Idiopathic Central Sleep Apnea Research Articles

Non-linear dynamics of human periodic breathing and implications for sleep apnea therapy

A mathematical model of non-obstructive human periodic breathing (Cheyne-Stokes respiration) or central sleep apnea (CSA) is described which focused on explaining recently reported non-linear behavior. Evidence was presented that CHF (chronic heart failure)-CSA and ICSA (idiopathic central sleep apnea) both involved limit cycle oscillations. The validity of applying linear control theory for stabilization must then be re-examined. Critical threshold values and ranges of parameters were predicted which caused a change (bifurcation) from limit cycle periodic breathing to stable breathing. Changes in lung volume were predicted to form a bifurcation during CHF-CSA where stability and instability can involve a lung volume change as small as 0.1 l. CSA therapy based on reducing control loop gain was predicted to be relatively ineffective during stable limit cycle oscillation. The relative ratios of durations of ventilation to apnea (T(v)/T(a)) during periodic breathing were primarily determined by peripheral chemoreceptor dynamics during crescendo, de-crescendo, and apnea phases of CSA.

Central Sleep Apnea: Pathophysiology and Treatment

Central sleep apnea (CSA) is characterized by a lack of drive to breathe during sleep, resulting in repetitive periods of insufficient ventilation and compromised gas exchange. These nighttime breathing disturbances can lead to important comorbidity and increased risk of adverse cardiovascular outcomes. There are several manifestations of CSA, including high altitude-induced periodic breathing, idiopathic CSA, narcotic-induced central apnea, obesity hypoventilation syndrome, and Cheyne-Stokes breathing. While unstable ventilatory control during sleep is the hallmark of CSA, the pathophysiology and the prevalence of the various forms of CSA vary greatly. This brief review summarizes the underlying physiology and modulating components influencing ventilatory control in CSA, describes the etiology of each of the various forms of CSA, and examines the key factors that may exacerbate apnea severity. The clinical implications of improved CSA pathophysiology knowledge and the potential for novel therapeutic treatment approaches are also discussed.

Association Between Atrial Fibrillation and Central Sleep Apnea

We previously described an association between atrial fibrillation and central sleep apnea in a group of patients with congestive heart failure. We hypothesized that the prevalence of atrial fibrillation might also be increased in patients with central sleep apnea in the absence of other cardiac disease. We compared the prevalence of atrial fibrillation in a series of 60 consecutive patients with idiopathic central sleep apnea (apnea-hypopnea index > 10 events per hour, > 50% central events) with that in 60 patients with obstructive sleep apnea (apnea-hypopnea index > 10, > 50% obstructive events) and 60 patients without sleep apnea (apnea-hypopnea index < 10), matched for age, sex, and body mass index. Subjects with a history of congestive heart failure, coronary artery disease, or stroke were excluded from the study. The prevalence of atrial fibrillation among patients with idiopathic central sleep apnea was found to be significantly higher than the prevalence among patients with obstructive sleep apnea or no sleep apnea (27%, 1.7%, and 3.3%, respectively, P < .001). However, hypertension was most common and oxygen desaturation most extreme among patients with obstructive sleep apnea. We conclude that there is a markedly increased prevalence of atrial fibrillation among patients with idiopathic central sleep apnea in the absence of congestive heart failure. Moreover, the high prevalence of atrial fibrillation among patients with idiopathic central sleep apnea is not explainable by the presence of hypertension or nocturnal oxygen desaturation, since both of these were more strongly associated with obstructive sleep apnea.

Effect of CO2 Inhalation on Central Sleep Apnea and Arousals from Sleep

Background: CO₂ inhalation reduces central sleep apnea (CSA) in patients with congestive heart failure (CHF) and idiopathic CSA. CO₂ is also a stimulus for cortical arousal, which has been linked to increased sympathetic nerve activity (SNA) and increased mortality in CHF patients with CSA. Objective: We have tested the hypothesis that during sleep, inhalation of CO₂ sufficient to reduce the apnea-hypopnea index (AHI) would not reduce the arousal index (AroI). Methods: In 10 male patients with CSA (7 with CHF and 3 with idiopathic CSA), the inspired CO₂ concentration was increased to raise the sleeping end-tidal CO₂ by 2–4 mm Hg during established stage 2 sleep. Each intervention was maintained for a 10-min period. Sleep stage was monitored with electroencephalograms, electrooculograms, submental electromyogram, airflow with pneumotachometer and respiratory effort and blood gases with oxygen saturation and end-tidal CO₂. During periods of air and CO₂ breathing, AHI and AroI were compared with paired t tests; patients acted as their own controls. Results: Inhalation of CO₂ produced a significant reduction in AHI (mean ± SEM) from 74.4 ± 12.4 events/h during air breathing to 25.8 ± 7.8 events/h with CO₂ inhalation (p = 0.002). However, the AroI was not significantly different between the two conditions, air 67.8 ± 12.3 events/h and CO₂ inhalation 52.8 ± 12.4 events/h (p = 0.264). Conclusion: CO₂ inhalation reverses CSA but not arousals from sleep. Our findings highlight the need for treatment options that reduce both respiratory events and decrease arousals from sleep, with their associated SNA sequelae.

Cardiorespiratory Effects of Added Dead Space in Patients With Heart Failure and Central Sleep Apnea

Inhaled CO(2) has been shown to stabilize the breathing pattern of patients with central sleep apnea (CSA) with and without congestive heart failure (CHF). Added dead space (DS) as a form of supplemental CO(2) was effective in eliminating idiopathic CSA. The efficacy and safety of DS has not yet been evaluated in patients with CHF and CSA. We examined the respiratory and cardiovascular effects of added DS in eight patients with CHF and CSA. The DS consisted of a facemask attached to a cylinder of adjustable volume. During wakefulness, the cardiorespiratory response to 200 to 600 mL of DS was tested. Cardiac output and stroke volume were measured using echocardiography with and without DS. During the nocturnal study, patients slept with and without DS, alternating at approximately 1-h intervals. Values are expressed as the mean +/- SE. The wakefulness study revealed a plateau in the partial pressure of end-tidal CO(2) (PETCO(2)) and the partial pressure of end-tidal O(2) between DS amounts of 400 and 600 mL. The mean stroke volume index (33 +/- 7 vs 34 +/- 7 mL/m(2), respectively) and the mean cardiac index (1.9 +/- 0.3 vs 1.9 +/- 0.4 L/min/m(2), respectively) were not affected by DS. Neither heart rate nor BP showed a significant change in response to DS of < or = 600 mL. During sleep, DS increased the PETCO(2) (40.7 +/- 2.7 vs 38.9 +/- 2.6 mm Hg, respectively; p < 0.05), reduced apnea (1 +/- 1 vs 29 +/- 7 episodes per hour, respectively; p < 0.01) and arousal (21 +/- 8 vs 30 +/- 8 arousals per hour, respectively; p < 0.05), increased the mean arterial oxygen saturation (SaO(2)) [94.4 +/- 1.0% vs 93.5 +/- 1.1%, respectively; p < 0.01), and reduced SaO(2) oscillations (DeltaSaO(2) from maximum to minimum, 1.8 +/- 0.4% vs 5.5 +/- 0.9%, respectively; p < 0.01). DS stabilized CSA and improved sleep quality in patients with CHF without significant acute adverse effects on the cardiovascular function.

Polysomnographic features of idiopathic central sleep apnea

Two patients with idiopathic central sleep apnea (ICSA), which is an uncommon condition, were recently encountered. This study examines the polysomnographic features of ICSA. The characteristic findings of ICSA are summarized as follows: (i) central apneas and hypopneas are progressively less frequent as sleep state deepens from stage 1 to stage 2 to stage 3 + 4 to stage REM (rapid eye movement); (ii) desaturation related to apneas and hypopneas is mild; and (iii) periodic breathing is commonly observed. However, the two patients demonstrated apparently different findings. It is suggested that the mechanisms underlying apnea and hypopnea in ICSA are heterogeneous.

Central sleep apnea syndrome and Cheyne-Stokes respiration

This overview discusses pathogenesis, clinical presentation, prognostic implications and therapy of central sleep apnea with special reference to Cheyne-Stokes-Respiration or periodic breathing. In contrast to obstructive sleep apnea due to upper airway collapse during sleep, central sleep apnea (CSA) is mainly due to an instability of the breathing control system. Causes of central sleep apnea include alveolar hypoventilation disorders, heart failure, neurologic and autonomic disorders and idiopathic forms of CSA. Patients with idiopathic CSA often complain of insomnia and awakening during sleep but may also suffer from daytime sleepiness. Cheyne-Stokes-Respiration or peridic breathing is often associated with heart failure and neurological disorders especially those involving the brainstem. In heart failure periodic breathing has enormous prognostic implications. Treatment options for central sleep apnea are oxygen supplementation, medical therapy (i.e. acetazolamide) and CPAP. For patients with central sleep apnoea associated with alveolar hypoventilation nasal ventilation is treatment of choice. Newer nasal ventilation techniques (BiPAP, AutoSetCS) are under investigation for heart failure patients with Cheyne-Stokes-Respiration.

Effects of inhaled CO2 and added dead space on idiopathic central sleep apnea.

We hypothesized that reductions in arterial PCO2 (PaCO2) below the apnea threshold play a key role in the pathogenesis of idiopathic central sleep apnea syndrome (ICSAS). If so, we reasoned that raising PaCO2 would abolish apneas in these patients. Accordingly, patients with ICSAS were studied overnight on four occasions during which the fraction of end-tidal CO2 and transcutaneous PCO2 were measured: during room air breathing (N1), alternating room air and CO2 breathing (N2), CO2 breathing all night (N3), and addition of dead space via a face mask all night (N4). Central apneas were invariably preceded by reductions in fraction of end-tidal CO2. Both administration of a CO2-enriched gas mixture and addition of dead space induced 1- to 3-Torr increases in transcutaneous PCO2, which virtually eliminated apneas and hypopneas; they decreased from 43.7 +/- 7.3 apneas and hypopneas/h on N1 to 5.8 +/- 0.9 apneas and hypopneas/h during N3 (P < 0.005), from 43.8 +/- 6.9 apneas and hypopneas/h during room air breathing to 5.9 +/- 2.5 apneas and hypopneas/h of sleep during CO2 inhalation during N2 (P < 0.01), and to 11.6% of the room air level while the patients were breathing through added dead space during N4 (P < 0.005). Because raising PaCO2 through two different means virtually eliminated central sleep apneas, we conclude that central apneas during sleep in ICSA are due to reductions in PaCO2 below the apnea threshold.

Hypocapnia and increased ventilatory responsiveness in patients with idiopathic central sleep apnea.

We previously demonstrated that central apneas during sleep in patients with idiopathic central sleep apnea (ICSA) are triggered by abrupt hyperventilation. In addition, baseline PCO2 at the time of augmented breaths which triggered central apneas was lower than for augmented breaths which did not trigger apneas. These observations led us to hypothesize that patients with ICSA chronically hyperventilate maintaining their PCO2 close to the threshold for apnea during sleep owing to increased chemical respiratory drive. To test these hypotheses, we recorded transcutaneous PCO2 (PtcCO2) during overnight sleep studies on nine consecutive patients with ICSA and nine sex-, age-, and body-mass-index-matched control subjects. Daytime PaCO2 as well as rebreathing and single breath ventilatory responses to CO2 were also measured. Compared with the control subjects, the patients had significantly lower mean PtcCO2 during sleep (37.8 +/- 1.2 versus 42.7 +/- 10.9 mm Hg, p < 0.01) and lower PaCO2 while awake (35.1 +/- 1.3 versus 38.8 +/- 0.9 mm Hg, p < 0.05). Furthermore, patients with ICSA had significantly higher ventilatory responses to CO2 for both the rebreathing (3.14 +/- 0.34 versus 1.60 +/- 0.32 L/min/mm Hg, p < 0.005) and single breath methods (0.51 +/- 0.10 versus 0.25 +/- 0.04 L/min/mm Hg, p < 0.05). We conclude that: (1) patients with ICSA chronically hyperventilate awake and asleep and (2) chronic hyperventilation is probably related to augmented central and peripheral respiratory drive which predisposes to respiratory control system instability.

Interaction of hyperventilation and arousal in the pathogenesis of idiopathic central sleep apnea.

Central apneas during sleep may arise as a result of reduction in PaCO2 below the apnea threshold. We therefore hypothesized that hyperventilation and arousals from sleep interact to cause hypocapnia and subsequent central apneas in patients with idiopathic central sleep apnea (ICSA). Accordingly, the relationships among preapneic ventilation, arousal from sleep, and the onset and duration of subsequent central apneas were examined during Stage 2 non-REM sleep in eight patients with ICSA (mean +/- SEM, 45.4 +/- 4.7 central apneas and hypopneas/h of sleep). During Stage 2 sleep, all episodes of periodic breathing with central apneas were triggered by hyperventilation. Minute ventilation (VI) was greater (6.3 +/- 0.7 versus 5.4 +/- 0.8 L/min, p < 0.05) and mean transcutaneous PCO2 (PtcCO2) was lower (37.8 +/- 1.3 versus 38.9 +/- 1.6 mm Hg, p < 0.05) during periodic breathing than during stable breathing. VI during the ventilatory phase of the periodic breathing cycle increased progressively with increasing grades of associated arousals from Grade 0 (no arousal) (10.3 +/- 1.4 L/min) to Grade 1 (EEG arousal) (12.6 +/- 1.6 L/min) to Grade 2 (movement arousal) (14.1 +/- 1.6 L/min, p < 0.01). There was a corresponding progressive increase in central apnea length following the ventilatory period from no arousal (14.1 +/- 2.0) to EEG arousal (16.4 +/- 1.8) to movement arousal (18.1 +/- 2.0 s, p < 0.01). We conclude that arousals and hyperventilation interact to trigger hypocapnia and central apneas in ICSA.

Differences in pharyngeal properties between snorers with predominantly central sleep apnea and those without sleep apnea.

The underlying cause of idiopathic central sleep apnea syndrome is not well understood. We therefore examined the possibility that patients with idiopathic central sleep apnea may have abnormalities of upper airway mechanics that might contribute to the pathogenesis of central apneas. The acoustic reflection technique was used to assess pharyngeal size, lung volume dependence, and pharyngeal "compliance" in 8 patients with idiopathic central sleep apnea, all of whom were snorers, and in 8 weight-matched, snoring control subjects with normal sleep studies. Patients with central sleep apnea when compared with control subjects exhibited markedly increased specific pharyngeal "compliance" (0.12 +/- 0.05 versus 0.03 +/- 0.01 cm H2O-1; p less than 0.001), increased change in pharyngeal area from FRC to RV (0.8 +/- 0.5 versus 0.03 +/- 0.3 cm2; p less than 0.05), and a larger pharyngeal area at FRC (4.7 +/- 0.9 versus 3.8 +/- 0.8 cm2; p less than 0.03). We conclude that increased pharyngeal "compliance" and lung volume dependence may play a role in the etiology of central apneas in this syndrome.