Review ArticleComplex Sleep Apnea Syndrome

Muhammad Talha Khan and Rose Amy Franco

Division of Pulmonary, Critical Care and Sleep Medicine, Medical College of Wisconsin, 9200 W. Wisconsin Avenue,Milwaukee, WI 53226, USA

Correspondence should be addressed to Muhammad Talha Khan; mukhan@mcw.edu

Received 30 September 2013; Revised 10 November 2013; Accepted 23 November 2013; Published 16 February 2014

Academic Editor: Michel M. Billiard

Copyright © 2014 M. T. Khan and R. A. Franco.This is an open access article distributed under the Creative Commons AttributionLicense, which permits unrestricted use, distribution, and reproduction in anymedium, provided the originalwork is properly cited.

Complex sleep apnea is the term used to describe a form of sleep disordered breathing in which repeated central apneas (>5/hour)persist or emerge when obstructive events are extinguished with positive airway pressure (PAP) and for which there is not a clearcause for the central apneas such as narcotics or systolic heart failure. The driving forces in the pathophysiology are felt to beventilator instability associated oscillation in PaCO

2arterial partial pressure of CarbonDioxide, continuous cositive airway pressure

(CPAP) related increased CO2carbon dioxide elimination, and activation of airway and pulmonary stretch receptors triggering

these central apneas. The prevalence ranges from 0.56% to 18% with no clear predictive characteristics as compared to simpleobstructive sleep apnea. Prognosis is similar to obstructive sleep apnea.The central apnea component in most patients on followupusing CPAP therap, has resolved. For those with continued central apneas on simple CPAP therapy, other treatment options includebilevel PAP, adaptive servoventilation, permissive flow limitation and/or drugs.

1. Introduction

Obstructive sleep apnea syndrome (OSAS) affects a growingproportion of general population affecting both men (15%)and woman (5%) and is commonly known as “sleep disor-dered breathing” [1]. OSAS is linked with significant cardio-vascular morbidity and mortality in those untreated [2]. InOSAS, repetitive collapse of the upper airway takes place,whichwill finally lead toO

2arterial Oxygen desaturation and

arousal. Continuous positive airway pressure (CPAP) is thestandard therapy to stabilize the airway preventing repeatedcollapse. To a lesser extent, central sleep apneas syndrome isdiagnosed in about 5% of those who undergo a sleep study.This condition is characterized by diminished respiratoryregulation during sleep, resulting in decreased or absentventilation and disturbed gas exchange [3]. Because themechanism behind the developing the central events is muchmore complicated, the response to CPAP is often incompleteand may lead to CPAP failure [4, 5]. For some patientswho undergo CPAP treatment for OSAS, CPAP therapyleads to the development of recurrent central apneas or evenclear periodic breathing. This phenomenon of obstructiveevents or mixed central and obstructive events with short

cycles of obstruction and the incomplete response to positiveairway pressure (PAP) due to CPAP treatment related centralevents has been labeled “complex sleep apnea syndrome”(CompSAS) [6–9].

2. Definition

Complex sleep apnea syndrome (CompSAS) is a form ofsleep disordered breathing in which central apneas persist oremerge when obstructive events have disappeared with PAPtherapy (see Figure 1). By the currently accepted definition,the central events must comprise more than half of the resid-ual sleep disordered breathing events or lead to a periodicbreathing pattern which on positive airway pressure therapybecomes predominant and disruptive and the central apneaindex (CAI) must be >5 events/hour. Bilevel positive airwaypressure ventilation in spontaneous mode may increase therisk of central apneas through augmenting ventilation witha proportionate decrease in carbon dioxide. It is activelybeing debated whether to include those with central apneasassociated with narcotics or Cheyne-Stokes breathing dueto systolic heart failure. In the current definition, CompSASwould include only patients whose central apnea could

Hindawi Publishing CorporationSleep DisordersVolume 2014, Article ID 798487, 6 pageshttp://dx.doi.org/10.1155/2014/798487

2 Sleep Disorders

(a) (b)

Figure 1: (a) Diagnostic polysomnogram showing obstructive events (arrows). Leads from top to bottom; eye, EEG, chin, ECG, snore, nasalpressure, thermal airflow, thoracic and abdominal effort, legs movement, saturation, and heart rate. (b) Development of central events onCPAP therapy (arrows). Leads from top to bottom; EEG, eye, chin, ECG, snore, legs movement, CPAP, flow, thoracic and abdominal effort,IPAP, saturation, leak, respiratory rate, and heart rate.

not be diagnosed elsewhere in the central apnea disordersspectrum. In an effort to better define this population andthe pathophysiology driving it, these groups are not includedin this discussion. While the diagnosis of CompSAS usingany criteria will continue to be controversial, there is aneed for a diagnostic category for patients with treatmentemergent central apneas—especially for those in whom thecentral apnea does not resolve with chronic CPAP treatment.Complex sleep apnea has also been variably termed CPAP-related periodic breathing [10], complex disturbed breathingduring sleep [11], and CPAP-related CSA [12], CSA duringCPAP [13].

The prevalence of complex sleep apnea has only recentlybeen evaluated. In a clinical review which did not excludethose with heart failure or narcotic use, 15% of patients(34/223) consecutively evaluated over 1 month for suspectedsleep-disordered breathing had CompSAS [9]. However, theprevalence of this syndrome is somewhat variable in partdue to the heterogeneous populations being reported/studiedand is significantly affected by factors such as narcotic use,BMI, and other comorbidities specially heart failure. Thedescribed sleep center prevalence ranges from 0.56% in theWesthoff study from Germany (excluded patients with BNPl > 100 pg/mL) [14] to 18% reported in series of patients withchronic heart failure and OSAS [15].

3. Pathophysiology

Differentiating CompSAS from both OSA and CSA arosefrom the need to characterize the pathophysiology of thissyndrome and formulate appropriate management strategies.The pathogenesis is not completely understood but there isthought to be interplay of several factors influencing thepathophysiology (see Figure 2). The key factors are thoughtto include the interaction of upper airway obstruction andunstable central ventilatory control factors as well as hostconditions/characteristics [16, 17]. It has been proposed thatCompSASoccurs predominantly during unstable sleep states.In this theory, the development of CompSAS depends onthe combination of breathing instability, changes in upper

airway related airflow resistance, variable PaCO2levels,

and oscillating sleep state. During wakefulness, breathing iscontrolled by combined behavioral and metabolic factors inaddition to central and peripheral chemoreceptors (carotidbodies and medulla). During sleep, the withdrawal of behav-ioral control of ventilation and blunted chemoresponsivenessto changes in arterial CO

2(PaCO

2) and oxygen (PaO

2), as

well as changes in lung volumes andminute ventilation due tosleep state (REM versus Non REM), leads to more variabilityin PaCO

2levels. In the setting of the recurring upper

airway obstructions with OSAS, the variability of PaCO2

is even more marked. When chronic recurrent obstructionis resolved by CPAP, ventilation stabilizes improving gasexchange and smoothens the CO

2elimination. If the ventila-

tory response to stimuli is exaggerated, the PaCO2can easily

drop below the apneic threshold resulting in a central apnea[18–21]. The central event in turn may trigger an awakeningthat leads to a sleep/wake state dependent change in ventilatordrive and the PaCO

2set points for ventilation. Under the

right circumstances, this leads to a cyclic phenomenon ofcentral apnea, sleep disturbance, sleep onset, central apnea,sleep disturbance, and so forth. Some patients may havea much tighter apnea threshold to hyperpnoea response(lower breakpoint)making themmore susceptible to periodicbreathing. It should also be noted that those more likelyto demonstrate treatment emergent centrals are also likelyto demonstrate central events on polysomnogram duringdiagnostic portion in addition to predominant obstructiveevents. Those central events become more prominent duringCPAP therapy. Another potential mechanism that wouldexplain central apneas developing with CPAP initiation is theeffect of PAP therapy on activation of lung stretch receptorsleading to ventilatory changes. When lung stretch receptorsare stimulated, a central apnea ensues via the Hering-Breuerreflex [22, 23]. Montesi et al. recently identified nasal maskswith inherent leak and mouth leak as potential sourcesfor hypocapnia triggered central apneas in the setting ofPAP therapy [24]. Finally, external and internal triggersrelated to the patients comorbidities and the intrusivenessof CPAP therapy can also trigger frequent arousals, whichin turn lead to unstable sleep and oscillation of PaCO

2. A

Sleep Disorders 3

Complex sleep apnea

Relief of upper airway obstruction Extrinsic/intrinsic

factorsOver titration

eliminationUnstable sleep state increased arousals

Lung stretch receptors

apneic threshold Central apneustic response

apneic threshold

Central apnea

PaCO2 drops below PaCO2 drops below

Increased PaCO2

Figure 2: Schematic representation of pathogenesis of complexsleep apnea syndrome.

schematic representation of the pathophysiology is illustratedin Figure 2.

4. Clinical Characteristics

Clinically speaking, the phenotype of patientswithCompSASis most similar to that of a patient with OSA, and only whenCPAP therapy is applied one can identify them (see Figure 1).From those studies we have in selected populations, it appearsthat those with complex sleep apnea are more often male(>80% versus 60% with OSA). While it is not clear whatthe exact mechanism is, increased hypercapnic ventilatoryresponse in males could be playing a role [25]. There is slighthigher incidence of ischemic heart disease or heart failurecompared to those with OSA [26] but this may be due tobias inherent to the populations being evaluated in thesestudies. The body mass index (BMI) is typically higher thanthe general population which is typical in OSAS; however, inone study, the BMI with CompSAS was slightly lower thanwith OSAS [9]. There may be clinically relevant symptomsthat leads to detection of CompSAS. In one study, there wasa significant difference in CPAP use and dyspnea comparedto those with OSA. The treated CompSAS patients reportedmore CPAP removal during sleep and dyspnea or air hungerat followup [27]. In fact predicting the presence of CompSASmay not be entirely complete after the initial sleep study. Onestudy reported that, if subject had evidence of central eventson baseline study (central apnea index > 5), they were morelikely to have CompSAS but this was not statistically signifi-cant and was not proven by multiple subsequent studies. Theseverity of sleep apnea present on initial evaluation seemsto predict persistent central apneas while on CPAP therapy.Those with severe OSA or CSA on diagnostic study weremore likely to have persistent central apneas on subsequenttitration studies completed in 2-3months into ongoing CPAPtherapy [28]. The degree of sleep architecture disruption andthe hypopnea density in NonREM versus REM sleep mayalso be predictive. As compare to those with simple OSAS,on subsequent CPAP titration study, those with complexsleep apnea had a higher events/hour index in nonREM sleep

compared to REM sleep and had a more elevated arousalindex [9].

5. Treatment

5.1. Positive Pressure Devices. An outline of treatment optionsis illustrated in Figure 4. Patients with CompSAS can rep-resent a treatment challenge, and the optimal therapeuticapproaches remain to be refined. Based on the proposedmechanisms, it appears that the most critical component ofany therapy for CompSAS is to minimize potential for devel-oping over ventilation or hypocapnia.This includes targetingCPAP at the lowest pressure that resolves most obstructiveevents and avoiding modalities that destabilize the airway orsleep state. In a recent retrospective review of 1286 patientsreceiving PAP therapy, only 6.5% of patients demonstratedCompSAS during the initial CPAP titration study. Of thoseinitially identified with CompSAS, half (𝑛 = 42) underwenta titration sleep study after an interval of CPAP therapy,and 78.6% (33/42) of those showed resolution of the centralapnea component with CPAP [28]. The CompSAS may notbe identified on initial sleep studies. The central apneasdeveloped de novo in 4% of OSAS patients during followupfor CPAP therapy in one retrospective study [29].

Up to this point, CompSAS has been defined by evalu-ation of an initial sleep study or on followup titration sleepstudies. Diagnosing CompSASwill becomemore challengingas practice protocols are driven out of the controlled envi-ronment of the observed sleep study to limited home-basedsleep studies followed by autotitrating PAP therapy by theimplementation of cost containment in sleep medicine. Itis understood that autotitrating PAP devices vary in abilityto warn clinician of emerging central apnea. Clinicians willneed to be aware of this condition as a possibility in thosewith either poor response to auto-titrating PAP therapy (lackof improvement in sleep related complaints) or inability totolerate this type of therapy and champion the need forobserved titration testing needed to confirm the presence ofCompSAS.

For those with CompSAS who fail CPAP, breaking thecycle of central apneas leading to arousals and instability inventilation can be achieved with respiratory assist devicesdesigned to better control ventilation. These devices includebilevel PAP in the spontaneous-timed (bilevel PAP-ST)modeand adaptive servoventilation (ASV) [11, 26]. Bilevel PAP-ST is a type of noninvasive ventilation that provides thepneumatic splint effect in the upper airways resolving theobstructive component as well as stabilizing ventilation dur-ing central apneas by forcing breaths (timed breath) duringepisodes of central apneas. The expiratory positive airwaypressure (EPAP) is set to eliminate obstructive apneas, whilethe inspiratory positive airway pressure (IPAP) and back-up ventilation frequency (ST mode) are set in order todecrease hypoventilation [30]. Even more refined ventilatorsupport can be found in ASV devices. This type of bilevelventilator has been shown to be effective in resolving not onlyCompSAS but also CSA as well as Cheyne-Stokes respirationand can be measurably effective both in the first night oftherapy and over long-term management (Figure 3) [26].

4 Sleep Disorders

Figure 3: Patient on adaptive servoventilation. Resolution of centralevents which were noted on CPAP therapy.

Adaptive servoventilators (ASV) vary bymanufacturer onhow it accomplishes stabilized ventilation. The most com-monly used devices available are of one of two types. Thefirst uses an automatic, minute ventilation-targeted algo-rithm (VPAP Adapt SV ResMed; Poway, CA, USA) andthe second uses an automatic adjustable tidal volume target(BiPAP autoSV; Respironics; Murrysville, PA, USA) whichperforms a a breath-to-breath analysis and alters settingsaccordingly [31]. In a recent retrospective study comparingthese two servoventilators, there was no significant differencein improvement in AHI [32]. With ASV, the end expira-tory pressure is determined during PSG by evaluating thepressure needed to eliminate obstructive apneas. The ASVdevice automatically determines the extent of the ventilatorysupport during inspiration (within a set pressure range)based on continuous analysis of the breathing pattern duringinspiration [30]. Recent further enhancements on the ASVtype of devices include an automatic expiratory pressureadjustment, an advanced algorithm for distinguishing openversus obstructed airway apnea, a modified auto backup ratewhich is proportional to subject’s baseline breathing rate, anda variable inspiratory support.

With these devices ability to assist ventilation with amore natural or gentle push in pressure support that leads toaugmentation of the intrinsic ventilation of the patient, thereis thought to be less tendency to cause excess ventilation ashas been reported to occur with bilevel PAP-ST.

When comparing bilevel PAP-ST with ASV, a prospec-tive randomized crossover clinical trial with patients withCSA/CSR, predominantly mixed apneas and CompSAS inan acute setting, apnea hypopnea index (AHI) and respira-tory arousal index (RAI) were markedly reduced with bothdevices. The AHI and RAI were both statistically lower usingASV as compared to bilevel PAP-ST ((𝑃 < 0.01) AHI 6.2versus 6.4, RAI 0.8 versus 2.4) [26]. Clinically significantimprovements in ventilatory parameters with the adaptiveservoventilators have been measured in other trials. In onerecent randomized trial, during initial titration bilevel PAP-ST and servoventilation both significantly improved the AHI,central apnea index (CAI), and oxygen desaturation index(ODI), when compared to CPAP treatment (all 𝑃 < 0.05).However, at six weeks, servoventilation treated respiratory

events more effectively than Bilevel PAP-ST in patientswith complex sleep apnea syndrome (Bilevel PAP-ST versusservoventilation, respectively: AHI (16.5 ± 8 versus 7.4 ± 4.2events/h,𝑃 = 0.027), CAI (10.2±5.1 versus 1.5±1.7 events/h,𝑃 < 0.0001), and ODI (21.1 ± 9.2 versus 4.8 ± 3.4 events/h,𝑃 < 0.0001)) [33].

When none of the previously discussed PAP therapiesor respiratory assist devices are well tolerated, using lowerpressures by allowing some obstruction to persist (permissiveflow limitation) may be successful in some patients [11].

5.2. Other Treatment Options. The evidence for drug therapyto treat central apneas in CompSAS is limited and includesusing drugs that either improve periodic breathing itself (e.g.,theophylline or acetazolamide) or increase the percentage ofNREM sleep that exhibits stable characteristics (slow wavesleep) [11, 31].

5.3. Experimental Therapies. Pulling from the findings thatincreasing the inhaled percentage of CO

2can resolve cen-

tral apneas (cite), experimentally successful treatment ofCompSAS with PAP therapy plus controlling inhalationgases blended with 0.5–1% CO

2resulted in an immediate

(1min) decrease in AHI to <5 events/h, without complaintsof dyspnea, palpitations, or headache [34]. Safety concerns ofgas application have to be addressed before the applicationof CO

2can be considered for clinical use. Finally, increasing

the overall dead space or enhancing expiratory rebreathingspace in positive airway pressure therapy has been shown tobe effective as well in the treatment of CompSAS; again thereports are of a limited number of subjects and for limitedduration, raising concerns of generalizablity and sustainablityof this therapy [35, 36].

6. Conclusions

Complex sleep apnea syndrome is the diagnostic term for theform of central sleep apnea that persists or develops upontreatment of primarily obstructive sleep apnea with CPAP.The pathogenesis likely is related to a combination of theimpact of CPAP therapy on ventilation, disturbed ventilatorycontrol related to sleep and host response, and other medicalcomorbidities. It is more common in men, coronary arterydisease, and those with congestive heart failure. The vastmajority will be successfully treated with CPAP but cautionis recommended to ensure that the CPAP pressure settingis limited to treating only the obstructive breaths (limitedover titration). For those who are poor candidates for CPAPtherapy and those who are CPAP therapy failures, moreadvanced respiratory assist devices including bilevel PAP-ST or adaptive servoventilation therapy can be effective.Other therapeutic medications such as acetazolamide ortheophylline may offer an alternative when positive pressuredevices of any type are ineffective or poorly tolerated. Newdevices aimed at increasing the amount of inhaled carbondioxide gas to stabilize the breathing pattern appear promis-ing and are under development.

Sleep Disorders 5

+

−

CompSASAssess/wean

narcoticsAssess/treat

CHF

CPAPOffer

ASV/bilevelPAP-ST

CPAP Continue treatment Continue treatment

+

− −

+

∙ Diamox∙ Theophylline∙ CO2 devices∙ Sleep aids

Alternatives

Figure 4: A schematic representation of treatment modalities of complex sleep apnea.

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper.

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