Chapter 22

Central sleep apnoea

D.G. McSharry*,#, D.J. Eckert# and A. Malhotra#

Summary
Central sleep apnoea (CSA) encompasses a diverse group of conditions from periodic breathing at altitude to opiateinduced CSA. Considerable overlap exists between obstructive sleep apnoea and CSA in terms of pathogenesis and pathophysiology. CSA syndromes can be broadly classified into patients with high drive and those with low drive. Many forms of CSA can ultimately lead to adverse cardiovascular outcomes. Treatment can be challenging and varies according to the underlying aetiology of the CSA. Some exciting new therapeutic options (e.g. phasic administration of CO2) require further research, in particular with respect to safety and potential outcome benefits. Keywords: Airway, apnoea, control of breathing, lung, sleepdisordered breathing
*St. Vincents University Hospital, Elm Park, Dublin, Ireland, and # Brigham and Womens Hospital and Harvard Medical School, Division of Sleep Medicine, Sleep Disorders Program, Boston, MA, USA. Correspondence: D.G. McSharry, Brigham and Womens Hospital and Harvard Medical School, Division of Sleep Medicine, Sleep Disorders Program, 221 Longwood Ave, Boston, MA 02115, USA, Email macsearraigh@ireland.com

entral sleep apnoea (CSA) is characterised by a lack of respiratory effort during sleep. These events result in insufficient or absent ventilation and compromised gas exchange. CSA is defined by a lack of respiratory effort during cessation of airflow, in contrast to obstructive sleep apnoea (OSA) in which respiratory effort is maintained despite upper airway compromise during respiratory events. Considerable overlap exists between OSA and CSA in terms of pathogenesis and pathophysiology. In addition, the two conditions frequently co-exist in the same individuals. Moreover, CSA and OSA can result in frequent nocturnal awakenings, excessive daytime somnolence and increased risk of cardiovascular outcomes [1, 2]. There are numerous manifestations of CSA as outlined in table 1. Unstable ventilatory drive during sleep is a major underlying feature. However, the exact mechanism varies between the different types of CSA. In many sleep apnoea patients, central apnoeas can lead to obstructive respiratory events and vice versa [3, 4]. Arbitrarily, CSA is considered the primary diagnosis if .50% of apnoeas are scored as central in origin. However, many patients have an overlap, or mixed apnoea syndrome. Even healthy individuals will have periodic breathing (giving rise to central apnoeas) if they ascend to sufficient altitude to cause important alveolar hypoxia [5].

CSA: important pathophysiological and general concepts

Control of breathing
In order to understand the mechanisms by which CSA occurs, an understanding of the control of breathing during wakefulness and sleep is vital. Figure 1 illustrates the control of breathing. Central chemoreceptors in the medulla respond to changes in arterial carbon dioxide tension (Pa,CO2)

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Eur Respir Mon 2010. 50, 381395. Printed in UK all rights reserved. Copyright ERS 2010. European Respiratory Monograph; ISSN: 1025-448x. DOI: 10.1183/1025448x.00026109

Table 1 Different manifestations of central sleep apnoea (CSA) Hypercapnic CSA: impaired central drive - wont breathe Brainstem pathology, e.g. infarct, tumour or rarities such as prion disease Congenital central hypoventilation syndrome (formerly known as Ondines curse) defined by PHOX2B mutation Narcotics: acute and chronic usage Obesity hypoventilation syndrome Hypercapnic CSA: impaired respiratory motor control - cant breathe Cervical cord pathology, e.g. disc disease Motor neuron pathology, e.g. amyotrophic lateral sclerosis Post-polio syndrome Neuro-muscular junction pathology, e.g. Myasthenia Gravis Myopathies, e.g. acid maltase deficiency Chest wall disease, e.g. Kyphoscoliosis Nonhypercapnic CSA CheyneStokes breathing Idiopathic CSA Periodic breathing: altitude-induced breathing instability Other CSA Mixed CSA and obstructive sleep apnoea

via shifts in H+ concentration. Peripheral chemoreceptors at the carotid body respond to changes in arterial oxygen tension (Pa,O2) and Pa,CO2. The ventilatory response to changes in Pa,O2 or Pa,CO2 etzinger (chemosensitivity) varies between individuals and different disease states. The Pre-Bo complex (PBC) is thought to be the major central-pattern generator in the brainstem, which generates the respiratory rhythm, although some debate exists regarding the potential role of the retrotrapezoid nucleus (RTN). Afferent signals from Golgi tendon organs and muscle spindles from the chest wall and respiratory muscles also contribute to the regulation of ventilation. During wakefulness, strong emotional influences can alter the rate and depth of breathing involving limbic forebrain structures. An independent background augmentation of ventilatory drive known as the wakefulness drive to breathe also exists, but is lost at the onset of sleep [7]. Indeed, with the transition from wakefulness to sleep, there is a withdrawal or downregulation of many of the inputs that regulate breathing such that the metabolic control of breathing becomes crucially important during sleep. At sleep onset even healthy individuals can demonstrate irregular breathing. Respiratory control is inherently unstable during the transition from wake to sleep [8]. Upper airway resistance increases through a reduction in the tone of the respiratory pump and upper airway dilator muscles. Thus, there is a reduction in ventilation for a given level of drive [9, 10]. Chemosensitivity is probably reduced at sleep onset [11]. A central apnoea can ensue if the awake-to-sleep transition is quick, with the loss of the wakefulness drive and the delay required to elicit an appropriate compensatory response from the chemoreceptors. Indeed, the chemical apnoea threshold during sleep is typically at approximately the waking eucapnic level [12, 13]. This level is 26 mmHg below the usual Pa,CO2 during stable non-rapid eye movement (NREM) sleep. During sleep (especially rapid eye movement; REM) there is reduced ventilatory response to hypoxia and hypercapnia, and reduced respiratory load compensation [1417]. If sleep is stable, a new CO2 set point is established and the chemoreceptor and respiratory reflex feedback become critical components regulating ventilation, albeit at a reduced homeostatic level compared to wakefulness. Arousal (brief awakening) from sleep can restore ventilation when other compensatory mechanisms fail but it can sometimes perpetuate apnoeic episodes. The arousal threshold and the ventilatory response to arousal are two key determinants that influence the propensity of an arousal to cause an apnoea. An individual with a low arousal threshold (wake up easily) is susceptible to sleep-state

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instability. Obstructive or central apnoea can result from state instability depending on the prevailing airway mechanics. The arousal threshold and breathing stability increase with slow wave sleep [18, 19]. This finding provides the rationale for the use of hypnotics in a select minority of non hypercapnic CSA patients [20, 21]. Alternatively, slow wave sleep might be the consequence rather than the cause of stable breathing and more research is required in this area. The rapid shift to wakefulness from an arousal results in the Pa,CO2 moving rapidly from ,45 mmHg to a lower value. In addition, airway resistance falls and the wakefulness drive reappears and a brisk ventilatory response occurs; the magnitude of which is dependent on the extent of the shift between the various state-related physiological changes. Moreover, if this individual promptly falls to sleep again, with a newly reduced Pa,CO2, the chemical apnoea threshold may be crossed resulting in a central or obstructive apnoea [22].

Higher brain centres (cerebral cortex: voluntary control over breathing) Emotional stimuli acting through the limbic system + _ + _ Respiratory centres (medulla and pons) + + _ Stretch receptors in lungs +

Peripheral chemoreceptors O2 , CO2 , H+ Central chemoreceptors CO2 , H+ Pons C C

Receptors for touch, temperature, and pain stimuli

Pyramid

Figure 1. Schematic diagram showing the control of breathing.

Reproduced from [6] with permission from the publisher.

Loop gain
The ventilatory system is controlled by a complex negative-feedback loop. Ultimately, the rate and depth of ventilation is maintained according to homeostasis. If a disturbance occurs to the normal equilibrium then alveolar ventilation will be altered and the Pa,CO2 will be adjusted by this corrective action. Loop gain is an engineering term used to describe the feedback mechanisms of a control system. Put simply, when applied to the ventilatory system, loop gain is the ratio of the magnitude of the corrective action (response) to the magnitude of the disturbance (stimulus) [23], i.e. loop gain 5 corrective action/disturbance or ventilatory response. There are two principal components to loop gain: controller gain and plant gain. Controller gain refers to the chemoresponsiveness of the system (i.e. hypoxic and hypercapnic ventilatory sensitivity plus responses). Plant gain primarily reflects the efficiency of CO2 excretion (i.e. the ability of a given level of ventilation to excrete CO2). Mixing gain is a function of circulatory delay, as well as haemoglobin binding of O2 and CO2. Mixing gain tends to be fairly constant, although circulatory delays may make mixing gain more clinically relevant in patients with congestive heart failure [24], which is discussed in another chapter [25]. The physical separation of the sensors and effectors makes the ventilatory feedback control system vulnerable to instability. That is, if the chemoreceptors were located in the pulmonary veins, the oscillatory behaviour seen in periodic breathing would be unlikely. For most individuals, breathing is relatively stable, unless periodic breathing is occurring. For example, if the ventilatory disturbance were a sigh, such a disturbance would not be self sustaining. A hypopnoea is another example of a disturbance. If the loop gain is high then the system will

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Receptors in muscles and joins

become unstable in response to such a perturbation. That is, if the corrective action were overzealous then an abnormal self-sustaining oscillatory system of periodic breathing with apnoeas occurs. Thus, a high loop gain can increase the propensity for the ventilatory control system to develop cyclical fluctuations in ventilatory output. A low loop gain, however, indicates a minimal or dampened response to a disturbance and tends to be less inherently unstable from a respiratory control perspective, but if markedly low may result in prolonged hypoventilation. The proportional assist ventilation (PAV) technique allows measurement of loop gain [26]. An example of PAV-induced periodic breathing is shown in figure 2 [27]. For each incremental level of PAV before periodic breathing occurs, the tidal volume amplification factor (VTAF) is measured. Loop gain is measured from the VTAF. Throughout the course of this chapter we shall return to the concept of loop gain as it relates to the different forms of CSA.

Manifestations of CSA
CSA can be broadly classified into two groups depending on the wakefulness CO2: hypercapnic and non-hypercapnic. The aetiologies of the different forms of CSA, even within the same class (e.g. hypercapnic), can be quiet different.

Hypercapnic CSA: impaired central drive Wont breathe Brainstem pathology

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Traumatic lesions or infarcts of the brainstem can directly diminish ventilatory output which can worsen during sleep resulting in CSA.

Congenital central hypoventilation syndrome

Congenital central hypoventilation syndrome (CCHS; previously known as Ondines Curse) results from a mutation in the PHOX2B gene. CCHS is inherited in an autosomal dominant manner with a stable mutation and affected individuals have diffuse autonomic nervous system dysregulation [28]. CCHS is rare and usually presents in the neonatal period but can present in infancy, childhood, adolescence and even rare cases in adulthood have been reported [29]. Characteristic profound alveolar hypoventilation during wakefulness and sleep can result in severe hypoxaemia and hypercapnia [30]. Recognised complications are secondary polycythaemia, pulmonary hypertension and right heart failure. Hypoventilation during sleep results from reduced tidal volume but the respiratory rate is near normal [31]. Ventilation is more stable during REM sleep than NREM sleep in contrast to OSA [32]. Ventilatory responses and sensing of dyspnoea in response to hypoxia and hypercapnia and processing of respiratory afferent information, as measured by cortical evoked potentials, are diminished in children with CCHS [30, 33]. The management of CCHS is generally supportive (genetic counselling, avoidance of sedatives, etc.) and may include tracheostomy and mechanical ventilation, diaphragmatic pacing and noninvasive ventilation [30].

Opioid-induced CSA
When used acutely, opioid medications have long been known to cause potent respiratory depression with accompanying blunting of the hypercapnic and the hypoxic ventilatory responses [34, 35]. The respiratory depression is principally due to a reduction in tidal volume though reduced respiratory rate becomes increasingly important with elevated opiate dosage. Understandably, both acute and chronic opiate usage can cause CSA [36, 37]. At present, there is little in

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the literature about this form of a) 200 100 CSA despite the widespread use of 0 opioid medication worldwide for -100 b) common medical complaints, such 30 as back pain, as well as from 20 10 narcotic abuse [38, 39]. However, WANG et al. [37] found 30% of c) 1.5 1.0 patients on a methadone mainte0.5 nance treatment programme (for 0.0 -0.5 heroin addiction) to have CSA. The cycle time of the apnoeas was much d) 5.0 shorter than CheyneStokes breath2.5 0.0 ing seen in chronic severe heart -2.5 failure; 30 s. The arousal index was 250 s similar between controls and methadone patients indicating that Figure 2. An example of periodic breathing induced by proporsleep/wake transitional changes are tional assist ventilation (PAV). V T: tidal volume; P mask: mask pressure. Arrows from left to right represent increase in PAV and unlikely to be important in the occurrence of an arousal reducing PAV to 0, respectively. perpetuation of the CSA cycles. There were only minor differences in Pa,O2 and Pa,CO2 between the methadone and control groups. Methadone blood levels correlated with the CSA in only a minority of patients in this study showing that other physiological variables were also contributing [37]. Thus, the pathophysiology of opiate-induced CSA remains incompletely understood. The depressant effects of morphine and other m-opiate receptor agonists on breathing probably relates to their action on chemosensitive areas in the brainstem and carotid body [34]. Intuitively, it is probable that this central respiratory depressant effect contributes to the central apnoeas. The cyclical nature of the apnoeas is incompletely understood. Numerous hypotheses exist. MOGRI et al. [40] found that a high proportion of patients on chronic opioid therapy for pain demonstrated important nocturnal hypoxaemia. The aetiology of the hypoxaemia varied but central apnoea was one mechanism. In contrast to studies performed on acute opioid usage, TEICHTAHL et al. [41] showed a heightened hypoxic ventilatory response in a cohort of methadone maintenance treatment patients. The response was largely mediated by an increase in respiratory rate, unlike previous studies. These patients had a blunted hypercapnic ventilatory response. Therefore, we hypothesise that the m-opioid agonist directly depresses respiratory control centrally in the brainstem triggering a central apnoea. The prevailing low-grade hypoxaemia worsens, precipitating an overzealous peripheral chemoreceptor response which corrects the hypoxia and then abates. Thus, the Pa,CO2 falls. The blunted central chemoreceptor responds poorly to carbon dioxide tension changes and so is vulnerable once again to the depressant effects of the opiate and so the cycle propagates. In addition, the m-opioid receptors have been used by GRAY et al. [42] to label the PBC. The PBC is thought to be the major central pattern generator in the brainstem which generates the respiratory rhythm. Thus, in theory, narcotics may be reducing output from the PBC and yielding cessations in airflow without respiratory effort. Animal studies [43] have shown that m-opioid agonists acting on the hypoglossal motor nucleus have a depressant effect on the genioglossus muscle (the chief airway dilator) which might underlie the coexistence of OSA with CSA in some chronic opiate users [40]. However, ROBINSON et al. [44] observed no major increase in OSA severity among normal individuals given narcotic therapy. There is a mounting body of evidence to suggest that poor sleep can worsen pain. Theoretically, if the patient on opiates has opiate-induced CSA then ironically the resultant sleep disturbance may increase the pain and hence the opiate requirement. Treatment specific to opiate-induced CSA is obviously cessation of the opioid agonist though this is often impractical. Some reports of a dosedependence to narcotic-induced central apnoeas would suggest that a reduction in medication
Flow L.s-1 VT L Pmask cmH2O EEG V
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dose may be helpful in alleviating the central apnoeas [45]. Reduced narcotic doses can sometimes be achieved with local analgesia (e.g. warm compresses for back pain) or using non-narcotic analgesics (e.g. gabapentin). Some data suggest that newer positive-pressure devices may have a role in stabilising breathing in these patients [46]. Other agents such as acetazolamide and theophylline have received minimal investigation in this area. Thus, further investigation is clearly needed. Moreover, the literature is extremely sparse on the beneficial effects that opioid withdrawal has on opiate-induced CSA [47].

Obesity hypoventilation syndrome

Obesity hypoventilation syndrome (OHS) is defined as a combination of obesity (body mass index .30 kg?m-2) and arterial hypercapnia (Pa,CO2 .45 mmHg) during wakefulness not explained by other known causes of hypoventilation [48]. Hypoventilation worsens during sleep and hypoxaemia ensues. Patients can present with morning headaches and daytime hypersomnolence. Obesity-related impairment of respiratory mechanics is at least partly responsible for the development of OHS. These patients are unable to compensate for the worsened respiratory mechanics and permissive hypercapnia and other sequelae, including cor pulmonalae, can ensue. However, the factors determining which obese people develop OHS are incompletely understood. The failed compensation may relate to differences in the anatomical distribution of fat combined with ventilatory control deficits, such as blunted chemosensitivity [4951]. The hormone leptin may be important in obesity-related hypoventilation in some animal models [52]. Whilst the incidence of OHS is likely to increase [53], it is probably underdiagnosed. Indeed, in our experience OHS is often misdiagnosed as congestive cardiac failure probably due to the presence of cor pulmonalae. In addition, the chest radiograph in OHS can give the impression of pulmonary congestion owing to the overlying adiposity. Also, the obesity-related restriction can accentuate pulmonary interstitial markings. In addition, OHS patients often present to the intensive care unit with acute decompensation, with blood gases revealing acute on chronic respiratory failure. During these acute presentations, hypoxaemia can impair left ventricular relaxation [54], and elevated right ventricular pressures can raise left ventricular pressures through diastolic interdependence [55]. As such, some mild pulmonary oedema may be present in these patients at presentation although left ventricular function is relatively normal once the acute exacerbation has resolved. Management of OHS principally involves the use of bi-level noninvasive ventilation. The expiratory pressure may need to be relatively high to treat OSA, a condition which is frequently co-existent. In addition, weight loss is likely to improve sleepdisordered breathing in these patients [48]. Indeed surgical weight loss may be an option for morbidly obese patients with OHS [56].

CENTRAL SLEEP APNOEA

Hypercapnic CSA: impaired respiratory motor control Cant breathe

Hypercapnic patients with CSA and an intact central respiratory output from pattern generator neurons may have a defect anywhere from the upper motor neurons to the respiratory muscles. This diverse group of conditions are listed in table 1. The aetiology and severity of the CSA relates to the underlying condition [57].

Nonhypercapnic CSA CheyneStokes breathing

The renowned Irish physicians, J. Cheyne and W. Stokes, gave their names to this characteristic crescendo/decrescendo pattern of breathing with a long circulation time and arousal occurring

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during the hyperpneic phase of respiratory effort. Figure 3 illustrates CheyneStokes breathing (CSB) and evidence of the long circulation time is seen because each oxygen desaturation corresponds to the previous apnoea. The cycle time of the unstable breathing is consequently long, typically 6090 s. The most common cause of CSB is congestive cardiac failure (CCF). CSB associated with CCF and its treatment is comprehensively dealt with later on in this monograph.

Idiopathic CSA
Patients who have central apnoeas during sleep who do not display the typical CSB pattern or sleep transition apnoea and who have normocapnia or hypocapnia during wakefulness fall into the category of idiopathic CSA (ICSA). The apnoeas may occur in isolation or in cycles lasting 40 s. Arousals typically occur at the end of apnoeas, which are themselves more common in stage 1 or 2 sleep. Patients may present with insomnia or hypersomnolence. The pathophysiology is poorly understood but is thought to relate to elevated hypercapnic ventilatory responses leading to hypocapnia and respiratory control instability [5860]. Arousal and the ensuing hypocapnia can further destabilise breathing [22]. These factors render the patient vulnerable to crossing the apnoea threshold, which may lie perilously close to the sleeping eucapnic Pa,CO2, particularly in those with daytime hypocapnia. Acetazolamide has been shown to improve sleep-disordered breathing in a study involving seven patients with ICSA [61]. Its mechanism of action is discussed later in this chapter. A recent report suggests that non-benzodiazepine hypnotics may be beneficial in some patients with ICSA [20]. However, randomised, controlled studies are required before this can be recommended as a safe and effective treatment approach. In our experience ICSA is quite uncommon, making definitive studies difficult to accomplish.

Periodic breathing at high altitude

The term periodic breathing (PB), in accordance with the Chicago criteria [62], refers to the characteristic cyclical breathing patterns with central apnoeas that occur at high altitude. The characteristics of hypobaric hypoxic PB are well described by BERSSENBRUGGE et al. [63] as follows: 1) repetitive breathing oscillations of reproducible cycle length (21.21.8 s); 2) clusters of two to five breaths of highly variable tidal volume and breath-to-breath ventilation alternating with a prolonged expiratory pause of the last breath of each cluster (apnoea); and 3) apnoeas of central origin occupying half the cycle time. PB is best appreciated graphically. Figure 4 shows the cyclical breathing pattern [64]. The cycle length (,20 s in this example) shortens as the climber ascends [65]. Disrupted sleep and tiredness can ensue and difficulty sleeping is one of the diagnostic criteria of acute mountain sickness (AMS) according to the Lake Louise Consensus of 1991. However, periodic breathing occurs as readily at high altitude in those without AMS as in those with it [66]. PB occurs in virtually all individuals given sufficient ascent and accompanying hypoxia. However, the altitude at which PB occurs and the characteristics of the EEG PB pattern vary between individuals Sa,O2 based, in part, on differences in Airflow physiological responsiveness to hypoxia. LAHIRI et al. [67] compared Chest ventilatory response to hypoxia in Himalayan sherpas to sojourners to Abdomen 5,200 m and the relationship of this response to nocturnal sleep apnoea 1 min and PB. Sojourners with a high venFigure 3. CheyneStokes breathing in a patient.% & : spontaneous tilatory response to hypoxia maniarousals; & %: desaturation; & %: central apnoea. Sa,O2: arterial oxygen fested periodic breathing and apnoeas saturation. Reproduced from [45] with permission from the while sleeping. In contrast the sherpas publisher. who had a low ventilatory response to
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hypoxia had no sustained apnoeas/PB. However, central apnoeas can occur in highlanders at very high altitudes [68]. The hypobaric hypoxia at altitude results in relative hyperventilation via activation of the peripheral chemoreceptors. The resultant hypocapnia during sleep triggers a central apnoea if Pa,CO2 falls below the chemical apnoea threshold. Thus, respiratory alkalosis ensues. However, what causes the periodicity is more complex. Using hypobaric hypoxic studies in normal individuals, BERSSENBRUGGE [63] theorised that the periodicity resulted from oscillations in Pa,CO2 around a CO2-apnoea threshold whose functional expression was critically linked to sleep state. In essence, hypoxia results in increased gain of the peripheral chemoreceptors with resultant hyperventilation, which drives the CO2 below the CO2apnoea threshold and an apnoea ensues. Meanwhile, during the apnoea the hypoxia worsens, further increasing the gain on the peripheral chemoreceptors. Thus, rather than slowly increasing tidal volume triggered by increasing CO2, a vigorous ventilatory response initiated by the peripheral chemoreceptors response to hypoxia ensues. Hence, the process is self-sustaining and periodic. Therefore, chemical control instability, not present when the individual was at sea level, is present at altitude. Continuous hypoxia increases baseline carotid body activity and sensitises the response to acute hypoxia. The enhanced hypoxic response is due to alterations in ion current densities, changes in neurotransmitter dynamics and recruitment of additional neuromodulators (endothelin-1) in glomus cells [69]. Moreover, hypoxia-induced central depression has been suggested to contribute to the PB [70]. Sleep fragmentation is common at altitude with resultant fatigue the following day [71]. Arousals can influence the occurrence of PB. In a simulated higha) 1.2 altitude study, ANHOLM et al. [71] 0.9 showed that brief arousals increased 0.6 from 226 arousals?h-1 of sleep at 0.3 sea level to 16166 arousals?h-1 at 0 282 mmHg. A study investigating b) 1.2 the effects of the hypnotic zolpidem 0.9 at simulated high altitude found that 0.6 arousals occur in synchrony with 0.3 the hyperpnoeic phase of PB [72]. 0 However, GOLDENBERG et al. [73] c) 1.2 found that the intercurrent wakeful0.9 ness duration correlated best with 0.6 PB and not the number of arousals 0.3 per se. 0
AB L RC L Sum vol L d) Sp,O2 % 100 90 80 70 60 120 100 80 60 40 Time in 5-s intervals

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e)

Figure 4. A nocturnal polygraph recording from a mountaineer at

4,559 m. The inductive plethysmographic volume signals of a) the sum volume of the ribcage (RC) and abdomen (AB). b) The RC volume and c) the AB volume show periodic breathing. Sp,O2: arterial oxygen saturation measured by pulse oximetry; HR: heart rate. Reproduced from [64] with permission from the publisher.

WHITE et al. [5] studied the effects of acclimatisation at high altitude during the first week in seven healthy males. Acclimatisation resulted in augmented hypoxic ventilatory responsiveness and the slope of the hypercapnic ventilatory response increased initially. The sleep-induced decrements in ventilation and hypercapnic responsiveness were equivalent to those at sea level and the quantity of PB was variable, occurring more frequently in those with higher hypoxic and hypercapnic responsiveness. The authors also found that acclimatisation reduced the latency to PB and that sleep quality improved [73].

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Medications suggested as putative treatment options for PB/apnoeas include respiratory stimulants (theophylline, medroxyprogesterone acetate, almitrine and acetazolamide) and, some might say, paradoxically hypnotics. Results have been mixed. Studies have shown that hypnotics have generally improved sleep quality (measured subjectively in some studies) without affecting oxygen saturations [72, 73]. However, the studies are both small and sparse. In addition, the subjects were healthy individuals, reducing the risk/impact of respiratory depression. Another study of temazepam showed a reduction in PB at 5,000 m and no effect on performance the next day but with a significant reduction of 2% in the arterial oxygen saturation (Sa,O2) [74]. Theophylline reduces PB/central apnoeas and seems well tolerated [75, 76]. Medroxyprogesterone remains unproven at altitude as does almitrine, which might actually increase PB [77]. Acetazolamide, a carbonic anhydrase inhibitor, has been shown to reduce PB and increase Sa,O2 during sleep at high altitude [77]. The respiratory stimulant action of acetazolamide at altitude probably comes from its induction of a metabolic acidosis rather than from another of its other numerous pharmacological effects [78], although the precise mechanisms of action remain uncertain. The hypoxic ventilatory response is key to the development of PB. The original experiments of BERSSENBRUGGE et al. [63] demonstrated elimination of PB with restoration of normoxia, coincident with a 36 Torr increase in Pa,CO2. Unsurprisingly oxygen therapy has been shown to improve PB and reduce apnoeas at altitude in the few studies addressing this issue [79, 80].

Other CSA Mixed CSA and OSA

In clinical practice CSA is frequently encountered in patients with predominant OSA. This complex apnoea syndrome is quite common with .50% of the apnoeas usually being obstructive. Considerable controversy exists regarding the entity of complex sleep apnoea, in part because its definition is quite vague. Some literature has suggested that OSA patients who develop central apnoeas upon initial continuous positive airway pressure (CPAP) exposure should be labelled as complex apnoea. These patients were traditionally labelled as having treatment-emergent central apnoea with spontaneous resolution of central apnoea occurring in the majority of these individuals. Significant pathophysiological similarities exist between OSA and CSA and interestingly central apnoeas lead to upper airway closure [3, 4]. SANKRITARBICHI et al. [4] have shown that central hypopnoeas lead to pharyngeal narrowing during the expiratory phase. They concluded that reduced ventilatory drive leads to increased expiratory, but not inspiratory, upper airway resistance [4]. During this study central hypocapnic hypopnoeas were induced by noninvasive positive-pressure ventilation. The drive to the genioglossus (as well as the other respiratory muscles) is reduced during a central apnoea [81], promoting upper airway collapse/obstruction. Like CSA, patients with OSA have unstable respiratory control [82, 83]. Thus, in patients with complex apnoea different perpetuating factors determine which type of apnoea occurs. For example, during REM sleep obstructive apnoeas will predominate. Generally, OSA worsens during REM sleep probably from reduced upper airway tone and reduced chemosensitivity [16, 84]. In contrast, CSA severity improves during REM probably from increased respiratory neuronal activity that occurs in this sleep state [85]. Also, mucosal factors such as the surface tension of the upper airway lining liquid (which is increased in OSA [86]) may play a role in the type of apnoea that occurs and how quickly the airway reopens. Treatment emergent CSA occurs in ,10% of patients diagnosed with OSA on the first night of CPAP treatment [87]. Important risk factors for this phenomenon are cardiac disease and some pre-existing CSA. Although poorly studied, these patients also probably have robust chemosensitivity compared to those without treatment-emergent CSA. The exact mechanisms
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by which CSA emerges on treatment are poorly understood. Reduced upper airway resistance might increase CO2 excretion leaving the patient vulnerable to crossing the apnoea threshold [88]. The application of CPAP also may wash out the anatomical dead space, particularly in the setting of mask leak leading to a fall in Pa,CO2 for a given minute ventilation. Lung stretch reflexes may also be important in inhibiting ventilatory motor output in some patients. These central apnoeas typically resolve on CPAP and so their clinical significance is uncertain. Indeed, SALLOUM et al. [89] recently showed ventilatory instability in OSA that was reversed after 1 month of CPAP. An increasingly used treatment option in these patients is adaptive servoventilation [90]. In a recent 2-week pilot study, RANDERATH et al. [91] studied the effects of combined adaptive servo-ventilation and automatic positive airway pressure on 12 patients with coexisting OSA and CSA syndrome and periodic breathing. Seven of the patients had cardiovascular disease. Considerable abolition of the apnoeas and improvements in arousals, O2 saturation and sleep profile were noted [91].

Treatment of CSA
CSA has diverse manifestations and aetiologies. Accordingly, the treatment options reflect this diversity and vary widely between the different forms of CSA. For example, noninvasive bi-level ventilation can be of benefit in OHS but could cause clinical worsening of some patients with hypocapnic CSB. Throughout the chapter we have discussed the specific treatment options of the various manifestations of CSA. The main treatment options for CSA are discussed further in this section. The treatment of CSB in heart failure is described in more detail elsewhere in this monograph.
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Oxygen
Hypoxia can be sustained in OHS or intermittent in other forms of CSA. Hypoxia can impair respiratory sensory processing and arousal responses to respiratory stimuli during sleep [92, 93]. This implies that hypoxia can worsen CSA syndromes such as OHS, which are characterised by sustained episodes of hypoxia. One case report provides evidence for the use of oxygen in OHS [94]. Oxygen is of benefit in periodic breathing at altitude, which has a much different aetiology [79, 80]. Indeed several forms of nonhypercapnic CSA (with heightened chemosensitivity) can potentially benefit from the stabilising respiratory control effects of oxygen. Improvements on oxygen therapy have been noted in ICSA and CSB. However, these trials have been short term [9597]. Larger trials are required to determine which CSA patients may benefit from oxygen therapy.

Carbon dioxide
Increasing the sleeping Pa,CO2 (eucapnic level) further above the apnoeic threshold could have a stabilising effect on some forms of CSA, minimising the risks of apnoeas. Recent studies have shown that mild increases in the inspired concentration of CO2 (by addition of CO2 or by increasing the dead space via a mask) have beneficial effects on central apnoeas in ICSA [98] and CSB [99]. The improved apnoea/hypopnoea index does not always translate into improved sleep quality [100] and concerns exist regarding CO2-induced sympatho-excitation [101]. A recent study using a standard mathematical model suggested that dynamic administration of CO2, adjusting the dose and duration in real time, could treat periodic breathing/CSA efficiently with much lesser doses than continuous administration [102]. If such a model was developed clinically it could lessen the acidosis and sympatho-excitation associated with CO2 administration. The studies so far have had small numbers and larger, longer studies are needed to determine the efficacy and safety of CO2 administration.

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Respiratory stimulants
The carbonic anhydrase inhibitor, acetazolamide, improves CSA in heart failure [110] and ICSA [61]. It induces a metabolic acidosis and its benefit in CSA probably relates to shifting the hypercapnic ventilatory response and lowering the apnoeic threshold [61, 111]. Acetazolamide has been shown to improve periodic breathing at high altitude [77]. Long-term, larger trials are required before acetazolamide can be safely recommended. Theophylline and progesterone have shown benefit in some types of CSA. However, theophylline has been associated with possible arrhythmias [112] and long-term safety data are not available for progesterone.

Conclusion
We have reviewed that CSA encompasses a diverse group of conditions from periodic breathing at altitude to opiate-induced CSA. The pathogenesis of CSA is summarised in figure 5. This diversity is reflected in the differing pathogenesis and treatment options. Indeed, a certain treatment which improves one form of CSA may have deleterious effects on another (e.g. bilevel noninvasive ventilation). However, all forms of CSA can ultimately lead to adverse cardiovascular outcomes. Some exciting new therapeutic options (e.g. phasic administration of CO2) require further research, in particular with respect to safety.

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CPAP has shown benefit in patients with ICSA possibly from stopping "Won't breathe" factors Loss of wakefulness the inhibitory reflex mechanisms i.e. CNS depression and CCHS stimulus that arise during airway closure Drive and increasing lung volumes and Chemosensitivity Change between eupnoea oxygen stores [103]. One could also Loss of CO2 and apnoea threshold behavioural speculate that in some cases the Inhibitory inputs increase in physiological dead space reflexes Hypocapnia from CPAP might be mildly inObstructive Central creasing the CO2 further above the apnoea/ apnoea/ apnoeic threshold. CPAP has been hypopnoea hypopnoea shown to improve sleep-disordered Hyperventilation UA anatomy breathing and haemodynamics in Chemosensitivity heart failure patients [104]. The Hypercapnia largest study on the effects of CPAP on CSA did not show improved Ventilatory Metabolic production response mortality and only showed a mild to arousal improvement in apnoea/hypopnoea Arousal index [105]. Limited data support Arousal threshold the role of increased inspired CO2 as an adjunct to CPAP in the treatment Figure 5. The pathogenesis of central sleep apnoea. CNS: central of mixed obstructive and central nervous system; CCHS: congenital central hypoventilation synapnoeas [106]. Larger trials on CO2 drome; UA: upper airway. Reproduced from [45] with permission from the publisher. administration are needed before it can be recommended given the danger of sympatho-excitation and other deleterious effects. Bilevel noninvasive ventilation can improve some forms of CSA (e.g. OHS [107]) but can worsen others by inducing hypocapnia [108]. The newer adaptive pressure support servo-ventilation can improve CSA in certain cases (e.g. CSB in heart failure [109]), although outcome data remain sparse precluding definitive recommendations.

"Can't breathe" factors i.e. respiratory motor output

Statement of Interest
D.J. Eckert is a consultant for Apnex Medical, receiving less than US$20,000 per year. Within the past 5 years, A. Malhotra has received consulting and/or research income from Philips, Ethicon, Medtronic, Pfizer, Sepracor, Cephalon, Apnex, SGS, SHC, Merck, NMT, IMI and Itamar.

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