Sleep-related breathing disorder

Sleep-related breathing disorder (SRBD) is the second most common category as classified by the International Classification of Sleep Disorders (ICSD-3), after insomnia, and the most common disorder encountered in sleep medicine labs.

SRBD can refer to an exclusively sleep-related disorder or as sleep-induced exacerbation of a baseline persistent disorder. SRBDs are divided into four main categories: obstructive sleep apnea (OSA) disorders, central sleep apnea (CSA) syndromes, sleep-related hypoventilation (SRHV) disorders, and sleep-related hypoxemia (SRHO) disorders. OSA accounts for about 90% of SRBDs, CSA syndromes 9%, and sleep-related hypoventilation/hypoxemia disorders 1% ( Box 1.1 ).

BOX 1.1

ICSD, International Classification of Sleep Disorders

Sleep-Related Breathing Disorders According to ICSD-3

Obstructive sleep apnea (OSA) disorders

1.
OSA, adult
2.
OSA, pediatric

Central sleep apnea (CSA) syndromes

1.
CSA with Cheyne-Stokes breathing (CSB)
2.
CSA due to a medical disorder without Cheyne-Stokes breathing
3.
CSA due to high-altitude periodic breathing (HAPB)
4.
CSA due to a medication or substance
5.
Primary CSA
6.
Primary CSA
7.
Primary CSA of prematurity
8.
Treatment-emergent CSA

Sleep-related hypoventilation (SRHV) disorders

1.
Obesity hypoventilation syndrome (OHS)
2.
Congenital central alveolar hypoventilation syndrome (CCAHS)
3.
Late-onset central hypoventilation with hypothalamic dysfunction
4.
Idiopathic central alveolar hypoventilation (ICAH)
5.
SRHV due to a medication or substance
6.
SRHV due to a medical disorder

Sleep-related hypoxemia (SRHO) disorder

Isolated symptoms and normal variants

1.
Snoring
2.
Catathrenia

Standardized classifications of sleep disorders serve as a tool for disease definition, establishing criteria for diagnosis and treatment, compiling epidemiologic data, and managing coding and billing.

Obstructive sleep apnea (OSA)

Adult OSA

OSA refers to decreased or absent airflow in the presence of muscular inspiratory effort. On the polysomnography (PSG) recording, obstructive apnea events can take one of three forms: apnea, hypopnea, or respiratory effort–related arousals (RERAs) ( Figs. 1.1 and 1.2 ). Defining these events depends on recordings of airflow, thoracic and abdominal respiratory muscle movement (Mvmt), oxygen saturation (Spo ₂ ), and electroencephalography (EEG). A duration of 10 seconds or more is required to score any of these respiratory events.

Apnea

Apnea is diagnosed based on the findings from a single PSG channel using a specific sensor. It is defined as a 90% or more reduction in the amplitude of airflow signal as measured by an oral/nasal thermal sensor, whose signal is not linear. Defining the type of apnea event requires examining two PSG channels: respiratory effort and airflow. Based on the respiratory effort recording that is coinciding with the airflow signal, the apnea event is classified into one of three types:

Obstructive apnea event: There is breathing effort during the apnea.
Central apnea event: There is no breathing effort during the apnea.
Mixed apnea event: The apnea event starts as a central apnea and ends as an obstructive apnea.

Hypopnea

Hypopnea is defined based on the findings of two or three PSG channels, using a nasal pressure sensor. The nasal pressure sensor is used for scoring hypopnea because its signal is linear, but it is not used for apnea scoring because it may be misleading in a mouth breather. The sensor for oxygen saturation is a pulse oximeter with signal averaging of 3 seconds (3 Hz) or less. The duration requirement for hypopnea is 10 seconds or more. Hypopnea events have two definitions, recommended and alternative.

The recommended definition of hypopnea is a drop of 30% or more in the amplitude of the nasal pressure sensor that lasts for 90% or more of the event and is associated with a 4% or more drop in Spo ₂ . This definition of hypopnea is simplified as the 30-4 rule. It is the recommended definition by the American Academy of Sleep Medicine (AASM) and the definition accepted by Medicare; therefore it is also known as the Medicare hypopnea rule. This definition requires examining two PSG channels: the airflow as measured by the nasal pressure sensor and Spo ₂ ( Fig. 1.3 ).

Fig. 1.3, Polysomnography (PSG) features of obstructive hypopnea event. The top channel (Press) displays airflow as measured by a nasal pressure transducer. It demonstrates 30% or more reduction from baseline in the amplitude of the signal that lasts for 90% or more of the event, which lasts 10 or more seconds. The channel Flow displays airflow as measured by a thermal sensor. It demonstrates less reduction from baseline in the amplitude of the signal. The channel Sao 2 demonstrates a drop in oxygen saturation by 4%, from 90% to 86%. Thus the findings on the two channels of airflow pressure and oxygen saturation meet the definition of the 30-4 rule for hypopnea. The bottom channels ( Chest and ABD ) display chest and abdomen movement as measured by inductance plethysmography. They demonstrate continuous respiratory effort during the hypopnea event, which defines it as an obstructive hypopnea.

An alternative definition of hypopnea is a drop of 50% or more in the amplitude of airflow as measured by nasal pressure sensor that lasts 90% or more of the event and is associated with either a 3% or more drop in Spo ₂ or EEG arousal. EEG arousal refers to an abrupt shift in EEG frequency lasting more than 3 seconds and preceded by more than 10 seconds of stable EEG and has different rules for scoring based on sleep stage (rapid eye movement [REM] or non-REM [NREM] sleep). In PSG sleep studies, arousal refers to EEG arousal, whereas awakening refers to clinical awakening. This alternative definition of hypopnea is simplified as the 50-3a rule, with the a standing for arousal . This is considered an alternative definition by AASM and is not accepted by Medicare for the purposes of scoring respiratory events, diagnosing OSA, or coding and billing.

The total number of apnea and hypopnea events during a PSG study is used to calculate an apnea-hypopnea index (AHI), defined as the number of apnea and hypopnea events per hour of sleep. The PSG-derived AHI is used in the diagnosis of sleep apnea disorders, assessing severity, titrating positive airway pressure (PAP) therapy, evaluating the therapeutic efficacy of various interventions, assessing the diagnostic utility of other tools and surveys, and establishing a severity-outcome relationship when studying the association between sleep apnea, or its treatment, and a given outcome.

Respiratory effort–related arousals

RERA is determined based on the findings of three PSG channels: airflow, respiratory effort, and EEG. RERA is defined as a limitation in the airflow followed by an arousal on the EEG channel, with the limitation in airflow being defined either by flattening of the airflow in a way that does not meet the criteria for apnea or hypopnea or by increased respiratory effort. Unlike apnea and hypopnea, the definition of RERA lacks numeric criteria, other than a duration of 10 seconds or more. Using RERA events as part of scoring respiratory events on the PSG is an option, not a recommendation. When RERA events are added to the apnea and hypopnea events, a respiratory disturbance index (RDI) is calculated. The ICSD-3 allows the use of RDI as a substitute for AHI in the diagnosis of OSA. Medicare allows only the use of AHI and allows only one rule for the definition of hypopnea.

Diagnosing OSA in adults

The diagnosis of OSA in adults can be based either on the presence of an AHI of 15 or above alone or on the combination of an AHI of 5 or above plus clinical signs and symptoms (associated sleepiness, fatigue, insomnia, snoring, subjective nocturnal respiratory disturbance, or observed apnea) or associated medical and psychiatric disorders (hypertension [HTN], coronary artery disease, atrial fibrillation [AF], congestive heart failure [CHF], stroke, diabetes mellitus, cognitive dysfunction, or mood disorder). The term obstructive sleep apnea syndrome (OSAS) refers to the combination of AHI of 5 or above and daytime somnolence that is present for 2 or more days/week. Based on this definition, the prevalence of OSAS is about 2% for women and 4% for men, while the prevalence of AHI of 5 or above alone is about 9% in women and 24% in men. In using AHI to assess the severity of OSA, three grades are defined: mild (AHI 5–15), moderate (AHI 15–30), and severe (AHI ≥30).

Levels of sleep apnea testing

There are four levels of sleep apnea testing. Level I is attended comprehensive (7–12 channels) PSG, the gold standard. Level II is unattended comprehensive PSG, which is rarely done. Level III is unattended four-channel portable monitoring, including airflow, respiratory effort, and Sao ₂ , with additional electrocardiography (ECG) and/or actigraphy. Level III is commonly used to diagnose OSA in someone with high pretest probability and no comorbidity. It cannot rule out OSA, lacks information about sleep stage and body position, and tends to underestimate AHI because it uses recording time as the denominator, which is usually longer than sleep time. Level IV is home monitoring of Sao ₂ with or without airflow. Level IV cannot diagnose OSA because it lacks a respiratory effort channel, but it can provide an oxygen desaturation index (ODI), the hourly rate of decreased Sao ₂ of 3% or more, and T-90, the total time spent with Sao ₂ of 90% or less. Level IV oximetry can be enhanced by adding both actigraphy, which measures wrist activity as an indication of sleep state, and peripheral arterial tonometry (PAT). PAT measures finger plethysmography as an indication of sympathetic α-adrenergic activity, which in turn is used as a marker of apnea, hypopnea, and hypoxia events.

Pathogenesis of OSA

Direct physiologic mechanisms involved in the pathogenesis of OSA include anatomic and functional upper airway obstruction (UAO), decreased respiratory-related EEG arousal response, and instability of the ventilatory response to chemical stimuli. The apnea episodes are resolved as a result of three events: (1) increased muscular activity at the upper airway muscles that restores airway patency; (2) increased muscular activity at the thoracoabdominal respiratory muscles that generates increased negative intrathoracic pressure; and (3) EEG arousal, which stimulates central respiratory centers. PSG recording can help elucidate the sequence of, and relationships between, events both during apnea episodes and their resolution ( Fig. 1.4 ).

Fig. 1.4, Experimental polysomnography (PSG) in obstructive sleep apnea showing sequence and resolution of apnea events. This experimental PSG in a patient with obstructive sleep apnea (OSA) includes recordings of electromyography (EMG) of upper airway muscles (genioglossus [EMGgg] and submental muscles [EMGsub] ), electroencephalography (EEG), intrathoracic pressure approximated by epiglottic catheter (Pepi), nasal airflow (Flow) by thermal sensor, and oxygen saturation (Sao 2 ) by pulse oximetry with a minimal sampling rate of 10 Hz. The top channel (EMGgg) demonstrates progressively increased EMGgg activity (amplitude) until this increased activity reaches a sufficient level to open the upper airway and allow breathing (Flow) to resume. The middle channel (Pepi) demonstrates a progressive increase in respiratory muscle effort until breathing (Flow) resumes. The increase in respiratory muscle effort is considered the primary stimulus for EEG arousal, through stimulation of the mechanoreceptors in the chest muscles, which provide input both to the medullary respiratory centers and the wake/sleep neurochemical pathways. The EEG channel shows that the occurrence of the EEG arousal occurs immediately following the peaks in EMGgg and Pepi and coincides with the resumption of breathing as demonstrated by nasal airflow (Flow). The airflow (Flow) thermal sensor channel shows the resumption of breathing at the time of EEG arousal, immediately after the peaks of upper airway (EMGgg) and respiratory (Pepi) muscle activity. The oxygen saturation channel (Sao 2 ) demonstrates the lag time between ventilation and oxygenation, which leads to paradoxic restoration of oxygen saturation during the apnea episode, and the occurrence of oxygen desaturation during the resumption of breathing period. The increased activity of EMG, Pepi, and EEG at the end of the apnea period results in a subsequent period of hyperpnea. The cyclic alteration of periods of apnea and hyperpnea disrupts the chemoreceptor stability of the respiratory control system and leads to a periodic breathing pattern similar to that encountered in several forms of central sleep apnea.

Cardiovascular consequences

Cardiovascular pathophysiologic consequences of OSA are the result of hypoxia/hypercarbia, EEG arousal, and increased inspiratory efforts. These physiologic disturbances affect cellular and tissue function of the cardiovascular system leading to a wide range of clinical morbidity and mortality ( Fig. 1.5 ).

Fig. 1.5, Schematic representation of cardiovascular pathophysiologic consequences of obstructive sleep apnea.

Pathophysiologic consequences of OSA contribute to the difference in timing of cardiac death between patients with OSA and the general population, in whom peak incidence of death due to cardiac arrhythmias and ischemia occurs during the daytime (06:00–12:00). In the patient with OSA the peak incidence of death due to cardiac arrhythmias and ischemia occurs at night (00:00–06:00).

The causal relationship between OSA and cardiovascular morbidity and mortality is supported by observational studies demonstrating (1) a dose-response relationship between severity of OSA and observed morbidity and mortality, (2) positive effect of OSA treatment, and (3) dose-response relationship between efficacy of treatment and observed morbidity and mortality. Outcomes for which such relationships have been found include all-cause mortality; a composite outcome of stroke, transient ischemic attack (TIA), and all-cause mortality; stroke; coronary artery disease; HTN; and need for repeat revascularization after percutaneous coronary intervention. The causal relationship between stroke and OSA may be bidirectional, as stroke is considered both a risk factor for and an outcome of OSA. The causal relationship between OSA and cardiovascular and metabolic disorders may also be bidirectional, or noncausal due to shared risk factors ( Fig. 1.6 ).

Fig. 1.6, Schematic representation of overlap between risk factors, symptoms, and outcomes of obstructive sleep apnea (OSA). There is significant overlap between what are considered risk factors, symptoms, and outcomes in OSA. Overlap can be seen between symptoms (e.g., excessive daytime sleepiness [EDS]) and outcomes. This overlap may be a causal association or due to shared risk factors of chronic sleep deprivation and disrupted sleep architecture. Overlap can be observed between risk factors and outcomes in the form of metabolic and cardiovascular disorders. This overlap may represent reciprocal causal association or noncausal association due to shared risk factors.

Neurocognitive consequences

Repeated EEG arousal, clinical awakening, and disrupted sleep architecture (decreased deep sleep and increased lighter sleep) induce a state of overall slowing of the EEG, chronic sleep deprivation, excessive daytime sleepiness (EDS), increased number of lapses on psychomotor vigilance task testing, decrease in cognition and performance (attention, memory, executive functioning), decreased quality of life, mood disorders, and increased rates of motor vehicle collisions.

Metabolic consequences

Pathophysiologic mechanisms for metabolic derangements in OSA include hypoxic injury, systemic inflammation, increased sympathetic activity, alterations in hypothalamic-pituitary-adrenal function, and hormonal changes. Metabolic derangements of OSA lead to worsening of OSA and produce a vicious perpetuating cycle. Metabolic derangements and disorders linked to OSA include insulin resistance, glucose intolerance, dyslipidemia, type 2 diabetes mellitus (T2DM), central obesity, and metabolic syndrome. OSA is common in patients with nonalcoholic steatohepatitis (50%) and polycystic ovarian syndrome (PCOS [30–50%]). Sleep deprivation has been implicated as a risk factor for common cancers, including cancers of the breast, colon and prostate.

Mortality and economic consequences

The mortality impact of OSA is evident in moderate to severe OSA. The economic impact is due to increased healthcare utilization, decreased productivity, and years of potential life lost. It is estimated that the yearly incidence of OSA-related motor vehicle accidents alone costs approximately $16 billion and 1400 lost lives. It is also estimated that treating all drivers with OSA with positive airway therapy (at a cost of ~$3 billion/year) would save about $11 billion and 1000 lives. OSA has a significant public health impact due to its high prevalence (estimated 25 million in United States), high proportion of undiagnosed cases (80% for men and 90% for women), and association with significant morbidity, mortality, and decreased quality of life.

Treatment of adult OSA

Treatment of OSA includes the use of devices, surgery, and medications. All modes of treatment should include patient education and long-term follow-up. General measures that should be applied with all modes of therapy include reducing modifiable risk factors and treating comorbid conditions. Potentially modifiable risk factors include alcohol consumption, use of sedative medication, cigarette smoking, obesity, nasal obstruction, and tonsils grade (≥3). Common comorbidities include difficult to control HTN, AF, coronary artery disease, myocardial infarction, CHF, stroke, T2DM, hypothyroidism, Graves disease, acromegaly, nonalcoholic steatohepatitis (NASH), and PCOS. Women with OSA are more likely than men to present with insomnia, thyroid disease, depression, and antidepressant use. General measures in the treatment of OSA include weight reduction, avoiding alcohol and central nervous system (CNS) depressant drugs, improving sleep hygiene, and refraining from driving when sleepy. In extreme cases of sleepiness (e.g., patients reporting the maximum score of 24 on the Epworth sleepiness scale [ESS]), patients should be forbidden from driving unless they are treated and their OSA and ESS improved.

PAP therapy for OSA

Positive airway pressure therapy is the most commonly studied and prescribed therapy for OSA as well as for some forms of central and mixed sleep apnea. PAP therapy is considered tier 1 therapy for OSA. The most common form of PAP is continuous PAP (CPAP). Other forms of PAP therapy consist of various electronic modifications of PAP delivery patterns such as bilevel PAP (BPAP), autotitrated PAP (APAP), and adaptive servo ventilation (ASV). The three elements of a PAP device are the flow generator, a connecting hose, and a patient interface, which has three forms: nasal mask, nasal pillows, and full-face mask. Technologic advancements have allowed reduction in the size and the noise level of flow generators as well as the options of PAP delivery patterns. The aim of these modifications is to enhance individual customization of PAP therapy, and therefore improve adherence to and effectiveness of the therapy. Critical steps in application of PAP therapy are patient education, mask fitting, and titration of therapy. Effective PAP titration can result in elimination of apnea events and normalization of oxygen saturation. Long-term effects of effective PAP therapy include improved sleep efficacy and architecture, improved neurocognitive function, and reversal of many of the metabolic and cardiovascular effects of OSA.

Adherence to PAP therapy is the major limitation of its effectiveness. Initial acceptance rates of PAP therapy of 70% might decrease to 50% or less over time. Complications of PAP therapy are uncommon and can be managed with therapy modification. The most common complications are mechanical and include nasal obstruction or stuffiness, facial pressure ulcers, and skin rash. Other complications are social or psychological in nature and are related to self-image and intimacy.

The goal of PAP titration is to select the lowest airway pressure that eliminates all respiratory events, including apneas, hypopneas, arousals, and snoring, so that the RDI decreases to less than 5/hour, with acceptable oxygenation (Spo ₂ ≥90%), and an acceptable mask leak level ( Fig. 1.7 ).

Fig. 1.7, All-night hypnogram demonstrating optimal continuous positive airway pressure (CPAP) titration. This is an all-night hypnogram of about 8-hour duration that represents a split-night PSG study, in which the first half of the study is used for diagnosis and the second half for therapeutic titration of CPAP. The time in hours is listed at the bottom of the graph. The first panel from the bottom shows the CPAP level. During the first half of the study, the diagnostic PSG study yields an AHI of 108/h. Toward the middle of the study, CPAP titration started at 6 cm H 2 O then increased to 8 cm H 2 O, which resulted in reducing the AHI to 11.7/h; progressive increases in CPAP and decreases in AHI follow. The second panel from the bottom shows the oxygen saturation (Sao 2 ) during the night and demonstrates the frequent desaturation episodes during the first half of the night to Sao 2 levels of 75%, and resolution during CPAP titration. The third panel from the bottom shows the apnea and hypopnea events, with frequent occurrence of these events during the first half of the night (AHI 108/h) and the significant resolution of these events by CPAP (AHI 4/h). The fourth panel from the bottom shows the patient position, which demonstrates that the patient avoided the supine position (labeled B for back) during the first half of the night and only maintained the supine position during the last period of sleep during the CPAP titration. The top panel shows the sleep stage with the REM sleep period indicated in black. It shows that CPAP titration achieved adequate resolution of the respiratory events even during REM sleep period. The patient was not able to achieve any deep sleep (N3) during the first half of the night, while compensatory N3 stage of sleep was reached during CPAP titration. N3 normally occurs during the first third of the night. This CPAP titration is considered optimal because it was the lowest level of CPAP that reduced AHI to 5/h or less and achieved that reduction during all sleep positions, including supine, and during all stages of sleep, including REM.

Suggested mechanisms of action of PAP therapy include (1) increasing the pharyngeal transmural pressure (pneumatic splint effect), (2) reducing pharyngeal wall thickness and airway edema, (3) increasing airway tone by mechanoreceptor stimulation, and (4) increasing end-expiratory lung volume and producing a tracheal tug effect. Manual in-laboratory, PSG-guided, full night titration of fixed PAP is considered the standard. APAP is an acceptable alternative for the treatment of uncomplicated moderate to severe OSA that is associated with snoring. APAP consists of a single variable PAP that is maintained during both inhalation and exhalation, with variation from breath to breath according to the presence or absence of apnea, hypopnea, or snoring. APAP mode may improve patient adherence and may minimize the average airway pressure by allowing higher PAP during periods of greater obstruction, such as in the supine position and during REM sleep, and lower PAP during periods of lesser obstruction.

Depending on the examined outcome, four levels of evidence are found in the literature regarding the efficacy of PAP therapy in OSA. There is clear evidence for reducing AHI; strong evidence for increasing deep sleep and decreasing EEG arousals; less clear evidence for improved sleep architecture; and equivocal evidence for improved daytime sleepiness, neurobehavioral performance, psychological functioning, quality of life, and cardiovascular outcomes, especially HTN. One example of establishing the efficacy of CPAP therapy in increasing deep sleep is through the demonstration of CPAP-induced restoration of nocturnal surge in the release of growth hormone during deep sleep, also known as slow-wave sleep (SWS) or non-REM sleep stage 3 (N3).

Oral appliance therapy for OSA

Oral appliance (OA) therapy is considered second tier treatment in the management of OSA. The most common forms of OA are mandibular advancement devices (MADs) and tongue retaining devices (TRDs). MADs are usually custom-made devices that are fitted to the teeth like a mouth guard and act to advance and stabilize the mandible to increase upper airway capacity. TRDs advance and retain the tongue in an anterior position by holding it by a suction cup placed over the front teeth. OA therapy is indicated for the treatment of snoring, mild-moderate OSA, and select cases of moderate-severe OSA, such as predominantly supine OSA or OSA due to a proportionally large tongue relative to oral cavity capacity. OA therapy is less effective than PAP therapy in reducing AHI, but may be better tolerated and preferred by patients, and has been shown to be effective in reducing sleep interruption, EDS, neurocognitive impairment and cardiovascular complications. Side effects include excessive salivation, temporomandibular joint discomfort, and long-term occlusion changes. OA therapy should be provided jointly by a qualified dentist and sleep medicine physician with appropriate follow-up testing to document maintained efficacy.

Other device therapy for OSA

Many forms of device therapy continue to be introduced for the treatment of OSA. These devices have a wide range of complexity, invasiveness, price, and need for medical prescription and application. Nasal expiratory PAP (EPAP) is a diaphragm-like membrane applied to both nares to provide resistance to exhalation and stent the upper airway. Oral pressure therapy is a mouthpiece attached to a vacuum source, which pulls the soft palate forward and increases the size of pharyngeal cavity.

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