Sleep Medicine

SLEEP AND CARDIOVASCULAR PHYSIOLOGY

Wakefullness and sleep, the latter comprised of non-rapid eye movement (NREM) sleep and rapid eye movement (REM) sleep, comprise our primary states of being. Sleep states oscillate between NREM and REM sleep. The first and shortest period of REM sleep typically occurs 90 to 120 minutes into the sleep cycle. Most REM sleep, including the longest period of REM sleep, occurs during the latter part of the sleep cycle.

With these sleep state changes, physiologic changes also occur, such as reduced heart rate and blood pressure because of enhanced parasympathetic tone. During REM sleep, there are also intermittent sympathetic nervous system surges. Other physiologic changes include a regular respiratory rate during NREM sleep and an irregular respiratory rate during REM sleep. Body temperature is normal during NREM sleep and poikilothermic (ie, tends to flucuate) during REM sleep. Blood pressure is reduced 10% to 15% during sleep¹ and then rises, so that the highest blood pressure occurs in the morning. Data from 10 million users of activity-monitoring devices show that the heart rate changes during sleep.² The heart rate is decreased in those who get less than 7 hours of sleep, then increases with longer sleep duration in a U-shaped distribution.

Cardiovascular events are more likely to occur at certain times of day. Myocardial infarction is more likely in the morning, with a threefold increased risk within the first 3 hours of awakening that peaks around 9 AM.^3,4 Similar diurnal patterns have been observed with other cardiovascular conditions such as sudden cardiac death and ischemic episodes, with the highest risk during morning hours (6 to 9 AM).⁴

The reason for this morning predisposition for cardio­vascular events is unclear, but it is thought that perhaps the autonomic fluctuations that occur during REM sleep and the predominance of REM sleep in early morning may be a factor. Diurnal changes in blood pressure and cortisol levels may also contribute, as well as levels of systemic inflammatory and thrombotic markers such as plasminogen activator inhibitor 1.

Arrhythmias are also more likely to occur in a diurnal pattern. Atrial fibrillation (AF), particularly paroxysmal AF, is believed to be vagally mediated in 10% to 25% of patients.⁵ Therefore, for those who are predisposed, sleep may represent a period of increased risk for AF. In a study of individuals 60 years and older, the maximum duration and peak frequency of AF occurred from midnight to 2 AM.⁵

Recent studies have found that REM-related obstructive sleep apnea (OSA) is associated with increased cardiovascular risk. Experimental models show that REM sleep may increase the risk for compromised coronary blood flow.⁶ Increased heart rate corresponds to reduced coronary blood flow and thus, to decreased coronary perfusion time and less time for relaxation of the heart, increasing the risk for coronary artery disease, thrombosis, and ischemia.

SLEEP APNEA PATHOPHYSIOLOGY

The normal physiology of the sleep-heart inter­action is disrupted by sleep apnea. OSA is defined as episodes of complete or partial airway obstruction that occur during sleep with thoraco­abdominal effort. Central sleep apnea (CSA) is the cessation of breathing with no thoracoabdominal effort. The pathophysiology of the sleep-heart interaction varies for OSA and CSA.

Obstructive sleep apnea

OSA is a nocturnal physiologic stressor that is highly prevalent and underrecognized. It affects approximately 17% of the adult population, and the prevalence is increasing with the obesity epidemic. Nearly 1 in 15 individuals is estimated to be affected by at least moderate OSA.^7,8 OSA is underdiagnosed particularly in minority populations.⁹ Data from the 2015 Multi-Ethnic Study of Atherosclerosis (MESA) showed undiagnosed moderate to severe sleep apnea in 84% to 93% of individuals,⁹ similar to an estimated 85% of undiagnosed cases in 2002.¹⁰

OSA is highly prevalent in individuals with underlying coronary disease^11–13 and in those with cardiovascular risk factors such as diabetes, hypertension, and heart failure. The prevalence of OSA in patients with cardiovascular disease ranges from 30% (hypertension) to 60% (stroke or transient ischemic attack, arrhythmia, end-stage renal disease).¹⁴

 

 

Pathophysiology of OSA

The pathophysiology of OSA can be observed during polysomnography, characterized by autonomic nervous system disturbances, intermittent hypoxia, and intrathoracic pressure alterations, (Figure 1). Intermittent bouts of hypoxia or oxygen-lowering occur because airflow is obstructed despite persistent thoracic and abdominal effort. Systemic inflammation and oxidative stress occur due to these intrathoracic pressure alterations, increased CO₂ and reduced oxygen levels, and autonomic nervous system disturbances.

The alterations in sympathetic activation that occur during sleep in patients with OSA persist during wakefulness. Microneurographic recording of sympathetic nerve activity in the peroneal nerve reveal that the rate of sympathetic bursts doubles and the amplitude is greater in individuals with OSA compared with a control group.¹⁵

Sympathetic nerve activity, blood pressure, and heart rate were shown to increase during REM sleep in individuals with OSA on continuous positive airway pressure (CPAP) during an induced apneic event (pressure reduction from 8 cm to 6 cm of water).¹⁵

During OSA episodes, there is an increased cardiac load. Impaired diastolic function and atrial and aortic enlargement, and in particular, the thin-walled atria are very susceptible to the intra­thoracic pressure swings caused by OSA. Physiologic changes with OSA from pressure changes in the chest result in shift of the intraventricular septum, causing a reduction in cardiac output.¹⁶ With the lowering of oxygen during episodes of apnea, constriction of the pulmonary vasculature leads to elevation of pressure in the pulmonary vasculature reflected by the increase in mean pulmonary arterial pressures.¹⁷

Other studies have shown that OSA increases upregulation of markers of systemic inflammation and prothrombotic markers, the very markers that can increase cardiovascular or atherogenic risk.^18–22 One example is the soluble interleukin 6 receptor, shown to be elevated in the morning relative to sleep apnea compared with the evening.²⁰ Other biomarkers observed to be associated with sleep apnea include markers of prothrombotic potentials such as plasminogen activator inhibitor 1.¹⁹ Oxidative stress occurs because intermittent bouts of lower oxygen can lead to oxidation of serum proteins and lipids. Endothelial dysfunction has been observed as well as insulin resistance and dyslipidemia.²³ Taken together, these are pathways that lead to atherogenesis and increased cardiovascular risk.

Central sleep apnea

CSA episodes are the cessation of breathing without thoracoabdominal effort, in contrast to the persistence of thoracoabdominal effort in OSA. CSA is characterized by breathing instability with highly sensitive chemoresponses and prolonged circulation time.²⁴ This can be physiologic in some cases, as when it occurs after a very large breath or sigh and then a central apnea event occurs after the sigh. The alterations in oxygen and CO₂ and the stretch of the receptors in the alveoli of the lungs initiate the Hering-Breuer inhalation reflex.

Pathophysiology of CSA

Complex pathways of medullary and aortic receptor chemosensitivity are at the root of the pathophysiology of CSA.²⁴ With CSA there is often a relative state of hypocapnia at baseline. During sleep, there is reduction in drive, thus chemo­sensitivity can be activated so that central apnea episodes can ensue as a result of alterations in CO₂ (ie, hypocapnia). Another factor that can contribute to the pathophysiology of CSA is arousal from sleep that can reduce CO₂ levels and therefore perpetuate central events.

The concept of loop gain is used to understand the pathophysiology of CSA. Loop gain is a measure of the relative stability of a ventilation system and indicates the likelihood of an individual to have periodic breathing. It is calculated by the response to a disturbance divided by the disturbance itself.²⁵ With a high loop gain, there is a more pronounced or exuberant response to the disturbance, indicating more instability in the system and increasing the tendency for irregular breathing and CSA episodes.

Hunter-Cheyne-Stokes respiration occurs with CSA and is characterized by cyclical crescendo-decrescendo respiratory effort that occurs during wakefulness and sleep without upper-airway obstruction.^26,27 Unlike OSA, which is worse during REM sleep, Hunter-Cheyne-Stokes breathing in CSA is typically worse in NREM sleep, during N1 and N2 in particular.

 

 

SLEEP APNEA AND HEART FAILURE

Both OSA and CSA are prevalent in patients with heart failure and may be associated with the progression of heart failure. CSA often occurs in patients with heart failure. The pathophysiology is multi­factorial, including pulmonary congestion that results in stretch of the J receptors in the alveoli, prolonged circulation time, and increased chemosensitivity.

Complex pathways in the neuroaxis or somnogenic biomarkers of inflammation or both may be implicated in the paradoxical lack of subjective sleepiness in the presence of increased objective measures of sleepiness in systolic heart failure. One study found a relationship with one biomarker of inflammation and oxidative stress as it relates to objective symptoms of sleepiness but not subjective symptoms of sleepiness.²⁸

Another contributing factor in the relationship between OSA and CSA in heart failure has also been described related to rostral shifts in fluid to the neck and to the pulmonary receptors in the alveoli of the lungs.²⁹ These rostral shifts in fluids may contribute to sleep apnea with parapharyngeal edema leading to OSA and pulmonary congestion leading to CSA.

Sleep apnea is associated with increased post-discharge mortality and hospitalization readmissions in the setting of acute heart failure.³⁰ Mortality analysis of 1,096 patients admitted for decompensated heart failure found CSA and OSA were independently associated with mortality in patients compared with patients with no or minimal sleep-disordered breathing.³⁰

CSA has also been shown to be a predictor of readmission in patients admitted for heart failure exacerbations.³¹ Targeting underlying CSA may reduce readmissions in those admitted with acute decompensated heart failure. While men were identified to be at increased risk of death relative to sleep-disordered breathing based on the initial results of the Sleep Heart Health Study, a subsequent epidemiologic substudy reflective of an older age group showed that OSA was more strongly associated with left ventricular mass index, risk of heart failure, or death in women compared with men.³²

Treatment

Standard therapy for treatment of OSA is CPAP. Adaptive servo-ventilation (ASV) and transvenous phrenic nerve stimulation are also available as treatment options in certain cases of CSA.

One of the first randomized controlled trials designed to assess the impact of CSA treatment on survival in patients with heart failure initially favored the control group then later the CPAP group and was terminated early based on stopping rules.^33,34 While adherence to therapy was suboptimal at an average of 3.6 hours, post hoc analysis showed that patients with CSA using CPAP with effective suppression of CSA had improved survival compared with patients who did not have effective suppression using CPAP.³⁴

ASV is mainly used for treatment of CSA. In ASV, positive airway pressure for ventilation support is provided and adjusts as apneic episodes are detected during sleep. The support provided adapts to the physiology of the patient and can deliver breaths and utilize anticyclic modes of ventilation to address crescendo-decrescendo breathing patterns observed in Hunter-Cheyne-Stokes respiration.

In the Treatment of Sleep-Disordered Breathing With Predominant Central Sleep Apnea by Adaptive Servo Ventilation in Patients With Heart Failure (SERVE-HF) trial, 1,300 patients with systolic heart failure and predominantly CSA were randomized to receive ASV vs solely standard medical management.³⁵ The primary composite end point included all-cause mortality or unplanned admission or hospitalization for heart failure. No difference was found in the primary end point between the ASV and the control group; however, there was an unanticipated negative impact of ASV on cardiovascular outcomes in some secondary end points. Based on the secondary outcome of cardiovascular-specific mortality, clinicians were advised that ASV was contraindicated for the treatment of CSA in patients with symptomatic heart failure with a left ventricular ejection fraction less than 45%. The interpretation of this study was complicated by several methodologic limitations.³⁶

The Cardiovascular Improvements With Minute Ventilation-Targeted Adaptive Servo-Ventilation Therapy in Heart Failure (CAT-HF) randomized controlled trial also evaluated ASV compared with standard medical management in 126 patients with heart failure.³⁷ This trial was terminated early because of the results of the SERVE-HF trial. Compliance with therapy was suboptimal at an average of 2.7 hours per day. The composite end point did not differ between the 2 groups; however, this was likely because the study was underpowered and was terminated early. Subgroup analysis revealed that patients with heart failure with preserved ejection fraction may benefit from ASV; however, additional studies are needed to confirm these findings.

Therefore, although ASV is not indicated when there is predominantly CSA in patients with systolic heart failure, preliminary results support potential benefit in patients with OSA and preserved ejection fraction.

Another novel treatment for CSA is transvenous phrenic nerve stimulation. A device is implanted that stimulates the phrenic nerve to initiate breaths. The initial study of trans­venous phrenic nerve stimulation reported a significant reduction in the number of episodes of central apnea per hour of sleep.^38,39 The apnea–hypopnea index improved overall and some types of obstructive apneic events were reduced with transvenous phrenic nerve stimulation.

A multicenter randomized control trial of trans­venous phrenic nerve stimulation found improvement in several sleep apnea indices, including central apnea, hypoxia, reduced arousals from sleep, and patient reported well-being.⁴⁰ Transvenous phrenic nerve stimulation holds promise as a novel therapy for central predominant sleep apnea not only in terms of improving the degree of central apnea and sleep-disordered breathing, but also in improving functional outcomes. Longitudinal and intereventional trial data are needed to clarify the impact of transvenous phrenic nerve stimulation on long-term cardiac outcomes.

SLEEP APNEA AND ATRIAL FIBRILLATION AND STROKE

Atrial fibrillation

AF is the most common sustained cardiac arrhythmia. The number of Americans with AF is projected to increase from 2.3 million to more than 10 million by the year 2050.⁴¹ The increasing incidence and prevalence of AF is not fully explained by the aging population and established risk factors.⁴² Unrecognized sleep apnea, estimated to exist in 85% or more of the population, may partially account for the increasing incidence of AF.⁴³

There are 3 types of AF, which are thought to follow a continuum: paroxysmal AF is characterized by episodes that occur intermittently; persistent AF is characterized by episodes that last longer than 7 days; chronic or permanent AF is typically characterized by AF that is ongoing over many years.⁴⁴ As with sleep apnea, AF is often asymptomatic and is likely underdiagnosed.

Sleep apnea and AF share several risk factors. Obesity is a risk factor for both OSA and AF; however, a meta-analysis supported a stronger association of OSA and AF vs obesity and AF.⁴⁵ Increasing age is a risk factor for both OSA and AF.^46,47 Although white populations are at higher risk for AF, OSA is associated with a 58% increased risk of AF in African Americans.⁴⁸ Nocturnal hypoxia has been associated with increased risk of AF in Asians.⁴⁹

In terms of pathophysiology of sleep apnea and cardiac arrhythmia, OSA increases inflammation, intrathoracic pressures, and CO₂ levels. The increase in inflammation and oxidative stress is thought to alter the cardiac electrophysiology of the heart and contribute to structural remodeling of the heart that increases the risk of cardiac arrhythmia (Figure 2).⁵⁰

Experimental data continue to accrue providing biologic plausibility of the relationship between sleep apnea and AF. OSA contributes to structural and electrical remodeling of the heart with evidence supporting increased fibrosis and electrical remodeling in patients with OSA compared with a control group.⁵¹ Markers of structural remodeling, such as atrial size, electrical silence, and atrial voltage conduction velocity, are altered in OSA.⁵⁰

Data from the Sleep Heart Health Study show very strong associations between atrial and ventricular cardiac arrhythmias and sleep apnea with two- to fivefold higher odds of arrhythmias in patients with severe OSA compared with controls even after accounting for confounding factors such as obesity.⁵²

A multicenter, epidemiological study of older men showed that increasing severity of sleep apnea corresponds with an increased prevalence of AF and ventricular ectopy.⁵³ This graded dose-response relationship suggests a causal relationship between sleep apnea and AF and ventricular ectopy. There also appears to be an immediate influence of apneic events and hypopneic events as it relates to arrhythmia. A case-crossover study showed an associated 18-fold increased risk of nocturnal arrhythmia within 90 seconds of an apneic or hypopneic event.⁵⁴ This association was found with paroxysms of AF and with episodes of nonsustained ventricular tachycardia.

Data from a clinic-based cohort study show an association between AF and OSA.⁵⁵ Specifically, increased severity of sleep apnea was associated with an increased prevalence of AF. Increasing degree of hypoxia or oxygen-lowering was also associated with increased incidence of AF or newly identified AF identified over time.

Longitudinal examination of 2 epidemiologic studies, the Sleep Heart Health Study and Outcomes of Sleep Disorders Study in Older Men, found CSA to be predictive of AF with a two- to threefold higher odds of developing incident AF as it related to baseline CSA.⁵⁶ According to these data, CSA may pose a greater risk for development of AF than OSA.

With respect to AF after cardiac surgery, patients with sleep apnea and obesity appear to be at higher risk for developing AF as measured by the apnea–hypopnea index and oxygen desaturation index.⁵⁷

Treatment of sleep apnea may improve arrhythmic burden. Case-based studies have shown reduced burden and resolution of baseline arrhythmia with CPAP treatment for OSA as therapeutic pressure was achieved.⁵⁸ Another case-based study involved an individual with snoring and OSA and AF at baseline.⁵⁹ Several retrospective studies have shown that treatment of OSA after ablation and after cardio­version results in reduced recurrence of AF; however, large definitive clinical trials are lacking.

Stroke

Sleep apnea is a risk factor for stroke due to intermittent hypoxia-mediated elevation of oxidative stress and systemic inflammation, hypercoaguability, and impairment of cerebral autoregulation.⁶⁰ However, the relationship may be bidirectional in that stroke may be a risk factor for sleep apnea in the post-stroke period. The prevalence of sleep apnea post-stroke has been reported to be up to 70%. CSA can occur in up to 26% during the post-stroke phase.⁶¹ Data are inconsistent in terms of the location and size of stroke and the risk of sleep apnea, though cerebrovascular neuronal damage to the brainstem and cortical areas are evident.⁶² In one study, the incidence of stroke appeared to increase with the severity of sleep apnea.⁶³ These findings were more pronounced in men than in women; however, this study may not have captured the increased cardiovascular risk in postmenopausal women. The Outcomes of Sleep Disorders in Older Men study found that severe hypoxia increased the incidence of stroke, and that hypoxia may be a predictor of newly diagnosed stroke in older men.⁶⁴ Although definitive clinical trials are underway, post-hoc propensity-score matched analysis from the Sleep Apnea Cardiovascular Endpoints (SAVE) study showed a lower stroke risk in those adherent to CPAP compared with the control group (HR=0.56, 95% CI: 0.30-0.90).⁶⁵

 

 

SLEEP APNEA, CORONARY ARTERY DISEASE, AND CARIOVASCULAR MORTALITY

The association between sleep apnea and coronary artery disease and cardiovascular mortality was considered in a Spanish study of 1,500 patients followed for 10 years, which reported that CPAP therapy reduced cardiac events in patients with OSA.⁶⁶ Patients with sleep apnea had an increased risk of fatal myocardial infarction or stroke. Survival of patients treated for sleep apnea approached that of patients without OSA.

In a study of a racially diverse cohort, an association of physician diagnosed sleep apnea with cardiovascular events and survival was identified.⁶⁷ Diagnosed sleep apnea was estimated to confer a two- to threefold increase in various cardiovascular outcomes and all-cause mortality.

Punjabi NM, et al. Sleep-disordered breathing and mortality: a prospective cohort study. PLoS Med 2009; 6(8):e1000132.

All-cause mortality data from the Sleep Heart Health Study of more than 6,000 participants showed that progressive worsening of OSA as defined by the apnea–hypopnea index resulted in poorer survival even after accounting for confounding factors (Figure 3).⁶⁸ Decreased survival appeared to mostly affect men or patients under age 70.

The diurnal pattern of cardiovascular physiology as it relates to sleep is thought to be cardioprotective because of reductions in blood pressure and heart rate. However, in the case of OSA, there appears to be a nocturnal vulnerability or predilection for sudden cardiac death. Patients with OSA were shown to have a higher risk of sudden nocturnal cardiac death occurring from midnight to 6 am compared with individuals without OSA and the general population (Table 1).⁶⁹

The effect of treatment for sleep apnea on cardiovascular outcomes was the focus of a recent randomized controlled trial of nearly 3,000 participants with a mean follow-up of 4 years.65 Use of CPAP compared with usual care found no difference in cardiovascular outcomes. However, secondary analysis revealed a possible benefit of a lower risk of stroke with use of CPAP therapy. Several factors should be considered in interpreting these findings: ie, low adherence with CPAP therapy (3 hours), whether the study was sufficiently powered to detect a change in cardiovascular outcomes, and if the duration of follow-up was adequate. In terms of patient demographics and study generalizability, the study did not include patients with severe sleep apnea and hypoxia, and most participants were men, of Asian descent, with a mean body mass index of 28 kg/m2, and low levels of sleepiness at baseline.

SLEEP AND CARDIOVASCULAR PHYSIOLOGY

Wakefullness and sleep, the latter comprised of non-rapid eye movement (NREM) sleep and rapid eye movement (REM) sleep, comprise our primary states of being. Sleep states oscillate between NREM and REM sleep. The first and shortest period of REM sleep typically occurs 90 to 120 minutes into the sleep cycle. Most REM sleep, including the longest period of REM sleep, occurs during the latter part of the sleep cycle.

With these sleep state changes, physiologic changes also occur, such as reduced heart rate and blood pressure because of enhanced parasympathetic tone. During REM sleep, there are also intermittent sympathetic nervous system surges. Other physiologic changes include a regular respiratory rate during NREM sleep and an irregular respiratory rate during REM sleep. Body temperature is normal during NREM sleep and poikilothermic (ie, tends to flucuate) during REM sleep. Blood pressure is reduced 10% to 15% during sleep¹ and then rises, so that the highest blood pressure occurs in the morning. Data from 10 million users of activity-monitoring devices show that the heart rate changes during sleep.² The heart rate is decreased in those who get less than 7 hours of sleep, then increases with longer sleep duration in a U-shaped distribution.

Cardiovascular events are more likely to occur at certain times of day. Myocardial infarction is more likely in the morning, with a threefold increased risk within the first 3 hours of awakening that peaks around 9 AM.^3,4 Similar diurnal patterns have been observed with other cardiovascular conditions such as sudden cardiac death and ischemic episodes, with the highest risk during morning hours (6 to 9 AM).⁴

The reason for this morning predisposition for cardio­vascular events is unclear, but it is thought that perhaps the autonomic fluctuations that occur during REM sleep and the predominance of REM sleep in early morning may be a factor. Diurnal changes in blood pressure and cortisol levels may also contribute, as well as levels of systemic inflammatory and thrombotic markers such as plasminogen activator inhibitor 1.

Arrhythmias are also more likely to occur in a diurnal pattern. Atrial fibrillation (AF), particularly paroxysmal AF, is believed to be vagally mediated in 10% to 25% of patients.⁵ Therefore, for those who are predisposed, sleep may represent a period of increased risk for AF. In a study of individuals 60 years and older, the maximum duration and peak frequency of AF occurred from midnight to 2 AM.⁵

Recent studies have found that REM-related obstructive sleep apnea (OSA) is associated with increased cardiovascular risk. Experimental models show that REM sleep may increase the risk for compromised coronary blood flow.⁶ Increased heart rate corresponds to reduced coronary blood flow and thus, to decreased coronary perfusion time and less time for relaxation of the heart, increasing the risk for coronary artery disease, thrombosis, and ischemia.

SLEEP APNEA PATHOPHYSIOLOGY

The normal physiology of the sleep-heart inter­action is disrupted by sleep apnea. OSA is defined as episodes of complete or partial airway obstruction that occur during sleep with thoraco­abdominal effort. Central sleep apnea (CSA) is the cessation of breathing with no thoracoabdominal effort. The pathophysiology of the sleep-heart interaction varies for OSA and CSA.

Obstructive sleep apnea

OSA is a nocturnal physiologic stressor that is highly prevalent and underrecognized. It affects approximately 17% of the adult population, and the prevalence is increasing with the obesity epidemic. Nearly 1 in 15 individuals is estimated to be affected by at least moderate OSA.^7,8 OSA is underdiagnosed particularly in minority populations.⁹ Data from the 2015 Multi-Ethnic Study of Atherosclerosis (MESA) showed undiagnosed moderate to severe sleep apnea in 84% to 93% of individuals,⁹ similar to an estimated 85% of undiagnosed cases in 2002.¹⁰

OSA is highly prevalent in individuals with underlying coronary disease^11–13 and in those with cardiovascular risk factors such as diabetes, hypertension, and heart failure. The prevalence of OSA in patients with cardiovascular disease ranges from 30% (hypertension) to 60% (stroke or transient ischemic attack, arrhythmia, end-stage renal disease).¹⁴

 

 

Pathophysiology of OSA

The pathophysiology of OSA can be observed during polysomnography, characterized by autonomic nervous system disturbances, intermittent hypoxia, and intrathoracic pressure alterations, (Figure 1). Intermittent bouts of hypoxia or oxygen-lowering occur because airflow is obstructed despite persistent thoracic and abdominal effort. Systemic inflammation and oxidative stress occur due to these intrathoracic pressure alterations, increased CO₂ and reduced oxygen levels, and autonomic nervous system disturbances.

The alterations in sympathetic activation that occur during sleep in patients with OSA persist during wakefulness. Microneurographic recording of sympathetic nerve activity in the peroneal nerve reveal that the rate of sympathetic bursts doubles and the amplitude is greater in individuals with OSA compared with a control group.¹⁵

Sympathetic nerve activity, blood pressure, and heart rate were shown to increase during REM sleep in individuals with OSA on continuous positive airway pressure (CPAP) during an induced apneic event (pressure reduction from 8 cm to 6 cm of water).¹⁵

During OSA episodes, there is an increased cardiac load. Impaired diastolic function and atrial and aortic enlargement, and in particular, the thin-walled atria are very susceptible to the intra­thoracic pressure swings caused by OSA. Physiologic changes with OSA from pressure changes in the chest result in shift of the intraventricular septum, causing a reduction in cardiac output.¹⁶ With the lowering of oxygen during episodes of apnea, constriction of the pulmonary vasculature leads to elevation of pressure in the pulmonary vasculature reflected by the increase in mean pulmonary arterial pressures.¹⁷

Other studies have shown that OSA increases upregulation of markers of systemic inflammation and prothrombotic markers, the very markers that can increase cardiovascular or atherogenic risk.^18–22 One example is the soluble interleukin 6 receptor, shown to be elevated in the morning relative to sleep apnea compared with the evening.²⁰ Other biomarkers observed to be associated with sleep apnea include markers of prothrombotic potentials such as plasminogen activator inhibitor 1.¹⁹ Oxidative stress occurs because intermittent bouts of lower oxygen can lead to oxidation of serum proteins and lipids. Endothelial dysfunction has been observed as well as insulin resistance and dyslipidemia.²³ Taken together, these are pathways that lead to atherogenesis and increased cardiovascular risk.

Central sleep apnea

CSA episodes are the cessation of breathing without thoracoabdominal effort, in contrast to the persistence of thoracoabdominal effort in OSA. CSA is characterized by breathing instability with highly sensitive chemoresponses and prolonged circulation time.²⁴ This can be physiologic in some cases, as when it occurs after a very large breath or sigh and then a central apnea event occurs after the sigh. The alterations in oxygen and CO₂ and the stretch of the receptors in the alveoli of the lungs initiate the Hering-Breuer inhalation reflex.

Pathophysiology of CSA

Complex pathways of medullary and aortic receptor chemosensitivity are at the root of the pathophysiology of CSA.²⁴ With CSA there is often a relative state of hypocapnia at baseline. During sleep, there is reduction in drive, thus chemo­sensitivity can be activated so that central apnea episodes can ensue as a result of alterations in CO₂ (ie, hypocapnia). Another factor that can contribute to the pathophysiology of CSA is arousal from sleep that can reduce CO₂ levels and therefore perpetuate central events.

The concept of loop gain is used to understand the pathophysiology of CSA. Loop gain is a measure of the relative stability of a ventilation system and indicates the likelihood of an individual to have periodic breathing. It is calculated by the response to a disturbance divided by the disturbance itself.²⁵ With a high loop gain, there is a more pronounced or exuberant response to the disturbance, indicating more instability in the system and increasing the tendency for irregular breathing and CSA episodes.

Hunter-Cheyne-Stokes respiration occurs with CSA and is characterized by cyclical crescendo-decrescendo respiratory effort that occurs during wakefulness and sleep without upper-airway obstruction.^26,27 Unlike OSA, which is worse during REM sleep, Hunter-Cheyne-Stokes breathing in CSA is typically worse in NREM sleep, during N1 and N2 in particular.

 

 

SLEEP APNEA AND HEART FAILURE

Both OSA and CSA are prevalent in patients with heart failure and may be associated with the progression of heart failure. CSA often occurs in patients with heart failure. The pathophysiology is multi­factorial, including pulmonary congestion that results in stretch of the J receptors in the alveoli, prolonged circulation time, and increased chemosensitivity.

Complex pathways in the neuroaxis or somnogenic biomarkers of inflammation or both may be implicated in the paradoxical lack of subjective sleepiness in the presence of increased objective measures of sleepiness in systolic heart failure. One study found a relationship with one biomarker of inflammation and oxidative stress as it relates to objective symptoms of sleepiness but not subjective symptoms of sleepiness.²⁸

Another contributing factor in the relationship between OSA and CSA in heart failure has also been described related to rostral shifts in fluid to the neck and to the pulmonary receptors in the alveoli of the lungs.²⁹ These rostral shifts in fluids may contribute to sleep apnea with parapharyngeal edema leading to OSA and pulmonary congestion leading to CSA.

Sleep apnea is associated with increased post-discharge mortality and hospitalization readmissions in the setting of acute heart failure.³⁰ Mortality analysis of 1,096 patients admitted for decompensated heart failure found CSA and OSA were independently associated with mortality in patients compared with patients with no or minimal sleep-disordered breathing.³⁰

CSA has also been shown to be a predictor of readmission in patients admitted for heart failure exacerbations.³¹ Targeting underlying CSA may reduce readmissions in those admitted with acute decompensated heart failure. While men were identified to be at increased risk of death relative to sleep-disordered breathing based on the initial results of the Sleep Heart Health Study, a subsequent epidemiologic substudy reflective of an older age group showed that OSA was more strongly associated with left ventricular mass index, risk of heart failure, or death in women compared with men.³²

Treatment

Standard therapy for treatment of OSA is CPAP. Adaptive servo-ventilation (ASV) and transvenous phrenic nerve stimulation are also available as treatment options in certain cases of CSA.

One of the first randomized controlled trials designed to assess the impact of CSA treatment on survival in patients with heart failure initially favored the control group then later the CPAP group and was terminated early based on stopping rules.^33,34 While adherence to therapy was suboptimal at an average of 3.6 hours, post hoc analysis showed that patients with CSA using CPAP with effective suppression of CSA had improved survival compared with patients who did not have effective suppression using CPAP.³⁴

ASV is mainly used for treatment of CSA. In ASV, positive airway pressure for ventilation support is provided and adjusts as apneic episodes are detected during sleep. The support provided adapts to the physiology of the patient and can deliver breaths and utilize anticyclic modes of ventilation to address crescendo-decrescendo breathing patterns observed in Hunter-Cheyne-Stokes respiration.

In the Treatment of Sleep-Disordered Breathing With Predominant Central Sleep Apnea by Adaptive Servo Ventilation in Patients With Heart Failure (SERVE-HF) trial, 1,300 patients with systolic heart failure and predominantly CSA were randomized to receive ASV vs solely standard medical management.³⁵ The primary composite end point included all-cause mortality or unplanned admission or hospitalization for heart failure. No difference was found in the primary end point between the ASV and the control group; however, there was an unanticipated negative impact of ASV on cardiovascular outcomes in some secondary end points. Based on the secondary outcome of cardiovascular-specific mortality, clinicians were advised that ASV was contraindicated for the treatment of CSA in patients with symptomatic heart failure with a left ventricular ejection fraction less than 45%. The interpretation of this study was complicated by several methodologic limitations.³⁶

The Cardiovascular Improvements With Minute Ventilation-Targeted Adaptive Servo-Ventilation Therapy in Heart Failure (CAT-HF) randomized controlled trial also evaluated ASV compared with standard medical management in 126 patients with heart failure.³⁷ This trial was terminated early because of the results of the SERVE-HF trial. Compliance with therapy was suboptimal at an average of 2.7 hours per day. The composite end point did not differ between the 2 groups; however, this was likely because the study was underpowered and was terminated early. Subgroup analysis revealed that patients with heart failure with preserved ejection fraction may benefit from ASV; however, additional studies are needed to confirm these findings.

Therefore, although ASV is not indicated when there is predominantly CSA in patients with systolic heart failure, preliminary results support potential benefit in patients with OSA and preserved ejection fraction.

Another novel treatment for CSA is transvenous phrenic nerve stimulation. A device is implanted that stimulates the phrenic nerve to initiate breaths. The initial study of trans­venous phrenic nerve stimulation reported a significant reduction in the number of episodes of central apnea per hour of sleep.^38,39 The apnea–hypopnea index improved overall and some types of obstructive apneic events were reduced with transvenous phrenic nerve stimulation.

A multicenter randomized control trial of trans­venous phrenic nerve stimulation found improvement in several sleep apnea indices, including central apnea, hypoxia, reduced arousals from sleep, and patient reported well-being.⁴⁰ Transvenous phrenic nerve stimulation holds promise as a novel therapy for central predominant sleep apnea not only in terms of improving the degree of central apnea and sleep-disordered breathing, but also in improving functional outcomes. Longitudinal and intereventional trial data are needed to clarify the impact of transvenous phrenic nerve stimulation on long-term cardiac outcomes.

SLEEP APNEA AND ATRIAL FIBRILLATION AND STROKE

Atrial fibrillation

AF is the most common sustained cardiac arrhythmia. The number of Americans with AF is projected to increase from 2.3 million to more than 10 million by the year 2050.⁴¹ The increasing incidence and prevalence of AF is not fully explained by the aging population and established risk factors.⁴² Unrecognized sleep apnea, estimated to exist in 85% or more of the population, may partially account for the increasing incidence of AF.⁴³

There are 3 types of AF, which are thought to follow a continuum: paroxysmal AF is characterized by episodes that occur intermittently; persistent AF is characterized by episodes that last longer than 7 days; chronic or permanent AF is typically characterized by AF that is ongoing over many years.⁴⁴ As with sleep apnea, AF is often asymptomatic and is likely underdiagnosed.

Sleep apnea and AF share several risk factors. Obesity is a risk factor for both OSA and AF; however, a meta-analysis supported a stronger association of OSA and AF vs obesity and AF.⁴⁵ Increasing age is a risk factor for both OSA and AF.^46,47 Although white populations are at higher risk for AF, OSA is associated with a 58% increased risk of AF in African Americans.⁴⁸ Nocturnal hypoxia has been associated with increased risk of AF in Asians.⁴⁹

In terms of pathophysiology of sleep apnea and cardiac arrhythmia, OSA increases inflammation, intrathoracic pressures, and CO₂ levels. The increase in inflammation and oxidative stress is thought to alter the cardiac electrophysiology of the heart and contribute to structural remodeling of the heart that increases the risk of cardiac arrhythmia (Figure 2).⁵⁰

Experimental data continue to accrue providing biologic plausibility of the relationship between sleep apnea and AF. OSA contributes to structural and electrical remodeling of the heart with evidence supporting increased fibrosis and electrical remodeling in patients with OSA compared with a control group.⁵¹ Markers of structural remodeling, such as atrial size, electrical silence, and atrial voltage conduction velocity, are altered in OSA.⁵⁰

Data from the Sleep Heart Health Study show very strong associations between atrial and ventricular cardiac arrhythmias and sleep apnea with two- to fivefold higher odds of arrhythmias in patients with severe OSA compared with controls even after accounting for confounding factors such as obesity.⁵²

A multicenter, epidemiological study of older men showed that increasing severity of sleep apnea corresponds with an increased prevalence of AF and ventricular ectopy.⁵³ This graded dose-response relationship suggests a causal relationship between sleep apnea and AF and ventricular ectopy. There also appears to be an immediate influence of apneic events and hypopneic events as it relates to arrhythmia. A case-crossover study showed an associated 18-fold increased risk of nocturnal arrhythmia within 90 seconds of an apneic or hypopneic event.⁵⁴ This association was found with paroxysms of AF and with episodes of nonsustained ventricular tachycardia.

Data from a clinic-based cohort study show an association between AF and OSA.⁵⁵ Specifically, increased severity of sleep apnea was associated with an increased prevalence of AF. Increasing degree of hypoxia or oxygen-lowering was also associated with increased incidence of AF or newly identified AF identified over time.

Longitudinal examination of 2 epidemiologic studies, the Sleep Heart Health Study and Outcomes of Sleep Disorders Study in Older Men, found CSA to be predictive of AF with a two- to threefold higher odds of developing incident AF as it related to baseline CSA.⁵⁶ According to these data, CSA may pose a greater risk for development of AF than OSA.

With respect to AF after cardiac surgery, patients with sleep apnea and obesity appear to be at higher risk for developing AF as measured by the apnea–hypopnea index and oxygen desaturation index.⁵⁷

Treatment of sleep apnea may improve arrhythmic burden. Case-based studies have shown reduced burden and resolution of baseline arrhythmia with CPAP treatment for OSA as therapeutic pressure was achieved.⁵⁸ Another case-based study involved an individual with snoring and OSA and AF at baseline.⁵⁹ Several retrospective studies have shown that treatment of OSA after ablation and after cardio­version results in reduced recurrence of AF; however, large definitive clinical trials are lacking.

Stroke

Sleep apnea is a risk factor for stroke due to intermittent hypoxia-mediated elevation of oxidative stress and systemic inflammation, hypercoaguability, and impairment of cerebral autoregulation.⁶⁰ However, the relationship may be bidirectional in that stroke may be a risk factor for sleep apnea in the post-stroke period. The prevalence of sleep apnea post-stroke has been reported to be up to 70%. CSA can occur in up to 26% during the post-stroke phase.⁶¹ Data are inconsistent in terms of the location and size of stroke and the risk of sleep apnea, though cerebrovascular neuronal damage to the brainstem and cortical areas are evident.⁶² In one study, the incidence of stroke appeared to increase with the severity of sleep apnea.⁶³ These findings were more pronounced in men than in women; however, this study may not have captured the increased cardiovascular risk in postmenopausal women. The Outcomes of Sleep Disorders in Older Men study found that severe hypoxia increased the incidence of stroke, and that hypoxia may be a predictor of newly diagnosed stroke in older men.⁶⁴ Although definitive clinical trials are underway, post-hoc propensity-score matched analysis from the Sleep Apnea Cardiovascular Endpoints (SAVE) study showed a lower stroke risk in those adherent to CPAP compared with the control group (HR=0.56, 95% CI: 0.30-0.90).⁶⁵

 

 

SLEEP APNEA, CORONARY ARTERY DISEASE, AND CARIOVASCULAR MORTALITY

The association between sleep apnea and coronary artery disease and cardiovascular mortality was considered in a Spanish study of 1,500 patients followed for 10 years, which reported that CPAP therapy reduced cardiac events in patients with OSA.⁶⁶ Patients with sleep apnea had an increased risk of fatal myocardial infarction or stroke. Survival of patients treated for sleep apnea approached that of patients without OSA.

In a study of a racially diverse cohort, an association of physician diagnosed sleep apnea with cardiovascular events and survival was identified.⁶⁷ Diagnosed sleep apnea was estimated to confer a two- to threefold increase in various cardiovascular outcomes and all-cause mortality.

Punjabi NM, et al. Sleep-disordered breathing and mortality: a prospective cohort study. PLoS Med 2009; 6(8):e1000132.

All-cause mortality data from the Sleep Heart Health Study of more than 6,000 participants showed that progressive worsening of OSA as defined by the apnea–hypopnea index resulted in poorer survival even after accounting for confounding factors (Figure 3).⁶⁸ Decreased survival appeared to mostly affect men or patients under age 70.

The diurnal pattern of cardiovascular physiology as it relates to sleep is thought to be cardioprotective because of reductions in blood pressure and heart rate. However, in the case of OSA, there appears to be a nocturnal vulnerability or predilection for sudden cardiac death. Patients with OSA were shown to have a higher risk of sudden nocturnal cardiac death occurring from midnight to 6 am compared with individuals without OSA and the general population (Table 1).⁶⁹

The effect of treatment for sleep apnea on cardiovascular outcomes was the focus of a recent randomized controlled trial of nearly 3,000 participants with a mean follow-up of 4 years.65 Use of CPAP compared with usual care found no difference in cardiovascular outcomes. However, secondary analysis revealed a possible benefit of a lower risk of stroke with use of CPAP therapy. Several factors should be considered in interpreting these findings: ie, low adherence with CPAP therapy (3 hours), whether the study was sufficiently powered to detect a change in cardiovascular outcomes, and if the duration of follow-up was adequate. In terms of patient demographics and study generalizability, the study did not include patients with severe sleep apnea and hypoxia, and most participants were men, of Asian descent, with a mean body mass index of 28 kg/m2, and low levels of sleepiness at baseline.

SLEEP AND CARDIOVASCULAR PHYSIOLOGY

Wakefullness and sleep, the latter comprised of non-rapid eye movement (NREM) sleep and rapid eye movement (REM) sleep, comprise our primary states of being. Sleep states oscillate between NREM and REM sleep. The first and shortest period of REM sleep typically occurs 90 to 120 minutes into the sleep cycle. Most REM sleep, including the longest period of REM sleep, occurs during the latter part of the sleep cycle.

With these sleep state changes, physiologic changes also occur, such as reduced heart rate and blood pressure because of enhanced parasympathetic tone. During REM sleep, there are also intermittent sympathetic nervous system surges. Other physiologic changes include a regular respiratory rate during NREM sleep and an irregular respiratory rate during REM sleep. Body temperature is normal during NREM sleep and poikilothermic (ie, tends to flucuate) during REM sleep. Blood pressure is reduced 10% to 15% during sleep¹ and then rises, so that the highest blood pressure occurs in the morning. Data from 10 million users of activity-monitoring devices show that the heart rate changes during sleep.² The heart rate is decreased in those who get less than 7 hours of sleep, then increases with longer sleep duration in a U-shaped distribution.

Cardiovascular events are more likely to occur at certain times of day. Myocardial infarction is more likely in the morning, with a threefold increased risk within the first 3 hours of awakening that peaks around 9 AM.^3,4 Similar diurnal patterns have been observed with other cardiovascular conditions such as sudden cardiac death and ischemic episodes, with the highest risk during morning hours (6 to 9 AM).⁴

The reason for this morning predisposition for cardio­vascular events is unclear, but it is thought that perhaps the autonomic fluctuations that occur during REM sleep and the predominance of REM sleep in early morning may be a factor. Diurnal changes in blood pressure and cortisol levels may also contribute, as well as levels of systemic inflammatory and thrombotic markers such as plasminogen activator inhibitor 1.

Arrhythmias are also more likely to occur in a diurnal pattern. Atrial fibrillation (AF), particularly paroxysmal AF, is believed to be vagally mediated in 10% to 25% of patients.⁵ Therefore, for those who are predisposed, sleep may represent a period of increased risk for AF. In a study of individuals 60 years and older, the maximum duration and peak frequency of AF occurred from midnight to 2 AM.⁵

Recent studies have found that REM-related obstructive sleep apnea (OSA) is associated with increased cardiovascular risk. Experimental models show that REM sleep may increase the risk for compromised coronary blood flow.⁶ Increased heart rate corresponds to reduced coronary blood flow and thus, to decreased coronary perfusion time and less time for relaxation of the heart, increasing the risk for coronary artery disease, thrombosis, and ischemia.

SLEEP APNEA PATHOPHYSIOLOGY

The normal physiology of the sleep-heart inter­action is disrupted by sleep apnea. OSA is defined as episodes of complete or partial airway obstruction that occur during sleep with thoraco­abdominal effort. Central sleep apnea (CSA) is the cessation of breathing with no thoracoabdominal effort. The pathophysiology of the sleep-heart interaction varies for OSA and CSA.

Obstructive sleep apnea

OSA is a nocturnal physiologic stressor that is highly prevalent and underrecognized. It affects approximately 17% of the adult population, and the prevalence is increasing with the obesity epidemic. Nearly 1 in 15 individuals is estimated to be affected by at least moderate OSA.^7,8 OSA is underdiagnosed particularly in minority populations.⁹ Data from the 2015 Multi-Ethnic Study of Atherosclerosis (MESA) showed undiagnosed moderate to severe sleep apnea in 84% to 93% of individuals,⁹ similar to an estimated 85% of undiagnosed cases in 2002.¹⁰

OSA is highly prevalent in individuals with underlying coronary disease^11–13 and in those with cardiovascular risk factors such as diabetes, hypertension, and heart failure. The prevalence of OSA in patients with cardiovascular disease ranges from 30% (hypertension) to 60% (stroke or transient ischemic attack, arrhythmia, end-stage renal disease).¹⁴

 

 

Pathophysiology of OSA

The pathophysiology of OSA can be observed during polysomnography, characterized by autonomic nervous system disturbances, intermittent hypoxia, and intrathoracic pressure alterations, (Figure 1). Intermittent bouts of hypoxia or oxygen-lowering occur because airflow is obstructed despite persistent thoracic and abdominal effort. Systemic inflammation and oxidative stress occur due to these intrathoracic pressure alterations, increased CO₂ and reduced oxygen levels, and autonomic nervous system disturbances.

The alterations in sympathetic activation that occur during sleep in patients with OSA persist during wakefulness. Microneurographic recording of sympathetic nerve activity in the peroneal nerve reveal that the rate of sympathetic bursts doubles and the amplitude is greater in individuals with OSA compared with a control group.¹⁵

Sympathetic nerve activity, blood pressure, and heart rate were shown to increase during REM sleep in individuals with OSA on continuous positive airway pressure (CPAP) during an induced apneic event (pressure reduction from 8 cm to 6 cm of water).¹⁵

During OSA episodes, there is an increased cardiac load. Impaired diastolic function and atrial and aortic enlargement, and in particular, the thin-walled atria are very susceptible to the intra­thoracic pressure swings caused by OSA. Physiologic changes with OSA from pressure changes in the chest result in shift of the intraventricular septum, causing a reduction in cardiac output.¹⁶ With the lowering of oxygen during episodes of apnea, constriction of the pulmonary vasculature leads to elevation of pressure in the pulmonary vasculature reflected by the increase in mean pulmonary arterial pressures.¹⁷

Other studies have shown that OSA increases upregulation of markers of systemic inflammation and prothrombotic markers, the very markers that can increase cardiovascular or atherogenic risk.^18–22 One example is the soluble interleukin 6 receptor, shown to be elevated in the morning relative to sleep apnea compared with the evening.²⁰ Other biomarkers observed to be associated with sleep apnea include markers of prothrombotic potentials such as plasminogen activator inhibitor 1.¹⁹ Oxidative stress occurs because intermittent bouts of lower oxygen can lead to oxidation of serum proteins and lipids. Endothelial dysfunction has been observed as well as insulin resistance and dyslipidemia.²³ Taken together, these are pathways that lead to atherogenesis and increased cardiovascular risk.

Central sleep apnea

CSA episodes are the cessation of breathing without thoracoabdominal effort, in contrast to the persistence of thoracoabdominal effort in OSA. CSA is characterized by breathing instability with highly sensitive chemoresponses and prolonged circulation time.²⁴ This can be physiologic in some cases, as when it occurs after a very large breath or sigh and then a central apnea event occurs after the sigh. The alterations in oxygen and CO₂ and the stretch of the receptors in the alveoli of the lungs initiate the Hering-Breuer inhalation reflex.

Pathophysiology of CSA

Complex pathways of medullary and aortic receptor chemosensitivity are at the root of the pathophysiology of CSA.²⁴ With CSA there is often a relative state of hypocapnia at baseline. During sleep, there is reduction in drive, thus chemo­sensitivity can be activated so that central apnea episodes can ensue as a result of alterations in CO₂ (ie, hypocapnia). Another factor that can contribute to the pathophysiology of CSA is arousal from sleep that can reduce CO₂ levels and therefore perpetuate central events.

The concept of loop gain is used to understand the pathophysiology of CSA. Loop gain is a measure of the relative stability of a ventilation system and indicates the likelihood of an individual to have periodic breathing. It is calculated by the response to a disturbance divided by the disturbance itself.²⁵ With a high loop gain, there is a more pronounced or exuberant response to the disturbance, indicating more instability in the system and increasing the tendency for irregular breathing and CSA episodes.

Hunter-Cheyne-Stokes respiration occurs with CSA and is characterized by cyclical crescendo-decrescendo respiratory effort that occurs during wakefulness and sleep without upper-airway obstruction.^26,27 Unlike OSA, which is worse during REM sleep, Hunter-Cheyne-Stokes breathing in CSA is typically worse in NREM sleep, during N1 and N2 in particular.

 

 

SLEEP APNEA AND HEART FAILURE

Both OSA and CSA are prevalent in patients with heart failure and may be associated with the progression of heart failure. CSA often occurs in patients with heart failure. The pathophysiology is multi­factorial, including pulmonary congestion that results in stretch of the J receptors in the alveoli, prolonged circulation time, and increased chemosensitivity.

Complex pathways in the neuroaxis or somnogenic biomarkers of inflammation or both may be implicated in the paradoxical lack of subjective sleepiness in the presence of increased objective measures of sleepiness in systolic heart failure. One study found a relationship with one biomarker of inflammation and oxidative stress as it relates to objective symptoms of sleepiness but not subjective symptoms of sleepiness.²⁸

Another contributing factor in the relationship between OSA and CSA in heart failure has also been described related to rostral shifts in fluid to the neck and to the pulmonary receptors in the alveoli of the lungs.²⁹ These rostral shifts in fluids may contribute to sleep apnea with parapharyngeal edema leading to OSA and pulmonary congestion leading to CSA.

Sleep apnea is associated with increased post-discharge mortality and hospitalization readmissions in the setting of acute heart failure.³⁰ Mortality analysis of 1,096 patients admitted for decompensated heart failure found CSA and OSA were independently associated with mortality in patients compared with patients with no or minimal sleep-disordered breathing.³⁰

CSA has also been shown to be a predictor of readmission in patients admitted for heart failure exacerbations.³¹ Targeting underlying CSA may reduce readmissions in those admitted with acute decompensated heart failure. While men were identified to be at increased risk of death relative to sleep-disordered breathing based on the initial results of the Sleep Heart Health Study, a subsequent epidemiologic substudy reflective of an older age group showed that OSA was more strongly associated with left ventricular mass index, risk of heart failure, or death in women compared with men.³²

Treatment

Standard therapy for treatment of OSA is CPAP. Adaptive servo-ventilation (ASV) and transvenous phrenic nerve stimulation are also available as treatment options in certain cases of CSA.

One of the first randomized controlled trials designed to assess the impact of CSA treatment on survival in patients with heart failure initially favored the control group then later the CPAP group and was terminated early based on stopping rules.^33,34 While adherence to therapy was suboptimal at an average of 3.6 hours, post hoc analysis showed that patients with CSA using CPAP with effective suppression of CSA had improved survival compared with patients who did not have effective suppression using CPAP.³⁴

ASV is mainly used for treatment of CSA. In ASV, positive airway pressure for ventilation support is provided and adjusts as apneic episodes are detected during sleep. The support provided adapts to the physiology of the patient and can deliver breaths and utilize anticyclic modes of ventilation to address crescendo-decrescendo breathing patterns observed in Hunter-Cheyne-Stokes respiration.

In the Treatment of Sleep-Disordered Breathing With Predominant Central Sleep Apnea by Adaptive Servo Ventilation in Patients With Heart Failure (SERVE-HF) trial, 1,300 patients with systolic heart failure and predominantly CSA were randomized to receive ASV vs solely standard medical management.³⁵ The primary composite end point included all-cause mortality or unplanned admission or hospitalization for heart failure. No difference was found in the primary end point between the ASV and the control group; however, there was an unanticipated negative impact of ASV on cardiovascular outcomes in some secondary end points. Based on the secondary outcome of cardiovascular-specific mortality, clinicians were advised that ASV was contraindicated for the treatment of CSA in patients with symptomatic heart failure with a left ventricular ejection fraction less than 45%. The interpretation of this study was complicated by several methodologic limitations.³⁶

The Cardiovascular Improvements With Minute Ventilation-Targeted Adaptive Servo-Ventilation Therapy in Heart Failure (CAT-HF) randomized controlled trial also evaluated ASV compared with standard medical management in 126 patients with heart failure.³⁷ This trial was terminated early because of the results of the SERVE-HF trial. Compliance with therapy was suboptimal at an average of 2.7 hours per day. The composite end point did not differ between the 2 groups; however, this was likely because the study was underpowered and was terminated early. Subgroup analysis revealed that patients with heart failure with preserved ejection fraction may benefit from ASV; however, additional studies are needed to confirm these findings.

Therefore, although ASV is not indicated when there is predominantly CSA in patients with systolic heart failure, preliminary results support potential benefit in patients with OSA and preserved ejection fraction.

Another novel treatment for CSA is transvenous phrenic nerve stimulation. A device is implanted that stimulates the phrenic nerve to initiate breaths. The initial study of trans­venous phrenic nerve stimulation reported a significant reduction in the number of episodes of central apnea per hour of sleep.^38,39 The apnea–hypopnea index improved overall and some types of obstructive apneic events were reduced with transvenous phrenic nerve stimulation.

A multicenter randomized control trial of trans­venous phrenic nerve stimulation found improvement in several sleep apnea indices, including central apnea, hypoxia, reduced arousals from sleep, and patient reported well-being.⁴⁰ Transvenous phrenic nerve stimulation holds promise as a novel therapy for central predominant sleep apnea not only in terms of improving the degree of central apnea and sleep-disordered breathing, but also in improving functional outcomes. Longitudinal and intereventional trial data are needed to clarify the impact of transvenous phrenic nerve stimulation on long-term cardiac outcomes.

SLEEP APNEA AND ATRIAL FIBRILLATION AND STROKE

Atrial fibrillation

AF is the most common sustained cardiac arrhythmia. The number of Americans with AF is projected to increase from 2.3 million to more than 10 million by the year 2050.⁴¹ The increasing incidence and prevalence of AF is not fully explained by the aging population and established risk factors.⁴² Unrecognized sleep apnea, estimated to exist in 85% or more of the population, may partially account for the increasing incidence of AF.⁴³

There are 3 types of AF, which are thought to follow a continuum: paroxysmal AF is characterized by episodes that occur intermittently; persistent AF is characterized by episodes that last longer than 7 days; chronic or permanent AF is typically characterized by AF that is ongoing over many years.⁴⁴ As with sleep apnea, AF is often asymptomatic and is likely underdiagnosed.

Sleep apnea and AF share several risk factors. Obesity is a risk factor for both OSA and AF; however, a meta-analysis supported a stronger association of OSA and AF vs obesity and AF.⁴⁵ Increasing age is a risk factor for both OSA and AF.^46,47 Although white populations are at higher risk for AF, OSA is associated with a 58% increased risk of AF in African Americans.⁴⁸ Nocturnal hypoxia has been associated with increased risk of AF in Asians.⁴⁹

In terms of pathophysiology of sleep apnea and cardiac arrhythmia, OSA increases inflammation, intrathoracic pressures, and CO₂ levels. The increase in inflammation and oxidative stress is thought to alter the cardiac electrophysiology of the heart and contribute to structural remodeling of the heart that increases the risk of cardiac arrhythmia (Figure 2).⁵⁰

Experimental data continue to accrue providing biologic plausibility of the relationship between sleep apnea and AF. OSA contributes to structural and electrical remodeling of the heart with evidence supporting increased fibrosis and electrical remodeling in patients with OSA compared with a control group.⁵¹ Markers of structural remodeling, such as atrial size, electrical silence, and atrial voltage conduction velocity, are altered in OSA.⁵⁰

Data from the Sleep Heart Health Study show very strong associations between atrial and ventricular cardiac arrhythmias and sleep apnea with two- to fivefold higher odds of arrhythmias in patients with severe OSA compared with controls even after accounting for confounding factors such as obesity.⁵²

A multicenter, epidemiological study of older men showed that increasing severity of sleep apnea corresponds with an increased prevalence of AF and ventricular ectopy.⁵³ This graded dose-response relationship suggests a causal relationship between sleep apnea and AF and ventricular ectopy. There also appears to be an immediate influence of apneic events and hypopneic events as it relates to arrhythmia. A case-crossover study showed an associated 18-fold increased risk of nocturnal arrhythmia within 90 seconds of an apneic or hypopneic event.⁵⁴ This association was found with paroxysms of AF and with episodes of nonsustained ventricular tachycardia.

Data from a clinic-based cohort study show an association between AF and OSA.⁵⁵ Specifically, increased severity of sleep apnea was associated with an increased prevalence of AF. Increasing degree of hypoxia or oxygen-lowering was also associated with increased incidence of AF or newly identified AF identified over time.

Longitudinal examination of 2 epidemiologic studies, the Sleep Heart Health Study and Outcomes of Sleep Disorders Study in Older Men, found CSA to be predictive of AF with a two- to threefold higher odds of developing incident AF as it related to baseline CSA.⁵⁶ According to these data, CSA may pose a greater risk for development of AF than OSA.

With respect to AF after cardiac surgery, patients with sleep apnea and obesity appear to be at higher risk for developing AF as measured by the apnea–hypopnea index and oxygen desaturation index.⁵⁷

Treatment of sleep apnea may improve arrhythmic burden. Case-based studies have shown reduced burden and resolution of baseline arrhythmia with CPAP treatment for OSA as therapeutic pressure was achieved.⁵⁸ Another case-based study involved an individual with snoring and OSA and AF at baseline.⁵⁹ Several retrospective studies have shown that treatment of OSA after ablation and after cardio­version results in reduced recurrence of AF; however, large definitive clinical trials are lacking.

Stroke

Sleep apnea is a risk factor for stroke due to intermittent hypoxia-mediated elevation of oxidative stress and systemic inflammation, hypercoaguability, and impairment of cerebral autoregulation.⁶⁰ However, the relationship may be bidirectional in that stroke may be a risk factor for sleep apnea in the post-stroke period. The prevalence of sleep apnea post-stroke has been reported to be up to 70%. CSA can occur in up to 26% during the post-stroke phase.⁶¹ Data are inconsistent in terms of the location and size of stroke and the risk of sleep apnea, though cerebrovascular neuronal damage to the brainstem and cortical areas are evident.⁶² In one study, the incidence of stroke appeared to increase with the severity of sleep apnea.⁶³ These findings were more pronounced in men than in women; however, this study may not have captured the increased cardiovascular risk in postmenopausal women. The Outcomes of Sleep Disorders in Older Men study found that severe hypoxia increased the incidence of stroke, and that hypoxia may be a predictor of newly diagnosed stroke in older men.⁶⁴ Although definitive clinical trials are underway, post-hoc propensity-score matched analysis from the Sleep Apnea Cardiovascular Endpoints (SAVE) study showed a lower stroke risk in those adherent to CPAP compared with the control group (HR=0.56, 95% CI: 0.30-0.90).⁶⁵

 

 

SLEEP APNEA, CORONARY ARTERY DISEASE, AND CARIOVASCULAR MORTALITY

The association between sleep apnea and coronary artery disease and cardiovascular mortality was considered in a Spanish study of 1,500 patients followed for 10 years, which reported that CPAP therapy reduced cardiac events in patients with OSA.⁶⁶ Patients with sleep apnea had an increased risk of fatal myocardial infarction or stroke. Survival of patients treated for sleep apnea approached that of patients without OSA.

In a study of a racially diverse cohort, an association of physician diagnosed sleep apnea with cardiovascular events and survival was identified.⁶⁷ Diagnosed sleep apnea was estimated to confer a two- to threefold increase in various cardiovascular outcomes and all-cause mortality.

Punjabi NM, et al. Sleep-disordered breathing and mortality: a prospective cohort study. PLoS Med 2009; 6(8):e1000132.

All-cause mortality data from the Sleep Heart Health Study of more than 6,000 participants showed that progressive worsening of OSA as defined by the apnea–hypopnea index resulted in poorer survival even after accounting for confounding factors (Figure 3).⁶⁸ Decreased survival appeared to mostly affect men or patients under age 70.

The diurnal pattern of cardiovascular physiology as it relates to sleep is thought to be cardioprotective because of reductions in blood pressure and heart rate. However, in the case of OSA, there appears to be a nocturnal vulnerability or predilection for sudden cardiac death. Patients with OSA were shown to have a higher risk of sudden nocturnal cardiac death occurring from midnight to 6 am compared with individuals without OSA and the general population (Table 1).⁶⁹

The effect of treatment for sleep apnea on cardiovascular outcomes was the focus of a recent randomized controlled trial of nearly 3,000 participants with a mean follow-up of 4 years.65 Use of CPAP compared with usual care found no difference in cardiovascular outcomes. However, secondary analysis revealed a possible benefit of a lower risk of stroke with use of CPAP therapy. Several factors should be considered in interpreting these findings: ie, low adherence with CPAP therapy (3 hours), whether the study was sufficiently powered to detect a change in cardiovascular outcomes, and if the duration of follow-up was adequate. In terms of patient demographics and study generalizability, the study did not include patients with severe sleep apnea and hypoxia, and most participants were men, of Asian descent, with a mean body mass index of 28 kg/m2, and low levels of sleepiness at baseline.

Obstructive sleep apnea (OSA) is a serious condition that impacts quality of life and causes drowsy driving and depression. Research also reveals an interrelationship between OSA and metabolic disease and an association between OSA and cognitive impairment.

The diagnostic criteria of OSA are based on the number of apneic or hypopneic episodes per hour of sleep, called the apnea–hypopnea index (AHI) as recorded during sleep testing. Diagnosis of OSA is warranted if the AHI is 15 or more per hour or if the AHI is 5 or more per hour with 1 or more of the following features: sleepiness; nonrestorative sleep; fatigue or insomnia; waking up with breath-holding spells, gasping, or choking; snoring or breathing interruptions; or a coexisting diagnosis of hypertension, mood disorder, cognitive dysfunction, coronary artery disease, stroke, congestive heart failure, atrial fibrillation, or type II diabetes.¹

Many patients with an AHI less than 15 may also have OSA, given the number of coexisting medical conditions included in the OSA diagnostic criteria. Heart conditions such as coronary artery disease, atrial fibrillation, and congestive heart failure encompassed in the OSA diagnostic criteria have increased awareness of the link between OSA and heart health. Less well-known, and the subject of this review, are the negative consequences of OSA, particularly poor quality of life, drowsy driving, depression, metabolic disease, and cognitive impairment.

QUALITY OF LIFE

Reduced quality of life is the most fundamental patient-reported outcome of OSA. OSA is associated with excessive daytime sleepiness, inattention, and fatigue, which increase the risk of accidents and medical disability. These quality-of-life impairments are often the main reason patients seek medical care for sleep disorders.² Improved quality of life is a central goal of OSA treatment and is the best indicator of the effectiveness of treatment.³ Sleep health and its effect on quality of life is an area of focus of Healthy People 2020 (healthypeople.gov).

The American Academy of Sleep Medicine identified quality of life, along with detection of disease and cardiovascular consequences, as an outcome measure for assessing the quality of care for adults with OSA.² The assessment of quality of life for patients with OSA is a 4-part process: use evidence-based therapy, monitor the therapy, assess symptoms with a validated tool such as Epworth Sleepiness Scale, and assess the incidence of motor vehicle accidents. Information from these 4 processes can inform changes in a patient’s quality of life.

Treatment for OSA has been shown to improve quality of life. A study of 2,027 patients with OSA evaluated therapy adherence relative to mean Functional Outcomes of Sleep Questionnaire and European Quality of Life-5D scores.⁴ In patients with the most impaired quality of life, those adherent to positive airway pressure (PAP) therapy had improved quality of life as measured by these scores.

With respect to sleepiness, a systematic review of continuous PAP (CPAP) in patients with OSA found a 2.7-point reduction (mean difference; 95% confidence interval 3.45–1.96) in the Epworth Sleepiness Scale in patients using CPAP compared with the control group.⁵ Treatment of OSA improves patient quality of life and symptoms such as sleepiness.

DROWSY DRIVING

Drowsy driving by people with OSA can lead to motor vehicle accidents, which result in economic and health burdens.^6,7 National Center for Statistics and Analysis data reveal that of 6 million motor vehicle accidents (5-year average, 2005–2009), 1.4% involve drowsy driving and 2.5% of fatal crashes involve drowsy driving.⁸ Among noncommercial drivers, untreated OSA increases the risk of motor vehicle accidents 3- to 13-fold.⁹ The odds ratio of traffic accidents in drivers with untreated OSA is 6 times greater than in the general population.⁷

In a study of men and women in the general population (N = 913), individuals with moderate to severe OSA (AHI > 15) were more likely to have multiple motor vehicle accidents in the course of 5 years (odds ratio = 7.3) compared with those with no sleep-disordered breathing.¹⁰ The association between OSA and motor vehicle accidents is independent of sleepiness, and drivers with OSA may not perceive performance impairment.

There are 2 main reasons OSA increases the risk and incidence of motor vehicle accidents. OSA causes changes in attention and vigilance resulting from sleep deprivation and fragmentation. OSA also affects global cognition function, which may be due to intermittent hypoxia attributable to OSA.²

Treatment for OSA is effective in reducing the incidence of motor vehicle accidents. One study found the risk of motor vehicle accidents was eliminated with the use of CPAP treatment in patients with OSA.¹¹ A recent study of nearly 2,000 patients with OSA found a reduction in self-reported near-accidents from 14% before PAP therapy to 5.3% after starting PAP therapy.¹²

 

 

DEPRESSION

Depression can occur as a consequence of OSA. Depression and OSA have several symptoms in common (Table 1).¹³

Estimates of the prevalence of depression in patients with OSA range from 5% to 63%.^13,14 One year after patients were diagnosed with OSA, the incidence of depression per 1,000 person-years was 18% compared with 8% in a group without OSA.¹⁴ Women with OSA reportedly have a higher risk of depression (adjusted hazard ratio [HR] 2.7) than men (HR 1.81) at 1-year follow-up.¹⁴ In the same study, with respect to age, there was no significant relationship noted between OSA and patients over age 64.

A one-level increase in the severity of OSA (ie, from minimal to mild) is associated with a nearly twofold increase in the adjusted odds for depression.¹⁵ On the other hand, studies have also found that patients on antidepressants may have an increased risk of OSA.¹⁶

Several potential mechanisms have been proposed to explain the link between depression and OSA.¹³ Poor-quality sleep, frequent arousal, and fragmentation of sleep in OSA may lead to frontal lobe emotional modulation changes. Intermittent hypoxia in OSA may result in neuronal injury and disruption of noradrenergic and dopaminergic pathways. Pro-inflammatory substances such as interleukin 6 and interleukin 1 are increased in OSA and depression and are mediators between both conditions. Neurotransmitters may be affected by a disrupted sleep-wake cycle. And serotonin, which may be impeded in depression, could influence the upper-airway dilator motor neurons.

Treatment of OSA improves symptoms of depression as measured by the Patient Health Questionnaire (PHQ-9). After 3 months of compliance with CPAP therapy, mean PHQ-9 scores decreased from 11.3 to 2.7 in a study of 228 patients with OSA.¹⁷ A study of 1,981 patients with sleep-disordered breathing found improved PHQ-9 scores in patients compliant with CPAP therapy and a greater improvement in patients with a baseline PHQ-9 higher than 10 (moderate severity).¹⁸

METABOLIC SYNDROME

OSA is associated with metabolic disorders, including metabolic syndrome, though the causality between these 2 conditions is yet to be illuminated. Metabolic syndrome is a term used when an individual has 3 or more of the following features or conditions:

• Waist circumference greater than 40 inches (men), greater than 35 inches (women)
• Triglycerides 150 mg/dL or greater or treatment for hypertriglyceridemia
• High-density lipoprotein cholesterol less than 40 mg/dL (men), less than 50 mg/dL (women), or treatment for cholesterol
• Blood pressure 130/85 mm Hg or greater, or treatment for hypertension
• Fasting blood glucose 100 mg/dL or greater, or treatment for hyperglycemia.¹⁹

Metabolic syndrome increases an individual’s risk of diabetes and cardiovascular disease and overall mortality. Like OSA, the prevalence of metabolic syndrome increases with age in both men and women.^20,21 The risk of metabolic syndrome is greater with more severe OSA. The Wisconsin Sleep Cohort (N = 546) reported an odds ratio for having metabolic syndrome of 2.5 for patients with mild OSA and 2.2 for patients with moderate or severe OSA.²² A meta-analysis also found a 2.4 times higher odds of metabolic syndrome in patients with mild OSA, but a 3.5 times higher odds of metabolic syndrome in patients with moderate to severe OSA compared with the control group.²³

Patients with both OSA and metabolic syndrome are said to have syndrome Z²⁴ and are at increased risk of cardiovascular morbidity and mortality.²⁵ Syndrome Z imparts a higher risk of atherogenic burden and prevalence of atheroma compared with patients with either condition alone.²⁶ In comparing patients with metabolic syndrome with and without OSA, those with OSA had increased atherosclerotic burden as measured by intima-media thickness and carotid femoral pulse-wave velocity.²⁷ Syndrome Z is also linked to intracoronary stenosis related to changes in cardiac morphology²⁸ and is associated with left ventricular hypertrophy and diastolic dysfunction.²⁹

OSA and hypertension

Hypertension is one of the conditions encompassed in metabolic syndrome. Several studies report increased risk and incidence of hypertension in patients with OSA. In a community-based study of 6,123 individuals age 40 and older, sleep-disordered breathing was associated with hypertension, and the odds ratio of hypertension was greater in individuals with more severe sleep apnea.³⁰ Similarly, a landmark prospective, population-based study of 709 individuals over 4 years reported a dose-response relationship between patients with OSA and newly diagnosed hypertension independent of confounding factors.³¹ Patients with moderate to severe OSA had an odds ratio of 2.89 of developing hypertension after adjusting for confounding variables.

A study of 1,889 individuals followed for 12 years found a dose-response relationship based on OSA severity for developing hypertension.³² This study also assessed the incidence of hypertension based on CPAP use. Patients with poor adherence to CPAP use had an 80% increased incidence of hypertension, whereas patients adhering to CPAP use had a 30% decrease in the incidence of hypertension.

Resistant hypertension (ie, uncontrolled hypertension despite use of 3 or more antihypertensive and diuretic medications) has been shown to be highly prevalent (85%) in patients with severe OSA.³³ An analysis of patients at increased risk of cardiovascular disease and untreated severe OSA was associated with a 4 times higher risk of elevated blood pressure despite intensive medical therapy.³⁴

 

 

Mechanisms of altered metabolic regulation in OSA

Mechanisms implicated in altering metabolic regulation in OSA include intermittent hypoxia, sleep fragmentation and glucose homeostasis, and obesity. Intermittent hypoxia from OSA results in sympathetic nervous system activation that affects the pancreas, skeletal muscle, liver, and fat cells resulting in altered insulin secretion, lipid-bile synthesis, glucose metabolism, and lipoprotein metabolism.³⁵

Sleep fragmentation is a cardinal feature of OSA and the resulting suppression of sleep may alter insulin sensitivity. Studies have implicated disruptions to slow-wave sleep specifically, as well as disruption of any stage of sleep in reduced insulin sensitivity.^35,36 In addition to decreased insulin sensitivity, sleep fragmentation also increases morning cortisol levels and increases sympathetic nervous system activation.³⁷

Obesity and OSA share a pathway imparting increased cardiometabolic risk.³⁸ Fat tissue causes higher systemic inflammation and inflammatory markers. A recent report describes a bidirectional relationship between metabolic syndrome and OSA.³⁹ While OSA increases the risk for metabolic syndrome, metabolic syndrome by virtue of body mass index with changes in mechanical load and narrow airway and physiology can predispose for OSA.

Effect of treatment for OSA on metabolic syndrome

Several studies have evaluated the effect of CPAP treatment for OSA on metabolic syndrome overall, as well as the specific conditions that comprise metabolic syndrome. In evaluating CPAP use and metabolic syndrome overall, studies have found a reduced prevalence of metabolic syndrome,^40,41 CPAP benefit only in complying patients,⁴² and a reduction in oxidative stress with a single-night use of CPAP.⁴³

With respect to insulin sensitivity, a study of 40 men with moderate OSA using CPAP therapy (mean use 5 hours) reported an increase in the insulin sensitivity index after 2 days, and a further increase after 3 months.⁴⁴ Another study found no improvement in insulin resistance in severe OSA.⁴⁵ A meta-analysis reported improved insulin resistance with CPAP,⁴⁶ although a recent meta-analysis assessing hemoglobin A_1c level, fasting insulin level, and fasting glucose did not show improvement in these parameters. Large-scale clinical trials with longer treatment duration and better CPAP compliance are warranted.⁴⁷

CPAP use in patients with OSA has been found to affect hypertension in a number of studies (Table 2).^48–55 In a comparison of therapeutic CPAP with suboptimal CPAP for 9 weeks, ambulatory blood pressure was reduced in the therapeutic group, and no change was seen in the subtherapeutic group, illustrating the importance of optimal pressure settings in treating OSA.⁴⁸

A randomized controlled trial of nearly 300 individuals found improvement in 6 blood pressure parameters in a group using CPAP compared with a group using sham CPAP after 12 weeks.⁵⁰ A large clinic-based cohort of 894 individuals with hypertension and resistant hypertension (15%) found that after 1 year, CPAP use was associated with 2 to 3 mm Hg of reduction in blood pressure (Figure 1).⁵⁶ Meta-analysis of randomized controlled trials on the effectiveness of CPAP on hypertension found reductions of 2 mm Hg to 3 mm Hg in blood pressure.⁵⁷ Another meta-analyses showed a reduction of 2.6 mm Hg in 24-hour mean blood pressure with CPAP therapy (Table 2).^48–55 This reduction may appear modest in nature; however, any reduction in blood pressure can result in decreased cardiovascular morbidity and mortality. A meta-analysis of randomized controlled trials indicated reductions in mean systolic blood pressure of 5.4 mm Hg and diastolic blood pressure of 3.86 mm Hg after CPAP in those with resistant hypertension and OSA.⁵⁸

Weight loss has been shown to reduce the AHI and other parameters related to sleep apnea such as oxygen desaturation index in patients with obesity and diabetes.⁵⁹ Weight loss combined with CPAP compared with CPAP or weight loss alone showed an incremental benefit in improving glucose parameters, triglycerides, and possibly systolic blood pressure and triglycerides.⁶⁰

 

 

COGNITIVE IMPAIRMENT

Data suggest that OSA is linked with cognitive impairment, may advance cognitive decline, and is a bidirectional relationship. Women with OSA were reportedly more likely to develop mild cognitive impairment compared with women without OSA.⁶¹ An elevated oxygen desaturation index and a high percentage of time spent with hypoxia was associated with increased risk of developing mild cognitive impairment and dementia.

OSA was found to be an independent risk factor for cerebral white matter changes in middle-age and older individuals. Moderate to severe OSA imparted a 2 times higher risk of cerebral white matter changes compared with individuals without OSA.⁶² Another study of 20 patients with severe OSA compared with 40 healthy volunteers found diffusion imaging consistent with impaired fibrin integrity in those with OSA, indicative of white matter microstructure damage, and the impairment was associated with increased disease severity and higher systemic inflammation.⁶³

Individuals with hypoxia for a high percentage of time during sleep had a 4 times higher odds of cerebral microinfarcts.⁶⁴ Cognitive scores decreased less in men. Men typically have more time in slow-wave sleep, suggesting that slow-wave sleep may be protective against cognitive decline. Mild cognitive impairment and Alzheimer disease were found more likely to develop and occur at an earlier age in individuals with sleep-disordered breathing compared with individuals without sleep-disordered breathing.⁶⁵

OSA was also associated with increased serum amyloid beta levels in a study of 45 cognitively normal patients with OSA compared with 49 age- and sex-matched control patients. Increased amyloid beta levels correlated with increasing severity of sleep apnea as measured by the AHI.⁶⁶

Mechanism linking OSA and cognition

One possible mechanism linking sleep quality and cognitive impairment or Alzheimer disease is the role of unfragmented sleep in attenuating the apolipo­protein E e4 allele on the incidence of Alzheimer disease.⁶⁷ Beta amyloid is released during synaptic activity. Neuronal and synaptic activity decreases during sleep, and disrupted sleep could increase beta amyloid release.⁶⁸ Sleep has been found to enhance the clearance of beta amyloid peptide from the brain interstitial fluid in a mice model.⁶⁹

Recent data point toward the bidirectional relationship between the sleep and Alzheimer disease in that excessive and prolonged neuronal activity in the absence of appropriately structured sleep may be the reason for both Alzheimer disease and OSA.^70,71

Effect of treatment for OSA on cognition

White matter integrity in 15 patients with OSA before and after treatment with CPAP was compared with 15 matched controls. Over 12 months, there was a nearly complete reversal of white matter abnormalities in patients on CPAP therapy.⁷² Improvement in memory, attention, and executive function paralleled the changes in white matter after the treatment.

CONCLUSION

OSA is a serious condition with far-reaching consequences associated with impaired quality of life, depressive symptoms, drowsy driving, metabolic disease, and cognitive decline. Treatment of OSA improves many of these health consequences, emphasizing the need for OSA screening. Large randomized studies are needed to assess the efficacy of CPAP on metabolic outcomes, including insulin sensitivity and glucose tolerance, in reducing disease burden. Study of the endophenotypes of patients with OSA is needed to define and target the mechanisms of OSA-induced adverse health outcomes and perhaps lead to personalized care for patients with OSA.

Obstructive sleep apnea (OSA) is a serious condition that impacts quality of life and causes drowsy driving and depression. Research also reveals an interrelationship between OSA and metabolic disease and an association between OSA and cognitive impairment.

The diagnostic criteria of OSA are based on the number of apneic or hypopneic episodes per hour of sleep, called the apnea–hypopnea index (AHI) as recorded during sleep testing. Diagnosis of OSA is warranted if the AHI is 15 or more per hour or if the AHI is 5 or more per hour with 1 or more of the following features: sleepiness; nonrestorative sleep; fatigue or insomnia; waking up with breath-holding spells, gasping, or choking; snoring or breathing interruptions; or a coexisting diagnosis of hypertension, mood disorder, cognitive dysfunction, coronary artery disease, stroke, congestive heart failure, atrial fibrillation, or type II diabetes.¹

Many patients with an AHI less than 15 may also have OSA, given the number of coexisting medical conditions included in the OSA diagnostic criteria. Heart conditions such as coronary artery disease, atrial fibrillation, and congestive heart failure encompassed in the OSA diagnostic criteria have increased awareness of the link between OSA and heart health. Less well-known, and the subject of this review, are the negative consequences of OSA, particularly poor quality of life, drowsy driving, depression, metabolic disease, and cognitive impairment.

QUALITY OF LIFE

Reduced quality of life is the most fundamental patient-reported outcome of OSA. OSA is associated with excessive daytime sleepiness, inattention, and fatigue, which increase the risk of accidents and medical disability. These quality-of-life impairments are often the main reason patients seek medical care for sleep disorders.² Improved quality of life is a central goal of OSA treatment and is the best indicator of the effectiveness of treatment.³ Sleep health and its effect on quality of life is an area of focus of Healthy People 2020 (healthypeople.gov).

The American Academy of Sleep Medicine identified quality of life, along with detection of disease and cardiovascular consequences, as an outcome measure for assessing the quality of care for adults with OSA.² The assessment of quality of life for patients with OSA is a 4-part process: use evidence-based therapy, monitor the therapy, assess symptoms with a validated tool such as Epworth Sleepiness Scale, and assess the incidence of motor vehicle accidents. Information from these 4 processes can inform changes in a patient’s quality of life.

Treatment for OSA has been shown to improve quality of life. A study of 2,027 patients with OSA evaluated therapy adherence relative to mean Functional Outcomes of Sleep Questionnaire and European Quality of Life-5D scores.⁴ In patients with the most impaired quality of life, those adherent to positive airway pressure (PAP) therapy had improved quality of life as measured by these scores.

With respect to sleepiness, a systematic review of continuous PAP (CPAP) in patients with OSA found a 2.7-point reduction (mean difference; 95% confidence interval 3.45–1.96) in the Epworth Sleepiness Scale in patients using CPAP compared with the control group.⁵ Treatment of OSA improves patient quality of life and symptoms such as sleepiness.

DROWSY DRIVING

Drowsy driving by people with OSA can lead to motor vehicle accidents, which result in economic and health burdens.^6,7 National Center for Statistics and Analysis data reveal that of 6 million motor vehicle accidents (5-year average, 2005–2009), 1.4% involve drowsy driving and 2.5% of fatal crashes involve drowsy driving.⁸ Among noncommercial drivers, untreated OSA increases the risk of motor vehicle accidents 3- to 13-fold.⁹ The odds ratio of traffic accidents in drivers with untreated OSA is 6 times greater than in the general population.⁷

In a study of men and women in the general population (N = 913), individuals with moderate to severe OSA (AHI > 15) were more likely to have multiple motor vehicle accidents in the course of 5 years (odds ratio = 7.3) compared with those with no sleep-disordered breathing.¹⁰ The association between OSA and motor vehicle accidents is independent of sleepiness, and drivers with OSA may not perceive performance impairment.

There are 2 main reasons OSA increases the risk and incidence of motor vehicle accidents. OSA causes changes in attention and vigilance resulting from sleep deprivation and fragmentation. OSA also affects global cognition function, which may be due to intermittent hypoxia attributable to OSA.²

Treatment for OSA is effective in reducing the incidence of motor vehicle accidents. One study found the risk of motor vehicle accidents was eliminated with the use of CPAP treatment in patients with OSA.¹¹ A recent study of nearly 2,000 patients with OSA found a reduction in self-reported near-accidents from 14% before PAP therapy to 5.3% after starting PAP therapy.¹²

 

 

DEPRESSION

Depression can occur as a consequence of OSA. Depression and OSA have several symptoms in common (Table 1).¹³

Estimates of the prevalence of depression in patients with OSA range from 5% to 63%.^13,14 One year after patients were diagnosed with OSA, the incidence of depression per 1,000 person-years was 18% compared with 8% in a group without OSA.¹⁴ Women with OSA reportedly have a higher risk of depression (adjusted hazard ratio [HR] 2.7) than men (HR 1.81) at 1-year follow-up.¹⁴ In the same study, with respect to age, there was no significant relationship noted between OSA and patients over age 64.

A one-level increase in the severity of OSA (ie, from minimal to mild) is associated with a nearly twofold increase in the adjusted odds for depression.¹⁵ On the other hand, studies have also found that patients on antidepressants may have an increased risk of OSA.¹⁶

Several potential mechanisms have been proposed to explain the link between depression and OSA.¹³ Poor-quality sleep, frequent arousal, and fragmentation of sleep in OSA may lead to frontal lobe emotional modulation changes. Intermittent hypoxia in OSA may result in neuronal injury and disruption of noradrenergic and dopaminergic pathways. Pro-inflammatory substances such as interleukin 6 and interleukin 1 are increased in OSA and depression and are mediators between both conditions. Neurotransmitters may be affected by a disrupted sleep-wake cycle. And serotonin, which may be impeded in depression, could influence the upper-airway dilator motor neurons.

Treatment of OSA improves symptoms of depression as measured by the Patient Health Questionnaire (PHQ-9). After 3 months of compliance with CPAP therapy, mean PHQ-9 scores decreased from 11.3 to 2.7 in a study of 228 patients with OSA.¹⁷ A study of 1,981 patients with sleep-disordered breathing found improved PHQ-9 scores in patients compliant with CPAP therapy and a greater improvement in patients with a baseline PHQ-9 higher than 10 (moderate severity).¹⁸

METABOLIC SYNDROME

OSA is associated with metabolic disorders, including metabolic syndrome, though the causality between these 2 conditions is yet to be illuminated. Metabolic syndrome is a term used when an individual has 3 or more of the following features or conditions:

• Waist circumference greater than 40 inches (men), greater than 35 inches (women)
• Triglycerides 150 mg/dL or greater or treatment for hypertriglyceridemia
• High-density lipoprotein cholesterol less than 40 mg/dL (men), less than 50 mg/dL (women), or treatment for cholesterol
• Blood pressure 130/85 mm Hg or greater, or treatment for hypertension
• Fasting blood glucose 100 mg/dL or greater, or treatment for hyperglycemia.¹⁹

Metabolic syndrome increases an individual’s risk of diabetes and cardiovascular disease and overall mortality. Like OSA, the prevalence of metabolic syndrome increases with age in both men and women.^20,21 The risk of metabolic syndrome is greater with more severe OSA. The Wisconsin Sleep Cohort (N = 546) reported an odds ratio for having metabolic syndrome of 2.5 for patients with mild OSA and 2.2 for patients with moderate or severe OSA.²² A meta-analysis also found a 2.4 times higher odds of metabolic syndrome in patients with mild OSA, but a 3.5 times higher odds of metabolic syndrome in patients with moderate to severe OSA compared with the control group.²³

Patients with both OSA and metabolic syndrome are said to have syndrome Z²⁴ and are at increased risk of cardiovascular morbidity and mortality.²⁵ Syndrome Z imparts a higher risk of atherogenic burden and prevalence of atheroma compared with patients with either condition alone.²⁶ In comparing patients with metabolic syndrome with and without OSA, those with OSA had increased atherosclerotic burden as measured by intima-media thickness and carotid femoral pulse-wave velocity.²⁷ Syndrome Z is also linked to intracoronary stenosis related to changes in cardiac morphology²⁸ and is associated with left ventricular hypertrophy and diastolic dysfunction.²⁹

OSA and hypertension

Hypertension is one of the conditions encompassed in metabolic syndrome. Several studies report increased risk and incidence of hypertension in patients with OSA. In a community-based study of 6,123 individuals age 40 and older, sleep-disordered breathing was associated with hypertension, and the odds ratio of hypertension was greater in individuals with more severe sleep apnea.³⁰ Similarly, a landmark prospective, population-based study of 709 individuals over 4 years reported a dose-response relationship between patients with OSA and newly diagnosed hypertension independent of confounding factors.³¹ Patients with moderate to severe OSA had an odds ratio of 2.89 of developing hypertension after adjusting for confounding variables.

A study of 1,889 individuals followed for 12 years found a dose-response relationship based on OSA severity for developing hypertension.³² This study also assessed the incidence of hypertension based on CPAP use. Patients with poor adherence to CPAP use had an 80% increased incidence of hypertension, whereas patients adhering to CPAP use had a 30% decrease in the incidence of hypertension.

Resistant hypertension (ie, uncontrolled hypertension despite use of 3 or more antihypertensive and diuretic medications) has been shown to be highly prevalent (85%) in patients with severe OSA.³³ An analysis of patients at increased risk of cardiovascular disease and untreated severe OSA was associated with a 4 times higher risk of elevated blood pressure despite intensive medical therapy.³⁴

 

 

Mechanisms of altered metabolic regulation in OSA

Mechanisms implicated in altering metabolic regulation in OSA include intermittent hypoxia, sleep fragmentation and glucose homeostasis, and obesity. Intermittent hypoxia from OSA results in sympathetic nervous system activation that affects the pancreas, skeletal muscle, liver, and fat cells resulting in altered insulin secretion, lipid-bile synthesis, glucose metabolism, and lipoprotein metabolism.³⁵

Sleep fragmentation is a cardinal feature of OSA and the resulting suppression of sleep may alter insulin sensitivity. Studies have implicated disruptions to slow-wave sleep specifically, as well as disruption of any stage of sleep in reduced insulin sensitivity.^35,36 In addition to decreased insulin sensitivity, sleep fragmentation also increases morning cortisol levels and increases sympathetic nervous system activation.³⁷

Obesity and OSA share a pathway imparting increased cardiometabolic risk.³⁸ Fat tissue causes higher systemic inflammation and inflammatory markers. A recent report describes a bidirectional relationship between metabolic syndrome and OSA.³⁹ While OSA increases the risk for metabolic syndrome, metabolic syndrome by virtue of body mass index with changes in mechanical load and narrow airway and physiology can predispose for OSA.

Effect of treatment for OSA on metabolic syndrome

Several studies have evaluated the effect of CPAP treatment for OSA on metabolic syndrome overall, as well as the specific conditions that comprise metabolic syndrome. In evaluating CPAP use and metabolic syndrome overall, studies have found a reduced prevalence of metabolic syndrome,^40,41 CPAP benefit only in complying patients,⁴² and a reduction in oxidative stress with a single-night use of CPAP.⁴³

With respect to insulin sensitivity, a study of 40 men with moderate OSA using CPAP therapy (mean use 5 hours) reported an increase in the insulin sensitivity index after 2 days, and a further increase after 3 months.⁴⁴ Another study found no improvement in insulin resistance in severe OSA.⁴⁵ A meta-analysis reported improved insulin resistance with CPAP,⁴⁶ although a recent meta-analysis assessing hemoglobin A_1c level, fasting insulin level, and fasting glucose did not show improvement in these parameters. Large-scale clinical trials with longer treatment duration and better CPAP compliance are warranted.⁴⁷

CPAP use in patients with OSA has been found to affect hypertension in a number of studies (Table 2).^48–55 In a comparison of therapeutic CPAP with suboptimal CPAP for 9 weeks, ambulatory blood pressure was reduced in the therapeutic group, and no change was seen in the subtherapeutic group, illustrating the importance of optimal pressure settings in treating OSA.⁴⁸

A randomized controlled trial of nearly 300 individuals found improvement in 6 blood pressure parameters in a group using CPAP compared with a group using sham CPAP after 12 weeks.⁵⁰ A large clinic-based cohort of 894 individuals with hypertension and resistant hypertension (15%) found that after 1 year, CPAP use was associated with 2 to 3 mm Hg of reduction in blood pressure (Figure 1).⁵⁶ Meta-analysis of randomized controlled trials on the effectiveness of CPAP on hypertension found reductions of 2 mm Hg to 3 mm Hg in blood pressure.⁵⁷ Another meta-analyses showed a reduction of 2.6 mm Hg in 24-hour mean blood pressure with CPAP therapy (Table 2).^48–55 This reduction may appear modest in nature; however, any reduction in blood pressure can result in decreased cardiovascular morbidity and mortality. A meta-analysis of randomized controlled trials indicated reductions in mean systolic blood pressure of 5.4 mm Hg and diastolic blood pressure of 3.86 mm Hg after CPAP in those with resistant hypertension and OSA.⁵⁸

Weight loss has been shown to reduce the AHI and other parameters related to sleep apnea such as oxygen desaturation index in patients with obesity and diabetes.⁵⁹ Weight loss combined with CPAP compared with CPAP or weight loss alone showed an incremental benefit in improving glucose parameters, triglycerides, and possibly systolic blood pressure and triglycerides.⁶⁰

 

 

COGNITIVE IMPAIRMENT

Data suggest that OSA is linked with cognitive impairment, may advance cognitive decline, and is a bidirectional relationship. Women with OSA were reportedly more likely to develop mild cognitive impairment compared with women without OSA.⁶¹ An elevated oxygen desaturation index and a high percentage of time spent with hypoxia was associated with increased risk of developing mild cognitive impairment and dementia.

OSA was found to be an independent risk factor for cerebral white matter changes in middle-age and older individuals. Moderate to severe OSA imparted a 2 times higher risk of cerebral white matter changes compared with individuals without OSA.⁶² Another study of 20 patients with severe OSA compared with 40 healthy volunteers found diffusion imaging consistent with impaired fibrin integrity in those with OSA, indicative of white matter microstructure damage, and the impairment was associated with increased disease severity and higher systemic inflammation.⁶³

Individuals with hypoxia for a high percentage of time during sleep had a 4 times higher odds of cerebral microinfarcts.⁶⁴ Cognitive scores decreased less in men. Men typically have more time in slow-wave sleep, suggesting that slow-wave sleep may be protective against cognitive decline. Mild cognitive impairment and Alzheimer disease were found more likely to develop and occur at an earlier age in individuals with sleep-disordered breathing compared with individuals without sleep-disordered breathing.⁶⁵

OSA was also associated with increased serum amyloid beta levels in a study of 45 cognitively normal patients with OSA compared with 49 age- and sex-matched control patients. Increased amyloid beta levels correlated with increasing severity of sleep apnea as measured by the AHI.⁶⁶

Mechanism linking OSA and cognition

One possible mechanism linking sleep quality and cognitive impairment or Alzheimer disease is the role of unfragmented sleep in attenuating the apolipo­protein E e4 allele on the incidence of Alzheimer disease.⁶⁷ Beta amyloid is released during synaptic activity. Neuronal and synaptic activity decreases during sleep, and disrupted sleep could increase beta amyloid release.⁶⁸ Sleep has been found to enhance the clearance of beta amyloid peptide from the brain interstitial fluid in a mice model.⁶⁹

Recent data point toward the bidirectional relationship between the sleep and Alzheimer disease in that excessive and prolonged neuronal activity in the absence of appropriately structured sleep may be the reason for both Alzheimer disease and OSA.^70,71

Effect of treatment for OSA on cognition

White matter integrity in 15 patients with OSA before and after treatment with CPAP was compared with 15 matched controls. Over 12 months, there was a nearly complete reversal of white matter abnormalities in patients on CPAP therapy.⁷² Improvement in memory, attention, and executive function paralleled the changes in white matter after the treatment.

CONCLUSION

OSA is a serious condition with far-reaching consequences associated with impaired quality of life, depressive symptoms, drowsy driving, metabolic disease, and cognitive decline. Treatment of OSA improves many of these health consequences, emphasizing the need for OSA screening. Large randomized studies are needed to assess the efficacy of CPAP on metabolic outcomes, including insulin sensitivity and glucose tolerance, in reducing disease burden. Study of the endophenotypes of patients with OSA is needed to define and target the mechanisms of OSA-induced adverse health outcomes and perhaps lead to personalized care for patients with OSA.

Obstructive sleep apnea (OSA) is a serious condition that impacts quality of life and causes drowsy driving and depression. Research also reveals an interrelationship between OSA and metabolic disease and an association between OSA and cognitive impairment.

The diagnostic criteria of OSA are based on the number of apneic or hypopneic episodes per hour of sleep, called the apnea–hypopnea index (AHI) as recorded during sleep testing. Diagnosis of OSA is warranted if the AHI is 15 or more per hour or if the AHI is 5 or more per hour with 1 or more of the following features: sleepiness; nonrestorative sleep; fatigue or insomnia; waking up with breath-holding spells, gasping, or choking; snoring or breathing interruptions; or a coexisting diagnosis of hypertension, mood disorder, cognitive dysfunction, coronary artery disease, stroke, congestive heart failure, atrial fibrillation, or type II diabetes.¹

Many patients with an AHI less than 15 may also have OSA, given the number of coexisting medical conditions included in the OSA diagnostic criteria. Heart conditions such as coronary artery disease, atrial fibrillation, and congestive heart failure encompassed in the OSA diagnostic criteria have increased awareness of the link between OSA and heart health. Less well-known, and the subject of this review, are the negative consequences of OSA, particularly poor quality of life, drowsy driving, depression, metabolic disease, and cognitive impairment.

QUALITY OF LIFE

Reduced quality of life is the most fundamental patient-reported outcome of OSA. OSA is associated with excessive daytime sleepiness, inattention, and fatigue, which increase the risk of accidents and medical disability. These quality-of-life impairments are often the main reason patients seek medical care for sleep disorders.² Improved quality of life is a central goal of OSA treatment and is the best indicator of the effectiveness of treatment.³ Sleep health and its effect on quality of life is an area of focus of Healthy People 2020 (healthypeople.gov).

The American Academy of Sleep Medicine identified quality of life, along with detection of disease and cardiovascular consequences, as an outcome measure for assessing the quality of care for adults with OSA.² The assessment of quality of life for patients with OSA is a 4-part process: use evidence-based therapy, monitor the therapy, assess symptoms with a validated tool such as Epworth Sleepiness Scale, and assess the incidence of motor vehicle accidents. Information from these 4 processes can inform changes in a patient’s quality of life.

Treatment for OSA has been shown to improve quality of life. A study of 2,027 patients with OSA evaluated therapy adherence relative to mean Functional Outcomes of Sleep Questionnaire and European Quality of Life-5D scores.⁴ In patients with the most impaired quality of life, those adherent to positive airway pressure (PAP) therapy had improved quality of life as measured by these scores.

With respect to sleepiness, a systematic review of continuous PAP (CPAP) in patients with OSA found a 2.7-point reduction (mean difference; 95% confidence interval 3.45–1.96) in the Epworth Sleepiness Scale in patients using CPAP compared with the control group.⁵ Treatment of OSA improves patient quality of life and symptoms such as sleepiness.

DROWSY DRIVING

Drowsy driving by people with OSA can lead to motor vehicle accidents, which result in economic and health burdens.^6,7 National Center for Statistics and Analysis data reveal that of 6 million motor vehicle accidents (5-year average, 2005–2009), 1.4% involve drowsy driving and 2.5% of fatal crashes involve drowsy driving.⁸ Among noncommercial drivers, untreated OSA increases the risk of motor vehicle accidents 3- to 13-fold.⁹ The odds ratio of traffic accidents in drivers with untreated OSA is 6 times greater than in the general population.⁷

In a study of men and women in the general population (N = 913), individuals with moderate to severe OSA (AHI > 15) were more likely to have multiple motor vehicle accidents in the course of 5 years (odds ratio = 7.3) compared with those with no sleep-disordered breathing.¹⁰ The association between OSA and motor vehicle accidents is independent of sleepiness, and drivers with OSA may not perceive performance impairment.

There are 2 main reasons OSA increases the risk and incidence of motor vehicle accidents. OSA causes changes in attention and vigilance resulting from sleep deprivation and fragmentation. OSA also affects global cognition function, which may be due to intermittent hypoxia attributable to OSA.²

Treatment for OSA is effective in reducing the incidence of motor vehicle accidents. One study found the risk of motor vehicle accidents was eliminated with the use of CPAP treatment in patients with OSA.¹¹ A recent study of nearly 2,000 patients with OSA found a reduction in self-reported near-accidents from 14% before PAP therapy to 5.3% after starting PAP therapy.¹²

 

 

DEPRESSION

Depression can occur as a consequence of OSA. Depression and OSA have several symptoms in common (Table 1).¹³

Estimates of the prevalence of depression in patients with OSA range from 5% to 63%.^13,14 One year after patients were diagnosed with OSA, the incidence of depression per 1,000 person-years was 18% compared with 8% in a group without OSA.¹⁴ Women with OSA reportedly have a higher risk of depression (adjusted hazard ratio [HR] 2.7) than men (HR 1.81) at 1-year follow-up.¹⁴ In the same study, with respect to age, there was no significant relationship noted between OSA and patients over age 64.

A one-level increase in the severity of OSA (ie, from minimal to mild) is associated with a nearly twofold increase in the adjusted odds for depression.¹⁵ On the other hand, studies have also found that patients on antidepressants may have an increased risk of OSA.¹⁶

Several potential mechanisms have been proposed to explain the link between depression and OSA.¹³ Poor-quality sleep, frequent arousal, and fragmentation of sleep in OSA may lead to frontal lobe emotional modulation changes. Intermittent hypoxia in OSA may result in neuronal injury and disruption of noradrenergic and dopaminergic pathways. Pro-inflammatory substances such as interleukin 6 and interleukin 1 are increased in OSA and depression and are mediators between both conditions. Neurotransmitters may be affected by a disrupted sleep-wake cycle. And serotonin, which may be impeded in depression, could influence the upper-airway dilator motor neurons.

Treatment of OSA improves symptoms of depression as measured by the Patient Health Questionnaire (PHQ-9). After 3 months of compliance with CPAP therapy, mean PHQ-9 scores decreased from 11.3 to 2.7 in a study of 228 patients with OSA.¹⁷ A study of 1,981 patients with sleep-disordered breathing found improved PHQ-9 scores in patients compliant with CPAP therapy and a greater improvement in patients with a baseline PHQ-9 higher than 10 (moderate severity).¹⁸

METABOLIC SYNDROME

OSA is associated with metabolic disorders, including metabolic syndrome, though the causality between these 2 conditions is yet to be illuminated. Metabolic syndrome is a term used when an individual has 3 or more of the following features or conditions:

• Waist circumference greater than 40 inches (men), greater than 35 inches (women)
• Triglycerides 150 mg/dL or greater or treatment for hypertriglyceridemia
• High-density lipoprotein cholesterol less than 40 mg/dL (men), less than 50 mg/dL (women), or treatment for cholesterol
• Blood pressure 130/85 mm Hg or greater, or treatment for hypertension
• Fasting blood glucose 100 mg/dL or greater, or treatment for hyperglycemia.¹⁹

Metabolic syndrome increases an individual’s risk of diabetes and cardiovascular disease and overall mortality. Like OSA, the prevalence of metabolic syndrome increases with age in both men and women.^20,21 The risk of metabolic syndrome is greater with more severe OSA. The Wisconsin Sleep Cohort (N = 546) reported an odds ratio for having metabolic syndrome of 2.5 for patients with mild OSA and 2.2 for patients with moderate or severe OSA.²² A meta-analysis also found a 2.4 times higher odds of metabolic syndrome in patients with mild OSA, but a 3.5 times higher odds of metabolic syndrome in patients with moderate to severe OSA compared with the control group.²³

Patients with both OSA and metabolic syndrome are said to have syndrome Z²⁴ and are at increased risk of cardiovascular morbidity and mortality.²⁵ Syndrome Z imparts a higher risk of atherogenic burden and prevalence of atheroma compared with patients with either condition alone.²⁶ In comparing patients with metabolic syndrome with and without OSA, those with OSA had increased atherosclerotic burden as measured by intima-media thickness and carotid femoral pulse-wave velocity.²⁷ Syndrome Z is also linked to intracoronary stenosis related to changes in cardiac morphology²⁸ and is associated with left ventricular hypertrophy and diastolic dysfunction.²⁹

OSA and hypertension

Hypertension is one of the conditions encompassed in metabolic syndrome. Several studies report increased risk and incidence of hypertension in patients with OSA. In a community-based study of 6,123 individuals age 40 and older, sleep-disordered breathing was associated with hypertension, and the odds ratio of hypertension was greater in individuals with more severe sleep apnea.³⁰ Similarly, a landmark prospective, population-based study of 709 individuals over 4 years reported a dose-response relationship between patients with OSA and newly diagnosed hypertension independent of confounding factors.³¹ Patients with moderate to severe OSA had an odds ratio of 2.89 of developing hypertension after adjusting for confounding variables.

A study of 1,889 individuals followed for 12 years found a dose-response relationship based on OSA severity for developing hypertension.³² This study also assessed the incidence of hypertension based on CPAP use. Patients with poor adherence to CPAP use had an 80% increased incidence of hypertension, whereas patients adhering to CPAP use had a 30% decrease in the incidence of hypertension.

Resistant hypertension (ie, uncontrolled hypertension despite use of 3 or more antihypertensive and diuretic medications) has been shown to be highly prevalent (85%) in patients with severe OSA.³³ An analysis of patients at increased risk of cardiovascular disease and untreated severe OSA was associated with a 4 times higher risk of elevated blood pressure despite intensive medical therapy.³⁴

 

 

Mechanisms of altered metabolic regulation in OSA

Mechanisms implicated in altering metabolic regulation in OSA include intermittent hypoxia, sleep fragmentation and glucose homeostasis, and obesity. Intermittent hypoxia from OSA results in sympathetic nervous system activation that affects the pancreas, skeletal muscle, liver, and fat cells resulting in altered insulin secretion, lipid-bile synthesis, glucose metabolism, and lipoprotein metabolism.³⁵

Sleep fragmentation is a cardinal feature of OSA and the resulting suppression of sleep may alter insulin sensitivity. Studies have implicated disruptions to slow-wave sleep specifically, as well as disruption of any stage of sleep in reduced insulin sensitivity.^35,36 In addition to decreased insulin sensitivity, sleep fragmentation also increases morning cortisol levels and increases sympathetic nervous system activation.³⁷

Obesity and OSA share a pathway imparting increased cardiometabolic risk.³⁸ Fat tissue causes higher systemic inflammation and inflammatory markers. A recent report describes a bidirectional relationship between metabolic syndrome and OSA.³⁹ While OSA increases the risk for metabolic syndrome, metabolic syndrome by virtue of body mass index with changes in mechanical load and narrow airway and physiology can predispose for OSA.

Effect of treatment for OSA on metabolic syndrome

Several studies have evaluated the effect of CPAP treatment for OSA on metabolic syndrome overall, as well as the specific conditions that comprise metabolic syndrome. In evaluating CPAP use and metabolic syndrome overall, studies have found a reduced prevalence of metabolic syndrome,^40,41 CPAP benefit only in complying patients,⁴² and a reduction in oxidative stress with a single-night use of CPAP.⁴³

With respect to insulin sensitivity, a study of 40 men with moderate OSA using CPAP therapy (mean use 5 hours) reported an increase in the insulin sensitivity index after 2 days, and a further increase after 3 months.⁴⁴ Another study found no improvement in insulin resistance in severe OSA.⁴⁵ A meta-analysis reported improved insulin resistance with CPAP,⁴⁶ although a recent meta-analysis assessing hemoglobin A_1c level, fasting insulin level, and fasting glucose did not show improvement in these parameters. Large-scale clinical trials with longer treatment duration and better CPAP compliance are warranted.⁴⁷

CPAP use in patients with OSA has been found to affect hypertension in a number of studies (Table 2).^48–55 In a comparison of therapeutic CPAP with suboptimal CPAP for 9 weeks, ambulatory blood pressure was reduced in the therapeutic group, and no change was seen in the subtherapeutic group, illustrating the importance of optimal pressure settings in treating OSA.⁴⁸

A randomized controlled trial of nearly 300 individuals found improvement in 6 blood pressure parameters in a group using CPAP compared with a group using sham CPAP after 12 weeks.⁵⁰ A large clinic-based cohort of 894 individuals with hypertension and resistant hypertension (15%) found that after 1 year, CPAP use was associated with 2 to 3 mm Hg of reduction in blood pressure (Figure 1).⁵⁶ Meta-analysis of randomized controlled trials on the effectiveness of CPAP on hypertension found reductions of 2 mm Hg to 3 mm Hg in blood pressure.⁵⁷ Another meta-analyses showed a reduction of 2.6 mm Hg in 24-hour mean blood pressure with CPAP therapy (Table 2).^48–55 This reduction may appear modest in nature; however, any reduction in blood pressure can result in decreased cardiovascular morbidity and mortality. A meta-analysis of randomized controlled trials indicated reductions in mean systolic blood pressure of 5.4 mm Hg and diastolic blood pressure of 3.86 mm Hg after CPAP in those with resistant hypertension and OSA.⁵⁸

Weight loss has been shown to reduce the AHI and other parameters related to sleep apnea such as oxygen desaturation index in patients with obesity and diabetes.⁵⁹ Weight loss combined with CPAP compared with CPAP or weight loss alone showed an incremental benefit in improving glucose parameters, triglycerides, and possibly systolic blood pressure and triglycerides.⁶⁰

 

 

COGNITIVE IMPAIRMENT

Data suggest that OSA is linked with cognitive impairment, may advance cognitive decline, and is a bidirectional relationship. Women with OSA were reportedly more likely to develop mild cognitive impairment compared with women without OSA.⁶¹ An elevated oxygen desaturation index and a high percentage of time spent with hypoxia was associated with increased risk of developing mild cognitive impairment and dementia.

OSA was found to be an independent risk factor for cerebral white matter changes in middle-age and older individuals. Moderate to severe OSA imparted a 2 times higher risk of cerebral white matter changes compared with individuals without OSA.⁶² Another study of 20 patients with severe OSA compared with 40 healthy volunteers found diffusion imaging consistent with impaired fibrin integrity in those with OSA, indicative of white matter microstructure damage, and the impairment was associated with increased disease severity and higher systemic inflammation.⁶³

Individuals with hypoxia for a high percentage of time during sleep had a 4 times higher odds of cerebral microinfarcts.⁶⁴ Cognitive scores decreased less in men. Men typically have more time in slow-wave sleep, suggesting that slow-wave sleep may be protective against cognitive decline. Mild cognitive impairment and Alzheimer disease were found more likely to develop and occur at an earlier age in individuals with sleep-disordered breathing compared with individuals without sleep-disordered breathing.⁶⁵

OSA was also associated with increased serum amyloid beta levels in a study of 45 cognitively normal patients with OSA compared with 49 age- and sex-matched control patients. Increased amyloid beta levels correlated with increasing severity of sleep apnea as measured by the AHI.⁶⁶

Mechanism linking OSA and cognition

One possible mechanism linking sleep quality and cognitive impairment or Alzheimer disease is the role of unfragmented sleep in attenuating the apolipo­protein E e4 allele on the incidence of Alzheimer disease.⁶⁷ Beta amyloid is released during synaptic activity. Neuronal and synaptic activity decreases during sleep, and disrupted sleep could increase beta amyloid release.⁶⁸ Sleep has been found to enhance the clearance of beta amyloid peptide from the brain interstitial fluid in a mice model.⁶⁹

Recent data point toward the bidirectional relationship between the sleep and Alzheimer disease in that excessive and prolonged neuronal activity in the absence of appropriately structured sleep may be the reason for both Alzheimer disease and OSA.^70,71

Effect of treatment for OSA on cognition

White matter integrity in 15 patients with OSA before and after treatment with CPAP was compared with 15 matched controls. Over 12 months, there was a nearly complete reversal of white matter abnormalities in patients on CPAP therapy.⁷² Improvement in memory, attention, and executive function paralleled the changes in white matter after the treatment.

CONCLUSION

OSA is a serious condition with far-reaching consequences associated with impaired quality of life, depressive symptoms, drowsy driving, metabolic disease, and cognitive decline. Treatment of OSA improves many of these health consequences, emphasizing the need for OSA screening. Large randomized studies are needed to assess the efficacy of CPAP on metabolic outcomes, including insulin sensitivity and glucose tolerance, in reducing disease burden. Study of the endophenotypes of patients with OSA is needed to define and target the mechanisms of OSA-induced adverse health outcomes and perhaps lead to personalized care for patients with OSA.

Positive airway pressure (PAP) therapy is used to open an obstructed upper airway (Figure 1). PAP therapy consists of a small bedside unit that creates a pressurized column of air that is delivered through tubing to a facial interface, which can be nasal, oral, or both. Collin Sullivan, MD, created the nasal continuous PAP (CPAP) in 1982 using parts of a vacuum cleaner to create positive pressure that successfully resolved hypoxemia in a patient.¹ Today, the various forms of PAP therapy include CPAP, the most common, auto-PAP (APAP), and bilevel PAP (BiPAP).

EFFICACY OF PAP THERAPY

The American Academy of Sleep Medicine practice guidelines for PAP are based on 342 articles, most rated as evidence levels I and II, concluding that CPAP is superior to conservative treatment to:

• Eliminate respiratory disturbances
• Reduce the apnea–hypopnea index
• Decrease the arousal index on electroencephalogram
• Increase in the total amount of slow-wave or N3 sleep
• Reduce daytime sleepiness.²

These practice parameters are based on evidence of improved daytime sleepiness and reduced incidence of cardiovascular events in patients with moderate to severe obstructive sleep apnea (OSA) treated with PAP. The evidence is less clear for neurocognitive markers and cardiovascular events in the treatment of patients with mild sleep apnea.

Sleepiness

A study evaluated sleepiness outcomes in 149 patients with severe sleep apnea with an average apnea–hypopnea index of 69 relative to the duration of nightly CPAP use. Sleepiness was measured using the Functional Outcomes of Sleep Questionnaire, Epworth Sleepiness Scale, and Multiple Sleep Latency Test. Results suggest that a greater percentage of patients had improved daytime sleepiness as the total hours of sleep using CPAP increased.³

The Apnea Positive Pressure Long-term Efficacy Study (APPLES) was a 6-month, multicenter, randomized study of neurocognitive function in patients with OSA (N = 1,098).⁴ Subjective sleepiness as measured by the Epworth Sleepiness Scale showed statistically significant improvement at 2 and 6 months for patients with moderate to severe OSA using CPAP. Objective sleepiness as measured by the Maintenance of Wakefulness Test showed statistically significant improvement (ie, improved daytime alertness) at 2 and 6 months for patients with severe OSA using CPAP.

Neurocognitive function

APPLES also tested for attention and psycho­motor function as well as verbal learning and memory, though no statistically significant improvements were found in these parameters.⁴ Executive function and frontal lobe function showed transient improvement at 2 months in patients with severe sleep apnea using CPAP, but the improvement was not statistically significant at 6 months.

Cardiovascular outcomes

Hypertension and cardiovascular disease. Use of CPAP therapy reduces blood pressure in individuals with hypertension. A study of 32 patients who had a baseline polysomnography with 19 hours of continuous mean arterial blood pressure monitoring were treated with therapeutic CPAP (n = 16) or subtherapeutic CPAP (n = 16).⁵ Therapeutic treatment with CPAP for patients with moderate to severe OSA resulted in statistically significant reductions in mean arterial pressure for both systolic and diastolic pressures. The blood pressure reductions achieved are estimated to reduce coronary artery diseases by 37% and stroke by 56%.⁵

The risk of cardiovascular events in men with severe sleep apnea is high but mitigated by the use of CPAP. In a cohort of 1,651 men, untreated severe sleep apnea resulted in a threefold increase in the rate of cardiovascular events per 1,000 patient-years compared with 4 other groups: a control group, men who snore, men with untreated mild to moderate sleep apnea, and men with OSA using CPAP.⁶ However, when men with severe sleep apnea use CPAP, the risk of cardiovascular events is reduced to the rate in men who snore.

Atrial fibrillation. In patients with atrial fibrillation treated with direct-current cardioversion-
defibrillation, the recurrence of atrial fibrillation at 12 months was greater in patients with untreated OSA (82%) compared with a control group (53%) and patients treated for OSA (42%).⁷

Heart failure. In a study of 24 patients with heart failure, an ejection fraction less than 45%, and OSA, patients were randomized to a control group for medical treatment or medical treatment and nasal CPAP for 1 month.⁸ In the CPAP group, mean systolic blood pressure and heart rate were reduced, resulting in an improved ejection fraction compared with baseline, as well as compared with patients in the control group.

In patients with heart failure (N = 66) with and without Cheyne-Stokes respirations in central sleep apnea, patients treated with CPAP were found to have a 60% relative risk reduction in mortality-cardiac transplant rate compared with the control group not using CPAP.⁹ Further stratification in this study showed that patients with significant Cheyne-Stokes respirations and central sleep apnea had an improved ejection fraction at 3 months and an 81% reduced mortality-cardiac transplant rate.⁹

 

 

ADHERENCE

Adherence to PAP therapy is a problem in terms of both frequency of use and duration of use per night. A review of randomized control trials of CPAP compliance between 2011 and 2015 found adherence varied widely from 35% to 87%.¹⁰ The average hours of PAP use per night was found to be 5 hours in APPLES.⁴ Patients adherent to PAP therapy at 1 month remained adherent at 1 year, suggesting patients using CPAP for 1 month were more likely to continue use at 1 year.¹⁰ Impediments to PAP use typically involve the facial interface discomfort, lack of humidity, and pressure intolerance.

FEATURES OF PAP DEVICES

Today’s PAP devices have features designed to make them easier to use and more comfortable to improve adherence to therapy. Facial interface options, heated humidifiers, tubing accessories, cleaning devices, reporting of compliance data via telecommunication, and pressure adjustment features of PAP devices may improve patient adherence and comfort, as highlighted in the case scenarios presented below.

Interfaces

Case scenario #1

A 32-year-old woman with moderate sleep apnea complains that her PAP nasal mask is making very loud noises and is disturbing her bed partner. She is a side sleeper and also reports that she wakes with an extremely dry mouth.

Management of the leak could include which of the following?

1. Chin strap
2. Avoidance of facial creams before bedtime
3. CPAP pillow
4. Clean the mask daily
5. All of the above

Answer: All of the above.

Figure 2 shows an overview of data from the patient’s machine for the past month and 1 night of leak data. Both the month-use data and single-night leak data show mask leakage.

There are many types of PAP interfaces such as nasal masks, nasal pillows, nasal cushions, full-face masks, and less frequently used oral and total face masks. The mask interface is a common impediment to use of PAP therapy often due to poor mask fit or leakage.

Nasal masks cover only the nose and require that the mouth remains closed, which can be achieved with the addition of a chin strap. Nasal masks are available in a variety of materials including cloth. Nasal pillows actually go into the nostrils whereas the nasal mask is positioned under the nose. A nasal cushion mask sits under the nose but does not go into the nostrils.

A study by Lanza and colleagues¹¹ evaluated patient comfort with PAP therapy based on the type of nasal interface mask. Patients using nasal pillows had improvement with respect to swollen eyes, discomfort, skin breakdown, and marks on the face compared with patients using nasal masks; however, nasal pillows can cause nostril pain.

Several types of full-face masks are available, some that fit over the bridge of the nose and some that fit just under the nose. A variety of head straps are available to secure full-face masks. One benefit of full-face masks is that air pressure is delivered to both the nose and the mouth, so the mouth can be open or closed. However, the larger surface area of the full-face mask increases the potential for leaks. A study of adherence in 20 patients using CPAP with nasal masks or full-face masks evaluated hours per use, adherence at 12 months, and comfort.¹² Patients using full-face masks had more hours per use, better adherence at 12 months, and more comfort than patients using nasal masks.

Interface skin irritation and leak management. To help combat skin irritation, particularly for patients with rosacea, cloth products are available for use beneath the mask and headgear. Silicone pads for masks that cause pressure on the bridge of the nose can help protect against skin breakdown. Sleeping positions other than the supine position can contribute to mask leak. CPAP pillows are designed to allow patients to sleep in their desired position while maintaining an adequate mask seal. The pillows are shaped or have cutouts that prevent the mask from pushing on the pillow and creating a leak.

Humidification

Case scenario #2

A 54-year-old man with severe sleep apnea recently initiated CPAP therapy. He quickly discontinued use due to nasal congestion.

Which of the following is NOT recommended?

1. Assure adequate heated humidification
2. Assure that the apnea is adequately treated
3. Use of a full-face mask
4. Use of short-acting nasal decongestants
5. Use of a topical nasal steroid

Answer: Use of short-acting nasal decongestants.

Nasal congestion is a common reason for nonadherence to CPAP therapy.¹³ Pressurized air is very drying and can be very uncomfortable. Residual apneic events can even precipitate further congestion. The use of humidification with CPAP can improve patient comfort and compliance. The vast majority of patients use CPAP devices with heated humidifiers. Heated humidification has been found to increase CPAP use and improve daytime sleepiness and feelings of satisfaction and being refreshed compared with cold humidity or no humidity.¹⁴ Cold humidification improved daytime sleepiness and satisfaction, but not to the degree found with heated humidification.

Heated humidifiers are incorporated in the CPAP machine or attach to it. Heated in-line tubing helps with “rain out,” which refers to water condensation inside the tubing and mask associated with CPAP humidification.

Topical decongestants can actually worsen congestion and cause a reflex vasodilation. Topical nasal steroids can be used for nasal congestion and may be beneficial.

 

 

Tubing

The tubing from the PAP device to the facial interface can be a source of irritation to patients due to rubbing against the skin or entanglement. Products to cover the tubing to reduce irritation and avoid entanglement are available. Extra-long tubing is also available.

Cleaning

Some people find cleaning CPAP equipment daunting. Cleaning devices are available and recommended to patients looking for reassurance about how to keep their CPAP equipment clean. There are also CPAP wipes to clean the mask of oils and creams from the skin to improve the mask seal and reduce leaks.

Pressure control

Advanced modalities are available to adjust how pressure is delivered by PAP devices, including ramp, APAP, pressure relief, and BiPAP. Ramp is a feature that delivers a lower pressure at the beginning of the sleep cycle and slowly increases pressure to therapeutic levels. The lower pressure makes it easier for the user to fall asleep and builds to therapeutic pressure once asleep. APAP adjusts the pressure automatically when needed and reduces the pressure when not needed. Pressure relief is a feature that allows the PAP pressure to decrease at the point of expiration. BiPAP gives a distinct pressure on inspiration and a distinctively different and lower pressure at the point of expiration.

Auto-PAP

Case scenario #3

A 52-year-old woman with hypertension and mild sleep apnea has a polysomnogram with an apnea–hypopnea index of 7 events per hour that increase to 32 events per hour in rapid eye movement (REM) sleep. She is on CPAP at 5 cm of water, but complains of waking every 2 hours with a sense of panic and hot flashes.

Which of the following is the most likely cause of her symptoms?

1. An underlying anxiety disorder
2. An underlying heart condition
3. Perimenopausal symptoms
4. Undertreated REM-related apnea
5. None of the above

Answer: While all of these choices can occur, the most likely cause is undertreated REM-related apnea.

The sleep study overview for this patient is shown in Figure 3. During REM sleep, arousals and apneas are clustered and associated with a severe drop in oxygen levels. While doing well on CPAP at 5 cm of water, when the patient dreams, the apnea may become worse and more pressure may be needed.

What would be the best next step in treatment for this patient?

1. Hormonal replacement therapy
2. Positional therapy in addition to CPAP
3. APAP
4. Anxiolytic medication
5. All of the above

Answer: APAP.

APAP incorporates an algorithm that detects and adjusts to airflow, pressure fluctuations, and airway resistance. The consensus from the American Academy of Sleep Medicine is that APAP is useful in the case of:

• Pressure intolerance
• REM apnea or positional apnea
• Inadequate in lab PAP titration
• Planned weight loss (bariatric surgery)
• Recurrent symptoms after long-term CPAP use.¹⁵

Pressure relief

Case scenario #4

A 45-year-old man with severe sleep apnea uses CPAP at 10 cm of water. He complains of the inability to exhale against the pressure from the device.

What would be the best next step?

1. Set the pressure relief to a maximum of 3
2. Lower the pressure of CPAP and check a download use at a lower pressure
3. BiPAP titration study in the laboratory
4. Switch to BiPAP if insurance allows
5. Change to a different mask

Answer: Set the pressure relief to a maximum of 3.

The CPAP device delivers pressure in conjunction with the patient’s inspiration and expiration. At the point of expiration, there is a decrease in the pressure delivered by the device to make it easier for the user to exhale. Three selectable settings provide flow-based pressure relief with a setting of 1 for the least degree of pressure reduction and a setting of 3 for the greatest degree of pressure reduction.¹⁶

In a study of the effect of PAP with pressure relief, 93 patients were assigned to use APAP without pressure relief, CPAP with pressure relief (C-Flex), or APAP with pressure relief (A-Flex).¹⁶ At 3 and 6 months, patients using A-Flex had the best adherence to therapy.

Quality of life was also examined in this same study.¹⁶ For patients using APAP alone, there was no statistically significant difference in the Epworth Sleepiness Scale measuring daytime sleepiness or the Pittsburgh Sleep Quality Index. However, in patients using A-Flex, daytime sleepiness improved, as did sleep quality, with statistically significant improvement at 3 months.

Bilevel PAP

Case scenario #5

A 62-year-old man with severe sleep apnea uses CPAP set at 17 cm of water and pressure relief set at 3. He stopped using CPAP due to abdominal pain, extreme belching, and pressure intolerance.

What would be the appropriate next step?

1. Use of simethicone
2. Elevate the head while using PAP therapy
3. BiPAP titration study in the laboratory
4. Switching directly to BiPAP if insurance allows
5. All of the above

Answer: All of the above.

BiPAP devices provide 2 distinct pressures, one for inhalation and one for exhalation. BiPAP also has the ability to deliver a higher overall pressure. A CPAP device typically has a maximum pressure of 20 cm of water, but BiPAP has a maximum pressure of 25 cm of water on inspiration. BiPAP may be helpful in patients with air aphasia and extreme belching. If a patient cannot tolerate CPAP because of the pressure, and if C-Flex has not alleviated the problem, BiPAP would be the next step.

The effectiveness and level of comfort of BiPAP compared with CPAP for the treatment of OSA was evaluated by the American Academy of Sleep Medicine.² The analysis of 7 randomized control trials reporting level I and II evidence found that BiPAP was as effective as CPAP in the treatment of OSA in patients with no comorbidities. For patients with OSA and comorbidities, a level III evidence study reported an increased level of comfort in patients using BiPAP.

 

 

PATIENT-CENTERED STRATEGIES TO IMPROVE ADHERENCE

Innovative strategies and approaches focusing on patient factors affecting PAP adherence include motivational interviewing, motivational enhancement, telemedicine, and desensitization techniques.

Motivational interviews and enhancement

Motivational interviewing and motivational enhancement were first used to help with alcohol abuse.¹⁷ Motivational interviewing is goal-oriented, patient-centered counseling to elicit a particular behavioral change. The goal is to explore and resolve ambivalence, increase engagement, and evoke a positive response and perspective that builds momentum and results in action.

Motivational enhancement and motivational engagement in the use of PAP therapy were evaluated in the Patient Engagement Study.¹⁸ Patients were assigned to usual care (n = 85,358) or active patient engagement (APE) (n = 42,679). Usual care involved diagnosis of apnea, initiation of CPAP, and follow-up, whereas APE included daily feedback (ie, daily scores of apnea–hypopnea index, mask leaks, hours used), positive praise messages, and personal coaching assistance. Overall adherence for patients assigned to APE was 87% compared with 70% in the usual-care group. The hours of use per night also increased for patients in the APE group.

The Best Apnea Interventions for Research trial randomized patients with or at risk of cardiovascular disease (N = 169) to CPAP alone or CPAP with motivational enhancements for 6 months.¹⁹ Motivational enhancements and interventions included brief in-person and phone interventions. An overall average difference of 99 minutes per night improvement in CPAP use was reported in the motivational enhancement group compared with CPAP alone.

The Motivational Interviewing Nurse Therapy study trained nurses in motivational interviewing and randomized 106 patients with newly diagnosed OSA to CPAP alone or CPAP plus motivational interviews.²⁰ Motivational interviews involved 3 sessions: 1 to build motivation prior to the CPAP titration, 1 to strengthen the commitment to achieve the prescribed time, and a booster session 1 month after CPAP setup. Adherence was found to improve at 1, 2, and 3 months in the motivational interview group; however, no difference between the 2 groups in adherence was noted at 12 months.

Telemedicine

The role of telemedicine in improving adherence with CPAP therapy was evaluated in 75 patients with moderate to severe apnea randomized to APAP alone or with phone call support from a research coordinator.²¹ Phone calls occurred 2 days after device setup, and daily monitoring of several factors was done via modem. Patients were contacted if the mask was leaking more than 30% of the night, use was less than 4 hours per night on 2 consecutive nights, the apnea–hypopnea index was greater than 10, or the average pressure needed was higher than 16 cm of water. Statistically significant improvement was found in the telemedicine group in mean adherence, minutes used per day, and mean amount of time spent with the patients.

Desensitization to PAP therapy

Case scenario #6

A 33-year-old woman with a history of anxiety and depression and a remote history of abuse as a child was diagnosed with severe apnea. When she tries to use her CPAP, she has a sense of panic and cannot proceed.

Which of the following has NOT been shown to be beneficial in this situation?

1. Psychologist for behavioral therapy
2. Desensitization protocol
3. PAP “NAP”
4. Short-acting hypnotics
5. None of the above

Answer: Short-acting hypnotics.

The short-acting hypnotic zaleplon (Sonata) was evaluated in a 1-month study of 88 patients compared with placebo control, and no difference was found between the 2 groups in measures of adherence to therapy or symptoms.²²

A protocol for desensitization to CPAP use is helpful to assist patients in acclimating to therapy. An example of the steps in a desensitization protocol that patients can do at home is provided in Table 1.

PAP NAP. For some people, at-home desensitization is not enough, and a sleep lab session may be needed. A PAP NAP is a daytime study conducted in the sleep lab. Patients do not necessarily sleep, but work with a technologist with a minimal hookup to polysomnography equipment on mask desensitization, as well as biofeedback techniques. PAP NAPs are indicated for patients with claustrophobia, anxiety surrounding PAP therapy, or pressure intolerance.

A study of 99 patients with moderate to severe apnea and insomnia and concomitant psychiatric disorders resistant to CPAP evaluated adherence in a group receiving a PAP NAP (n = 39) compared with a control group (n = 60).²³ The PAP NAP group had marked improvement in completion of CPAP titration in the lab, filling the CPAP prescription, and using CPAP more than 5 days a week and more than 4 hours a night.

A new innovative concept called the Sleep Apnea Patient-Centered Outcomes Network is a collaborative group that includes patients, researchers, and clinicians.²⁴ The group addresses issues such as cost, outcomes, and value in the diagnosis and treatment of sleep apnea. A patient-centered website provides forums, education, and data collection capability for researchers (myapnea.org).

SUMMARY

PAP therapy is the gold standard for treatment of patients with moderate to severe OSA, though poor adherence to PAP therapy is a persistent problem. Advanced features in PAP devices such as APAP and other innovative strategies like motivational enhancement and desensitization protocols and PAP NAP are being used to address poor adherence. More randomized controlled trials are needed to evaluate PAP for sleep apnea.

Positive airway pressure (PAP) therapy is used to open an obstructed upper airway (Figure 1). PAP therapy consists of a small bedside unit that creates a pressurized column of air that is delivered through tubing to a facial interface, which can be nasal, oral, or both. Collin Sullivan, MD, created the nasal continuous PAP (CPAP) in 1982 using parts of a vacuum cleaner to create positive pressure that successfully resolved hypoxemia in a patient.¹ Today, the various forms of PAP therapy include CPAP, the most common, auto-PAP (APAP), and bilevel PAP (BiPAP).

EFFICACY OF PAP THERAPY

The American Academy of Sleep Medicine practice guidelines for PAP are based on 342 articles, most rated as evidence levels I and II, concluding that CPAP is superior to conservative treatment to:

• Eliminate respiratory disturbances
• Reduce the apnea–hypopnea index
• Decrease the arousal index on electroencephalogram
• Increase in the total amount of slow-wave or N3 sleep
• Reduce daytime sleepiness.²

These practice parameters are based on evidence of improved daytime sleepiness and reduced incidence of cardiovascular events in patients with moderate to severe obstructive sleep apnea (OSA) treated with PAP. The evidence is less clear for neurocognitive markers and cardiovascular events in the treatment of patients with mild sleep apnea.

Sleepiness

A study evaluated sleepiness outcomes in 149 patients with severe sleep apnea with an average apnea–hypopnea index of 69 relative to the duration of nightly CPAP use. Sleepiness was measured using the Functional Outcomes of Sleep Questionnaire, Epworth Sleepiness Scale, and Multiple Sleep Latency Test. Results suggest that a greater percentage of patients had improved daytime sleepiness as the total hours of sleep using CPAP increased.³

The Apnea Positive Pressure Long-term Efficacy Study (APPLES) was a 6-month, multicenter, randomized study of neurocognitive function in patients with OSA (N = 1,098).⁴ Subjective sleepiness as measured by the Epworth Sleepiness Scale showed statistically significant improvement at 2 and 6 months for patients with moderate to severe OSA using CPAP. Objective sleepiness as measured by the Maintenance of Wakefulness Test showed statistically significant improvement (ie, improved daytime alertness) at 2 and 6 months for patients with severe OSA using CPAP.

Neurocognitive function

APPLES also tested for attention and psycho­motor function as well as verbal learning and memory, though no statistically significant improvements were found in these parameters.⁴ Executive function and frontal lobe function showed transient improvement at 2 months in patients with severe sleep apnea using CPAP, but the improvement was not statistically significant at 6 months.

Cardiovascular outcomes

Hypertension and cardiovascular disease. Use of CPAP therapy reduces blood pressure in individuals with hypertension. A study of 32 patients who had a baseline polysomnography with 19 hours of continuous mean arterial blood pressure monitoring were treated with therapeutic CPAP (n = 16) or subtherapeutic CPAP (n = 16).⁵ Therapeutic treatment with CPAP for patients with moderate to severe OSA resulted in statistically significant reductions in mean arterial pressure for both systolic and diastolic pressures. The blood pressure reductions achieved are estimated to reduce coronary artery diseases by 37% and stroke by 56%.⁵

The risk of cardiovascular events in men with severe sleep apnea is high but mitigated by the use of CPAP. In a cohort of 1,651 men, untreated severe sleep apnea resulted in a threefold increase in the rate of cardiovascular events per 1,000 patient-years compared with 4 other groups: a control group, men who snore, men with untreated mild to moderate sleep apnea, and men with OSA using CPAP.⁶ However, when men with severe sleep apnea use CPAP, the risk of cardiovascular events is reduced to the rate in men who snore.

Atrial fibrillation. In patients with atrial fibrillation treated with direct-current cardioversion-
defibrillation, the recurrence of atrial fibrillation at 12 months was greater in patients with untreated OSA (82%) compared with a control group (53%) and patients treated for OSA (42%).⁷

Heart failure. In a study of 24 patients with heart failure, an ejection fraction less than 45%, and OSA, patients were randomized to a control group for medical treatment or medical treatment and nasal CPAP for 1 month.⁸ In the CPAP group, mean systolic blood pressure and heart rate were reduced, resulting in an improved ejection fraction compared with baseline, as well as compared with patients in the control group.

In patients with heart failure (N = 66) with and without Cheyne-Stokes respirations in central sleep apnea, patients treated with CPAP were found to have a 60% relative risk reduction in mortality-cardiac transplant rate compared with the control group not using CPAP.⁹ Further stratification in this study showed that patients with significant Cheyne-Stokes respirations and central sleep apnea had an improved ejection fraction at 3 months and an 81% reduced mortality-cardiac transplant rate.⁹

 

 

ADHERENCE

Adherence to PAP therapy is a problem in terms of both frequency of use and duration of use per night. A review of randomized control trials of CPAP compliance between 2011 and 2015 found adherence varied widely from 35% to 87%.¹⁰ The average hours of PAP use per night was found to be 5 hours in APPLES.⁴ Patients adherent to PAP therapy at 1 month remained adherent at 1 year, suggesting patients using CPAP for 1 month were more likely to continue use at 1 year.¹⁰ Impediments to PAP use typically involve the facial interface discomfort, lack of humidity, and pressure intolerance.

FEATURES OF PAP DEVICES

Today’s PAP devices have features designed to make them easier to use and more comfortable to improve adherence to therapy. Facial interface options, heated humidifiers, tubing accessories, cleaning devices, reporting of compliance data via telecommunication, and pressure adjustment features of PAP devices may improve patient adherence and comfort, as highlighted in the case scenarios presented below.

Interfaces

Case scenario #1

A 32-year-old woman with moderate sleep apnea complains that her PAP nasal mask is making very loud noises and is disturbing her bed partner. She is a side sleeper and also reports that she wakes with an extremely dry mouth.

Management of the leak could include which of the following?

1. Chin strap
2. Avoidance of facial creams before bedtime
3. CPAP pillow
4. Clean the mask daily
5. All of the above

Answer: All of the above.

Figure 2 shows an overview of data from the patient’s machine for the past month and 1 night of leak data. Both the month-use data and single-night leak data show mask leakage.

There are many types of PAP interfaces such as nasal masks, nasal pillows, nasal cushions, full-face masks, and less frequently used oral and total face masks. The mask interface is a common impediment to use of PAP therapy often due to poor mask fit or leakage.

Nasal masks cover only the nose and require that the mouth remains closed, which can be achieved with the addition of a chin strap. Nasal masks are available in a variety of materials including cloth. Nasal pillows actually go into the nostrils whereas the nasal mask is positioned under the nose. A nasal cushion mask sits under the nose but does not go into the nostrils.

A study by Lanza and colleagues¹¹ evaluated patient comfort with PAP therapy based on the type of nasal interface mask. Patients using nasal pillows had improvement with respect to swollen eyes, discomfort, skin breakdown, and marks on the face compared with patients using nasal masks; however, nasal pillows can cause nostril pain.

Several types of full-face masks are available, some that fit over the bridge of the nose and some that fit just under the nose. A variety of head straps are available to secure full-face masks. One benefit of full-face masks is that air pressure is delivered to both the nose and the mouth, so the mouth can be open or closed. However, the larger surface area of the full-face mask increases the potential for leaks. A study of adherence in 20 patients using CPAP with nasal masks or full-face masks evaluated hours per use, adherence at 12 months, and comfort.¹² Patients using full-face masks had more hours per use, better adherence at 12 months, and more comfort than patients using nasal masks.

Interface skin irritation and leak management. To help combat skin irritation, particularly for patients with rosacea, cloth products are available for use beneath the mask and headgear. Silicone pads for masks that cause pressure on the bridge of the nose can help protect against skin breakdown. Sleeping positions other than the supine position can contribute to mask leak. CPAP pillows are designed to allow patients to sleep in their desired position while maintaining an adequate mask seal. The pillows are shaped or have cutouts that prevent the mask from pushing on the pillow and creating a leak.

Humidification

Case scenario #2

A 54-year-old man with severe sleep apnea recently initiated CPAP therapy. He quickly discontinued use due to nasal congestion.

Which of the following is NOT recommended?

1. Assure adequate heated humidification
2. Assure that the apnea is adequately treated
3. Use of a full-face mask
4. Use of short-acting nasal decongestants
5. Use of a topical nasal steroid

Answer: Use of short-acting nasal decongestants.

Nasal congestion is a common reason for nonadherence to CPAP therapy.¹³ Pressurized air is very drying and can be very uncomfortable. Residual apneic events can even precipitate further congestion. The use of humidification with CPAP can improve patient comfort and compliance. The vast majority of patients use CPAP devices with heated humidifiers. Heated humidification has been found to increase CPAP use and improve daytime sleepiness and feelings of satisfaction and being refreshed compared with cold humidity or no humidity.¹⁴ Cold humidification improved daytime sleepiness and satisfaction, but not to the degree found with heated humidification.

Heated humidifiers are incorporated in the CPAP machine or attach to it. Heated in-line tubing helps with “rain out,” which refers to water condensation inside the tubing and mask associated with CPAP humidification.

Topical decongestants can actually worsen congestion and cause a reflex vasodilation. Topical nasal steroids can be used for nasal congestion and may be beneficial.

 

 

Tubing

The tubing from the PAP device to the facial interface can be a source of irritation to patients due to rubbing against the skin or entanglement. Products to cover the tubing to reduce irritation and avoid entanglement are available. Extra-long tubing is also available.

Cleaning

Some people find cleaning CPAP equipment daunting. Cleaning devices are available and recommended to patients looking for reassurance about how to keep their CPAP equipment clean. There are also CPAP wipes to clean the mask of oils and creams from the skin to improve the mask seal and reduce leaks.

Pressure control

Advanced modalities are available to adjust how pressure is delivered by PAP devices, including ramp, APAP, pressure relief, and BiPAP. Ramp is a feature that delivers a lower pressure at the beginning of the sleep cycle and slowly increases pressure to therapeutic levels. The lower pressure makes it easier for the user to fall asleep and builds to therapeutic pressure once asleep. APAP adjusts the pressure automatically when needed and reduces the pressure when not needed. Pressure relief is a feature that allows the PAP pressure to decrease at the point of expiration. BiPAP gives a distinct pressure on inspiration and a distinctively different and lower pressure at the point of expiration.

Auto-PAP

Case scenario #3

A 52-year-old woman with hypertension and mild sleep apnea has a polysomnogram with an apnea–hypopnea index of 7 events per hour that increase to 32 events per hour in rapid eye movement (REM) sleep. She is on CPAP at 5 cm of water, but complains of waking every 2 hours with a sense of panic and hot flashes.

Which of the following is the most likely cause of her symptoms?

1. An underlying anxiety disorder
2. An underlying heart condition
3. Perimenopausal symptoms
4. Undertreated REM-related apnea
5. None of the above

Answer: While all of these choices can occur, the most likely cause is undertreated REM-related apnea.

The sleep study overview for this patient is shown in Figure 3. During REM sleep, arousals and apneas are clustered and associated with a severe drop in oxygen levels. While doing well on CPAP at 5 cm of water, when the patient dreams, the apnea may become worse and more pressure may be needed.

What would be the best next step in treatment for this patient?

1. Hormonal replacement therapy
2. Positional therapy in addition to CPAP
3. APAP
4. Anxiolytic medication
5. All of the above

Answer: APAP.

APAP incorporates an algorithm that detects and adjusts to airflow, pressure fluctuations, and airway resistance. The consensus from the American Academy of Sleep Medicine is that APAP is useful in the case of:

• Pressure intolerance
• REM apnea or positional apnea
• Inadequate in lab PAP titration
• Planned weight loss (bariatric surgery)
• Recurrent symptoms after long-term CPAP use.¹⁵

Pressure relief

Case scenario #4

A 45-year-old man with severe sleep apnea uses CPAP at 10 cm of water. He complains of the inability to exhale against the pressure from the device.

What would be the best next step?

1. Set the pressure relief to a maximum of 3
2. Lower the pressure of CPAP and check a download use at a lower pressure
3. BiPAP titration study in the laboratory
4. Switch to BiPAP if insurance allows
5. Change to a different mask

Answer: Set the pressure relief to a maximum of 3.

The CPAP device delivers pressure in conjunction with the patient’s inspiration and expiration. At the point of expiration, there is a decrease in the pressure delivered by the device to make it easier for the user to exhale. Three selectable settings provide flow-based pressure relief with a setting of 1 for the least degree of pressure reduction and a setting of 3 for the greatest degree of pressure reduction.¹⁶

In a study of the effect of PAP with pressure relief, 93 patients were assigned to use APAP without pressure relief, CPAP with pressure relief (C-Flex), or APAP with pressure relief (A-Flex).¹⁶ At 3 and 6 months, patients using A-Flex had the best adherence to therapy.

Quality of life was also examined in this same study.¹⁶ For patients using APAP alone, there was no statistically significant difference in the Epworth Sleepiness Scale measuring daytime sleepiness or the Pittsburgh Sleep Quality Index. However, in patients using A-Flex, daytime sleepiness improved, as did sleep quality, with statistically significant improvement at 3 months.

Bilevel PAP

Case scenario #5

A 62-year-old man with severe sleep apnea uses CPAP set at 17 cm of water and pressure relief set at 3. He stopped using CPAP due to abdominal pain, extreme belching, and pressure intolerance.

What would be the appropriate next step?

1. Use of simethicone
2. Elevate the head while using PAP therapy
3. BiPAP titration study in the laboratory
4. Switching directly to BiPAP if insurance allows
5. All of the above

Answer: All of the above.

BiPAP devices provide 2 distinct pressures, one for inhalation and one for exhalation. BiPAP also has the ability to deliver a higher overall pressure. A CPAP device typically has a maximum pressure of 20 cm of water, but BiPAP has a maximum pressure of 25 cm of water on inspiration. BiPAP may be helpful in patients with air aphasia and extreme belching. If a patient cannot tolerate CPAP because of the pressure, and if C-Flex has not alleviated the problem, BiPAP would be the next step.

The effectiveness and level of comfort of BiPAP compared with CPAP for the treatment of OSA was evaluated by the American Academy of Sleep Medicine.² The analysis of 7 randomized control trials reporting level I and II evidence found that BiPAP was as effective as CPAP in the treatment of OSA in patients with no comorbidities. For patients with OSA and comorbidities, a level III evidence study reported an increased level of comfort in patients using BiPAP.

 

 

PATIENT-CENTERED STRATEGIES TO IMPROVE ADHERENCE

Innovative strategies and approaches focusing on patient factors affecting PAP adherence include motivational interviewing, motivational enhancement, telemedicine, and desensitization techniques.

Motivational interviews and enhancement

Motivational interviewing and motivational enhancement were first used to help with alcohol abuse.¹⁷ Motivational interviewing is goal-oriented, patient-centered counseling to elicit a particular behavioral change. The goal is to explore and resolve ambivalence, increase engagement, and evoke a positive response and perspective that builds momentum and results in action.

Motivational enhancement and motivational engagement in the use of PAP therapy were evaluated in the Patient Engagement Study.¹⁸ Patients were assigned to usual care (n = 85,358) or active patient engagement (APE) (n = 42,679). Usual care involved diagnosis of apnea, initiation of CPAP, and follow-up, whereas APE included daily feedback (ie, daily scores of apnea–hypopnea index, mask leaks, hours used), positive praise messages, and personal coaching assistance. Overall adherence for patients assigned to APE was 87% compared with 70% in the usual-care group. The hours of use per night also increased for patients in the APE group.

The Best Apnea Interventions for Research trial randomized patients with or at risk of cardiovascular disease (N = 169) to CPAP alone or CPAP with motivational enhancements for 6 months.¹⁹ Motivational enhancements and interventions included brief in-person and phone interventions. An overall average difference of 99 minutes per night improvement in CPAP use was reported in the motivational enhancement group compared with CPAP alone.

The Motivational Interviewing Nurse Therapy study trained nurses in motivational interviewing and randomized 106 patients with newly diagnosed OSA to CPAP alone or CPAP plus motivational interviews.²⁰ Motivational interviews involved 3 sessions: 1 to build motivation prior to the CPAP titration, 1 to strengthen the commitment to achieve the prescribed time, and a booster session 1 month after CPAP setup. Adherence was found to improve at 1, 2, and 3 months in the motivational interview group; however, no difference between the 2 groups in adherence was noted at 12 months.

Telemedicine

The role of telemedicine in improving adherence with CPAP therapy was evaluated in 75 patients with moderate to severe apnea randomized to APAP alone or with phone call support from a research coordinator.²¹ Phone calls occurred 2 days after device setup, and daily monitoring of several factors was done via modem. Patients were contacted if the mask was leaking more than 30% of the night, use was less than 4 hours per night on 2 consecutive nights, the apnea–hypopnea index was greater than 10, or the average pressure needed was higher than 16 cm of water. Statistically significant improvement was found in the telemedicine group in mean adherence, minutes used per day, and mean amount of time spent with the patients.

Desensitization to PAP therapy

Case scenario #6

A 33-year-old woman with a history of anxiety and depression and a remote history of abuse as a child was diagnosed with severe apnea. When she tries to use her CPAP, she has a sense of panic and cannot proceed.

Which of the following has NOT been shown to be beneficial in this situation?

1. Psychologist for behavioral therapy
2. Desensitization protocol
3. PAP “NAP”
4. Short-acting hypnotics
5. None of the above

Answer: Short-acting hypnotics.

The short-acting hypnotic zaleplon (Sonata) was evaluated in a 1-month study of 88 patients compared with placebo control, and no difference was found between the 2 groups in measures of adherence to therapy or symptoms.²²

A protocol for desensitization to CPAP use is helpful to assist patients in acclimating to therapy. An example of the steps in a desensitization protocol that patients can do at home is provided in Table 1.

PAP NAP. For some people, at-home desensitization is not enough, and a sleep lab session may be needed. A PAP NAP is a daytime study conducted in the sleep lab. Patients do not necessarily sleep, but work with a technologist with a minimal hookup to polysomnography equipment on mask desensitization, as well as biofeedback techniques. PAP NAPs are indicated for patients with claustrophobia, anxiety surrounding PAP therapy, or pressure intolerance.

A study of 99 patients with moderate to severe apnea and insomnia and concomitant psychiatric disorders resistant to CPAP evaluated adherence in a group receiving a PAP NAP (n = 39) compared with a control group (n = 60).²³ The PAP NAP group had marked improvement in completion of CPAP titration in the lab, filling the CPAP prescription, and using CPAP more than 5 days a week and more than 4 hours a night.

A new innovative concept called the Sleep Apnea Patient-Centered Outcomes Network is a collaborative group that includes patients, researchers, and clinicians.²⁴ The group addresses issues such as cost, outcomes, and value in the diagnosis and treatment of sleep apnea. A patient-centered website provides forums, education, and data collection capability for researchers (myapnea.org).

SUMMARY

PAP therapy is the gold standard for treatment of patients with moderate to severe OSA, though poor adherence to PAP therapy is a persistent problem. Advanced features in PAP devices such as APAP and other innovative strategies like motivational enhancement and desensitization protocols and PAP NAP are being used to address poor adherence. More randomized controlled trials are needed to evaluate PAP for sleep apnea.

Positive airway pressure (PAP) therapy is used to open an obstructed upper airway (Figure 1). PAP therapy consists of a small bedside unit that creates a pressurized column of air that is delivered through tubing to a facial interface, which can be nasal, oral, or both. Collin Sullivan, MD, created the nasal continuous PAP (CPAP) in 1982 using parts of a vacuum cleaner to create positive pressure that successfully resolved hypoxemia in a patient.¹ Today, the various forms of PAP therapy include CPAP, the most common, auto-PAP (APAP), and bilevel PAP (BiPAP).

EFFICACY OF PAP THERAPY

The American Academy of Sleep Medicine practice guidelines for PAP are based on 342 articles, most rated as evidence levels I and II, concluding that CPAP is superior to conservative treatment to:

• Eliminate respiratory disturbances
• Reduce the apnea–hypopnea index
• Decrease the arousal index on electroencephalogram
• Increase in the total amount of slow-wave or N3 sleep
• Reduce daytime sleepiness.²

These practice parameters are based on evidence of improved daytime sleepiness and reduced incidence of cardiovascular events in patients with moderate to severe obstructive sleep apnea (OSA) treated with PAP. The evidence is less clear for neurocognitive markers and cardiovascular events in the treatment of patients with mild sleep apnea.

Sleepiness

A study evaluated sleepiness outcomes in 149 patients with severe sleep apnea with an average apnea–hypopnea index of 69 relative to the duration of nightly CPAP use. Sleepiness was measured using the Functional Outcomes of Sleep Questionnaire, Epworth Sleepiness Scale, and Multiple Sleep Latency Test. Results suggest that a greater percentage of patients had improved daytime sleepiness as the total hours of sleep using CPAP increased.³

The Apnea Positive Pressure Long-term Efficacy Study (APPLES) was a 6-month, multicenter, randomized study of neurocognitive function in patients with OSA (N = 1,098).⁴ Subjective sleepiness as measured by the Epworth Sleepiness Scale showed statistically significant improvement at 2 and 6 months for patients with moderate to severe OSA using CPAP. Objective sleepiness as measured by the Maintenance of Wakefulness Test showed statistically significant improvement (ie, improved daytime alertness) at 2 and 6 months for patients with severe OSA using CPAP.

Neurocognitive function

APPLES also tested for attention and psycho­motor function as well as verbal learning and memory, though no statistically significant improvements were found in these parameters.⁴ Executive function and frontal lobe function showed transient improvement at 2 months in patients with severe sleep apnea using CPAP, but the improvement was not statistically significant at 6 months.

Cardiovascular outcomes

Hypertension and cardiovascular disease. Use of CPAP therapy reduces blood pressure in individuals with hypertension. A study of 32 patients who had a baseline polysomnography with 19 hours of continuous mean arterial blood pressure monitoring were treated with therapeutic CPAP (n = 16) or subtherapeutic CPAP (n = 16).⁵ Therapeutic treatment with CPAP for patients with moderate to severe OSA resulted in statistically significant reductions in mean arterial pressure for both systolic and diastolic pressures. The blood pressure reductions achieved are estimated to reduce coronary artery diseases by 37% and stroke by 56%.⁵

The risk of cardiovascular events in men with severe sleep apnea is high but mitigated by the use of CPAP. In a cohort of 1,651 men, untreated severe sleep apnea resulted in a threefold increase in the rate of cardiovascular events per 1,000 patient-years compared with 4 other groups: a control group, men who snore, men with untreated mild to moderate sleep apnea, and men with OSA using CPAP.⁶ However, when men with severe sleep apnea use CPAP, the risk of cardiovascular events is reduced to the rate in men who snore.

Atrial fibrillation. In patients with atrial fibrillation treated with direct-current cardioversion-
defibrillation, the recurrence of atrial fibrillation at 12 months was greater in patients with untreated OSA (82%) compared with a control group (53%) and patients treated for OSA (42%).⁷

Heart failure. In a study of 24 patients with heart failure, an ejection fraction less than 45%, and OSA, patients were randomized to a control group for medical treatment or medical treatment and nasal CPAP for 1 month.⁸ In the CPAP group, mean systolic blood pressure and heart rate were reduced, resulting in an improved ejection fraction compared with baseline, as well as compared with patients in the control group.

In patients with heart failure (N = 66) with and without Cheyne-Stokes respirations in central sleep apnea, patients treated with CPAP were found to have a 60% relative risk reduction in mortality-cardiac transplant rate compared with the control group not using CPAP.⁹ Further stratification in this study showed that patients with significant Cheyne-Stokes respirations and central sleep apnea had an improved ejection fraction at 3 months and an 81% reduced mortality-cardiac transplant rate.⁹

 

 

ADHERENCE

Adherence to PAP therapy is a problem in terms of both frequency of use and duration of use per night. A review of randomized control trials of CPAP compliance between 2011 and 2015 found adherence varied widely from 35% to 87%.¹⁰ The average hours of PAP use per night was found to be 5 hours in APPLES.⁴ Patients adherent to PAP therapy at 1 month remained adherent at 1 year, suggesting patients using CPAP for 1 month were more likely to continue use at 1 year.¹⁰ Impediments to PAP use typically involve the facial interface discomfort, lack of humidity, and pressure intolerance.

FEATURES OF PAP DEVICES

Today’s PAP devices have features designed to make them easier to use and more comfortable to improve adherence to therapy. Facial interface options, heated humidifiers, tubing accessories, cleaning devices, reporting of compliance data via telecommunication, and pressure adjustment features of PAP devices may improve patient adherence and comfort, as highlighted in the case scenarios presented below.

Interfaces

Case scenario #1

A 32-year-old woman with moderate sleep apnea complains that her PAP nasal mask is making very loud noises and is disturbing her bed partner. She is a side sleeper and also reports that she wakes with an extremely dry mouth.

Management of the leak could include which of the following?

1. Chin strap
2. Avoidance of facial creams before bedtime
3. CPAP pillow
4. Clean the mask daily
5. All of the above

Answer: All of the above.

Figure 2 shows an overview of data from the patient’s machine for the past month and 1 night of leak data. Both the month-use data and single-night leak data show mask leakage.

There are many types of PAP interfaces such as nasal masks, nasal pillows, nasal cushions, full-face masks, and less frequently used oral and total face masks. The mask interface is a common impediment to use of PAP therapy often due to poor mask fit or leakage.

Nasal masks cover only the nose and require that the mouth remains closed, which can be achieved with the addition of a chin strap. Nasal masks are available in a variety of materials including cloth. Nasal pillows actually go into the nostrils whereas the nasal mask is positioned under the nose. A nasal cushion mask sits under the nose but does not go into the nostrils.

A study by Lanza and colleagues¹¹ evaluated patient comfort with PAP therapy based on the type of nasal interface mask. Patients using nasal pillows had improvement with respect to swollen eyes, discomfort, skin breakdown, and marks on the face compared with patients using nasal masks; however, nasal pillows can cause nostril pain.

Several types of full-face masks are available, some that fit over the bridge of the nose and some that fit just under the nose. A variety of head straps are available to secure full-face masks. One benefit of full-face masks is that air pressure is delivered to both the nose and the mouth, so the mouth can be open or closed. However, the larger surface area of the full-face mask increases the potential for leaks. A study of adherence in 20 patients using CPAP with nasal masks or full-face masks evaluated hours per use, adherence at 12 months, and comfort.¹² Patients using full-face masks had more hours per use, better adherence at 12 months, and more comfort than patients using nasal masks.

Interface skin irritation and leak management. To help combat skin irritation, particularly for patients with rosacea, cloth products are available for use beneath the mask and headgear. Silicone pads for masks that cause pressure on the bridge of the nose can help protect against skin breakdown. Sleeping positions other than the supine position can contribute to mask leak. CPAP pillows are designed to allow patients to sleep in their desired position while maintaining an adequate mask seal. The pillows are shaped or have cutouts that prevent the mask from pushing on the pillow and creating a leak.

Humidification

Case scenario #2

A 54-year-old man with severe sleep apnea recently initiated CPAP therapy. He quickly discontinued use due to nasal congestion.

Which of the following is NOT recommended?

1. Assure adequate heated humidification
2. Assure that the apnea is adequately treated
3. Use of a full-face mask
4. Use of short-acting nasal decongestants
5. Use of a topical nasal steroid

Answer: Use of short-acting nasal decongestants.

Nasal congestion is a common reason for nonadherence to CPAP therapy.¹³ Pressurized air is very drying and can be very uncomfortable. Residual apneic events can even precipitate further congestion. The use of humidification with CPAP can improve patient comfort and compliance. The vast majority of patients use CPAP devices with heated humidifiers. Heated humidification has been found to increase CPAP use and improve daytime sleepiness and feelings of satisfaction and being refreshed compared with cold humidity or no humidity.¹⁴ Cold humidification improved daytime sleepiness and satisfaction, but not to the degree found with heated humidification.

Heated humidifiers are incorporated in the CPAP machine or attach to it. Heated in-line tubing helps with “rain out,” which refers to water condensation inside the tubing and mask associated with CPAP humidification.

Topical decongestants can actually worsen congestion and cause a reflex vasodilation. Topical nasal steroids can be used for nasal congestion and may be beneficial.

 

 

Tubing

The tubing from the PAP device to the facial interface can be a source of irritation to patients due to rubbing against the skin or entanglement. Products to cover the tubing to reduce irritation and avoid entanglement are available. Extra-long tubing is also available.

Cleaning

Some people find cleaning CPAP equipment daunting. Cleaning devices are available and recommended to patients looking for reassurance about how to keep their CPAP equipment clean. There are also CPAP wipes to clean the mask of oils and creams from the skin to improve the mask seal and reduce leaks.

Pressure control

Advanced modalities are available to adjust how pressure is delivered by PAP devices, including ramp, APAP, pressure relief, and BiPAP. Ramp is a feature that delivers a lower pressure at the beginning of the sleep cycle and slowly increases pressure to therapeutic levels. The lower pressure makes it easier for the user to fall asleep and builds to therapeutic pressure once asleep. APAP adjusts the pressure automatically when needed and reduces the pressure when not needed. Pressure relief is a feature that allows the PAP pressure to decrease at the point of expiration. BiPAP gives a distinct pressure on inspiration and a distinctively different and lower pressure at the point of expiration.

Auto-PAP

Case scenario #3

A 52-year-old woman with hypertension and mild sleep apnea has a polysomnogram with an apnea–hypopnea index of 7 events per hour that increase to 32 events per hour in rapid eye movement (REM) sleep. She is on CPAP at 5 cm of water, but complains of waking every 2 hours with a sense of panic and hot flashes.

Which of the following is the most likely cause of her symptoms?

1. An underlying anxiety disorder
2. An underlying heart condition
3. Perimenopausal symptoms
4. Undertreated REM-related apnea
5. None of the above

Answer: While all of these choices can occur, the most likely cause is undertreated REM-related apnea.

The sleep study overview for this patient is shown in Figure 3. During REM sleep, arousals and apneas are clustered and associated with a severe drop in oxygen levels. While doing well on CPAP at 5 cm of water, when the patient dreams, the apnea may become worse and more pressure may be needed.

What would be the best next step in treatment for this patient?

1. Hormonal replacement therapy
2. Positional therapy in addition to CPAP
3. APAP
4. Anxiolytic medication
5. All of the above

Answer: APAP.

APAP incorporates an algorithm that detects and adjusts to airflow, pressure fluctuations, and airway resistance. The consensus from the American Academy of Sleep Medicine is that APAP is useful in the case of:

• Pressure intolerance
• REM apnea or positional apnea
• Inadequate in lab PAP titration
• Planned weight loss (bariatric surgery)
• Recurrent symptoms after long-term CPAP use.¹⁵

Pressure relief

Case scenario #4

A 45-year-old man with severe sleep apnea uses CPAP at 10 cm of water. He complains of the inability to exhale against the pressure from the device.

What would be the best next step?

1. Set the pressure relief to a maximum of 3
2. Lower the pressure of CPAP and check a download use at a lower pressure
3. BiPAP titration study in the laboratory
4. Switch to BiPAP if insurance allows
5. Change to a different mask

Answer: Set the pressure relief to a maximum of 3.

The CPAP device delivers pressure in conjunction with the patient’s inspiration and expiration. At the point of expiration, there is a decrease in the pressure delivered by the device to make it easier for the user to exhale. Three selectable settings provide flow-based pressure relief with a setting of 1 for the least degree of pressure reduction and a setting of 3 for the greatest degree of pressure reduction.¹⁶

In a study of the effect of PAP with pressure relief, 93 patients were assigned to use APAP without pressure relief, CPAP with pressure relief (C-Flex), or APAP with pressure relief (A-Flex).¹⁶ At 3 and 6 months, patients using A-Flex had the best adherence to therapy.

Quality of life was also examined in this same study.¹⁶ For patients using APAP alone, there was no statistically significant difference in the Epworth Sleepiness Scale measuring daytime sleepiness or the Pittsburgh Sleep Quality Index. However, in patients using A-Flex, daytime sleepiness improved, as did sleep quality, with statistically significant improvement at 3 months.

Bilevel PAP

Case scenario #5

A 62-year-old man with severe sleep apnea uses CPAP set at 17 cm of water and pressure relief set at 3. He stopped using CPAP due to abdominal pain, extreme belching, and pressure intolerance.

What would be the appropriate next step?

1. Use of simethicone
2. Elevate the head while using PAP therapy
3. BiPAP titration study in the laboratory
4. Switching directly to BiPAP if insurance allows
5. All of the above

Answer: All of the above.

BiPAP devices provide 2 distinct pressures, one for inhalation and one for exhalation. BiPAP also has the ability to deliver a higher overall pressure. A CPAP device typically has a maximum pressure of 20 cm of water, but BiPAP has a maximum pressure of 25 cm of water on inspiration. BiPAP may be helpful in patients with air aphasia and extreme belching. If a patient cannot tolerate CPAP because of the pressure, and if C-Flex has not alleviated the problem, BiPAP would be the next step.

The effectiveness and level of comfort of BiPAP compared with CPAP for the treatment of OSA was evaluated by the American Academy of Sleep Medicine.² The analysis of 7 randomized control trials reporting level I and II evidence found that BiPAP was as effective as CPAP in the treatment of OSA in patients with no comorbidities. For patients with OSA and comorbidities, a level III evidence study reported an increased level of comfort in patients using BiPAP.

 

 

PATIENT-CENTERED STRATEGIES TO IMPROVE ADHERENCE

Innovative strategies and approaches focusing on patient factors affecting PAP adherence include motivational interviewing, motivational enhancement, telemedicine, and desensitization techniques.

Motivational interviews and enhancement

Motivational interviewing and motivational enhancement were first used to help with alcohol abuse.¹⁷ Motivational interviewing is goal-oriented, patient-centered counseling to elicit a particular behavioral change. The goal is to explore and resolve ambivalence, increase engagement, and evoke a positive response and perspective that builds momentum and results in action.

Motivational enhancement and motivational engagement in the use of PAP therapy were evaluated in the Patient Engagement Study.¹⁸ Patients were assigned to usual care (n = 85,358) or active patient engagement (APE) (n = 42,679). Usual care involved diagnosis of apnea, initiation of CPAP, and follow-up, whereas APE included daily feedback (ie, daily scores of apnea–hypopnea index, mask leaks, hours used), positive praise messages, and personal coaching assistance. Overall adherence for patients assigned to APE was 87% compared with 70% in the usual-care group. The hours of use per night also increased for patients in the APE group.

The Best Apnea Interventions for Research trial randomized patients with or at risk of cardiovascular disease (N = 169) to CPAP alone or CPAP with motivational enhancements for 6 months.¹⁹ Motivational enhancements and interventions included brief in-person and phone interventions. An overall average difference of 99 minutes per night improvement in CPAP use was reported in the motivational enhancement group compared with CPAP alone.

The Motivational Interviewing Nurse Therapy study trained nurses in motivational interviewing and randomized 106 patients with newly diagnosed OSA to CPAP alone or CPAP plus motivational interviews.²⁰ Motivational interviews involved 3 sessions: 1 to build motivation prior to the CPAP titration, 1 to strengthen the commitment to achieve the prescribed time, and a booster session 1 month after CPAP setup. Adherence was found to improve at 1, 2, and 3 months in the motivational interview group; however, no difference between the 2 groups in adherence was noted at 12 months.

Telemedicine

The role of telemedicine in improving adherence with CPAP therapy was evaluated in 75 patients with moderate to severe apnea randomized to APAP alone or with phone call support from a research coordinator.²¹ Phone calls occurred 2 days after device setup, and daily monitoring of several factors was done via modem. Patients were contacted if the mask was leaking more than 30% of the night, use was less than 4 hours per night on 2 consecutive nights, the apnea–hypopnea index was greater than 10, or the average pressure needed was higher than 16 cm of water. Statistically significant improvement was found in the telemedicine group in mean adherence, minutes used per day, and mean amount of time spent with the patients.

Desensitization to PAP therapy

Case scenario #6

A 33-year-old woman with a history of anxiety and depression and a remote history of abuse as a child was diagnosed with severe apnea. When she tries to use her CPAP, she has a sense of panic and cannot proceed.

Which of the following has NOT been shown to be beneficial in this situation?

1. Psychologist for behavioral therapy
2. Desensitization protocol
3. PAP “NAP”
4. Short-acting hypnotics
5. None of the above

Answer: Short-acting hypnotics.

The short-acting hypnotic zaleplon (Sonata) was evaluated in a 1-month study of 88 patients compared with placebo control, and no difference was found between the 2 groups in measures of adherence to therapy or symptoms.²²

A protocol for desensitization to CPAP use is helpful to assist patients in acclimating to therapy. An example of the steps in a desensitization protocol that patients can do at home is provided in Table 1.

PAP NAP. For some people, at-home desensitization is not enough, and a sleep lab session may be needed. A PAP NAP is a daytime study conducted in the sleep lab. Patients do not necessarily sleep, but work with a technologist with a minimal hookup to polysomnography equipment on mask desensitization, as well as biofeedback techniques. PAP NAPs are indicated for patients with claustrophobia, anxiety surrounding PAP therapy, or pressure intolerance.

A study of 99 patients with moderate to severe apnea and insomnia and concomitant psychiatric disorders resistant to CPAP evaluated adherence in a group receiving a PAP NAP (n = 39) compared with a control group (n = 60).²³ The PAP NAP group had marked improvement in completion of CPAP titration in the lab, filling the CPAP prescription, and using CPAP more than 5 days a week and more than 4 hours a night.

A new innovative concept called the Sleep Apnea Patient-Centered Outcomes Network is a collaborative group that includes patients, researchers, and clinicians.²⁴ The group addresses issues such as cost, outcomes, and value in the diagnosis and treatment of sleep apnea. A patient-centered website provides forums, education, and data collection capability for researchers (myapnea.org).

SUMMARY

PAP therapy is the gold standard for treatment of patients with moderate to severe OSA, though poor adherence to PAP therapy is a persistent problem. Advanced features in PAP devices such as APAP and other innovative strategies like motivational enhancement and desensitization protocols and PAP NAP are being used to address poor adherence. More randomized controlled trials are needed to evaluate PAP for sleep apnea.

The most widely used treatment for patients with obstructive sleep apnea (OSA) is positive airway pressure (PAP) therapy. Improved quality of life and cardiovascular outcomes for patients with OSA using PAP have been demonstrated. However, for some patients with OSA, PAP therapy is difficult to use or tolerate. Fortunately, there are other available treatment interventions for patients with OSA such as lifestyle interventions, surgical interventions, hypoglossal nerve stimulation (HNS), oral appliance therapy (OAT), and expiratory PAP (EPAP) devices. These alternative treatments can also improve symptoms of OSA though data regarding cardiovascular outcomes are lacking.

LIFESTYLE INTERVENTIONS

Weight loss

Because a higher body mass index (BMI) increases the risk for OSA, weight loss should be recommended for patients with OSA who are overweight. Much of the research evaluating the effect of weight loss on OSA has methodologic limitations such as lack of randomization or controls, potential confounding variables, and limited follow-up. A randomized controlled trial of 72 overweight patients with mild OSA (apnea–hypopnea index [AHI] of 5 to 15) compared a group assigned to a very low calorie diet and lifestyle counseling with a control group.¹ At 1 year, weight loss of 15 kg or more resulted in a statistically significant reduction in their AHI to normal, resolving their OSA. A 15 kg weight loss in this study was associated with an overall reduction in the AHI of at least 2 units.

Exercise

Exercise is also recommended for patients with OSA, and it can lessen the severity of symptoms even without weight loss. A meta-analysis of 5 randomized trials of 129 patients reported a reduction in the AHI of as much as 6 events per hour in individuals assigned to a strict exercise regimen.² The reduction in the AHI occurred despite a slight reduction in BMI (1.37 kg/m²).

Sleep position

For some patients, sleeping in the supine position may worsen their OSA, in which case avoiding the supine sleep position is recommended. A sleep study such as polysomnography should be performed to confirm the resolution of OSA in the nonsupine position.³ Products such as pillows or vibratory feedback devices can help the patient avoid sleeping on the back. The ability to monitor patient adherence to sleep position therapy alone is very limited.

Alcohol avoidance

Alcohol consumption depresses the central nervous system, promotes waking, and increases daytime sleepiness, thus exacerbating OSA. Patients with untreated OSA should avoid alcohol because it worsens the duration and frequency of obstructive respiratory events during sleep, and it can worsen the degree of oxygen desaturation that occurs during abnormal respiratory events.⁴

Concomitant medications

A review of medications in patients with OSA is warranted. Use of benzodiazepines, benzodiazepine-receptor agonists, barbiturates, and opiates in patients with OSA should be avoided especially if OSA is untreated. If these medications are necessary, careful monitoring is recommended. Medications that can cause weight gain such as some antidepressants should also be avoided.

SURGICAL INTERVENTIONS

Surgical interventions for OSA target the location of the obstruction in the upper airway. The upper airway consists of 3 regions: the palate, oropharynx, and larynx.⁵ More than 30 surgical soft-tissue and skeletal interventions for OSA are reported in the literature.⁶

Evaluating the outcomes of various surgical interventions for OSA is hindered by differences in the definition of surgical success or cure. As such, surgical interventions for OSA remain controversial. The practice parameters from 2010 reviewed surgical modifications of the upper airway for adults with OSA.^7,8 Success is defined as a greater than 50% reduction in the AHI to fewer than 20 events per hour, whereas surgical cure is defined as a reduction in the AHI to fewer than 5 events per hour.⁷

Table 1 lists commonly used surgical procedures for OSA and reported outcomes, though the quality of evidence to evaluate these procedures is low.⁸

Uvulopalatopharyngoplasty

Uvulopalatopharyngoplasty (UPPP) is a surgical procedure that remodels the throat via removal of the tonsils and the posterior surface of the soft palate and uvula and closure of the tonsillar pillars, and thus addresses retropalatal collapse. UPPP rarely achieves a surgical cure (ie, AHI < 5) and has been shown to have a 33% reduction in the AHI, with a postoperative average AHI remaining elevated at 29.⁸ (ie, moderate to severe OSA).8 In general, 50% of patients have a 50% reduction in AHI.⁹ The 4-year responder rate for UPPP is 44% to 50%.¹⁰ Factors limiting the long-term success of this procedure include weight gain, assessment of surgical candidates,¹¹ and decreased adherence to PAP therapy after the procedure.

The use of UPPP in combination with other surgical procedures has also been evaluated.⁸ The AHI in patients with OSA improved postoperatively when UPPP was done simultaneously or in a multiphase approach with radiofrequency ablation, midline glossectomy, tongue advancement, hyoid suspension, or maxillomandibular advancement, though greater improvement was noted with the multiphase approach.

Maxillomandibular advancement

Maxillomandibular advancement is a surgical procedure that moves the maxilla and mandible forward and expands the facial skeletal framework via LeFort I maxillary and sagittal split mandibular osteotomies. Maxillomandibular advancement achieves enlargement of the nasopharyngeal, retropalatal, and hypopharyngeal airway. This increases tension on the pharyngeal soft tissue, which enlarges the medial-lateral and anteroposterior dimensions of the upper airway.¹⁴

A meta-analysis of 45 studies evaluated the change in the AHI after maxillomandibular advancement in 518 patients.¹⁵ Secondary outcomes were surgical success (> 50% reduction in AHI to < 20 events per hour) and surgical cure (AHI < 5). Patients with a higher preoperative AHI achieved the greatest magnitude reduction in AHI but were less likely to achieve surgical success or cure. Patients with a lower preoperative AHI had a greater likelihood of surgical success and cure.

Bariatric surgery

Bariatric surgery is increasingly used for treatment of OSA in individuals with morbid obesity. A systematic review of bariatric surgery including the roux-en-Y gastric bypass, laparoscopic sleeve gastrectomy, and biliopancreatic diversion evaluated 69 studies with 13,900 patients with OSA.¹⁶ OSA was found to be improved or eliminated in 75% of patients for all bariatric surgery procedures.

 

 

HYPOGLOSSAL NERVE STIMULATION

Used with permission from Inspire Medical Systems, Inc.

HNS, or upper airway stimulation, is a new, fully implantable treatment for patients with OSA. The system consists of an implanted pulse generator (IPG), sensing lead, and stimulation lead.¹⁷ The device is implanted unilaterally via incisions under the clavicle for the IPG, on the chest for the sensing lead, and on the neck for the stimulation lead (Figure 1).

The IPG contains a battery, computer, and lead connector block. It receives information from the sensing lead, operates timing and output algorithms, conveys energy to the stimulation lead, and also serves as a return electrode for advanced stimulation configurations. The sensing lead monitors breathing during sleep and detects pressure changes in the respiratory cycle and conveys this information to the IPG. The stimulation lead encircles the medial branch of the hypoglossal nerve (cranial nerve XII) with an electrode cuff. Stimulation as generated from the IPG is delivered to key airway muscles, which are controlled by the hypoglossal nerve, primarily the genioglossus muscle responsible for tongue protrusion. The device can be turned on and off with a handheld sleep remote.

Indications and contraindications

The indications and contraindications for HNS are shown in Table 2.

Efficacy and outcomes

Stimulation of the hypoglossal nerve results in a multilevel mechanism of action: activation and protrusion of the tongue opens the oropharyngeal airway directly but also affects the retropalatal airway by a palatoglossal coupling action.¹⁹ Sleep lab testing with polysomnography is used to titrate the voltage of HNS to achieve an open airway that resolves apneic events and normalizes airflow, breathing patterns, and oxygen saturation levels.

Approval of HNS for OSA by the US Food and Drug Administration was based on findings in the Stimulation Therapy for Apnea Reduction (STAR) trial,¹⁷ a prospective trial of 126 patients at 22 centers in the United States and Europe with the primary outcomes of AHI and oxygen desaturation index. Secondary outcomes included quality of life as measured by the Functional Outcomes of Sleep Questionnaire and Epworth Sleepiness Scale (ESS). Patient demographics included mean age 54.5, 83% men, mean BMI of 28 kg/m², and mean baseline AHI of 34 (ie, severe OSA).

Data at 5 years for 97 of the 126 patients on HNS in the STAR trial is available.²⁰ The AHI was reduced an average of 70% to levels in the mild OSA range.^20,21 Overall, 85% of the patients had improved quality-of-life measures after HNS implantation, with increased Functional Outcomes of Sleep Questionnaire scores and ESS scores in the normal range over time. Consistent HNS therapy demonstrated sustained benefits at 5 years. The AHI improved by 50% or to less than 20 in 75% of patients, with 44% having resolved OSA and 78% improved to mild OSA (AHI < 15). Device-related adverse events occurred in 6% (9 of 126) of patients requiring replacement or repositioning of the stimulator or leads.²⁰

Moderate to severe snoring was prevalent at baseline in the STAR trial, but over the course of 5 years, 85% of bed partners of patients on HNS reported no or soft snoring.^17,21 Nightly use averaged 80% over 60 months based on patient reporting, with 87% reporting use at least 5 nights per week at 36 weeks.²⁰

In terms of predictors of response to HNS therapy, the oxygen desaturation index is the only characteristic that reached a level of statistical significance; patients with higher levels of oxygen desaturation tended to improve and tolerate therapy better long-term.²⁰ A randomized controlled trial of withdrawal of HNS therapy demonstrated increased AHI and oxygen desaturation index when therapy was withdrawn, followed by improvement when therapy resumed.²²

A clinical trial of 20 patients implanted with HNS after its approval in 2014 reported that the mean AHI decreased from 33 before implant to 5.1 after implant.²³ The ESS also improved from 10.3 before implant to 6 after implant. Mean adherence to device use was 7 (± 2) hours per night. The average stimulation amplitude was 1.89 (± 0.5) volts after the titration sleep study was completed. Similar reductions in AHI were reported by Huntley et al²⁴ for patients receiving HNS implant at 2 academic centers, with no differences between the 2 cohorts in postoperative AHI.

Adverse events

The adverse events reported with HNS are related to the implant procedure or the device.²¹ Procedure-related adverse events are incision discomfort, temporary tongue weakness, headache, and mild infection of incisions. The most common device-related adverse event is discomfort from the electrical stimulation. Tongue abrasion can also occur if the tongue protrudes and rubs against a sharp tooth. Dry mouth is also commonly reported.

HNS compared with UPPP

Outcomes in patients with moderate to severe OSA matched for BMI, demographics, and preoperative AHI were evaluated comparing patients undergoing HNS (n = 20) with patients receiving UPPP (n = 20).²⁵ The AHI decreased 29% postoperatively in patients with UPPP compared with 88% in patients with HNS, 65% of which had normalization of their AHI. Surgical success was achieved in 40% of patients in the UPPP group compared with 100% in the HNS group. Greater improvement in daytime sleepiness was noted in patients in the HNS group compared with the UPPP group.

 

 

ORAL APPLIANCE THERAPY

OAT devices help protrude the mandible forward and stabilize it to maintain a more patent airway during sleep. Oral appliances can be custom-made or prefabricated. Oral appliances can be titratable or nontitratable: titration provides a mechanism to adjust mandibular protrusion analogous to PAP titration, whereas the absence of titration holds the mandible in a single position. The most effective oral appliances are custom-made and titratable.

Types of OAT devices

Custom oral appliances. Custom oral appliances are fabricated using digital or physical impressions of the patient’s oral structures. Custom oral appliances are made of biocompatible materials and engage both the maxillary and mandibular arches.

Custom oral appliances are made by a qualified dentist who takes maxillary and mandibular impressions with a bite registration using the George Gauge with 40% to 50% of maximum protrusion. The appliance is fabricated in a laboratory and then fitted to the patient, who is instructed to titrate the device 0.5 mm to 1 mm per week and follow-up with the dentist at 2-week intervals. Once the patient has titrated the device to the point of comfort or improved sleep quality or snoring, polysomnography should be done with the device in place and titrated to improve the AHI as much as possible. Follow-up is recommended at 6 months and annually thereafter.

Prefabricated oral appliances. Prefabricated oral appliances are of the boil-and-bite type, only partially modified to the patient’s oral structures.

Tongue-retaining devices. Another type of oral appliance is a tongue-retaining device, which is designed to hold the tongue forward and can be custom-made or prefabricated.

Patient considerations for OAT

OAT is not appropriate for all patients with OSA, and the indications and contraindications for use of OAT are presented in Table 3. If OAT is indicated, several considerations may influence the type of device that is most appropriate for the patient (Table 4).

Practice recommendations

The American Academy of Sleep Medicine and American Academy of Dental Sleep Medicine established clinical practice guidelines and recommendations for OAT in patients with OSA:

• Prescribed OAT should be done by a qualified dentist, and a custom, titratable appliance is preferred
• OAT is preferred over no therapy for adults with OSA who are intolerant to PAP or prefer alternative therapies
• A qualified dentist should provide oversight for dental-related side effects or occlusal changes
• Follow-up sleep testing should be conducted to confirm efficacy or titrate treatment
• Periodic office visits with the sleep physician and qualified dentist are recommended.²⁶

The quality of evidence for these recommendations is low, with the exception of use of OAT rather than no therapy, which is considered of moderate quality.

Effects of OAT

Anatomic and physiologic effects. With OAT in place in the mouth, the airway caliber in the lateral dimension are increased, and the airway size at the retropalatal level is increased.^27–30 With respect to the tongue, increased genioglossus muscle activity has been reported with OAT.

Side effects. Side effects of OAT include excess salivation, dry mouth, tooth tenderness, soft-tissue changes, jaw discomfort, tooth movement, and occlusal changes such as difficulty chewing in the morning. Feelings of suffocation, vivid dreams, and anxiety have also been reported with OAT.^31–33

Efficacy and outcomes

Review of the data on the efficacy of OAT did not illuminate factors that predict treatment success.²⁶ Data indicate that in patients with mild OSA using OAT or PAP therapy, there was no significant difference in the percentage achieving their target AHI; however, patients with moderate to severe OSA had a statistically significant greater odds of achieving their target AHI using PAP therapy compared with OAT. Therefore, OAT should be reserved for patients with severe OSA who cannot use or are intolerant to PAP.

Moderate-grade quality of evidence was reviewed for the established OAT practice recommendations for OSA outcomes before and after use of custom, titratable OAT devices.²⁶ Use of a custom OAT device reduced the mean AHI, increased mean oxygen saturation, decreased the mean oxygen desaturation, decreased the arousal index, decreased the ESS, and increased quality of life compared with values prior to use of OAT.

With respect to adherence and discontinuation, patients using OAT had higher mean adherence and lower discontinuation because of side effects compared with patients using continuous PAP.²⁶

 

 

NASAL EPAP THERAPY

Nasal EPAP is a new treatment for OSA that consists of a mechanical valve worn in each naris at night. The valves have a low inspiratory resistance and a high expiratory resistance thus increased pressure occurs at exhalation.

Pressure at exhalation may counter the airway collapse in OSA. With the mouth closed and use of the nasal valves, the positive pressure during the normal respiratory cycle is utilized to maintain an open airway.³⁴ At the onset and throughout inspiration, the activity of the airway dilator muscles increases. At maximum expiration, right before the end of the expiratory pause, the dilator muscle stops abruptly and the airway is of its smallest caliber. The presence of the nasal valve at this point is thought to act as a pneumatic splint to the airway, and the nasal EPAP helps keep the airway patent during the next inspiratory phase.

Nasal EPAP valves are available in a 30-day starter kit. Intended for single-night use, the kit includes valves of increasing levels of expiration resistance: low (nights 1 and 2), medium (nights 3 and 4), and normal (nights 5–30).

Outcomes of nasal EPAP therapy

A multicenter 30-day in-home trial evaluated efficacy and compliance of nasal EPAP therapy.³⁵ The AHI was reduced by 50% or more in 14 of 34 (41%) patients using nasal EPAP compared with the control group at the 30-day follow-up. The patient-reported compliance with nasal EPAP was 94%. Patients in this study had mild to moderate OSA and did not have obesity or other comorbidities such as pulmonary hypertension or cardiovascular disease.

A randomized controlled trial compared nasal EPAP with a sham device in patients with newly diagnosed or untreated OSA (N = 250) for 3 months.³⁶ A median reduction of 52% in the AHI was noted in the intention-to-treat group (N = 229) during rapid eye movement (REM) and non-REM sleep, though it was statistically significant only during REM sleep and supine sleep. At 3 months, improved OSA was maintained in 42% of the patients using nasal EPAP compared with 10% of patients using a sham device. Improvements in daytime sleepiness and adherence with 88% using EPAP the entire night were also noted.

In a 12-month study of nasal EPAP, 67% of patients (34 of 51) used nasal EPAP for the full trial duration.³⁷ Of patients using nasal EPAP for 12 months, the median AHI was reduced by 71%, the ESS improved, and adherence to full-night use was 89%.

Patient considerations for nasal EPAP

In clinical practice, nasal EPAP therapy requires nasal patency and use of a chin strap in patients with mouth leakage. Nasal EPAP may be recommended for patients who travel frequently and can go without continuous PAP or bilevel PAP for short periods of time, and for patients who do not have significant medical comorbidities.

Side effects and limitations of nasal EPAP

Reported side effects of nasal EPAP include difficulty with exhalation, nasal discomfort, dry mouth, and headache. Nasal EPAP therapy is of limited use in patients with severe OSA and severe oxygen desaturation. The efficacy of nasal EPAP beyond 12 months is unknown. Use of nasal EPAP in patients with prior upper-airway surgery and in combination with other therapies is yet to be evaluated.

The most widely used treatment for patients with obstructive sleep apnea (OSA) is positive airway pressure (PAP) therapy. Improved quality of life and cardiovascular outcomes for patients with OSA using PAP have been demonstrated. However, for some patients with OSA, PAP therapy is difficult to use or tolerate. Fortunately, there are other available treatment interventions for patients with OSA such as lifestyle interventions, surgical interventions, hypoglossal nerve stimulation (HNS), oral appliance therapy (OAT), and expiratory PAP (EPAP) devices. These alternative treatments can also improve symptoms of OSA though data regarding cardiovascular outcomes are lacking.

LIFESTYLE INTERVENTIONS

Weight loss

Because a higher body mass index (BMI) increases the risk for OSA, weight loss should be recommended for patients with OSA who are overweight. Much of the research evaluating the effect of weight loss on OSA has methodologic limitations such as lack of randomization or controls, potential confounding variables, and limited follow-up. A randomized controlled trial of 72 overweight patients with mild OSA (apnea–hypopnea index [AHI] of 5 to 15) compared a group assigned to a very low calorie diet and lifestyle counseling with a control group.¹ At 1 year, weight loss of 15 kg or more resulted in a statistically significant reduction in their AHI to normal, resolving their OSA. A 15 kg weight loss in this study was associated with an overall reduction in the AHI of at least 2 units.

Exercise

Exercise is also recommended for patients with OSA, and it can lessen the severity of symptoms even without weight loss. A meta-analysis of 5 randomized trials of 129 patients reported a reduction in the AHI of as much as 6 events per hour in individuals assigned to a strict exercise regimen.² The reduction in the AHI occurred despite a slight reduction in BMI (1.37 kg/m²).

Sleep position

For some patients, sleeping in the supine position may worsen their OSA, in which case avoiding the supine sleep position is recommended. A sleep study such as polysomnography should be performed to confirm the resolution of OSA in the nonsupine position.³ Products such as pillows or vibratory feedback devices can help the patient avoid sleeping on the back. The ability to monitor patient adherence to sleep position therapy alone is very limited.

Alcohol avoidance

Alcohol consumption depresses the central nervous system, promotes waking, and increases daytime sleepiness, thus exacerbating OSA. Patients with untreated OSA should avoid alcohol because it worsens the duration and frequency of obstructive respiratory events during sleep, and it can worsen the degree of oxygen desaturation that occurs during abnormal respiratory events.⁴

Concomitant medications

A review of medications in patients with OSA is warranted. Use of benzodiazepines, benzodiazepine-receptor agonists, barbiturates, and opiates in patients with OSA should be avoided especially if OSA is untreated. If these medications are necessary, careful monitoring is recommended. Medications that can cause weight gain such as some antidepressants should also be avoided.

SURGICAL INTERVENTIONS

Surgical interventions for OSA target the location of the obstruction in the upper airway. The upper airway consists of 3 regions: the palate, oropharynx, and larynx.⁵ More than 30 surgical soft-tissue and skeletal interventions for OSA are reported in the literature.⁶

Evaluating the outcomes of various surgical interventions for OSA is hindered by differences in the definition of surgical success or cure. As such, surgical interventions for OSA remain controversial. The practice parameters from 2010 reviewed surgical modifications of the upper airway for adults with OSA.^7,8 Success is defined as a greater than 50% reduction in the AHI to fewer than 20 events per hour, whereas surgical cure is defined as a reduction in the AHI to fewer than 5 events per hour.⁷

Table 1 lists commonly used surgical procedures for OSA and reported outcomes, though the quality of evidence to evaluate these procedures is low.⁸

Uvulopalatopharyngoplasty

Uvulopalatopharyngoplasty (UPPP) is a surgical procedure that remodels the throat via removal of the tonsils and the posterior surface of the soft palate and uvula and closure of the tonsillar pillars, and thus addresses retropalatal collapse. UPPP rarely achieves a surgical cure (ie, AHI < 5) and has been shown to have a 33% reduction in the AHI, with a postoperative average AHI remaining elevated at 29.⁸ (ie, moderate to severe OSA).8 In general, 50% of patients have a 50% reduction in AHI.⁹ The 4-year responder rate for UPPP is 44% to 50%.¹⁰ Factors limiting the long-term success of this procedure include weight gain, assessment of surgical candidates,¹¹ and decreased adherence to PAP therapy after the procedure.

The use of UPPP in combination with other surgical procedures has also been evaluated.⁸ The AHI in patients with OSA improved postoperatively when UPPP was done simultaneously or in a multiphase approach with radiofrequency ablation, midline glossectomy, tongue advancement, hyoid suspension, or maxillomandibular advancement, though greater improvement was noted with the multiphase approach.

Maxillomandibular advancement

Maxillomandibular advancement is a surgical procedure that moves the maxilla and mandible forward and expands the facial skeletal framework via LeFort I maxillary and sagittal split mandibular osteotomies. Maxillomandibular advancement achieves enlargement of the nasopharyngeal, retropalatal, and hypopharyngeal airway. This increases tension on the pharyngeal soft tissue, which enlarges the medial-lateral and anteroposterior dimensions of the upper airway.¹⁴

A meta-analysis of 45 studies evaluated the change in the AHI after maxillomandibular advancement in 518 patients.¹⁵ Secondary outcomes were surgical success (> 50% reduction in AHI to < 20 events per hour) and surgical cure (AHI < 5). Patients with a higher preoperative AHI achieved the greatest magnitude reduction in AHI but were less likely to achieve surgical success or cure. Patients with a lower preoperative AHI had a greater likelihood of surgical success and cure.

Bariatric surgery

Bariatric surgery is increasingly used for treatment of OSA in individuals with morbid obesity. A systematic review of bariatric surgery including the roux-en-Y gastric bypass, laparoscopic sleeve gastrectomy, and biliopancreatic diversion evaluated 69 studies with 13,900 patients with OSA.¹⁶ OSA was found to be improved or eliminated in 75% of patients for all bariatric surgery procedures.

 

 

HYPOGLOSSAL NERVE STIMULATION

Used with permission from Inspire Medical Systems, Inc.

HNS, or upper airway stimulation, is a new, fully implantable treatment for patients with OSA. The system consists of an implanted pulse generator (IPG), sensing lead, and stimulation lead.¹⁷ The device is implanted unilaterally via incisions under the clavicle for the IPG, on the chest for the sensing lead, and on the neck for the stimulation lead (Figure 1).

The IPG contains a battery, computer, and lead connector block. It receives information from the sensing lead, operates timing and output algorithms, conveys energy to the stimulation lead, and also serves as a return electrode for advanced stimulation configurations. The sensing lead monitors breathing during sleep and detects pressure changes in the respiratory cycle and conveys this information to the IPG. The stimulation lead encircles the medial branch of the hypoglossal nerve (cranial nerve XII) with an electrode cuff. Stimulation as generated from the IPG is delivered to key airway muscles, which are controlled by the hypoglossal nerve, primarily the genioglossus muscle responsible for tongue protrusion. The device can be turned on and off with a handheld sleep remote.

Indications and contraindications

The indications and contraindications for HNS are shown in Table 2.

Efficacy and outcomes

Stimulation of the hypoglossal nerve results in a multilevel mechanism of action: activation and protrusion of the tongue opens the oropharyngeal airway directly but also affects the retropalatal airway by a palatoglossal coupling action.¹⁹ Sleep lab testing with polysomnography is used to titrate the voltage of HNS to achieve an open airway that resolves apneic events and normalizes airflow, breathing patterns, and oxygen saturation levels.

Approval of HNS for OSA by the US Food and Drug Administration was based on findings in the Stimulation Therapy for Apnea Reduction (STAR) trial,¹⁷ a prospective trial of 126 patients at 22 centers in the United States and Europe with the primary outcomes of AHI and oxygen desaturation index. Secondary outcomes included quality of life as measured by the Functional Outcomes of Sleep Questionnaire and Epworth Sleepiness Scale (ESS). Patient demographics included mean age 54.5, 83% men, mean BMI of 28 kg/m², and mean baseline AHI of 34 (ie, severe OSA).

Data at 5 years for 97 of the 126 patients on HNS in the STAR trial is available.²⁰ The AHI was reduced an average of 70% to levels in the mild OSA range.^20,21 Overall, 85% of the patients had improved quality-of-life measures after HNS implantation, with increased Functional Outcomes of Sleep Questionnaire scores and ESS scores in the normal range over time. Consistent HNS therapy demonstrated sustained benefits at 5 years. The AHI improved by 50% or to less than 20 in 75% of patients, with 44% having resolved OSA and 78% improved to mild OSA (AHI < 15). Device-related adverse events occurred in 6% (9 of 126) of patients requiring replacement or repositioning of the stimulator or leads.²⁰

Moderate to severe snoring was prevalent at baseline in the STAR trial, but over the course of 5 years, 85% of bed partners of patients on HNS reported no or soft snoring.^17,21 Nightly use averaged 80% over 60 months based on patient reporting, with 87% reporting use at least 5 nights per week at 36 weeks.²⁰

In terms of predictors of response to HNS therapy, the oxygen desaturation index is the only characteristic that reached a level of statistical significance; patients with higher levels of oxygen desaturation tended to improve and tolerate therapy better long-term.²⁰ A randomized controlled trial of withdrawal of HNS therapy demonstrated increased AHI and oxygen desaturation index when therapy was withdrawn, followed by improvement when therapy resumed.²²

A clinical trial of 20 patients implanted with HNS after its approval in 2014 reported that the mean AHI decreased from 33 before implant to 5.1 after implant.²³ The ESS also improved from 10.3 before implant to 6 after implant. Mean adherence to device use was 7 (± 2) hours per night. The average stimulation amplitude was 1.89 (± 0.5) volts after the titration sleep study was completed. Similar reductions in AHI were reported by Huntley et al²⁴ for patients receiving HNS implant at 2 academic centers, with no differences between the 2 cohorts in postoperative AHI.

Adverse events

The adverse events reported with HNS are related to the implant procedure or the device.²¹ Procedure-related adverse events are incision discomfort, temporary tongue weakness, headache, and mild infection of incisions. The most common device-related adverse event is discomfort from the electrical stimulation. Tongue abrasion can also occur if the tongue protrudes and rubs against a sharp tooth. Dry mouth is also commonly reported.

HNS compared with UPPP

Outcomes in patients with moderate to severe OSA matched for BMI, demographics, and preoperative AHI were evaluated comparing patients undergoing HNS (n = 20) with patients receiving UPPP (n = 20).²⁵ The AHI decreased 29% postoperatively in patients with UPPP compared with 88% in patients with HNS, 65% of which had normalization of their AHI. Surgical success was achieved in 40% of patients in the UPPP group compared with 100% in the HNS group. Greater improvement in daytime sleepiness was noted in patients in the HNS group compared with the UPPP group.

 

 

ORAL APPLIANCE THERAPY

OAT devices help protrude the mandible forward and stabilize it to maintain a more patent airway during sleep. Oral appliances can be custom-made or prefabricated. Oral appliances can be titratable or nontitratable: titration provides a mechanism to adjust mandibular protrusion analogous to PAP titration, whereas the absence of titration holds the mandible in a single position. The most effective oral appliances are custom-made and titratable.

Types of OAT devices

Custom oral appliances. Custom oral appliances are fabricated using digital or physical impressions of the patient’s oral structures. Custom oral appliances are made of biocompatible materials and engage both the maxillary and mandibular arches.

Custom oral appliances are made by a qualified dentist who takes maxillary and mandibular impressions with a bite registration using the George Gauge with 40% to 50% of maximum protrusion. The appliance is fabricated in a laboratory and then fitted to the patient, who is instructed to titrate the device 0.5 mm to 1 mm per week and follow-up with the dentist at 2-week intervals. Once the patient has titrated the device to the point of comfort or improved sleep quality or snoring, polysomnography should be done with the device in place and titrated to improve the AHI as much as possible. Follow-up is recommended at 6 months and annually thereafter.

Prefabricated oral appliances. Prefabricated oral appliances are of the boil-and-bite type, only partially modified to the patient’s oral structures.

Tongue-retaining devices. Another type of oral appliance is a tongue-retaining device, which is designed to hold the tongue forward and can be custom-made or prefabricated.

Patient considerations for OAT

OAT is not appropriate for all patients with OSA, and the indications and contraindications for use of OAT are presented in Table 3. If OAT is indicated, several considerations may influence the type of device that is most appropriate for the patient (Table 4).

Practice recommendations

The American Academy of Sleep Medicine and American Academy of Dental Sleep Medicine established clinical practice guidelines and recommendations for OAT in patients with OSA:

• Prescribed OAT should be done by a qualified dentist, and a custom, titratable appliance is preferred
• OAT is preferred over no therapy for adults with OSA who are intolerant to PAP or prefer alternative therapies
• A qualified dentist should provide oversight for dental-related side effects or occlusal changes
• Follow-up sleep testing should be conducted to confirm efficacy or titrate treatment
• Periodic office visits with the sleep physician and qualified dentist are recommended.²⁶

The quality of evidence for these recommendations is low, with the exception of use of OAT rather than no therapy, which is considered of moderate quality.

Effects of OAT

Anatomic and physiologic effects. With OAT in place in the mouth, the airway caliber in the lateral dimension are increased, and the airway size at the retropalatal level is increased.^27–30 With respect to the tongue, increased genioglossus muscle activity has been reported with OAT.

Side effects. Side effects of OAT include excess salivation, dry mouth, tooth tenderness, soft-tissue changes, jaw discomfort, tooth movement, and occlusal changes such as difficulty chewing in the morning. Feelings of suffocation, vivid dreams, and anxiety have also been reported with OAT.^31–33

Efficacy and outcomes

Review of the data on the efficacy of OAT did not illuminate factors that predict treatment success.²⁶ Data indicate that in patients with mild OSA using OAT or PAP therapy, there was no significant difference in the percentage achieving their target AHI; however, patients with moderate to severe OSA had a statistically significant greater odds of achieving their target AHI using PAP therapy compared with OAT. Therefore, OAT should be reserved for patients with severe OSA who cannot use or are intolerant to PAP.

Moderate-grade quality of evidence was reviewed for the established OAT practice recommendations for OSA outcomes before and after use of custom, titratable OAT devices.²⁶ Use of a custom OAT device reduced the mean AHI, increased mean oxygen saturation, decreased the mean oxygen desaturation, decreased the arousal index, decreased the ESS, and increased quality of life compared with values prior to use of OAT.

With respect to adherence and discontinuation, patients using OAT had higher mean adherence and lower discontinuation because of side effects compared with patients using continuous PAP.²⁶

 

 

NASAL EPAP THERAPY

Nasal EPAP is a new treatment for OSA that consists of a mechanical valve worn in each naris at night. The valves have a low inspiratory resistance and a high expiratory resistance thus increased pressure occurs at exhalation.

Pressure at exhalation may counter the airway collapse in OSA. With the mouth closed and use of the nasal valves, the positive pressure during the normal respiratory cycle is utilized to maintain an open airway.³⁴ At the onset and throughout inspiration, the activity of the airway dilator muscles increases. At maximum expiration, right before the end of the expiratory pause, the dilator muscle stops abruptly and the airway is of its smallest caliber. The presence of the nasal valve at this point is thought to act as a pneumatic splint to the airway, and the nasal EPAP helps keep the airway patent during the next inspiratory phase.

Nasal EPAP valves are available in a 30-day starter kit. Intended for single-night use, the kit includes valves of increasing levels of expiration resistance: low (nights 1 and 2), medium (nights 3 and 4), and normal (nights 5–30).

Outcomes of nasal EPAP therapy

A multicenter 30-day in-home trial evaluated efficacy and compliance of nasal EPAP therapy.³⁵ The AHI was reduced by 50% or more in 14 of 34 (41%) patients using nasal EPAP compared with the control group at the 30-day follow-up. The patient-reported compliance with nasal EPAP was 94%. Patients in this study had mild to moderate OSA and did not have obesity or other comorbidities such as pulmonary hypertension or cardiovascular disease.

A randomized controlled trial compared nasal EPAP with a sham device in patients with newly diagnosed or untreated OSA (N = 250) for 3 months.³⁶ A median reduction of 52% in the AHI was noted in the intention-to-treat group (N = 229) during rapid eye movement (REM) and non-REM sleep, though it was statistically significant only during REM sleep and supine sleep. At 3 months, improved OSA was maintained in 42% of the patients using nasal EPAP compared with 10% of patients using a sham device. Improvements in daytime sleepiness and adherence with 88% using EPAP the entire night were also noted.

In a 12-month study of nasal EPAP, 67% of patients (34 of 51) used nasal EPAP for the full trial duration.³⁷ Of patients using nasal EPAP for 12 months, the median AHI was reduced by 71%, the ESS improved, and adherence to full-night use was 89%.

Patient considerations for nasal EPAP

In clinical practice, nasal EPAP therapy requires nasal patency and use of a chin strap in patients with mouth leakage. Nasal EPAP may be recommended for patients who travel frequently and can go without continuous PAP or bilevel PAP for short periods of time, and for patients who do not have significant medical comorbidities.

Side effects and limitations of nasal EPAP

Reported side effects of nasal EPAP include difficulty with exhalation, nasal discomfort, dry mouth, and headache. Nasal EPAP therapy is of limited use in patients with severe OSA and severe oxygen desaturation. The efficacy of nasal EPAP beyond 12 months is unknown. Use of nasal EPAP in patients with prior upper-airway surgery and in combination with other therapies is yet to be evaluated.

The most widely used treatment for patients with obstructive sleep apnea (OSA) is positive airway pressure (PAP) therapy. Improved quality of life and cardiovascular outcomes for patients with OSA using PAP have been demonstrated. However, for some patients with OSA, PAP therapy is difficult to use or tolerate. Fortunately, there are other available treatment interventions for patients with OSA such as lifestyle interventions, surgical interventions, hypoglossal nerve stimulation (HNS), oral appliance therapy (OAT), and expiratory PAP (EPAP) devices. These alternative treatments can also improve symptoms of OSA though data regarding cardiovascular outcomes are lacking.

LIFESTYLE INTERVENTIONS

Weight loss

Because a higher body mass index (BMI) increases the risk for OSA, weight loss should be recommended for patients with OSA who are overweight. Much of the research evaluating the effect of weight loss on OSA has methodologic limitations such as lack of randomization or controls, potential confounding variables, and limited follow-up. A randomized controlled trial of 72 overweight patients with mild OSA (apnea–hypopnea index [AHI] of 5 to 15) compared a group assigned to a very low calorie diet and lifestyle counseling with a control group.¹ At 1 year, weight loss of 15 kg or more resulted in a statistically significant reduction in their AHI to normal, resolving their OSA. A 15 kg weight loss in this study was associated with an overall reduction in the AHI of at least 2 units.

Exercise

Exercise is also recommended for patients with OSA, and it can lessen the severity of symptoms even without weight loss. A meta-analysis of 5 randomized trials of 129 patients reported a reduction in the AHI of as much as 6 events per hour in individuals assigned to a strict exercise regimen.² The reduction in the AHI occurred despite a slight reduction in BMI (1.37 kg/m²).

Sleep position

For some patients, sleeping in the supine position may worsen their OSA, in which case avoiding the supine sleep position is recommended. A sleep study such as polysomnography should be performed to confirm the resolution of OSA in the nonsupine position.³ Products such as pillows or vibratory feedback devices can help the patient avoid sleeping on the back. The ability to monitor patient adherence to sleep position therapy alone is very limited.

Alcohol avoidance

Alcohol consumption depresses the central nervous system, promotes waking, and increases daytime sleepiness, thus exacerbating OSA. Patients with untreated OSA should avoid alcohol because it worsens the duration and frequency of obstructive respiratory events during sleep, and it can worsen the degree of oxygen desaturation that occurs during abnormal respiratory events.⁴

Concomitant medications

A review of medications in patients with OSA is warranted. Use of benzodiazepines, benzodiazepine-receptor agonists, barbiturates, and opiates in patients with OSA should be avoided especially if OSA is untreated. If these medications are necessary, careful monitoring is recommended. Medications that can cause weight gain such as some antidepressants should also be avoided.

SURGICAL INTERVENTIONS

Surgical interventions for OSA target the location of the obstruction in the upper airway. The upper airway consists of 3 regions: the palate, oropharynx, and larynx.⁵ More than 30 surgical soft-tissue and skeletal interventions for OSA are reported in the literature.⁶

Evaluating the outcomes of various surgical interventions for OSA is hindered by differences in the definition of surgical success or cure. As such, surgical interventions for OSA remain controversial. The practice parameters from 2010 reviewed surgical modifications of the upper airway for adults with OSA.^7,8 Success is defined as a greater than 50% reduction in the AHI to fewer than 20 events per hour, whereas surgical cure is defined as a reduction in the AHI to fewer than 5 events per hour.⁷

Table 1 lists commonly used surgical procedures for OSA and reported outcomes, though the quality of evidence to evaluate these procedures is low.⁸

Uvulopalatopharyngoplasty

Uvulopalatopharyngoplasty (UPPP) is a surgical procedure that remodels the throat via removal of the tonsils and the posterior surface of the soft palate and uvula and closure of the tonsillar pillars, and thus addresses retropalatal collapse. UPPP rarely achieves a surgical cure (ie, AHI < 5) and has been shown to have a 33% reduction in the AHI, with a postoperative average AHI remaining elevated at 29.⁸ (ie, moderate to severe OSA).8 In general, 50% of patients have a 50% reduction in AHI.⁹ The 4-year responder rate for UPPP is 44% to 50%.¹⁰ Factors limiting the long-term success of this procedure include weight gain, assessment of surgical candidates,¹¹ and decreased adherence to PAP therapy after the procedure.

The use of UPPP in combination with other surgical procedures has also been evaluated.⁸ The AHI in patients with OSA improved postoperatively when UPPP was done simultaneously or in a multiphase approach with radiofrequency ablation, midline glossectomy, tongue advancement, hyoid suspension, or maxillomandibular advancement, though greater improvement was noted with the multiphase approach.

Maxillomandibular advancement

Maxillomandibular advancement is a surgical procedure that moves the maxilla and mandible forward and expands the facial skeletal framework via LeFort I maxillary and sagittal split mandibular osteotomies. Maxillomandibular advancement achieves enlargement of the nasopharyngeal, retropalatal, and hypopharyngeal airway. This increases tension on the pharyngeal soft tissue, which enlarges the medial-lateral and anteroposterior dimensions of the upper airway.¹⁴

A meta-analysis of 45 studies evaluated the change in the AHI after maxillomandibular advancement in 518 patients.¹⁵ Secondary outcomes were surgical success (> 50% reduction in AHI to < 20 events per hour) and surgical cure (AHI < 5). Patients with a higher preoperative AHI achieved the greatest magnitude reduction in AHI but were less likely to achieve surgical success or cure. Patients with a lower preoperative AHI had a greater likelihood of surgical success and cure.

Bariatric surgery

Bariatric surgery is increasingly used for treatment of OSA in individuals with morbid obesity. A systematic review of bariatric surgery including the roux-en-Y gastric bypass, laparoscopic sleeve gastrectomy, and biliopancreatic diversion evaluated 69 studies with 13,900 patients with OSA.¹⁶ OSA was found to be improved or eliminated in 75% of patients for all bariatric surgery procedures.

 

 

HYPOGLOSSAL NERVE STIMULATION

Used with permission from Inspire Medical Systems, Inc.

HNS, or upper airway stimulation, is a new, fully implantable treatment for patients with OSA. The system consists of an implanted pulse generator (IPG), sensing lead, and stimulation lead.¹⁷ The device is implanted unilaterally via incisions under the clavicle for the IPG, on the chest for the sensing lead, and on the neck for the stimulation lead (Figure 1).

The IPG contains a battery, computer, and lead connector block. It receives information from the sensing lead, operates timing and output algorithms, conveys energy to the stimulation lead, and also serves as a return electrode for advanced stimulation configurations. The sensing lead monitors breathing during sleep and detects pressure changes in the respiratory cycle and conveys this information to the IPG. The stimulation lead encircles the medial branch of the hypoglossal nerve (cranial nerve XII) with an electrode cuff. Stimulation as generated from the IPG is delivered to key airway muscles, which are controlled by the hypoglossal nerve, primarily the genioglossus muscle responsible for tongue protrusion. The device can be turned on and off with a handheld sleep remote.

Indications and contraindications

The indications and contraindications for HNS are shown in Table 2.

Efficacy and outcomes

Stimulation of the hypoglossal nerve results in a multilevel mechanism of action: activation and protrusion of the tongue opens the oropharyngeal airway directly but also affects the retropalatal airway by a palatoglossal coupling action.¹⁹ Sleep lab testing with polysomnography is used to titrate the voltage of HNS to achieve an open airway that resolves apneic events and normalizes airflow, breathing patterns, and oxygen saturation levels.

Approval of HNS for OSA by the US Food and Drug Administration was based on findings in the Stimulation Therapy for Apnea Reduction (STAR) trial,¹⁷ a prospective trial of 126 patients at 22 centers in the United States and Europe with the primary outcomes of AHI and oxygen desaturation index. Secondary outcomes included quality of life as measured by the Functional Outcomes of Sleep Questionnaire and Epworth Sleepiness Scale (ESS). Patient demographics included mean age 54.5, 83% men, mean BMI of 28 kg/m², and mean baseline AHI of 34 (ie, severe OSA).

Data at 5 years for 97 of the 126 patients on HNS in the STAR trial is available.²⁰ The AHI was reduced an average of 70% to levels in the mild OSA range.^20,21 Overall, 85% of the patients had improved quality-of-life measures after HNS implantation, with increased Functional Outcomes of Sleep Questionnaire scores and ESS scores in the normal range over time. Consistent HNS therapy demonstrated sustained benefits at 5 years. The AHI improved by 50% or to less than 20 in 75% of patients, with 44% having resolved OSA and 78% improved to mild OSA (AHI < 15). Device-related adverse events occurred in 6% (9 of 126) of patients requiring replacement or repositioning of the stimulator or leads.²⁰

Moderate to severe snoring was prevalent at baseline in the STAR trial, but over the course of 5 years, 85% of bed partners of patients on HNS reported no or soft snoring.^17,21 Nightly use averaged 80% over 60 months based on patient reporting, with 87% reporting use at least 5 nights per week at 36 weeks.²⁰

In terms of predictors of response to HNS therapy, the oxygen desaturation index is the only characteristic that reached a level of statistical significance; patients with higher levels of oxygen desaturation tended to improve and tolerate therapy better long-term.²⁰ A randomized controlled trial of withdrawal of HNS therapy demonstrated increased AHI and oxygen desaturation index when therapy was withdrawn, followed by improvement when therapy resumed.²²

A clinical trial of 20 patients implanted with HNS after its approval in 2014 reported that the mean AHI decreased from 33 before implant to 5.1 after implant.²³ The ESS also improved from 10.3 before implant to 6 after implant. Mean adherence to device use was 7 (± 2) hours per night. The average stimulation amplitude was 1.89 (± 0.5) volts after the titration sleep study was completed. Similar reductions in AHI were reported by Huntley et al²⁴ for patients receiving HNS implant at 2 academic centers, with no differences between the 2 cohorts in postoperative AHI.

Adverse events

The adverse events reported with HNS are related to the implant procedure or the device.²¹ Procedure-related adverse events are incision discomfort, temporary tongue weakness, headache, and mild infection of incisions. The most common device-related adverse event is discomfort from the electrical stimulation. Tongue abrasion can also occur if the tongue protrudes and rubs against a sharp tooth. Dry mouth is also commonly reported.

HNS compared with UPPP

Outcomes in patients with moderate to severe OSA matched for BMI, demographics, and preoperative AHI were evaluated comparing patients undergoing HNS (n = 20) with patients receiving UPPP (n = 20).²⁵ The AHI decreased 29% postoperatively in patients with UPPP compared with 88% in patients with HNS, 65% of which had normalization of their AHI. Surgical success was achieved in 40% of patients in the UPPP group compared with 100% in the HNS group. Greater improvement in daytime sleepiness was noted in patients in the HNS group compared with the UPPP group.

 

 

ORAL APPLIANCE THERAPY

OAT devices help protrude the mandible forward and stabilize it to maintain a more patent airway during sleep. Oral appliances can be custom-made or prefabricated. Oral appliances can be titratable or nontitratable: titration provides a mechanism to adjust mandibular protrusion analogous to PAP titration, whereas the absence of titration holds the mandible in a single position. The most effective oral appliances are custom-made and titratable.

Types of OAT devices

Custom oral appliances. Custom oral appliances are fabricated using digital or physical impressions of the patient’s oral structures. Custom oral appliances are made of biocompatible materials and engage both the maxillary and mandibular arches.

Custom oral appliances are made by a qualified dentist who takes maxillary and mandibular impressions with a bite registration using the George Gauge with 40% to 50% of maximum protrusion. The appliance is fabricated in a laboratory and then fitted to the patient, who is instructed to titrate the device 0.5 mm to 1 mm per week and follow-up with the dentist at 2-week intervals. Once the patient has titrated the device to the point of comfort or improved sleep quality or snoring, polysomnography should be done with the device in place and titrated to improve the AHI as much as possible. Follow-up is recommended at 6 months and annually thereafter.

Prefabricated oral appliances. Prefabricated oral appliances are of the boil-and-bite type, only partially modified to the patient’s oral structures.

Tongue-retaining devices. Another type of oral appliance is a tongue-retaining device, which is designed to hold the tongue forward and can be custom-made or prefabricated.

Patient considerations for OAT

OAT is not appropriate for all patients with OSA, and the indications and contraindications for use of OAT are presented in Table 3. If OAT is indicated, several considerations may influence the type of device that is most appropriate for the patient (Table 4).

Practice recommendations

The American Academy of Sleep Medicine and American Academy of Dental Sleep Medicine established clinical practice guidelines and recommendations for OAT in patients with OSA:

• Prescribed OAT should be done by a qualified dentist, and a custom, titratable appliance is preferred
• OAT is preferred over no therapy for adults with OSA who are intolerant to PAP or prefer alternative therapies
• A qualified dentist should provide oversight for dental-related side effects or occlusal changes
• Follow-up sleep testing should be conducted to confirm efficacy or titrate treatment
• Periodic office visits with the sleep physician and qualified dentist are recommended.²⁶

The quality of evidence for these recommendations is low, with the exception of use of OAT rather than no therapy, which is considered of moderate quality.

Effects of OAT

Anatomic and physiologic effects. With OAT in place in the mouth, the airway caliber in the lateral dimension are increased, and the airway size at the retropalatal level is increased.^27–30 With respect to the tongue, increased genioglossus muscle activity has been reported with OAT.

Side effects. Side effects of OAT include excess salivation, dry mouth, tooth tenderness, soft-tissue changes, jaw discomfort, tooth movement, and occlusal changes such as difficulty chewing in the morning. Feelings of suffocation, vivid dreams, and anxiety have also been reported with OAT.^31–33

Efficacy and outcomes

Review of the data on the efficacy of OAT did not illuminate factors that predict treatment success.²⁶ Data indicate that in patients with mild OSA using OAT or PAP therapy, there was no significant difference in the percentage achieving their target AHI; however, patients with moderate to severe OSA had a statistically significant greater odds of achieving their target AHI using PAP therapy compared with OAT. Therefore, OAT should be reserved for patients with severe OSA who cannot use or are intolerant to PAP.

Moderate-grade quality of evidence was reviewed for the established OAT practice recommendations for OSA outcomes before and after use of custom, titratable OAT devices.²⁶ Use of a custom OAT device reduced the mean AHI, increased mean oxygen saturation, decreased the mean oxygen desaturation, decreased the arousal index, decreased the ESS, and increased quality of life compared with values prior to use of OAT.

With respect to adherence and discontinuation, patients using OAT had higher mean adherence and lower discontinuation because of side effects compared with patients using continuous PAP.²⁶

 

 

NASAL EPAP THERAPY

Nasal EPAP is a new treatment for OSA that consists of a mechanical valve worn in each naris at night. The valves have a low inspiratory resistance and a high expiratory resistance thus increased pressure occurs at exhalation.

Pressure at exhalation may counter the airway collapse in OSA. With the mouth closed and use of the nasal valves, the positive pressure during the normal respiratory cycle is utilized to maintain an open airway.³⁴ At the onset and throughout inspiration, the activity of the airway dilator muscles increases. At maximum expiration, right before the end of the expiratory pause, the dilator muscle stops abruptly and the airway is of its smallest caliber. The presence of the nasal valve at this point is thought to act as a pneumatic splint to the airway, and the nasal EPAP helps keep the airway patent during the next inspiratory phase.

Nasal EPAP valves are available in a 30-day starter kit. Intended for single-night use, the kit includes valves of increasing levels of expiration resistance: low (nights 1 and 2), medium (nights 3 and 4), and normal (nights 5–30).

Outcomes of nasal EPAP therapy

A multicenter 30-day in-home trial evaluated efficacy and compliance of nasal EPAP therapy.³⁵ The AHI was reduced by 50% or more in 14 of 34 (41%) patients using nasal EPAP compared with the control group at the 30-day follow-up. The patient-reported compliance with nasal EPAP was 94%. Patients in this study had mild to moderate OSA and did not have obesity or other comorbidities such as pulmonary hypertension or cardiovascular disease.

A randomized controlled trial compared nasal EPAP with a sham device in patients with newly diagnosed or untreated OSA (N = 250) for 3 months.³⁶ A median reduction of 52% in the AHI was noted in the intention-to-treat group (N = 229) during rapid eye movement (REM) and non-REM sleep, though it was statistically significant only during REM sleep and supine sleep. At 3 months, improved OSA was maintained in 42% of the patients using nasal EPAP compared with 10% of patients using a sham device. Improvements in daytime sleepiness and adherence with 88% using EPAP the entire night were also noted.

In a 12-month study of nasal EPAP, 67% of patients (34 of 51) used nasal EPAP for the full trial duration.³⁷ Of patients using nasal EPAP for 12 months, the median AHI was reduced by 71%, the ESS improved, and adherence to full-night use was 89%.

Patient considerations for nasal EPAP

In clinical practice, nasal EPAP therapy requires nasal patency and use of a chin strap in patients with mouth leakage. Nasal EPAP may be recommended for patients who travel frequently and can go without continuous PAP or bilevel PAP for short periods of time, and for patients who do not have significant medical comorbidities.

Side effects and limitations of nasal EPAP

Reported side effects of nasal EPAP include difficulty with exhalation, nasal discomfort, dry mouth, and headache. Nasal EPAP therapy is of limited use in patients with severe OSA and severe oxygen desaturation. The efficacy of nasal EPAP beyond 12 months is unknown. Use of nasal EPAP in patients with prior upper-airway surgery and in combination with other therapies is yet to be evaluated.

Supplement Editor:
Nancy Foldvary-Schaefer

Contents

Introduction—Obstructive sleep apnea: A wake-up call for better outcomes
Nancy Foldvary-Schaefer

Obstructive sleep apnea basics
Jessica Vensel Rundo

Sleep apnea and the heart
Reena Mehra

Beyond heart health: Consequences of obstructive sleep apnea
Harneet K. Walia

Positive airway pressure: Making an impact on sleep apnea
Colleen G. Lance

Alternative interventions for obstructive sleep apnea
Tina Waters

Click for related Cleveland Clinic CME activities.

 

Supplement Editor:
Nancy Foldvary-Schaefer

Contents

Introduction—Obstructive sleep apnea: A wake-up call for better outcomes
Nancy Foldvary-Schaefer

Obstructive sleep apnea basics
Jessica Vensel Rundo

Sleep apnea and the heart
Reena Mehra

Beyond heart health: Consequences of obstructive sleep apnea
Harneet K. Walia

Positive airway pressure: Making an impact on sleep apnea
Colleen G. Lance

Alternative interventions for obstructive sleep apnea
Tina Waters

Click for related Cleveland Clinic CME activities.

 

Supplement Editor:
Nancy Foldvary-Schaefer

Contents

Introduction—Obstructive sleep apnea: A wake-up call for better outcomes
Nancy Foldvary-Schaefer

Obstructive sleep apnea basics
Jessica Vensel Rundo

Sleep apnea and the heart
Reena Mehra

Beyond heart health: Consequences of obstructive sleep apnea
Harneet K. Walia

Positive airway pressure: Making an impact on sleep apnea
Colleen G. Lance

Alternative interventions for obstructive sleep apnea
Tina Waters

Click for related Cleveland Clinic CME activities.

 

 

The Food and Drug Administration has approved pitolisant (Wakix) for excessive daytime sleepiness among patients with narcolepsy, according to a release from the drug’s developer.

Wikimedia Commons/FitzColinGerald/Creative Commons License

Approval of this once-daily, selective histamine 3–receptor antagonist/inverse agonist was based on a pair of multicenter, randomized, double-blind, placebo-controlled studies that included a total of 261 patients. Patients in both studies experienced statistically significant improvements in excessive daytime sleepiness according to Epworth Sleepiness Scale scores.

Rates of adverse advents at or greater than 5% and more than double that of placebo included insomnia (6%), nausea (6%), and anxiety (5%). Patients with severe liver disease should not use pitolisant. Pitolisant has not been evaluated in patients under 18 years of age, and patients who are pregnant or planning to become pregnant are encouraged to enroll in a pregnancy exposure registry.

Full prescribing information, including contraindications and warnings, can be found on the FDA website.

cpalmer@mdedge.com

 

The Food and Drug Administration has approved pitolisant (Wakix) for excessive daytime sleepiness among patients with narcolepsy, according to a release from the drug’s developer.

Wikimedia Commons/FitzColinGerald/Creative Commons License

Approval of this once-daily, selective histamine 3–receptor antagonist/inverse agonist was based on a pair of multicenter, randomized, double-blind, placebo-controlled studies that included a total of 261 patients. Patients in both studies experienced statistically significant improvements in excessive daytime sleepiness according to Epworth Sleepiness Scale scores.

Rates of adverse advents at or greater than 5% and more than double that of placebo included insomnia (6%), nausea (6%), and anxiety (5%). Patients with severe liver disease should not use pitolisant. Pitolisant has not been evaluated in patients under 18 years of age, and patients who are pregnant or planning to become pregnant are encouraged to enroll in a pregnancy exposure registry.

Full prescribing information, including contraindications and warnings, can be found on the FDA website.

cpalmer@mdedge.com

 

The Food and Drug Administration has approved pitolisant (Wakix) for excessive daytime sleepiness among patients with narcolepsy, according to a release from the drug’s developer.

Wikimedia Commons/FitzColinGerald/Creative Commons License

Approval of this once-daily, selective histamine 3–receptor antagonist/inverse agonist was based on a pair of multicenter, randomized, double-blind, placebo-controlled studies that included a total of 261 patients. Patients in both studies experienced statistically significant improvements in excessive daytime sleepiness according to Epworth Sleepiness Scale scores.

Rates of adverse advents at or greater than 5% and more than double that of placebo included insomnia (6%), nausea (6%), and anxiety (5%). Patients with severe liver disease should not use pitolisant. Pitolisant has not been evaluated in patients under 18 years of age, and patients who are pregnant or planning to become pregnant are encouraged to enroll in a pregnancy exposure registry.

Full prescribing information, including contraindications and warnings, can be found on the FDA website.

cpalmer@mdedge.com

 

Insomnia, sleep-related disordered breathing, and nightmares were associated with suicide attempts in a large case-control matched study of patients in the Veterans Health Administration database.

However, treatment for sleep disorders was correlated to a reduced risk for suicide attempts.

Todd M. Bishop, PhD, of the Center of Excellence for Suicide Prevention, Canandaigua (N.Y.) VA Medical Center, and the department of psychiatry, University of Rochester (N.Y.) Medical Center, and his colleagues wrote that suicide is the 10th most frequent cause of death in the United States, and “nowhere is the suicide rate more alarming than among military veterans, who after adjusting for age and gender, have an approximately 1.5 times greater risk for suicide as compared to the civilian population.”

Previous research has explored the link between sleep disturbances and suicide attempts. But less has been done to look at specific sleep problems, and little research has examined the role of sleep medicine interventions and suicide attempt risk.

The investigators conducted a study to establish the association between suicide attempts and specific sleep disorders, and to examine the correlation between sleep medicine treatment and suicide attempts. Their sample consisted of 60,102 veterans who had received care within the VHA between Oct. 1, 2012, and Sept. 20, 2014. Half of the sample had a documented suicide attempt in the medical record (n = 30,051) and half did not (n = 30,051). The overall sample was predominately male (87.1%) with a mean age of 48.6 years. More than half the sample identified as white (67.4%).

Suicide attempts, sleep disturbance, and medical and mental health comorbidities were identified via ICD codes and prescription records. The predominant sleep disorders studied were insomnia, sleep-related breathing disorder (SRBD), and nightmares. The first suicide attempt in the study period was determined to be the index date for the case-control matching.

Overall, sleep disturbances were much more prevalent among cases than controls (insomnia, 46.2% vs. 12.6%), sleep-related breathing disorder (8.6% vs. 4.8%), and nightmares (7.1% vs. 1.6%). A logistic regression analysis was undertaken to examine the relationship between specific sleep disorders and suicide attempts. Insomnia, nightmares, and SRBD were each associated with increased odds of a suicide attempt with the following odds ratios: insomnia (odds ratio, 5.62; 95% confidence interval, 5.39-5.86), nightmares (OR, 2.49; 95% CI, 2.23-2.77), and sleep-related breathing disorder (OR, 1.37; 95% CI, 1.27-1.48).

A second model included known drivers of suicide attempts (PTSD, depression, anxiety disorders, schizophrenia, bipolar disorder, substance use disorder, medical comorbidity, and obesity). But after controlling for these factors, neither nightmares (OR, 0.96; 95% CI, 0.85-1.09) nor sleep-related breathing disorders (OR, 0.87, 95% CI, 0.79-0.94) remained positively associated with suicide attempt, but the association of insomnia with suicide attempt was maintained (OR, 1.51; 95% CI, 1.43-1.59).

The question of the impact of sleep medicine interventions on suicide attempts was studied with a third regression model adding the number of sleep medicine clinic visits in the 180 days prior to the suicide attempt index date as an independent variable. The variables in this model were limited to insomnia, SRBD, and nightmares. The investigators found that “for each sleep medicine clinic visit within the 6 months prior to index date the likelihood of suicide attempt is 11% less (OR, 0.89; 95% CI, 0.82-0.97).”

The limitations of the study include the lack of information on sleep treatment modalities or medications provided during the clinic visits, and the overlapping of sleep disturbance with other mental health conditions, such as alcohol dependence and PTSD. In addition, “some insomnia medications are labeled for risk of suicidal ideation and behavior, so there is some chance that the medications rather than insomnia itself were associated with the increased suicidal behavior,” the investigators wrote.

In addition to an analysis of specific types of sleep disorders associated with suicide attempts, the study showed that treatment of sleep disorders may have an important role in suicide prevention. The investigators concluded: “Identifying populations at risk for suicide prior to a first attempt is an important, but difficult task of suicide prevention. Prevention efforts can be aimed at modifiable risk factors that arise early on a patient’s trajectory toward a suicide attempt.”

The study was supported by the VISN 2 Center of Excellence for Suicide Prevention, Canandaigua VAMC. The authors had no disclosures.

tborden@mdedge.com

SOURCE: Bishop TM et al. Sleep Med. 2019 Jul 25. doi: 10.1016/j.sleep.2019.07.016.

 

Insomnia, sleep-related disordered breathing, and nightmares were associated with suicide attempts in a large case-control matched study of patients in the Veterans Health Administration database.

However, treatment for sleep disorders was correlated to a reduced risk for suicide attempts.

Todd M. Bishop, PhD, of the Center of Excellence for Suicide Prevention, Canandaigua (N.Y.) VA Medical Center, and the department of psychiatry, University of Rochester (N.Y.) Medical Center, and his colleagues wrote that suicide is the 10th most frequent cause of death in the United States, and “nowhere is the suicide rate more alarming than among military veterans, who after adjusting for age and gender, have an approximately 1.5 times greater risk for suicide as compared to the civilian population.”

Previous research has explored the link between sleep disturbances and suicide attempts. But less has been done to look at specific sleep problems, and little research has examined the role of sleep medicine interventions and suicide attempt risk.

The investigators conducted a study to establish the association between suicide attempts and specific sleep disorders, and to examine the correlation between sleep medicine treatment and suicide attempts. Their sample consisted of 60,102 veterans who had received care within the VHA between Oct. 1, 2012, and Sept. 20, 2014. Half of the sample had a documented suicide attempt in the medical record (n = 30,051) and half did not (n = 30,051). The overall sample was predominately male (87.1%) with a mean age of 48.6 years. More than half the sample identified as white (67.4%).

Suicide attempts, sleep disturbance, and medical and mental health comorbidities were identified via ICD codes and prescription records. The predominant sleep disorders studied were insomnia, sleep-related breathing disorder (SRBD), and nightmares. The first suicide attempt in the study period was determined to be the index date for the case-control matching.

Overall, sleep disturbances were much more prevalent among cases than controls (insomnia, 46.2% vs. 12.6%), sleep-related breathing disorder (8.6% vs. 4.8%), and nightmares (7.1% vs. 1.6%). A logistic regression analysis was undertaken to examine the relationship between specific sleep disorders and suicide attempts. Insomnia, nightmares, and SRBD were each associated with increased odds of a suicide attempt with the following odds ratios: insomnia (odds ratio, 5.62; 95% confidence interval, 5.39-5.86), nightmares (OR, 2.49; 95% CI, 2.23-2.77), and sleep-related breathing disorder (OR, 1.37; 95% CI, 1.27-1.48).

A second model included known drivers of suicide attempts (PTSD, depression, anxiety disorders, schizophrenia, bipolar disorder, substance use disorder, medical comorbidity, and obesity). But after controlling for these factors, neither nightmares (OR, 0.96; 95% CI, 0.85-1.09) nor sleep-related breathing disorders (OR, 0.87, 95% CI, 0.79-0.94) remained positively associated with suicide attempt, but the association of insomnia with suicide attempt was maintained (OR, 1.51; 95% CI, 1.43-1.59).

The question of the impact of sleep medicine interventions on suicide attempts was studied with a third regression model adding the number of sleep medicine clinic visits in the 180 days prior to the suicide attempt index date as an independent variable. The variables in this model were limited to insomnia, SRBD, and nightmares. The investigators found that “for each sleep medicine clinic visit within the 6 months prior to index date the likelihood of suicide attempt is 11% less (OR, 0.89; 95% CI, 0.82-0.97).”

The limitations of the study include the lack of information on sleep treatment modalities or medications provided during the clinic visits, and the overlapping of sleep disturbance with other mental health conditions, such as alcohol dependence and PTSD. In addition, “some insomnia medications are labeled for risk of suicidal ideation and behavior, so there is some chance that the medications rather than insomnia itself were associated with the increased suicidal behavior,” the investigators wrote.

In addition to an analysis of specific types of sleep disorders associated with suicide attempts, the study showed that treatment of sleep disorders may have an important role in suicide prevention. The investigators concluded: “Identifying populations at risk for suicide prior to a first attempt is an important, but difficult task of suicide prevention. Prevention efforts can be aimed at modifiable risk factors that arise early on a patient’s trajectory toward a suicide attempt.”

The study was supported by the VISN 2 Center of Excellence for Suicide Prevention, Canandaigua VAMC. The authors had no disclosures.

tborden@mdedge.com

SOURCE: Bishop TM et al. Sleep Med. 2019 Jul 25. doi: 10.1016/j.sleep.2019.07.016.

 

Insomnia, sleep-related disordered breathing, and nightmares were associated with suicide attempts in a large case-control matched study of patients in the Veterans Health Administration database.

However, treatment for sleep disorders was correlated to a reduced risk for suicide attempts.

Todd M. Bishop, PhD, of the Center of Excellence for Suicide Prevention, Canandaigua (N.Y.) VA Medical Center, and the department of psychiatry, University of Rochester (N.Y.) Medical Center, and his colleagues wrote that suicide is the 10th most frequent cause of death in the United States, and “nowhere is the suicide rate more alarming than among military veterans, who after adjusting for age and gender, have an approximately 1.5 times greater risk for suicide as compared to the civilian population.”

Previous research has explored the link between sleep disturbances and suicide attempts. But less has been done to look at specific sleep problems, and little research has examined the role of sleep medicine interventions and suicide attempt risk.

The investigators conducted a study to establish the association between suicide attempts and specific sleep disorders, and to examine the correlation between sleep medicine treatment and suicide attempts. Their sample consisted of 60,102 veterans who had received care within the VHA between Oct. 1, 2012, and Sept. 20, 2014. Half of the sample had a documented suicide attempt in the medical record (n = 30,051) and half did not (n = 30,051). The overall sample was predominately male (87.1%) with a mean age of 48.6 years. More than half the sample identified as white (67.4%).

Suicide attempts, sleep disturbance, and medical and mental health comorbidities were identified via ICD codes and prescription records. The predominant sleep disorders studied were insomnia, sleep-related breathing disorder (SRBD), and nightmares. The first suicide attempt in the study period was determined to be the index date for the case-control matching.

Overall, sleep disturbances were much more prevalent among cases than controls (insomnia, 46.2% vs. 12.6%), sleep-related breathing disorder (8.6% vs. 4.8%), and nightmares (7.1% vs. 1.6%). A logistic regression analysis was undertaken to examine the relationship between specific sleep disorders and suicide attempts. Insomnia, nightmares, and SRBD were each associated with increased odds of a suicide attempt with the following odds ratios: insomnia (odds ratio, 5.62; 95% confidence interval, 5.39-5.86), nightmares (OR, 2.49; 95% CI, 2.23-2.77), and sleep-related breathing disorder (OR, 1.37; 95% CI, 1.27-1.48).

A second model included known drivers of suicide attempts (PTSD, depression, anxiety disorders, schizophrenia, bipolar disorder, substance use disorder, medical comorbidity, and obesity). But after controlling for these factors, neither nightmares (OR, 0.96; 95% CI, 0.85-1.09) nor sleep-related breathing disorders (OR, 0.87, 95% CI, 0.79-0.94) remained positively associated with suicide attempt, but the association of insomnia with suicide attempt was maintained (OR, 1.51; 95% CI, 1.43-1.59).

The question of the impact of sleep medicine interventions on suicide attempts was studied with a third regression model adding the number of sleep medicine clinic visits in the 180 days prior to the suicide attempt index date as an independent variable. The variables in this model were limited to insomnia, SRBD, and nightmares. The investigators found that “for each sleep medicine clinic visit within the 6 months prior to index date the likelihood of suicide attempt is 11% less (OR, 0.89; 95% CI, 0.82-0.97).”

The limitations of the study include the lack of information on sleep treatment modalities or medications provided during the clinic visits, and the overlapping of sleep disturbance with other mental health conditions, such as alcohol dependence and PTSD. In addition, “some insomnia medications are labeled for risk of suicidal ideation and behavior, so there is some chance that the medications rather than insomnia itself were associated with the increased suicidal behavior,” the investigators wrote.

In addition to an analysis of specific types of sleep disorders associated with suicide attempts, the study showed that treatment of sleep disorders may have an important role in suicide prevention. The investigators concluded: “Identifying populations at risk for suicide prior to a first attempt is an important, but difficult task of suicide prevention. Prevention efforts can be aimed at modifiable risk factors that arise early on a patient’s trajectory toward a suicide attempt.”

The study was supported by the VISN 2 Center of Excellence for Suicide Prevention, Canandaigua VAMC. The authors had no disclosures.

tborden@mdedge.com

SOURCE: Bishop TM et al. Sleep Med. 2019 Jul 25. doi: 10.1016/j.sleep.2019.07.016.

LOS ANGELES – While a large number of older adults take prescription and nonprescription medications to help them sleep, the effect of these medications on dementia risk is unclear, with most researchers advocating a cautious and conservative approach to prescribing.

Nastasic/iStockphoto.com

Research is increasingly revealing a bidirectional relationship between sleep and dementia. Poor sleep – especially from insomnia, sleep deprivation, or obstructive sleep apnea – is known to increase dementia risk. Dementias, meanwhile, are associated with serious circadian rhythm disturbances, leading to nighttime sleep loss and increasing the likelihood of institutionalization.

At the Alzheimer’s Association International Conference, researchers presented findings assessing the links between sleep medication use and dementia and also what agents or approaches might safely improve sleep in people with sleep disorders who are at risk for dementia or who have been diagnosed with dementia.
 

Sex- and race-based differences in risk

Yue Leng, PhD, of the University of California, San Francisco, reported a link between frequent sleep medication use and later dementia – but only in white adults. Dr. Leng presented findings from the National Institutes of Health–funded Health, Aging, and Body Composition Study, which recruited 3,068 subjects aged 70-79 and followed them for 15 years. At baseline, 2.7% of African Americans and 7.7% of whites in the study reported taking sleep medications “often” or “almost always.”

Dr. Leng and her colleagues found that white subjects who reported taking sleep aids five or more times a month at baseline had a nearly 80% higher risk of developing dementia during the course of the study (hazard ratio, 1.79; 95% confidence interval, 1.21-2.66), compared with people who reported never taking sleep aids or taking them less frequently.

The researchers saw no between-sex differences for this finding, and adjusted for a variety of genetic and lifestyle confounders. Importantly, no significant increase in dementia risk was seen for black subjects, who made up more than one-third of the cohort.

Dr. Leng told the conference that the researchers could not explain why black participants did not see similarly increased dementia risk. Also, she noted, researchers did not have information on the specific sleep medications people used: benzodiazepines, antihistamines, antidepressants, or other types of drugs. Nonetheless, she told the conference, the findings ratified the cautious approach many dementia experts are already stressing.


“Do we really need to prescribe so many sleep meds to older adults who are already at risk for cognitive impairment?” Dr. Leng said, adding: “I am a big advocate of behavioral sleep interventions.” People with clinical sleep problems “should be referred to sleep centers” for a fuller assessment before medication is prescribed, she said.

Findings from another cohort study, meanwhile, suggest that there could be sex-related differences in how sleep aids affect dementia risk. Investigators at Utah State University in Logan used data from some 3,656 older adults in the Cache County Study on Memory and Aging, an NIH-backed cohort study of white adults in Utah without dementia at baseline who were followed for 12 years.

The investigators, led by doctoral student Elizabeth Vernon, found that men reporting use of sleep medication saw more than threefold higher risk of developing Alzheimer’s disease than did men who did not use sleep aids (HR, 3.604; P = .0001).

Women who did not report having sleep disturbance but used sleep-inducing medications were at nearly fourfold greater risk for developing Alzheimer’s disease (HR, 3.916; P = .0001). Women who self-reported sleep disturbances at baseline, meanwhile, saw a reduction in Alzheimer’s risk of about one-third associated with the use of sleep medications.

Ms. Vernon told the conference that, despite the finding of risk reduction for this particular group of women, caution in prescribing sleep aids was warranted.

 

Common sleep drugs linked to cognitive aging

Chris Fox, MD, a researcher at the University of East Anglia in Norwich, England, and his colleagues demonstrated in 2018 that long-term exposure to anticholinergic drugs, a class that includes some antidepressants and antihistamines used to promote sleep, was associated with a higher risk of dementia, while use of benzodiazepines, a class of sedatives used commonly in older people as sleep aids, was not. (Whether benzodiazepine exposure relates to dementia remains controversial.)

At AAIC 2019, Dr. Fox presented findings from a study of 337 brains in a U.K. brain bank, of which 17% and 21% came from users of benzodiazepines and anticholinergic drugs, whose usage history was well documented. Dr. Fox and his colleagues found that, while neither anticholinergic nor benzodiazepine exposure was associated with brain pathology specific to that seen in Alzheimer’s disease, both classes of drugs were associated with “slight signals in neuronal loss” in one brain region, the nucleus basalis of Meynert. Dr. Fox described the drugs as causing “an increase in cognitive aging” which could bear on Alzheimer’s risk without being directly causative.
 

Newer sleep drugs may help Alzheimer’s patients

Scientists working for drug manufacturers presented findings on agents to counter the circadian rhythm disturbances seen in people with Alzheimer’s disease. Margaret Moline, PhD, of Eisai in Woodcliff Lake, N.J., showed some results from a phase 2, dose-ranging, placebo-controlled study of the experimental agent lemborexant in 62 subjects aged 60-90 with mild to moderate Alzheimer’s disease and sleep disturbances. (Lemborexant, an orexin receptor agonist that acts to regulate wakefulness, is being investigated in a broad range of sleep disorders.) Patients were randomized to one of four doses of lemborexant or placebo and wore a device for sleep monitoring. Nighttime activity indicating arousal was significantly lower for people in two dosage arms, 5 mg and 10 mg, compared with placebo, and treatment groups saw trends toward less sleep fragmentation and higher total sleep time, Dr. Moline told the conference.

Suvorexant (Belsomra), the only orexin receptor antagonist currently licensed as a sleep aid, is also being tested in people with Alzheimer’s disease. At AAIC 2019, Joseph Herring, MD, PhD, of Merck in Kenilworth, N.J., presented results from a placebo-controlled trial of 277 patients with Alzheimer’s disease and insomnia, and reported that treatment with 10 or 20 mg of suvorexant over 4 weeks was associated with about an extra half hour of total nightly sleep, with a 73-minute mean increase from baseline, compared with 45 minutes for patients receiving placebo (95% CI, 11-45; P less than .005).
 

Trazodone linked to slower cognitive decline

An inexpensive antidepressant used in low doses as a sleep aid, including in people with Alzheimer’s disease, was associated with a delay in cognitive decline in older adults, according to results from a retrospective study. Elissaios Karageorgiou, MD, PhD, of the University of California, San Francisco, and the Neurological Institute of Athens presented results derived from two cohorts: patients enrolled at the UCSF Memory and Aging Center and women enrolled in the Study for Osteoporotic Fractures (SOF) in Women. The investigators were able to identify trazodone users in the studies (with two or more contiguous study visits reporting trazodone use) and match them with control patients from the same cohorts who did not use trazodone.

 

Trazodone was studied because previous research suggests it increases total sleep time in patients with Alzheimer’s disease without affecting next-day cognitive performance.

Trazodone-using patients in the UCSF cohort (n = 25) saw significantly less decline in Mini Mental State Exam (MMSE) scores over 4 years, compared with nonusers (0.27 vs. 0.70 points per year; P = .023), an effect that remained statistically significant even after adjusting for sedative and stimulant use and the expected progression of Alzheimer’s disease pathology. Importantly, the slower decline was seen only among subjects with sleep complaints at baseline and especially those whose sleep improved over time, suggesting that the cognitive benefit was mediated by improved sleep.

In the SOF cohort of 46 trazodone users matched with 148 nonusers, no significant protective or negative effect related to long-term trazodone use was found using the MMSE or the Trails Making Test. In this analysis, however, baseline and longitudinal sleep quality was not captured in the group-matching process, neither was the use of other medications. The patient group was slightly older, and all patients were women.

Dr. Karageorgiou said in an interview that the link between improved sleep, trazodone, and cognition needs to be validated in prospective intervention studies. Trazodone, he said, appears to work best in people with a specific type of insomnia characterized by cortical and behavioral hyperarousal, and its cognitive effect appears limited to people whose sleep improves with treatment. “You’re not going to see long-term cognitive benefits if it’s not improving your sleep,” Dr. Karageorgiou said. “So, whether trazodone improves sleep or not in a patient after a few months can be an early indicator for the clinician to continue using it or suspend it, because it is unlikely to help their cognition otherwise.”

He stressed that physicians need to be broadly focused on improving sleep to help patients with, or at risk for, dementia by consolidating their sleep rhythms.

“Trazodone is not the magic bullet, and I don’t think we will ever have a magic bullet,” Dr. Karageorgiou said. “Because when our brain degenerates, it’s not just one chemical, or one system, it’s many. And our body changes as well. The important thing is to help the patient consolidate their rhythms, whether through light therapy, daily exercise, cognitive behavioral therapy for insomnia, or other evidence-based interventions and their combination. The same applies for a person with dementia as for the rest of us.”

None of the investigators outside of the industry-sponsored studies had relevant disclosures.

LOS ANGELES – While a large number of older adults take prescription and nonprescription medications to help them sleep, the effect of these medications on dementia risk is unclear, with most researchers advocating a cautious and conservative approach to prescribing.

Nastasic/iStockphoto.com

Research is increasingly revealing a bidirectional relationship between sleep and dementia. Poor sleep – especially from insomnia, sleep deprivation, or obstructive sleep apnea – is known to increase dementia risk. Dementias, meanwhile, are associated with serious circadian rhythm disturbances, leading to nighttime sleep loss and increasing the likelihood of institutionalization.

At the Alzheimer’s Association International Conference, researchers presented findings assessing the links between sleep medication use and dementia and also what agents or approaches might safely improve sleep in people with sleep disorders who are at risk for dementia or who have been diagnosed with dementia.
 

Sex- and race-based differences in risk

Yue Leng, PhD, of the University of California, San Francisco, reported a link between frequent sleep medication use and later dementia – but only in white adults. Dr. Leng presented findings from the National Institutes of Health–funded Health, Aging, and Body Composition Study, which recruited 3,068 subjects aged 70-79 and followed them for 15 years. At baseline, 2.7% of African Americans and 7.7% of whites in the study reported taking sleep medications “often” or “almost always.”

Dr. Leng and her colleagues found that white subjects who reported taking sleep aids five or more times a month at baseline had a nearly 80% higher risk of developing dementia during the course of the study (hazard ratio, 1.79; 95% confidence interval, 1.21-2.66), compared with people who reported never taking sleep aids or taking them less frequently.

The researchers saw no between-sex differences for this finding, and adjusted for a variety of genetic and lifestyle confounders. Importantly, no significant increase in dementia risk was seen for black subjects, who made up more than one-third of the cohort.

Dr. Leng told the conference that the researchers could not explain why black participants did not see similarly increased dementia risk. Also, she noted, researchers did not have information on the specific sleep medications people used: benzodiazepines, antihistamines, antidepressants, or other types of drugs. Nonetheless, she told the conference, the findings ratified the cautious approach many dementia experts are already stressing.


“Do we really need to prescribe so many sleep meds to older adults who are already at risk for cognitive impairment?” Dr. Leng said, adding: “I am a big advocate of behavioral sleep interventions.” People with clinical sleep problems “should be referred to sleep centers” for a fuller assessment before medication is prescribed, she said.

Findings from another cohort study, meanwhile, suggest that there could be sex-related differences in how sleep aids affect dementia risk. Investigators at Utah State University in Logan used data from some 3,656 older adults in the Cache County Study on Memory and Aging, an NIH-backed cohort study of white adults in Utah without dementia at baseline who were followed for 12 years.

The investigators, led by doctoral student Elizabeth Vernon, found that men reporting use of sleep medication saw more than threefold higher risk of developing Alzheimer’s disease than did men who did not use sleep aids (HR, 3.604; P = .0001).

Women who did not report having sleep disturbance but used sleep-inducing medications were at nearly fourfold greater risk for developing Alzheimer’s disease (HR, 3.916; P = .0001). Women who self-reported sleep disturbances at baseline, meanwhile, saw a reduction in Alzheimer’s risk of about one-third associated with the use of sleep medications.

Ms. Vernon told the conference that, despite the finding of risk reduction for this particular group of women, caution in prescribing sleep aids was warranted.

 

Common sleep drugs linked to cognitive aging

Chris Fox, MD, a researcher at the University of East Anglia in Norwich, England, and his colleagues demonstrated in 2018 that long-term exposure to anticholinergic drugs, a class that includes some antidepressants and antihistamines used to promote sleep, was associated with a higher risk of dementia, while use of benzodiazepines, a class of sedatives used commonly in older people as sleep aids, was not. (Whether benzodiazepine exposure relates to dementia remains controversial.)

At AAIC 2019, Dr. Fox presented findings from a study of 337 brains in a U.K. brain bank, of which 17% and 21% came from users of benzodiazepines and anticholinergic drugs, whose usage history was well documented. Dr. Fox and his colleagues found that, while neither anticholinergic nor benzodiazepine exposure was associated with brain pathology specific to that seen in Alzheimer’s disease, both classes of drugs were associated with “slight signals in neuronal loss” in one brain region, the nucleus basalis of Meynert. Dr. Fox described the drugs as causing “an increase in cognitive aging” which could bear on Alzheimer’s risk without being directly causative.
 

Newer sleep drugs may help Alzheimer’s patients

Scientists working for drug manufacturers presented findings on agents to counter the circadian rhythm disturbances seen in people with Alzheimer’s disease. Margaret Moline, PhD, of Eisai in Woodcliff Lake, N.J., showed some results from a phase 2, dose-ranging, placebo-controlled study of the experimental agent lemborexant in 62 subjects aged 60-90 with mild to moderate Alzheimer’s disease and sleep disturbances. (Lemborexant, an orexin receptor agonist that acts to regulate wakefulness, is being investigated in a broad range of sleep disorders.) Patients were randomized to one of four doses of lemborexant or placebo and wore a device for sleep monitoring. Nighttime activity indicating arousal was significantly lower for people in two dosage arms, 5 mg and 10 mg, compared with placebo, and treatment groups saw trends toward less sleep fragmentation and higher total sleep time, Dr. Moline told the conference.

Suvorexant (Belsomra), the only orexin receptor antagonist currently licensed as a sleep aid, is also being tested in people with Alzheimer’s disease. At AAIC 2019, Joseph Herring, MD, PhD, of Merck in Kenilworth, N.J., presented results from a placebo-controlled trial of 277 patients with Alzheimer’s disease and insomnia, and reported that treatment with 10 or 20 mg of suvorexant over 4 weeks was associated with about an extra half hour of total nightly sleep, with a 73-minute mean increase from baseline, compared with 45 minutes for patients receiving placebo (95% CI, 11-45; P less than .005).
 

Trazodone linked to slower cognitive decline

An inexpensive antidepressant used in low doses as a sleep aid, including in people with Alzheimer’s disease, was associated with a delay in cognitive decline in older adults, according to results from a retrospective study. Elissaios Karageorgiou, MD, PhD, of the University of California, San Francisco, and the Neurological Institute of Athens presented results derived from two cohorts: patients enrolled at the UCSF Memory and Aging Center and women enrolled in the Study for Osteoporotic Fractures (SOF) in Women. The investigators were able to identify trazodone users in the studies (with two or more contiguous study visits reporting trazodone use) and match them with control patients from the same cohorts who did not use trazodone.

 

Trazodone was studied because previous research suggests it increases total sleep time in patients with Alzheimer’s disease without affecting next-day cognitive performance.

Trazodone-using patients in the UCSF cohort (n = 25) saw significantly less decline in Mini Mental State Exam (MMSE) scores over 4 years, compared with nonusers (0.27 vs. 0.70 points per year; P = .023), an effect that remained statistically significant even after adjusting for sedative and stimulant use and the expected progression of Alzheimer’s disease pathology. Importantly, the slower decline was seen only among subjects with sleep complaints at baseline and especially those whose sleep improved over time, suggesting that the cognitive benefit was mediated by improved sleep.

In the SOF cohort of 46 trazodone users matched with 148 nonusers, no significant protective or negative effect related to long-term trazodone use was found using the MMSE or the Trails Making Test. In this analysis, however, baseline and longitudinal sleep quality was not captured in the group-matching process, neither was the use of other medications. The patient group was slightly older, and all patients were women.

Dr. Karageorgiou said in an interview that the link between improved sleep, trazodone, and cognition needs to be validated in prospective intervention studies. Trazodone, he said, appears to work best in people with a specific type of insomnia characterized by cortical and behavioral hyperarousal, and its cognitive effect appears limited to people whose sleep improves with treatment. “You’re not going to see long-term cognitive benefits if it’s not improving your sleep,” Dr. Karageorgiou said. “So, whether trazodone improves sleep or not in a patient after a few months can be an early indicator for the clinician to continue using it or suspend it, because it is unlikely to help their cognition otherwise.”

He stressed that physicians need to be broadly focused on improving sleep to help patients with, or at risk for, dementia by consolidating their sleep rhythms.

“Trazodone is not the magic bullet, and I don’t think we will ever have a magic bullet,” Dr. Karageorgiou said. “Because when our brain degenerates, it’s not just one chemical, or one system, it’s many. And our body changes as well. The important thing is to help the patient consolidate their rhythms, whether through light therapy, daily exercise, cognitive behavioral therapy for insomnia, or other evidence-based interventions and their combination. The same applies for a person with dementia as for the rest of us.”

None of the investigators outside of the industry-sponsored studies had relevant disclosures.

LOS ANGELES – While a large number of older adults take prescription and nonprescription medications to help them sleep, the effect of these medications on dementia risk is unclear, with most researchers advocating a cautious and conservative approach to prescribing.

Nastasic/iStockphoto.com

Research is increasingly revealing a bidirectional relationship between sleep and dementia. Poor sleep – especially from insomnia, sleep deprivation, or obstructive sleep apnea – is known to increase dementia risk. Dementias, meanwhile, are associated with serious circadian rhythm disturbances, leading to nighttime sleep loss and increasing the likelihood of institutionalization.

At the Alzheimer’s Association International Conference, researchers presented findings assessing the links between sleep medication use and dementia and also what agents or approaches might safely improve sleep in people with sleep disorders who are at risk for dementia or who have been diagnosed with dementia.
 

Sex- and race-based differences in risk

Yue Leng, PhD, of the University of California, San Francisco, reported a link between frequent sleep medication use and later dementia – but only in white adults. Dr. Leng presented findings from the National Institutes of Health–funded Health, Aging, and Body Composition Study, which recruited 3,068 subjects aged 70-79 and followed them for 15 years. At baseline, 2.7% of African Americans and 7.7% of whites in the study reported taking sleep medications “often” or “almost always.”

Dr. Leng and her colleagues found that white subjects who reported taking sleep aids five or more times a month at baseline had a nearly 80% higher risk of developing dementia during the course of the study (hazard ratio, 1.79; 95% confidence interval, 1.21-2.66), compared with people who reported never taking sleep aids or taking them less frequently.

The researchers saw no between-sex differences for this finding, and adjusted for a variety of genetic and lifestyle confounders. Importantly, no significant increase in dementia risk was seen for black subjects, who made up more than one-third of the cohort.

Dr. Leng told the conference that the researchers could not explain why black participants did not see similarly increased dementia risk. Also, she noted, researchers did not have information on the specific sleep medications people used: benzodiazepines, antihistamines, antidepressants, or other types of drugs. Nonetheless, she told the conference, the findings ratified the cautious approach many dementia experts are already stressing.


“Do we really need to prescribe so many sleep meds to older adults who are already at risk for cognitive impairment?” Dr. Leng said, adding: “I am a big advocate of behavioral sleep interventions.” People with clinical sleep problems “should be referred to sleep centers” for a fuller assessment before medication is prescribed, she said.

Findings from another cohort study, meanwhile, suggest that there could be sex-related differences in how sleep aids affect dementia risk. Investigators at Utah State University in Logan used data from some 3,656 older adults in the Cache County Study on Memory and Aging, an NIH-backed cohort study of white adults in Utah without dementia at baseline who were followed for 12 years.

The investigators, led by doctoral student Elizabeth Vernon, found that men reporting use of sleep medication saw more than threefold higher risk of developing Alzheimer’s disease than did men who did not use sleep aids (HR, 3.604; P = .0001).

Women who did not report having sleep disturbance but used sleep-inducing medications were at nearly fourfold greater risk for developing Alzheimer’s disease (HR, 3.916; P = .0001). Women who self-reported sleep disturbances at baseline, meanwhile, saw a reduction in Alzheimer’s risk of about one-third associated with the use of sleep medications.

Ms. Vernon told the conference that, despite the finding of risk reduction for this particular group of women, caution in prescribing sleep aids was warranted.

 

Common sleep drugs linked to cognitive aging

Chris Fox, MD, a researcher at the University of East Anglia in Norwich, England, and his colleagues demonstrated in 2018 that long-term exposure to anticholinergic drugs, a class that includes some antidepressants and antihistamines used to promote sleep, was associated with a higher risk of dementia, while use of benzodiazepines, a class of sedatives used commonly in older people as sleep aids, was not. (Whether benzodiazepine exposure relates to dementia remains controversial.)

At AAIC 2019, Dr. Fox presented findings from a study of 337 brains in a U.K. brain bank, of which 17% and 21% came from users of benzodiazepines and anticholinergic drugs, whose usage history was well documented. Dr. Fox and his colleagues found that, while neither anticholinergic nor benzodiazepine exposure was associated with brain pathology specific to that seen in Alzheimer’s disease, both classes of drugs were associated with “slight signals in neuronal loss” in one brain region, the nucleus basalis of Meynert. Dr. Fox described the drugs as causing “an increase in cognitive aging” which could bear on Alzheimer’s risk without being directly causative.
 

Newer sleep drugs may help Alzheimer’s patients

Scientists working for drug manufacturers presented findings on agents to counter the circadian rhythm disturbances seen in people with Alzheimer’s disease. Margaret Moline, PhD, of Eisai in Woodcliff Lake, N.J., showed some results from a phase 2, dose-ranging, placebo-controlled study of the experimental agent lemborexant in 62 subjects aged 60-90 with mild to moderate Alzheimer’s disease and sleep disturbances. (Lemborexant, an orexin receptor agonist that acts to regulate wakefulness, is being investigated in a broad range of sleep disorders.) Patients were randomized to one of four doses of lemborexant or placebo and wore a device for sleep monitoring. Nighttime activity indicating arousal was significantly lower for people in two dosage arms, 5 mg and 10 mg, compared with placebo, and treatment groups saw trends toward less sleep fragmentation and higher total sleep time, Dr. Moline told the conference.

Suvorexant (Belsomra), the only orexin receptor antagonist currently licensed as a sleep aid, is also being tested in people with Alzheimer’s disease. At AAIC 2019, Joseph Herring, MD, PhD, of Merck in Kenilworth, N.J., presented results from a placebo-controlled trial of 277 patients with Alzheimer’s disease and insomnia, and reported that treatment with 10 or 20 mg of suvorexant over 4 weeks was associated with about an extra half hour of total nightly sleep, with a 73-minute mean increase from baseline, compared with 45 minutes for patients receiving placebo (95% CI, 11-45; P less than .005).
 

Trazodone linked to slower cognitive decline

An inexpensive antidepressant used in low doses as a sleep aid, including in people with Alzheimer’s disease, was associated with a delay in cognitive decline in older adults, according to results from a retrospective study. Elissaios Karageorgiou, MD, PhD, of the University of California, San Francisco, and the Neurological Institute of Athens presented results derived from two cohorts: patients enrolled at the UCSF Memory and Aging Center and women enrolled in the Study for Osteoporotic Fractures (SOF) in Women. The investigators were able to identify trazodone users in the studies (with two or more contiguous study visits reporting trazodone use) and match them with control patients from the same cohorts who did not use trazodone.

 

Trazodone was studied because previous research suggests it increases total sleep time in patients with Alzheimer’s disease without affecting next-day cognitive performance.

Trazodone-using patients in the UCSF cohort (n = 25) saw significantly less decline in Mini Mental State Exam (MMSE) scores over 4 years, compared with nonusers (0.27 vs. 0.70 points per year; P = .023), an effect that remained statistically significant even after adjusting for sedative and stimulant use and the expected progression of Alzheimer’s disease pathology. Importantly, the slower decline was seen only among subjects with sleep complaints at baseline and especially those whose sleep improved over time, suggesting that the cognitive benefit was mediated by improved sleep.

In the SOF cohort of 46 trazodone users matched with 148 nonusers, no significant protective or negative effect related to long-term trazodone use was found using the MMSE or the Trails Making Test. In this analysis, however, baseline and longitudinal sleep quality was not captured in the group-matching process, neither was the use of other medications. The patient group was slightly older, and all patients were women.

Dr. Karageorgiou said in an interview that the link between improved sleep, trazodone, and cognition needs to be validated in prospective intervention studies. Trazodone, he said, appears to work best in people with a specific type of insomnia characterized by cortical and behavioral hyperarousal, and its cognitive effect appears limited to people whose sleep improves with treatment. “You’re not going to see long-term cognitive benefits if it’s not improving your sleep,” Dr. Karageorgiou said. “So, whether trazodone improves sleep or not in a patient after a few months can be an early indicator for the clinician to continue using it or suspend it, because it is unlikely to help their cognition otherwise.”

He stressed that physicians need to be broadly focused on improving sleep to help patients with, or at risk for, dementia by consolidating their sleep rhythms.

“Trazodone is not the magic bullet, and I don’t think we will ever have a magic bullet,” Dr. Karageorgiou said. “Because when our brain degenerates, it’s not just one chemical, or one system, it’s many. And our body changes as well. The important thing is to help the patient consolidate their rhythms, whether through light therapy, daily exercise, cognitive behavioral therapy for insomnia, or other evidence-based interventions and their combination. The same applies for a person with dementia as for the rest of us.”

None of the investigators outside of the industry-sponsored studies had relevant disclosures.

 

LOS ANGELES – Dysregulated sleep-wake cycles may be linked to cerebral glucose hypometabolism and subtle cognitive changes, both of which are early signs of Alzheimer’s disease–like neurodegeneration, according to a 2-year study of older Korean adults.

Michele G. Sullivan/MDedge News

The association was particularly strong in subjects who experienced delayed acrophase, the peak of the normal sleep-wake cycle, So-Yeon Jeon, MD, said at the Alzheimer’s Association International Conference. It’s not yet clear whether the changes are a risk factor for dementia or a prodromal sign of neurodegeneration, but even without full elucidation, the findings could have value as a signal of impending neurodegeneration, said Dr. Jeon of Seoul (South Korea) National University.

“Our findings suggest that delayed acrophase may be used as a predictor for the progression of Alzheimer’s-type neurodegeneration and cognitive decline in the near future in old individuals with diverse cognitive status,” she said. “But the relationship between circadian phases and neurodegeneration is complex and not yet well understood.”

The 24-month study comprised 215 elderly adults enrolled in the Korean Brain Aging Study for the Early Diagnosis and Prediction of Alzheimer’s Disease (KBASE). They were a mean of 70 years old at baseline; 143 were cognitively normal, 40 had mild cognitive impairment, and 32 had Alzheimer’s dementia. Both at baseline and 2 years, everyone underwent a comprehensive neuropsychological assessment, amyloid PET brain imaging with Pittsburgh compound B, and an [18F]-fluorodeoxyglucose PET scan to determine brain glucose metabolic rate.

Before each assessment, the investigators measured sleep and circadian rhythms with 8 days of actigraphy. This assessed sleep variables (total sleep time, sleep latency, sleep efficiency, and wakefulness after sleep); rest-activity rhythm variables (midline estimated statistic of rhythm, amplitude, and acrophase), and some nonparametric values including interdaily stability, intradaily variability, and relative amplitude of sleep cycles. Subjects also completed sleep diaries during these periods.

The study’s main outcomes were 2-year changes in the Mini Mental State Exam (MMSE) score and in Alzheimer’s imaging biomarkers, including glucose metabolism and amyloid deposition. All analyses controlled for age, sex, Clinical Dementia Rating score, apolipoprotein E allele status, and baseline cognition.

At baseline, lower total sleep time was significantly associated with hypometabolism in areas associated with Alzheimer’s pathology as well as lower mean MMSE scores. Circadian variables showed no significant associations with these characteristics. However, the relative amplitude of circadian rhythm was significantly associated with hypometabolism and with lower MMSE score. There were no associations with brain amyloid load.

At 2 years, acrophase was associated with declines in cerebral glucose metabolism and further changes in the MMSE, even after the researchers controlled for the potential confounders. Delayed acrophase, although not associated with either metabolic rate or cognition at baseline, did significantly influence both at 2 years, suggesting a rapidly eroding clinical picture.

“Neurodegeneration over 2 years means the disease is progressing rapidly and subjects are likely to have tauopathies or other proteinopathy,” Dr. Jeon said. “These pathologies may either be resulting in delayed acrophase followed by neurodegeneration, or they may be prodromal symptoms of impending neurodegeneration. Whether they are early symptoms or early risk factors is not currently known, however. Two years is too short of a follow-up to determine these questions.”

Dr. Jeon had no financial declarations.

msullivan@mdedge.com

SOURCE: Jeon SY et al. AAIC 2019, abstract 33543.

 

LOS ANGELES – Dysregulated sleep-wake cycles may be linked to cerebral glucose hypometabolism and subtle cognitive changes, both of which are early signs of Alzheimer’s disease–like neurodegeneration, according to a 2-year study of older Korean adults.

Michele G. Sullivan/MDedge News

The association was particularly strong in subjects who experienced delayed acrophase, the peak of the normal sleep-wake cycle, So-Yeon Jeon, MD, said at the Alzheimer’s Association International Conference. It’s not yet clear whether the changes are a risk factor for dementia or a prodromal sign of neurodegeneration, but even without full elucidation, the findings could have value as a signal of impending neurodegeneration, said Dr. Jeon of Seoul (South Korea) National University.

“Our findings suggest that delayed acrophase may be used as a predictor for the progression of Alzheimer’s-type neurodegeneration and cognitive decline in the near future in old individuals with diverse cognitive status,” she said. “But the relationship between circadian phases and neurodegeneration is complex and not yet well understood.”

The 24-month study comprised 215 elderly adults enrolled in the Korean Brain Aging Study for the Early Diagnosis and Prediction of Alzheimer’s Disease (KBASE). They were a mean of 70 years old at baseline; 143 were cognitively normal, 40 had mild cognitive impairment, and 32 had Alzheimer’s dementia. Both at baseline and 2 years, everyone underwent a comprehensive neuropsychological assessment, amyloid PET brain imaging with Pittsburgh compound B, and an [18F]-fluorodeoxyglucose PET scan to determine brain glucose metabolic rate.

Before each assessment, the investigators measured sleep and circadian rhythms with 8 days of actigraphy. This assessed sleep variables (total sleep time, sleep latency, sleep efficiency, and wakefulness after sleep); rest-activity rhythm variables (midline estimated statistic of rhythm, amplitude, and acrophase), and some nonparametric values including interdaily stability, intradaily variability, and relative amplitude of sleep cycles. Subjects also completed sleep diaries during these periods.

The study’s main outcomes were 2-year changes in the Mini Mental State Exam (MMSE) score and in Alzheimer’s imaging biomarkers, including glucose metabolism and amyloid deposition. All analyses controlled for age, sex, Clinical Dementia Rating score, apolipoprotein E allele status, and baseline cognition.

At baseline, lower total sleep time was significantly associated with hypometabolism in areas associated with Alzheimer’s pathology as well as lower mean MMSE scores. Circadian variables showed no significant associations with these characteristics. However, the relative amplitude of circadian rhythm was significantly associated with hypometabolism and with lower MMSE score. There were no associations with brain amyloid load.

At 2 years, acrophase was associated with declines in cerebral glucose metabolism and further changes in the MMSE, even after the researchers controlled for the potential confounders. Delayed acrophase, although not associated with either metabolic rate or cognition at baseline, did significantly influence both at 2 years, suggesting a rapidly eroding clinical picture.

“Neurodegeneration over 2 years means the disease is progressing rapidly and subjects are likely to have tauopathies or other proteinopathy,” Dr. Jeon said. “These pathologies may either be resulting in delayed acrophase followed by neurodegeneration, or they may be prodromal symptoms of impending neurodegeneration. Whether they are early symptoms or early risk factors is not currently known, however. Two years is too short of a follow-up to determine these questions.”

Dr. Jeon had no financial declarations.

msullivan@mdedge.com

SOURCE: Jeon SY et al. AAIC 2019, abstract 33543.

 

LOS ANGELES – Dysregulated sleep-wake cycles may be linked to cerebral glucose hypometabolism and subtle cognitive changes, both of which are early signs of Alzheimer’s disease–like neurodegeneration, according to a 2-year study of older Korean adults.

Michele G. Sullivan/MDedge News

The association was particularly strong in subjects who experienced delayed acrophase, the peak of the normal sleep-wake cycle, So-Yeon Jeon, MD, said at the Alzheimer’s Association International Conference. It’s not yet clear whether the changes are a risk factor for dementia or a prodromal sign of neurodegeneration, but even without full elucidation, the findings could have value as a signal of impending neurodegeneration, said Dr. Jeon of Seoul (South Korea) National University.

“Our findings suggest that delayed acrophase may be used as a predictor for the progression of Alzheimer’s-type neurodegeneration and cognitive decline in the near future in old individuals with diverse cognitive status,” she said. “But the relationship between circadian phases and neurodegeneration is complex and not yet well understood.”

The 24-month study comprised 215 elderly adults enrolled in the Korean Brain Aging Study for the Early Diagnosis and Prediction of Alzheimer’s Disease (KBASE). They were a mean of 70 years old at baseline; 143 were cognitively normal, 40 had mild cognitive impairment, and 32 had Alzheimer’s dementia. Both at baseline and 2 years, everyone underwent a comprehensive neuropsychological assessment, amyloid PET brain imaging with Pittsburgh compound B, and an [18F]-fluorodeoxyglucose PET scan to determine brain glucose metabolic rate.

Before each assessment, the investigators measured sleep and circadian rhythms with 8 days of actigraphy. This assessed sleep variables (total sleep time, sleep latency, sleep efficiency, and wakefulness after sleep); rest-activity rhythm variables (midline estimated statistic of rhythm, amplitude, and acrophase), and some nonparametric values including interdaily stability, intradaily variability, and relative amplitude of sleep cycles. Subjects also completed sleep diaries during these periods.

The study’s main outcomes were 2-year changes in the Mini Mental State Exam (MMSE) score and in Alzheimer’s imaging biomarkers, including glucose metabolism and amyloid deposition. All analyses controlled for age, sex, Clinical Dementia Rating score, apolipoprotein E allele status, and baseline cognition.

At baseline, lower total sleep time was significantly associated with hypometabolism in areas associated with Alzheimer’s pathology as well as lower mean MMSE scores. Circadian variables showed no significant associations with these characteristics. However, the relative amplitude of circadian rhythm was significantly associated with hypometabolism and with lower MMSE score. There were no associations with brain amyloid load.

At 2 years, acrophase was associated with declines in cerebral glucose metabolism and further changes in the MMSE, even after the researchers controlled for the potential confounders. Delayed acrophase, although not associated with either metabolic rate or cognition at baseline, did significantly influence both at 2 years, suggesting a rapidly eroding clinical picture.

“Neurodegeneration over 2 years means the disease is progressing rapidly and subjects are likely to have tauopathies or other proteinopathy,” Dr. Jeon said. “These pathologies may either be resulting in delayed acrophase followed by neurodegeneration, or they may be prodromal symptoms of impending neurodegeneration. Whether they are early symptoms or early risk factors is not currently known, however. Two years is too short of a follow-up to determine these questions.”

Dr. Jeon had no financial declarations.

msullivan@mdedge.com

SOURCE: Jeon SY et al. AAIC 2019, abstract 33543.

Restless legs syndrome (RLS) is a very common disease affecting about 10% of Caucasian adults with about one third of them having RLS symptoms severe enough to require treatment.

Although many patients still go undiagnosed or misdiagnosed, the diagnosis is easily established with the five diagnostic criteria that are simplified by the acronym URGES:

1. Urge to move the legs associated with unpleasant leg sensations.

2. Rest induces symptoms.

3. Gets better with activity.

4. Evening and nighttime worsening.

5. Solely not accounted by another medical or behavioral condition.

The diagnosis is based completely upon the history. However, supplemental tests can be helpful to rule out underlying conditions that increase the risk of RLS. Routine lab tests, such as serum creatinine (to rule out renal disease), TSH (to rule out thyroid disease), and a CBC/ferritin/iron with transferrin saturation (to rule out low iron stores) should be ordered if not done recently.

A polysomnographic sleep study should not be ordered unless there is a strong suspicion that sleep apnea is present. Even very frequent PLM (periodic limb movements) are not that helpful in confirming the diagnosis of RLS since they are nonspecific and often occurring with drug treatment (SSRIs, SNRIs) and many medical conditions such as sleep apnea, narcolepsy, and REM behavior disorder.

The paradigm for treating RLS has been presented in the consensus article published in 2013 (Silber MH, et al. Mayo Clin Proc. 2013 Sep;88[9]:977). Since 2013, there has been a gradual shift of that paradigm that recommended starting an approved dopamine agonist (pramipexole, ropinirole, or rotigotine) or an alpha-2-delta ligand (gabapentin enacarbil, gabapentin, or pregabalin) as first-line treatment. Although dopamine agonists provide excellent relief of RLS symptoms initially, with time, they tend to markedly worsen RLS. This process is called RLS augmentation and has become one of the most common causes of refractory RLS and difficult-to-treat patients.

RLS augmentation typically onsets a few months to several years after starting a short-acting dopamine agonist (DA) like pramipexole or ropinirole. It presents with symptoms occurring a few hours earlier than prior to starting the medication, symptoms becoming more intense with less rest time needed to trigger RLS symptoms, drugs becoming less effective both in effectiveness and duration of action, and spread of symptoms to other body parts (arms, trunk, and even head). The majority of physicians mistake this worsening of RLS for the natural progression of the disease and, thus, increase the dose of the DA, which provides temporary improvement. Further increases become progressively necessary until the patient is receiving very large doses, often exceeding 10 times the FDA maximum recommended doses. Eventually, further dose increments provide minimal additional benefit, leaving patients with severe, around the clock RLS symptoms causing extreme misery. To be more aware of augmentation, physicians should consider augmentation may be occurring whenever a patient who has been on a regimen of stable dopamine agonist treatment for at least 6 months requests more medication.

 

The incidence of augmentation for patients taking short-acting DA drugs is about 7% to 8% per year so that by 10 years, the vast majority of these patients with RLS are experiencing augmentation. Since it has been over 13 years since pramipexole and ropinirole have been approved for treating RLS, currently, over 75% of patients referred to national RLS experts are referred due to augmentation (although the actual referral diagnosis is often “refractory RLS”). Despite the concerns about augmentation, the short-acting DA drugs are by far the most commonly prescribed medications for initial treatment of RLS.

To help educate doctors about RLS augmentation, a consensus article was published in 2016 promoting guidelines for the prevention and treatment of RLS augmentation (Garcia-Borreguero D, et al. Sleep Med. 2016;21:1-11). Since augmentation occurs only with dopaminergic drugs (with the exception of tramadol), considering the use of nondopaminergic drugs for first-line therapy of RLS would dramatically decrease the occurrence of augmentation. This is a clear shift in the paradigm of choosing equally amongst the approved RLS drugs.

Unless contraindicated, the alpha-2-delta drugs should be the first consideration for treating new RLS patients. These drugs can be as effective as the DA drugs but cannot cause augmentation and, also, do not cause Impulse control disorders, which occur with the use of DAs. Furthermore, they reduce insomnia and anxiety that are both associated with RLS. The use of these drugs may be limited by their side effects, which include CNS depressive effects (sedation, dizziness, decreased balance or cognition) or depression.

When the alpha-2-delta ligands can’t be used due to lack of efficacy, side effects or cost, the DA drugs may then be appropriate. The rotigotine patch has the lowest incidence of augmentation, especially at the approved doses of up to 3 mg. If the rotigotine patch cannot be used (most often due to skin side effects or cost), then the short-acting DA drugs may be employed. Augmentation may be prevented or significantly delayed by starting these drugs at their lowest dose (.125 mg for pramipexole and .25 mg for ropinirole) and increasing the dose as little as possible, definitely not exceeding the approved RLS limits of .5 mg for pramipexole and 4 mg for ropinirole. My personal suggestion is not to exceed .25 mg for pramipexole and 1 mg for ropinirole as augmentation is dose-related but may occur at even the lowest doses. When patients need and request increased treatment for their RLS, rather than increasing the dose of the DA, instead, consider adding other medications, such as the alpha-2-delta ligands or even low dose opioids.

Managing augmentation is typically a very challenging problem for both the physician and patient; this is described in detail in the augmentation article referenced above. Decreasing, or better yet eliminating , the short-acting DA is the preferred method for treating augmentation. However, upon elimination of the DA, there is a short period of 1 to 4 weeks (average of 10-12 days) when the RLS symptoms get dramatically worse. Patients typically experience extremely severe RLS symptoms around the clock and may not be able to sleep at all until the RLS calms down. Most often, only low dose opioid treatment will enable them to get through this transition. The augmentation article (with its algorithm) may help physicians manage augmentation, but patients with severe augmentation may need referral to an RLS specialist who is experienced in this area and who is comfortable managing the disease with opioids.

Low iron levels are often associated with RLS, cause RLS symptoms to worsen, and increase the risk of augmentation (Allen RP, et al, and the International Restless Legs Syndrome Study Group (IRLSSG). Sleep Med. 2018;41:27). We typically suggest that patients with ferritin levels under 100 mcg/L should get supplemental iron. However, oral iron absorption is very limited when the patient’s ferritin is above 50 mcg/L and, therefore, most patients may require IV iron to improve their RLS symptoms. There are several IV iron preparations but only iron dextrose, iron carboxymaltose, and ferumoxytol are effective. When the ferritin level is increased to over 200 µg/L, RLS symptoms may be dramatically improved.

With the currently available treatment options, most patients should have their RLS symptoms well controlled without developing augmentation.


Dr. Buchfuhrer is with Stanford University, Department of Psychiatry and Behavioral Sciences in the School of Medicine, Division of Sleep Medicine, Stanford, Calif.

Restless legs syndrome (RLS) is a very common disease affecting about 10% of Caucasian adults with about one third of them having RLS symptoms severe enough to require treatment.

Although many patients still go undiagnosed or misdiagnosed, the diagnosis is easily established with the five diagnostic criteria that are simplified by the acronym URGES:

1. Urge to move the legs associated with unpleasant leg sensations.

2. Rest induces symptoms.

3. Gets better with activity.

4. Evening and nighttime worsening.

5. Solely not accounted by another medical or behavioral condition.

The diagnosis is based completely upon the history. However, supplemental tests can be helpful to rule out underlying conditions that increase the risk of RLS. Routine lab tests, such as serum creatinine (to rule out renal disease), TSH (to rule out thyroid disease), and a CBC/ferritin/iron with transferrin saturation (to rule out low iron stores) should be ordered if not done recently.

A polysomnographic sleep study should not be ordered unless there is a strong suspicion that sleep apnea is present. Even very frequent PLM (periodic limb movements) are not that helpful in confirming the diagnosis of RLS since they are nonspecific and often occurring with drug treatment (SSRIs, SNRIs) and many medical conditions such as sleep apnea, narcolepsy, and REM behavior disorder.

The paradigm for treating RLS has been presented in the consensus article published in 2013 (Silber MH, et al. Mayo Clin Proc. 2013 Sep;88[9]:977). Since 2013, there has been a gradual shift of that paradigm that recommended starting an approved dopamine agonist (pramipexole, ropinirole, or rotigotine) or an alpha-2-delta ligand (gabapentin enacarbil, gabapentin, or pregabalin) as first-line treatment. Although dopamine agonists provide excellent relief of RLS symptoms initially, with time, they tend to markedly worsen RLS. This process is called RLS augmentation and has become one of the most common causes of refractory RLS and difficult-to-treat patients.

RLS augmentation typically onsets a few months to several years after starting a short-acting dopamine agonist (DA) like pramipexole or ropinirole. It presents with symptoms occurring a few hours earlier than prior to starting the medication, symptoms becoming more intense with less rest time needed to trigger RLS symptoms, drugs becoming less effective both in effectiveness and duration of action, and spread of symptoms to other body parts (arms, trunk, and even head). The majority of physicians mistake this worsening of RLS for the natural progression of the disease and, thus, increase the dose of the DA, which provides temporary improvement. Further increases become progressively necessary until the patient is receiving very large doses, often exceeding 10 times the FDA maximum recommended doses. Eventually, further dose increments provide minimal additional benefit, leaving patients with severe, around the clock RLS symptoms causing extreme misery. To be more aware of augmentation, physicians should consider augmentation may be occurring whenever a patient who has been on a regimen of stable dopamine agonist treatment for at least 6 months requests more medication.

 

The incidence of augmentation for patients taking short-acting DA drugs is about 7% to 8% per year so that by 10 years, the vast majority of these patients with RLS are experiencing augmentation. Since it has been over 13 years since pramipexole and ropinirole have been approved for treating RLS, currently, over 75% of patients referred to national RLS experts are referred due to augmentation (although the actual referral diagnosis is often “refractory RLS”). Despite the concerns about augmentation, the short-acting DA drugs are by far the most commonly prescribed medications for initial treatment of RLS.

To help educate doctors about RLS augmentation, a consensus article was published in 2016 promoting guidelines for the prevention and treatment of RLS augmentation (Garcia-Borreguero D, et al. Sleep Med. 2016;21:1-11). Since augmentation occurs only with dopaminergic drugs (with the exception of tramadol), considering the use of nondopaminergic drugs for first-line therapy of RLS would dramatically decrease the occurrence of augmentation. This is a clear shift in the paradigm of choosing equally amongst the approved RLS drugs.

Unless contraindicated, the alpha-2-delta drugs should be the first consideration for treating new RLS patients. These drugs can be as effective as the DA drugs but cannot cause augmentation and, also, do not cause Impulse control disorders, which occur with the use of DAs. Furthermore, they reduce insomnia and anxiety that are both associated with RLS. The use of these drugs may be limited by their side effects, which include CNS depressive effects (sedation, dizziness, decreased balance or cognition) or depression.

When the alpha-2-delta ligands can’t be used due to lack of efficacy, side effects or cost, the DA drugs may then be appropriate. The rotigotine patch has the lowest incidence of augmentation, especially at the approved doses of up to 3 mg. If the rotigotine patch cannot be used (most often due to skin side effects or cost), then the short-acting DA drugs may be employed. Augmentation may be prevented or significantly delayed by starting these drugs at their lowest dose (.125 mg for pramipexole and .25 mg for ropinirole) and increasing the dose as little as possible, definitely not exceeding the approved RLS limits of .5 mg for pramipexole and 4 mg for ropinirole. My personal suggestion is not to exceed .25 mg for pramipexole and 1 mg for ropinirole as augmentation is dose-related but may occur at even the lowest doses. When patients need and request increased treatment for their RLS, rather than increasing the dose of the DA, instead, consider adding other medications, such as the alpha-2-delta ligands or even low dose opioids.

Managing augmentation is typically a very challenging problem for both the physician and patient; this is described in detail in the augmentation article referenced above. Decreasing, or better yet eliminating , the short-acting DA is the preferred method for treating augmentation. However, upon elimination of the DA, there is a short period of 1 to 4 weeks (average of 10-12 days) when the RLS symptoms get dramatically worse. Patients typically experience extremely severe RLS symptoms around the clock and may not be able to sleep at all until the RLS calms down. Most often, only low dose opioid treatment will enable them to get through this transition. The augmentation article (with its algorithm) may help physicians manage augmentation, but patients with severe augmentation may need referral to an RLS specialist who is experienced in this area and who is comfortable managing the disease with opioids.

Low iron levels are often associated with RLS, cause RLS symptoms to worsen, and increase the risk of augmentation (Allen RP, et al, and the International Restless Legs Syndrome Study Group (IRLSSG). Sleep Med. 2018;41:27). We typically suggest that patients with ferritin levels under 100 mcg/L should get supplemental iron. However, oral iron absorption is very limited when the patient’s ferritin is above 50 mcg/L and, therefore, most patients may require IV iron to improve their RLS symptoms. There are several IV iron preparations but only iron dextrose, iron carboxymaltose, and ferumoxytol are effective. When the ferritin level is increased to over 200 µg/L, RLS symptoms may be dramatically improved.

With the currently available treatment options, most patients should have their RLS symptoms well controlled without developing augmentation.


Dr. Buchfuhrer is with Stanford University, Department of Psychiatry and Behavioral Sciences in the School of Medicine, Division of Sleep Medicine, Stanford, Calif.

Restless legs syndrome (RLS) is a very common disease affecting about 10% of Caucasian adults with about one third of them having RLS symptoms severe enough to require treatment.

Although many patients still go undiagnosed or misdiagnosed, the diagnosis is easily established with the five diagnostic criteria that are simplified by the acronym URGES:

1. Urge to move the legs associated with unpleasant leg sensations.

2. Rest induces symptoms.

3. Gets better with activity.

4. Evening and nighttime worsening.

5. Solely not accounted by another medical or behavioral condition.

The diagnosis is based completely upon the history. However, supplemental tests can be helpful to rule out underlying conditions that increase the risk of RLS. Routine lab tests, such as serum creatinine (to rule out renal disease), TSH (to rule out thyroid disease), and a CBC/ferritin/iron with transferrin saturation (to rule out low iron stores) should be ordered if not done recently.

A polysomnographic sleep study should not be ordered unless there is a strong suspicion that sleep apnea is present. Even very frequent PLM (periodic limb movements) are not that helpful in confirming the diagnosis of RLS since they are nonspecific and often occurring with drug treatment (SSRIs, SNRIs) and many medical conditions such as sleep apnea, narcolepsy, and REM behavior disorder.

The paradigm for treating RLS has been presented in the consensus article published in 2013 (Silber MH, et al. Mayo Clin Proc. 2013 Sep;88[9]:977). Since 2013, there has been a gradual shift of that paradigm that recommended starting an approved dopamine agonist (pramipexole, ropinirole, or rotigotine) or an alpha-2-delta ligand (gabapentin enacarbil, gabapentin, or pregabalin) as first-line treatment. Although dopamine agonists provide excellent relief of RLS symptoms initially, with time, they tend to markedly worsen RLS. This process is called RLS augmentation and has become one of the most common causes of refractory RLS and difficult-to-treat patients.

RLS augmentation typically onsets a few months to several years after starting a short-acting dopamine agonist (DA) like pramipexole or ropinirole. It presents with symptoms occurring a few hours earlier than prior to starting the medication, symptoms becoming more intense with less rest time needed to trigger RLS symptoms, drugs becoming less effective both in effectiveness and duration of action, and spread of symptoms to other body parts (arms, trunk, and even head). The majority of physicians mistake this worsening of RLS for the natural progression of the disease and, thus, increase the dose of the DA, which provides temporary improvement. Further increases become progressively necessary until the patient is receiving very large doses, often exceeding 10 times the FDA maximum recommended doses. Eventually, further dose increments provide minimal additional benefit, leaving patients with severe, around the clock RLS symptoms causing extreme misery. To be more aware of augmentation, physicians should consider augmentation may be occurring whenever a patient who has been on a regimen of stable dopamine agonist treatment for at least 6 months requests more medication.

 

The incidence of augmentation for patients taking short-acting DA drugs is about 7% to 8% per year so that by 10 years, the vast majority of these patients with RLS are experiencing augmentation. Since it has been over 13 years since pramipexole and ropinirole have been approved for treating RLS, currently, over 75% of patients referred to national RLS experts are referred due to augmentation (although the actual referral diagnosis is often “refractory RLS”). Despite the concerns about augmentation, the short-acting DA drugs are by far the most commonly prescribed medications for initial treatment of RLS.

To help educate doctors about RLS augmentation, a consensus article was published in 2016 promoting guidelines for the prevention and treatment of RLS augmentation (Garcia-Borreguero D, et al. Sleep Med. 2016;21:1-11). Since augmentation occurs only with dopaminergic drugs (with the exception of tramadol), considering the use of nondopaminergic drugs for first-line therapy of RLS would dramatically decrease the occurrence of augmentation. This is a clear shift in the paradigm of choosing equally amongst the approved RLS drugs.

Unless contraindicated, the alpha-2-delta drugs should be the first consideration for treating new RLS patients. These drugs can be as effective as the DA drugs but cannot cause augmentation and, also, do not cause Impulse control disorders, which occur with the use of DAs. Furthermore, they reduce insomnia and anxiety that are both associated with RLS. The use of these drugs may be limited by their side effects, which include CNS depressive effects (sedation, dizziness, decreased balance or cognition) or depression.

When the alpha-2-delta ligands can’t be used due to lack of efficacy, side effects or cost, the DA drugs may then be appropriate. The rotigotine patch has the lowest incidence of augmentation, especially at the approved doses of up to 3 mg. If the rotigotine patch cannot be used (most often due to skin side effects or cost), then the short-acting DA drugs may be employed. Augmentation may be prevented or significantly delayed by starting these drugs at their lowest dose (.125 mg for pramipexole and .25 mg for ropinirole) and increasing the dose as little as possible, definitely not exceeding the approved RLS limits of .5 mg for pramipexole and 4 mg for ropinirole. My personal suggestion is not to exceed .25 mg for pramipexole and 1 mg for ropinirole as augmentation is dose-related but may occur at even the lowest doses. When patients need and request increased treatment for their RLS, rather than increasing the dose of the DA, instead, consider adding other medications, such as the alpha-2-delta ligands or even low dose opioids.

Managing augmentation is typically a very challenging problem for both the physician and patient; this is described in detail in the augmentation article referenced above. Decreasing, or better yet eliminating , the short-acting DA is the preferred method for treating augmentation. However, upon elimination of the DA, there is a short period of 1 to 4 weeks (average of 10-12 days) when the RLS symptoms get dramatically worse. Patients typically experience extremely severe RLS symptoms around the clock and may not be able to sleep at all until the RLS calms down. Most often, only low dose opioid treatment will enable them to get through this transition. The augmentation article (with its algorithm) may help physicians manage augmentation, but patients with severe augmentation may need referral to an RLS specialist who is experienced in this area and who is comfortable managing the disease with opioids.

Low iron levels are often associated with RLS, cause RLS symptoms to worsen, and increase the risk of augmentation (Allen RP, et al, and the International Restless Legs Syndrome Study Group (IRLSSG). Sleep Med. 2018;41:27). We typically suggest that patients with ferritin levels under 100 mcg/L should get supplemental iron. However, oral iron absorption is very limited when the patient’s ferritin is above 50 mcg/L and, therefore, most patients may require IV iron to improve their RLS symptoms. There are several IV iron preparations but only iron dextrose, iron carboxymaltose, and ferumoxytol are effective. When the ferritin level is increased to over 200 µg/L, RLS symptoms may be dramatically improved.

With the currently available treatment options, most patients should have their RLS symptoms well controlled without developing augmentation.


Dr. Buchfuhrer is with Stanford University, Department of Psychiatry and Behavioral Sciences in the School of Medicine, Division of Sleep Medicine, Stanford, Calif.