cases are related to de novo mutations of the PHOX2B gene. In contrast, little is known about the epidemiology of adult idiopathic sleep-related non-obstructive alveolar hypoventilation syndrome, whose onset is during adolescence and early adulthood.

Pathophysiology of SRH

Idiopathic and congenital forms of SRH are characterized by decreased ventilatory responsiveness to hypercapnia or hypoxia during both wakefulness and sleep. Such altered responsiveness is due to a postulated lesion in the medullary chemoreceptors (adult idiopathic type) or to an abnormality in brainstem integration of chemoreceptor afferents (congenital type). Mutations of PHOX2B, which has an autosomal dominant mode of transmission with incomplete penetrance, appear to impair respiratory control function of the retrotrapezoid nucleus in the rostral medulla in infants with CCAHS (Chap. 11). By comparison, SRH due to medical conditions most often is traceable to ventilation-perfusion abnormalities (Chap. 8) including mechanical ventilatory insufficiencies that are associated with these serious conditions.

Differential Diagnosis of SRH

CCAHS is suspected in a newborn who presents with sustained shallow breathing, cyanosis, and apnea during sleep (Fig. 25.8). In older patients, a diagnosis of idiopathic SRH is made in adolescents and adults only after excluding medical conditions that can cause secondary SRH. The syndrome is characterized by blunted chemoresponsiveness that causes daytime hypercapnia and hypoxemia despite normal mechanical properties of the lungs and chest. When left untreated, these primary alveolar hypoventilation syndromes can progress to pulmonary hypertension and death.

In SRH secondary to medical conditions, the diagnosis requires a polysomnogram and/or arterial blood gases that demonstrate persistent nocturnal hypoxemia and/or hypercapnia in the absence of obvious obstructive apneas or periodic breathing in a patient with a predisposing medical, neurologic, or muscular condition (Table 25.9).

Therapeutic Approaches to SRH

Optimal therapy of underlying medical conditions ameliorates many secondary SRH, including nocturnal O₂ and long-acting bronchodilators in COPD patients. Drugs that improve ventilatory drive (theophylline, progesterone, acetazolamide) or enhance muscle strength such as anabolic steroids, growth hormone, and insulin-like growth factor-1 (IGF-1), have not been reliably effective in ameliorating the chronic hypoventilation of SRH. Non-invasive positive pressure ventilation, either via a nasal or orofacial mask using a BiPAP device or by mechanical ventilator, is indicated in patients with fatigue, dyspnea, morning headache, or chronic respiratory failure. In a subgroup of OHS patients, both CPAP and BiPAP are effective in reducing daytime hypercapnia, and BIPAP substantially improves oxygenation, sleep quality, and health-related quality of life. Average volume-assured pressure support (AVAPS) ventilation combines the pressure-limited and volume-limited modes of assisted ventilation to ensure a more consistent V_T while delivering the comfort and advantages of pressure support (Chap. 30). While AVAPS and BiPAP provide similar sleep and health quality benefits, AVAPS achieves better ventilatory efficacy as assessed by P_tcCO₂ in OHS patients.