Trained to identify typical obstructive and central sleep apnea phenotypes of sleep disordered breathing (SDB), many sleep lab clinicians and technicians remain unfamiliar with complex sleep apnea syndrome (complex SAS). This syndrome can be considered the simultaneous presence of upper airway obstruction and chemoreflex-driven respiratory oscillations during sleep. Complex SAS is often encountered in the clinical sleep laboratory. The complex-pattern breathing of predominantly mixed apneas and obstructed periodic breathing in some patients or obstructive apneas that resolve with continuous positive airway pressure (CPAP) only to reveal central apnea or the Cheyne-Stokes breathing pattern is not classified as a distinct breathing disorder.1,2,3 Their prevalence ranges from 15% 1 to as high as 48%4 in clinical practice, based on study population characteristics. The difficulty in recognition may be directly related to the standard practice in sleep labs of not scoring mixed apneas and hypopneas and limitations of viewing the polysomnography (PSG) in 30 second epochs and the scoring guidelines governing it.5 Moreover, the International Classification of Sleep Disorders–2 explicitly states that mixed apneas should be considered obstructive. The purpose of this review is to enhance the knowledge base of SDB phenotypes, to create greater awareness of complex SAS among sleep lab clinicians and technicians, and to define complex SAS in objective terms that are extracted from the current literature.

Table 1 Significant patient characteristics of SDB phenotypes


Complex SAS



p value

Sex (male) (%)





Sleep maintenance insomnia (%)





Complex SAS patient characteristics

Several demographic and clinical variables were investigated to determine if any characteristics discriminated complex SAS patients from obstructive sleep apnea (OSA) and central sleep apnea (CSA) patients. The variables included physiological measures, Epworth Sleepiness Scale (ESS) score, patient history of sleep events, Echo Ejection Fraction, Echo right ventricular systolic pressure, and atrial fibrillation.1 The male sex was more predominant in complex SAS than in OSA and CSA (81% versus 60% versus 43%, respectively; p=0.027) and complex SAS patients had less sleep- maintenance insomnia than did OSA and CSA patients (32%, 45% versus 79%, respectively; p<.05). No other patient characteristics were statistically significant to distinguish complex SAS from OSA and CSA patients (see Table 1).

Table 2 Hypocapnic complex diseases characteristics in sleep.


Hypocapnic Complex Disease


‘Mixed’ rather than pure obstructive or central SDB pattern


Various degrees of flow-limitation inter mixed with periodic breathing

Sleep position

Position-dependent variability (central in nonsupine position, obstructive in supine position)

Sleep stage

Stage dependent variability (obstructed periodic breathing during NREM that improves in REM sleep—the most char acteristic pattern. Some patients will have REM-related obstructions in addition to NREM periodic breathing.)

Treatment response

Variable CPAP response due to unmasked central apneas with EEG arousals

Identifying Complex SAS Patients Using PSG data: Complex SAS phenotypic features

Two types of complex disease are described: hypocapnic and hyper-capnic (ie central congenital hypoventilation, chronic obstructive lung disease, obesity hypoventilation, congestive heart failure. The reader is referred to White6 for a complete review of these hypercap-nic disorders). Gilmartin et al7 reported several identifiable variables linked to the hypocapnic variety (see Table 2).

Complex SAS patients present with mixed types of apneas (repetitive, ~ every 25 seconds) rather than pure obstructive or central apneas on the PSG.7 The hypopneas are obstructive but oscillate similar to periodic breathing-waxing and waning symmetrically. From the baseline PSG data, the total apnea hypopnea index (AHI, no./hr) was statistically different between the complex SAS, CSA and OSA groups (Mean±SD: 38.3±36.2, 32.3±26.8, 20.6±23.7; respectively) with the OSA group having the lowest AHI. Complex SAS patients also had a statistically significant higher nonrapid eye movement (NREM) sleep obstructive AHI than did CSA and OSA patients (Mean±SD: 21.8±24.6, 5.93 ± 6.07, 11.7±19.6; respectively) and total obstructive AHI (Mean±SD: 21.8±23.8, 6.57±6.55, 12.2±18.9; respectively).1 (see Figure 1). It is not known what minimum number of mixed apneas indicate complex SAS in SDB patients, but it is possible that recognition of one mixed apnea during the automated or manual scoring of the PSG breathing events may point toward the existence of complex SAS.

Figure 1: Comparison of Mean (±SD) Total Apnea Hypopnea Index, NREM Apnea Hypopnea Index, and Total Obstructive Apnea Hypopnea Index in Complex SAS, OSA and CSA phenotypes

Click for full size image.
SDB = sleep disordered breathing; AHI = apnea hypopnea index; Complex SAS = complex sleep apnea syndrome; OSA = obstructive sleep apnea; CSA = central sleep apnea; p values were obtained from Linear contrasts of pair-wise comparisons among the three groups. (Data extracted from Table 2 in Morgenthaler et al, 2006)
Figure 2: Apnea Hypopnea Index, Respiratory-related Arousal Index, Total Apnea Hypopnea Index and NREM Central Apnea Index comparison between Complex SAS, OSA and CSA patients on CPAP

Click for full size image.
AHI = apnea hypopnea index; Complex SAS = complex sleep apnea syndrome; OSA = obstructive sleep apnea; CSA = central sleep apnea; p values were obtained from Linear contrasts of pairwise comparisons among the three groups. (Data extracted from Table 3 in Morgenthaler et al, 2006)

The nasal pressure cannula airflow signal showing variations relative to the upper airway obstruction that are intermixed with periodic breathing respiratory effort suggest the presence of complex SAS. These variations are better observed by increasing the epoch size from 30 to 90 or 120 seconds.

When patients change their sleep position from supine to side, a change from obstructive to central type of SDB events imply complex SAS. The reverse scenario is also possible where central type apneas are first observed on the side and then assume an obstructive character as soon as the patient is supine. Morgenthaler et al1 found that patients with complex SAS on continuous positive airway pressure (CPAP) had a significantly higher total mean arousal index (24.8±15.5/hour, n=29) compared to OSA patients (18.2±11.2/hour, n=153) but were similar compared to CSA patients (24.5±14.8 /hour, n=11). The respiratory-related arousal index with CPAP was significantly higher in complex SAS (12.2±9.4) compared to OSA (2.06±3.04, p=<.001) and similar to CSA (11.5±10.6) patients. CPAP did not resolve SDB in complex SAS and CSA patients. The total AHI and central apnea index (CAI, no./h) on CPAP were statistically significant between the three groups, lowest in OSA patients (2.14±3.14; 0.75±0.98, respectively) compared to complex SAS patients (21.7±18.6; 17.1±15.3, respectively) and highest in CSA patients (32.9±29.8; 31.5±29.8, respectively), reflecting CPAP as an ineffective therapy in these two groups (see Figure 2). The CPAP findings in patients with CSA are comparable to those reported by Teschler et al8 using a full night PSG where an effort band AHI was 28.5±4.6 / hour. The CAI however was approximately half (18.5±3.2) compared to the Morgenthaler study, and this disparity is likely due to the difference in methodologies between the two studies, split-night versus full-night PSGs.

In cases where periodic breathing is observed during unstable NREM sleep and severe obstructive events with corresponding oxygen desaturations in REM sleep also suggest that the patient might have complex SAS. This type of variability is easily seen in the first half of the night with predominant unstable NREM periodic breathing and in the second half of the night where REM sleep is more prevalent, severe obstructive sleep apnea might be the more prevailing SDB.

A more subtle form of complex SAS can present with minimal SDB events in REM sleep, periodic short cycles of obstruction during unstable NREM sleep and incomplete tolerance to positive airway pressure.7 Some noncom-pliers to CPAP therapy may fall into this category.

Therapeutic approaches to complex SAS patients

CPAP titration is usually initiated following the positive identification of obstructive respiratory events (AHI ≥ 52,3) and a minimum recording time of 2 hours.9 In some complex SAS patients, CPAP may unmask an underlying chemo-reflex gain-control aberration once the obstruction is resolved. The result is the emergence of periodic breathing and central apneas with arousals that persist to produce continued poor sleep quality. CAI criteria of ≥ 5 central events per hour or a prominent Cheyne-Stokes breathing pattern was used to identify complex SAS patients on CPAP.1 It is not given in this study what the duration of periodic breathing or the number of cycles of waxing and waning respiratory effort that was used to ascertain complex SAS.

Table 3: Therapeutic protocol for treating complex SAS patients with CO2





CPAP titration

Titrate minimal CPAP to eliminate obstructive apnea and hypopnea events



Discontinue use of any routine supplemental oxygen


CAP + CO2 titration

Identify stable stage-2 NREM sleep using described cyclic alternating pattern (CAP) atlas morphology (11) and restrict CPAP pressure changes and CO2 gas adjust ments to unstable sleep.


CPAP adjustment

Adjust CPAP pressure once periodic nonobstructive breathing is normalized to eliminate any residual airway flow limitations (ie, snoring)


BiPAP initiation

If hypoventilation persists in REM sleep, switch to Bilevel PAP to obtain optimal respiratory setti


BiPAP adjustment

Turn off any back-up rate once optimal CO2 level is attained to determine the need for the back-up mode


CO2 adjustment

At optimal control of respiration with CO2, ‘dial-down’ CO2 in 0.25% increments to determine the least effective CO2 concentration

Typically, CPAP titration starts at 4 to 5 cm H2O pressure and is increased by increments of 1 to 2 cm H2O until obstructive events and snoring are eliminated. On the PSG, persistent arousals resulting from central events and periodic breathing are continued to be titrated in the hope of elimination with higher CPAP, often as high as 5 cm H2O above the pressure that eliminated obstructive events.1 This ‘over-titration’ is unsuccessful in eliminating arousals and can result in increased patient discomfort, intolerance of the therapy, and technician frustration.

Thomas et al10 titrated CO2 using a novel device, the Positive Airway Pressure Gas Modulator, in six patients with complex SAS using PAP and reported that CO2 levels of 0.5% to 1.5% delivered in increments of 0.25% was highly effective in normalizing respiration. CPAP adjustment of 1 to 2 cm H2O was required in some patients to optimize the elimination of obstructive events. The investigators developed an experimental therapeutic protocol for treating complex SAS patients with CO2 following confirmation of SDB (see Table 3).

The supplemental CO2 therapeutic approach in complex SAS is supported by the near complete abolition of the AHI, and entire elimination of apneas and CSR with the addition of a constant FiCO2 of 0.03% via full face mask to congestive heart failure patients (n=6).12

Adaptive ventilation approaches have not been adequately evaluated in true complex SAS. Nearly all the published data have described those with more pure central sleep apnea or Cheyne-Stokes respiration. This is an important area of study. Use of dead space with positive airway pressure may also be effective (Thomas, personal communication), but prospective trials of such approaches are required before widespread adoption occurs in clinical practice.


Upon clinical evaluation, complex SAS patients presented similarly to OSA and CSA patients except for a higher proportion of males among the complex SAS group. The clinical features to predict complex SAS patients remain somewhat obscure. There is published evidence that counting of standard sleep stages is not sensitive to existent pathology in some sleep disorders.3,14-16 and that the indexes derived (ie AHI) can distort some sleep vari-ables.17 Until more refined methods, like time-series analysis are developed for clinical application, predictive identification of the complex SAS phenotype will be unlikely revealed from standard PSG data.

What’s ‘in’?

  • Complex SAS phenotype
  • Evidence based treatment
  • Combination treatment therapy with PAP plus some form of increasing CO2 for effective management of SDB in complex SAS
  • Unstable NREM sleep: periods of NREM sleep with SDB events to describe unbiased apnea hypopnea indexes
  • CAP (cyclic alternating pattern): an endogenous CNS rhythm of NREM sleep that demonstrates an oscillation between a state of high arousal threshold (phase A) and a lower threshold arousal state (phase B)
  • Time-series PSG analysis: simple method to identify SDB phenotypes

What’s ‘out’?

  • OSA and CSA as the only phenotypes of SDB
  • CPAP alone as treatment therapy for patients with CSA or complex SAS
  • Patient characteristics to differentiate SDB phenotypes
  • Counting sleep stages to identify all sleep disorders

What’s ‘needed’?

  • Longitudinal analysis of CO2 usage in complex SAS patients
  • Controlled clinical research studies on the long-term effects of CO2 in complex

SAS patients

  • More clinical prevalence studies of complex SAS
  • Analytical tools to assist in the identification of SDB phenotypes

The role of Pco2 in maintaining normal rhythmic ventilation during sleep has been well documented and reviewed extensively.6 Its efficacy has been demonstrated in CHF patients with OSA and Cheyne-Stokes respiration.18 Below an ‘apnea threshold’, reduced Pco2 during sleep may produce a decrease in respiratory drive to breathe, resulting in sleep-wake transitions throughout the night in some individuals. When this central form of sleep and respiratory disruption presents clinically, it is likely due to defective metabolic mechanisms.12 It is possible that patients earlier described as having ‘idiopathic central sleep apnea’ are now being relabeled complex sleep apnea patients. However, the recent evidence does seem to distinguish OSAS from CSA and from complex SAS patients.

Mixed apneas composed of a central component followed by an obstructive component are seen in many patients.1,7,19 Complex diseases that present clinically with mixed apneas are described in two separate forms: a hypercapnic and hypocapnic type. It is in sleep where the hypocapnic type becomes evident and can, in some cases, be clearly seen after CPAP initiation with the emergence of periodic breathing and persistent sleep fragmentation. Treatment recommendations are for PAP with an increase of CO2 as adjunct therapy in the form of a nonvented mask, increasing dead space by adding an extra length of tubing between the CPAP and face mask, or addition of supplemental CO2 in 0.25% increments. The use of pharmacotherapy in combination with PAP and CO2 is an alternative to those with ensuing insomnia.

As research analytical tools become validated and move into the mainstream sleep lab, clinicians and technicians will have additional methods at hand to aid in the differentiation, identification, treatment and assessment of compliance of complex SAS patients on therapy. The long-term effects of supplemental CO2 are unknown and it remains unclear how long the therapy should be used and if the need for supplemental CO2 diminishes over a certain period of time. These questions will need to be addressed in additional research.

Preetam Schramm, PhD, RPSGT is principle clinical specialist, Embla Inc, Broomfield, Colo.

The author acknowledges the contribution of Robert Thomas, MD at Beth Israel Deaconess Medical Center for his valuable comments, editing and suggestions on this manuscript.


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