Chapter 22

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

SummaryCentral sleep apnoea (CSA) encompasses a diverse group ofconditions from periodic breathing at altitude to opiate-induced CSA. Considerable overlap exists between obstructivesleep apnoea and CSA in terms of pathogenesis andpathophysiology. CSA syndromes can be broadly classifiedinto patients with high drive and those with low drive. Manyforms of CSA can ultimately lead to adverse cardiovascularoutcomes. Treatment can be challenging and varies accordingto the underlying aetiology of the CSA. Some exciting newtherapeutic options (e.g. phasic administration of CO2)require further research, in particular with respect to safetyand potential outcome benefits.

Keywords: Airway, apnoea, control of breathing, lung, sleep-disordered breathing

*St. Vincent’s University Hospital,Elm Park, Dublin, Ireland, and#Brigham and Women’s Hospital andHarvard Medical School, Division ofSleep Medicine, Sleep DisordersProgram, Boston, MA, USA.

Correspondence: D.G. McSharry,Brigham and Women’s Hospital andHarvard Medical School, Division ofSleep Medicine, Sleep DisordersProgram, 221 Longwood Ave,Boston, MA 02115, USA,Email macsearraigh@ireland.com

Eur Respir Mon 2010. 50, 381–395.Printed in UK – all rights reserved.Copyright ERS 2010.European Respiratory Monograph;ISSN: 1025-448x.DOI: 10.1183/1025448x.00026109

Central sleep apnoea (CSA) is characterised by a lack of respiratory effort during sleep. Theseevents 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 sleepapnoea (OSA) in which respiratory effort is maintained despite upper airway compromise duringrespiratory events. Considerable overlap exists between OSA and CSA in terms of pathogenesisand pathophysiology. In addition, the two conditions frequently co-exist in the same individuals.Moreover, CSA and OSA can result in frequent nocturnal awakenings, excessive daytimesomnolence and increased risk of cardiovascular outcomes [1, 2].

There are numerous manifestations of CSA as outlined in table 1. Unstable ventilatory driveduring sleep is a major underlying feature. However, the exact mechanism varies between thedifferent types of CSA. In many sleep apnoea patients, central apnoeas can lead to obstructiverespiratory 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, ormixed apnoea syndrome. Even healthy individuals will have periodic breathing (giving rise tocentral 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 ofbreathing during wakefulness and sleep is vital. Figure 1 illustrates the control of breathing. Centralchemoreceptors in the medulla respond to changes in arterial carbon dioxide tension (Pa,CO2)

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via shifts in H+ concentration. Peripheral chemoreceptors at the carotid body respond to changes inarterial oxygen tension (Pa,O2) and Pa,CO2. The ventilatory response to changes in Pa,O2 or Pa,CO2

(chemosensitivity) varies between individuals and different disease states. The Pre-Boetzingercomplex (PBC) is thought to be the major central-pattern generator in the brainstem, whichgenerates the respiratory rhythm, although some debate exists regarding the potential role of theretrotrapezoid nucleus (RTN). Afferent signals from Golgi tendon organs and muscle spindles fromthe chest wall and respiratory muscles also contribute to the regulation of ventilation. Duringwakefulness, strong emotional influences can alter the rate and depth of breathing involving limbicforebrain structures. An independent background augmentation of ventilatory drive known as thewakefulness drive to breathe also exists, but is lost at the onset of sleep [7]. Indeed, with thetransition from wakefulness to sleep, there is a withdrawal or downregulation of many of the inputsthat regulate breathing such that the metabolic control of breathing becomes crucially importantduring sleep.

At sleep onset even healthy individuals can demonstrate irregular breathing. Respiratory control isinherently unstable during the transition from wake to sleep [8]. Upper airway resistance increasesthrough 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 probablyreduced 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 compensatoryresponse from the chemoreceptors. Indeed, the chemical apnoea threshold during sleep is typicallyat approximately the waking eucapnic level [12, 13]. This level is 2–6 mmHg below the usualPa,CO2 during stable non-rapid eye movement (NREM) sleep.

During sleep (especially rapid eye movement; REM) there is reduced ventilatory response to hypoxiaand hypercapnia, and reduced respiratory load compensation [14–17]. If sleep is stable, a new CO2

set point is established and the chemoreceptor and respiratory reflex feedback become criticalcomponents regulating ventilation, albeit at a reduced homeostatic level compared to wakefulness.Arousal (brief awakening) from sleep can restore ventilation when other compensatory mechanismsfail but it can sometimes perpetuate apnoeic episodes. The arousal threshold and the ventilatoryresponse to arousal are two key determinants that influence the propensity of an arousal to cause anapnoea. An individual with a low arousal threshold (wake up easily) is susceptible to sleep-state

Table 1 Different manifestations of central sleep apnoea (CSA)

Hypercapnic CSA: impaired central drive - won’t breatheBrainstem pathology, e.g. infarct, tumour or rarities such as prion diseaseCongenital central hypoventilation syndrome (formerly known as Ondine’s curse) defined by

PHOX2B mutationNarcotics: acute and chronic usageObesity hypoventilation syndrome

Hypercapnic CSA: impaired respiratory motor control - can’t breatheCervical cord pathology, e.g. disc diseaseMotor neuron pathology, e.g. amyotrophic lateral sclerosisPost-polio syndromeNeuro-muscular junction pathology, e.g. Myasthenia GravisMyopathies, e.g. acid maltase deficiencyChest wall disease, e.g. Kyphoscoliosis

Nonhypercapnic CSACheyne–Stokes breathingIdiopathic CSAPeriodic breathing: altitude-induced breathing instability

Other CSAMixed CSA and obstructive sleep apnoea

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instability. Obstructive or centralapnoea can result from state instabil-ity depending on the prevailing air-way mechanics. The arousal thresh-old and breathing stability increasewith slow wave sleep [18, 19]. Thisfinding provides the rationale for theuse of hypnotics in a select minorityof non hypercapnic CSA patients [20,21]. Alternatively, slow wave sleepmight be the consequence rather thanthe cause of stable breathing andmore research is required in this area.

The rapid shift to wakefulness froman arousal results in the Pa,CO2

moving rapidly from ,45 mmHgto a lower value. In addition, airwayresistance falls and the wakefulnessdrive reappears and a brisk ventila-tory response occurs; the magni-tude of which is dependent on theextent of the shift between thevarious state-related physiologicalchanges. Moreover, if this indivi-dual promptly falls to sleep again,with a newly reduced Pa,CO2, thechemical apnoea threshold may becrossed resulting in a central orobstructive apnoea [22].

Loop gain

The ventilatory system is controlled by a complex negative-feedback loop. Ultimately, the rate anddepth of ventilation is maintained according to homeostasis. If a ‘‘disturbance’’ occurs to thenormal 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 ofa control system. Put simply, when applied to the ventilatory system, loop gain is the ratio of themagnitude 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 gainrefers to the chemoresponsiveness of the system (i.e. hypoxic and hypercapnic ventilatorysensitivity plus responses). Plant gain primarily reflects the efficiency of CO2 excretion (i.e. theability 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, althoughcirculatory delays may make mixing gain more clinically relevant in patients with congestive heartfailure [24], which is discussed in another chapter [25]. The physical separation of the sensors andeffectors makes the ventilatory feedback control system vulnerable to instability. That is, if thechemoreceptors were located in the pulmonary veins, the oscillatory behaviour seen in periodicbreathing would be unlikely.

For most individuals, breathing is relatively stable, unless periodic breathing is occurring. Forexample, 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

Higher brain centres(cerebral cortex: voluntarycontrol over breathing)

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Figure 1. Schematic diagram showing the control of breathing.Reproduced from [6] with permission from the publisher.

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become unstable in response to such a perturbation. That is, if the corrective action wereoverzealous then an abnormal self-sustaining oscillatory system of periodic breathing with apnoeasoccurs. Thus, a high loop gain can increase the propensity for the ventilatory control system todevelop cyclical fluctuations in ventilatory output. A low loop gain, however, indicates a minimalor dampened response to a disturbance and tends to be less inherently unstable from a respiratorycontrol perspective, but if markedly low may result in prolonged hypoventilation. Theproportional assist ventilation (PAV) technique allows measurement of loop gain [26]. Anexample of PAV-induced periodic breathing is shown in figure 2 [27]. For each incremental levelof PAV before periodic breathing occurs, the tidal volume amplification factor (VTAF) ismeasured. 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 tothe different forms of CSA.

Manifestations of CSA

CSA can be broadly classified into two groups depending on the wakefulness CO2: hypercapnicand 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

Won’t breathe

Brainstem pathology

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

Congenital central hypoventilation syndrome

Congenital central hypoventilation syndrome (CCHS; previously known as Ondine’s Curse) resultsfrom a mutation in the PHOX2B gene. CCHS is inherited in an autosomal dominant manner witha 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]. Characteristicprofound alveolar hypoventilation during wakefulness and sleep can result in severe hypoxaemiaand hypercapnia [30]. Recognised complications are secondary polycythaemia, pulmonaryhypertension and right heart failure. Hypoventilation during sleep results from reduced tidalvolume but the respiratory rate is near normal [31]. Ventilation is more stable during REM sleepthan NREM sleep in contrast to OSA [32]. Ventilatory responses and sensing of dyspnoea inresponse to hypoxia and hypercapnia and processing of respiratory afferent information, asmeasured by cortical evoked potentials, are diminished in children with CCHS [30, 33]. Themanagement of CCHS is generally supportive (genetic counselling, avoidance of sedatives, etc.) andmay include tracheostomy and mechanical ventilation, diaphragmatic pacing and noninvasiveventilation [30].

Opioid-induced CSA

When used acutely, opioid medications have long been known to cause potent respiratorydepression 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 thoughreduced respiratory rate becomes increasingly important with elevated opiate dosage. Under-standably, 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 ofCSA despite the widespread use ofopioid medication worldwide forcommon medical complaints, suchas back pain, as well as fromnarcotic abuse [38, 39]. However,WANG et al. [37] found 30% ofpatients on a methadone mainte-nance treatment programme (forheroin addiction) to have CSA. Thecycle time of the apnoeas was muchshorter than Cheyne–Stokes breath-ing seen in chronic severe heartfailure; 30 s. The arousal index wassimilar between controls andmethadone patients indicating thatsleep/wake transitional changes areunlikely to be important in theperpetuation of the CSA cycles.There were only minor differencesin Pa,O2 and Pa,CO2 between the methadone and control groups. Methadone blood levels correlatedwith the CSA in only a minority of patients in this study showing that other physiological variableswere also contributing [37]. Thus, the pathophysiology of opiate-induced CSA remains incompletelyunderstood.

The depressant effects of morphine and other m-opiate receptor agonists on breathing probablyrelates 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. Thecyclical nature of the apnoeas is incompletely understood. Numerous hypotheses exist. MOGRI etal. [40] found that a high proportion of patients on chronic opioid therapy for pain demonstratedimportant nocturnal hypoxaemia. The aetiology of the hypoxaemia varied but central apnoea wasone 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 maintenancetreatment patients. The response was largely mediated by an increase in respiratory rate, unlikeprevious studies. These patients had a blunted hypercapnic ventilatory response. Therefore, wehypothesise that the m-opioid agonist directly depresses respiratory control centrally in thebrainstem triggering a central apnoea. The prevailing low-grade hypoxaemia worsens, pre-cipitating an overzealous peripheral chemoreceptor response which corrects the hypoxia and thenabates. Thus, the Pa,CO2 falls. The blunted central chemoreceptor responds poorly to carbondioxide tension changes and so is vulnerable once again to the depressant effects of the opiate andso the cycle propagates. In addition, the m-opioid receptors have been used by GRAY et al. [42] tolabel the PBC. The PBC is thought to be the major central pattern generator in the brainstemwhich generates the respiratory rhythm. Thus, in theory, narcotics may be reducing output fromthe PBC and yielding cessations in airflow without respiratory effort.

Animal studies [43] have shown that m-opioid agonists acting on the hypoglossal motor nucleushave a depressant effect on the genioglossus muscle (the chief airway dilator) which might underliethe 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, ifthe patient on opiates has opiate-induced CSA then ironically the resultant sleep disturbance mayincrease the pain and hence the opiate requirement. Treatment specific to opiate-induced CSA isobviously cessation of the opioid agonist though this is often impractical. Some reports of a dose-dependence to narcotic-induced central apnoeas would suggest that a reduction in medication

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dose may be helpful in alleviating the central apnoeas [45]. Reduced narcotic doses can sometimesbe achieved with local analgesia (e.g. warm compresses for back pain) or using non-narcoticanalgesics (e.g. gabapentin). Some data suggest that newer positive-pressure devices may have arole in stabilising breathing in these patients [46]. Other agents such as acetazolamide andtheophylline have received minimal investigation in this area. Thus, further investigation is clearlyneeded. Moreover, the literature is extremely sparse on the beneficial effects that opioidwithdrawal 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 byother known causes of hypoventilation [48]. Hypoventilation worsens during sleep andhypoxaemia ensues. Patients can present with morning headaches and daytime hypersomnolence.Obesity-related impairment of respiratory mechanics is at least partly responsible for thedevelopment of OHS. These patients are unable to compensate for the worsened respiratorymechanics 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 combinedwith ventilatory control deficits, such as blunted chemosensitivity [49–51]. The hormone leptinmay 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, inour experience OHS is often misdiagnosed as congestive cardiac failure probably due to thepresence of cor pulmonalae. In addition, the chest radiograph in OHS can give the impression ofpulmonary congestion owing to the overlying adiposity. Also, the obesity-related restriction canaccentuate pulmonary interstitial markings. In addition, OHS patients often present to theintensive care unit with acute decompensation, with blood gases revealing acute on chronicrespiratory failure. During these acute presentations, hypoxaemia can impair left ventricularrelaxation [54], and elevated right ventricular pressures can raise left ventricular pressures throughdiastolic interdependence [55]. As such, some mild pulmonary oedema may be present in thesepatients at presentation although left ventricular function is relatively normal once the acuteexacerbation has resolved. Management of OHS principally involves the use of bi-levelnoninvasive ventilation. The expiratory pressure may need to be relatively high to treat OSA, acondition which is frequently co-existent. In addition, weight loss is likely to improve sleep-disordered breathing in these patients [48]. Indeed surgical weight loss may be an option formorbidly obese patients with OHS [56].

Hypercapnic CSA: impaired respiratory motor control

Can’t breathe

Hypercapnic patients with CSA and an intact central respiratory output from pattern generatorneurons 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 relatesto the underlying condition [57].

Nonhypercapnic CSA

Cheyne–Stokes breathing

The renowned Irish physicians, J. Cheyne and W. Stokes, gave their names to this characteristiccrescendo/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 Cheyne–Stokes breathing(CSB) and evidence of the long circulation time is seen because each oxygen desaturationcorresponds to the previous apnoea. The cycle time of the unstable breathing is consequently long,typically 60–90 s. The most common cause of CSB is congestive cardiac failure (CCF). CSBassociated 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 orsleep transition apnoea and who have normocapnia or hypocapnia during wakefulness fall into thecategory 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 2sleep. Patients may present with insomnia or hypersomnolence. The pathophysiology is poorlyunderstood but is thought to relate to elevated hypercapnic ventilatory responses leading tohypocapnia and respiratory control instability [58–60]. Arousal and the ensuing hypocapnia canfurther destabilise breathing [22]. These factors render the patient vulnerable to crossing theapnoea threshold, which may lie perilously close to the sleeping eucapnic Pa,CO2, particularly inthose with daytime hypocapnia. Acetazolamide has been shown to improve sleep-disorderedbreathing in a study involving seven patients with ICSA [61]. Its mechanism of action is discussedlater in this chapter. A recent report suggests that non-benzodiazepine hypnotics may be beneficialin some patients with ICSA [20]. However, randomised, controlled studies are required before thiscan be recommended as a safe and effective treatment approach. In our experience ICSA is quiteuncommon, 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 thecharacteristic cyclical breathing patterns with central apnoeas that occur at high altitude. Thecharacteristics of hypobaric hypoxic PB are well described by BERSSENBRUGGE et al. [63] as follows:1) repetitive breathing oscillations of reproducible cycle length (21.2¡1.8 s); 2) clusters of two tofive breaths of highly variable tidal volume and breath-to-breath ventilation alternating with aprolonged expiratory pause of the last breath of each cluster (apnoea); and 3) apnoeas of centralorigin occupying half the cycle time. PB is best appreciated graphically. Figure 4 shows the cyclicalbreathing 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 diagnosticcriteria 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 thosewith it [66]. PB occurs in virtually all individuals given sufficient ascent and accompanying hypoxia.However, the altitude at which PBoccurs and the characteristics of thePB pattern vary between individualsbased, in part, on differences inphysiological responsiveness to hy-poxia. LAHIRI et al. [67] comparedventilatory response to hypoxia inHimalayan sherpas to sojourners to5,200 m and the relationship of thisresponse to nocturnal sleep apnoeaand PB. Sojourners with a high ven-tilatory response to hypoxia mani-fested periodic breathing and apnoeaswhile sleeping. In contrast the sherpaswho had a low ventilatory response to

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Figure 3. Cheyne–Stokes breathing in a patient. &%: spontaneousarousals; &%: desaturation; &%: central apnoea. Sa,O2: arterial oxygensaturation. Reproduced from [45] with permission from thepublisher.

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hypoxia had no sustained apnoeas/PB. However, central apnoeas can occur in highlanders at veryhigh altitudes [68].

The hypobaric hypoxia at altitude results in relative hyperventilation via activation of the peripheralchemoreceptors. The resultant hypocapnia during sleep triggers a central apnoea if Pa,CO2 falls below thechemical apnoea threshold. Thus, respiratory alkalosis ensues. However, what causes the periodicity ismore complex. Using hypobaric hypoxic studies in normal individuals, BERSSENBRUGGE [63] theorisedthat the periodicity resulted from oscillations in Pa,CO2 around a CO2-apnoea threshold whosefunctional expression was critically linked to sleep state. In essence, hypoxia results in increased gain ofthe peripheral chemoreceptors with resultant hyperventilation, which drives the CO2 below the CO2-apnoea threshold and an apnoea ensues. Meanwhile, during the apnoea the hypoxia worsens, furtherincreasing the gain on the peripheral chemoreceptors. Thus, rather than slowly increasing tidal volumetriggered by increasing CO2, a vigorous ventilatory response initiated by the peripheral chemoreceptor’sresponse to hypoxia ensues. Hence, the process is self-sustaining and periodic. Therefore, chemicalcontrol 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 acutehypoxia. The enhanced hypoxic response is due to alterations in ion current densities, changes inneurotransmitter dynamics and recruitment of additional neuromodulators (endothelin-1) inglomus cells [69]. Moreover, hypoxia-induced central depression has been suggested to contribute tothe PB [70]. Sleep fragmentation is common at altitude with resultant fatigue the following day [71].

Arousals can influence the occur-rence of PB. In a simulated high-altitude study, ANHOLM et al. [71]showed that brief arousals increasedfrom 22¡6 arousals?h-1 of sleep atsea level to 161¡66 arousals?h-1 at282 mmHg. A study investigatingthe effects of the hypnotic zolpidemat simulated high altitude found thatarousals occur in synchrony withthe hyperpnoeic phase of PB [72].However, GOLDENBERG et al. [73]found that the intercurrent wakeful-ness duration correlated best withPB and not the number of arousalsper se.

WHITE et al. [5] studied the effects ofacclimatisation at high altitude duringthe first week in seven healthy males.Acclimatisation resulted in augmen-ted hypoxic ventilatory responsive-ness and the slope of the hypercapnicventilatory response increased initi-ally. The sleep-induced decrements inventilation and hypercapnic respon-siveness were equivalent to those atsea level and the quantity of PB wasvariable, occurring more frequently inthose with higher hypoxic and hyper-capnic responsiveness. The authorsalso found that acclimatisation re-duced the latency to PB and that sleepquality improved [73].

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Figure 4. A nocturnal polygraph recording from a mountaineer at4,559 m. The inductive plethysmographic volume signals of a) thesum volume of the ribcage (RC) and abdomen (AB). b) The RCvolume and c) the AB volume show periodic breathing. Sp,O2:arterial oxygen saturation measured by pulse oximetry; HR: heartrate. Reproduced from [64] with permission from the publisher.

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Medications suggested as putative treatment options for PB/apnoeas include respiratorystimulants (theophylline, medroxyprogesterone acetate, almitrine and acetazolamide) and, somemight say, paradoxically hypnotics. Results have been mixed. Studies have shown that hypnoticshave generally improved sleep quality (measured subjectively in some studies) without affectingoxygen saturations [72, 73]. However, the studies are both small and sparse. In addition, thesubjects were healthy individuals, reducing the risk/impact of respiratory depression. Anotherstudy of temazepam showed a reduction in PB at 5,000 m and no effect on performance the nextday 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]. Medroxyprogesteroneremains 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 altitudeprobably comes from its induction of a metabolic acidosis rather than from another of its othernumerous pharmacological effects [78], although the precise mechanisms of action remainuncertain.

The hypoxic ventilatory response is key to the development of PB. The original experiments ofBERSSENBRUGGE et al. [63] demonstrated elimination of PB with restoration of normoxia,coincident with a 3–6 Torr increase in Pa,CO2. Unsurprisingly oxygen therapy has been shown toimprove 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 beingobstructive. Considerable controversy exists regarding the entity of complex sleep apnoea, inpart because its definition is quite vague. Some literature has suggested that OSA patients whodevelop central apnoeas upon initial continuous positive airway pressure (CPAP) exposureshould be labelled as complex apnoea. These patients were traditionally labelled as having‘‘treatment-emergent central apnoea’’ with spontaneous resolution of central apnoea occurringin the majority of these individuals. Significant pathophysiological similarities exist betweenOSA and CSA and interestingly central apnoeas lead to upper airway closure [3, 4]. SANKRI-TARBICHI et al. [4] have shown that central hypopnoeas lead to pharyngeal narrowing during theexpiratory phase. They concluded that reduced ventilatory drive leads to increased expiratory,but not inspiratory, upper airway resistance [4]. During this study central hypocapnichypopnoeas were induced by noninvasive positive-pressure ventilation. The drive to thegenioglossus (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 unstablerespiratory control [82, 83]. Thus, in patients with complex apnoea different perpetuatingfactors determine which type of apnoea occurs. For example, during REM sleep obstructiveapnoeas will predominate. Generally, OSA worsens during REM sleep probably from reducedupper airway tone and reduced chemosensitivity [16, 84]. In contrast, CSA severity improvesduring 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 (whichis increased in OSA [86]) may play a role in the type of apnoea that occurs and how quickly theairway reopens.

Treatment emergent CSA occurs in ,10% of patients diagnosed with OSA on the first night ofCPAP treatment [87]. Important risk factors for this phenomenon are cardiac disease and somepre-existing CSA. Although poorly studied, these patients also probably have robustchemosensitivity 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 resistancemight 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 thesetting of mask leak leading to a fall in Pa,CO2 for a given minute ventilation. Lung stretchreflexes may also be important in inhibiting ventilatory motor output in some patients. Thesecentral 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 after1 month of CPAP. An increasingly used treatment option in these patients is adaptiveservoventilation [90]. In a recent 2-week pilot study, RANDERATH et al. [91] studied the effects ofcombined adaptive servo-ventilation and automatic positive airway pressure on 12 patients with co-existing OSA and CSA syndrome and periodic breathing. Seven of the patients had cardiovasculardisease. Considerable abolition of the apnoeas and improvements in arousals, O2 saturation andsleep profile were noted [91].

Treatment of CSA

CSA has diverse manifestations and aetiologies. Accordingly, the treatment options reflect thisdiversity and vary widely between the different forms of CSA. For example, noninvasive bi-levelventilation can be of benefit in OHS but could cause clinical worsening of some patients withhypocapnic CSB. Throughout the chapter we have discussed the specific treatment options of thevarious manifestations of CSA. The main treatment options for CSA are discussed further in thissection. The treatment of CSB in heart failure is described in more detail elsewhere in thismonograph.

Oxygen

Hypoxia can be sustained in OHS or intermittent in other forms of CSA. Hypoxia can impairrespiratory 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 bysustained 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) canpotentially benefit from the stabilising respiratory control effects of oxygen. Improvements onoxygen therapy have been noted in ICSA and CSB. However, these trials have been short term[95–97]. Larger trials are required to determine which CSA patients may benefit from oxygentherapy.

Carbon dioxide

Increasing the sleeping Pa,CO2 (eucapnic level) further above the apnoeic threshold could have astabilising effect on some forms of CSA, minimising the risks of apnoeas. Recent studies haveshown that mild increases in the inspired concentration of CO2 (by addition of CO2 or byincreasing the dead space via a mask) have beneficial effects on central apnoeas in ICSA [98] andCSB [99]. The improved apnoea/hypopnoea index does not always translate into improved sleepquality [100] and concerns exist regarding CO2-induced sympatho-excitation [101]. A recentstudy 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 withmuch lesser doses than continuous administration [102]. If such a model was developed clinicallyit could lessen the acidosis and sympatho-excitation associated with CO2 administration. Thestudies so far have had small numbers and larger, longer studies are needed to determine theefficacy and safety of CO2 administration.

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Noninvasive ventilation

CPAP has shown benefit in patientswith ICSA possibly from stoppingthe inhibitory reflex mechanismsthat arise during airway closureand increasing lung volumes andoxygen stores [103]. One could alsospeculate that in some cases theincrease in physiological dead spacefrom CPAP might be mildly in-creasing the CO2 further above theapnoeic threshold. CPAP has beenshown to improve sleep-disorderedbreathing and haemodynamics inheart failure patients [104]. Thelargest study on the effects of CPAPon CSA did not show improvedmortality and only showed a mildimprovement in apnoea/hypopnoeaindex [105]. Limited data supportthe role of increased inspired CO2 asan adjunct to CPAP in the treatmentof mixed obstructive and centralapnoeas [106]. Larger trials on CO2

administration are needed before itcan be recommended given thedanger of sympatho-excitation and other deleterious effects. Bilevel noninvasive ventilation canimprove 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 definitiverecommendations.

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 thehypercapnic ventilatory response and lowering the apnoeic threshold [61, 111]. Acetazolamide hasbeen shown to improve periodic breathing at high altitude [77]. Long-term, larger trials arerequired before acetazolamide can be safely recommended. Theophylline and progesterone haveshown benefit in some types of CSA. However, theophylline has been associated with possiblearrhythmias [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 ataltitude to opiate-induced CSA. The pathogenesis of CSA is summarised in figure 5. This diversityis reflected in the differing pathogenesis and treatment options. Indeed, a certain treatment whichimproves one form of CSA may have deleterious effects on another (e.g. bilevel noninvasiveventilation). However, all forms of CSA can ultimately lead to adverse cardiovascular outcomes.Some exciting new therapeutic options (e.g. phasic administration of CO2) require furtherresearch, in particular with respect to safety.

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

Inhibitoryreflexes

Chemosensitivity

Obstructiveapnoea/

hypopnoea

Drive

Centralapnoea/

hypopnoea

Hypocapnia

Hypercapnia

Metabolic production

Chemosensitivity

ArousalArousal threshold

Ventilatory responseto arousal

UA anatomyHyperventilation

Loss of wakefulnessstimulus

Change between eupnoeaCO2 and apnoea threshold

Loss of behavioural

inputs

"Won't breathe" factorsi.e. CNS depression and CCHS

Figure 5. The pathogenesis of central sleep apnoea. CNS: centralnervous system; CCHS: congenital central hypoventilation syn-drome; UA: upper airway. Reproduced from [45] with permissionfrom the publisher.

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Statement of Interest

D.J. Eckert is a consultant for Apnex Medical, receiving less than US$20,000 per year. Within thepast 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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