The clinical challenge of treating complex sleep apnea.

Patients with sleep disordered breathing (SDB) who demonstrate classic obstructive sleep apnea (OSA) during diagnostic polysomnography (PSG) commonly respond well to CPAP therapy. A challenge arises with types of SDB other than OSA, such as central sleep apnea (CSA), Cheyne-Stokes respiration (CSR), mixed apnea, or complex sleep apnea (CompSA). When exposed to CPAP therapy, many of the patients with these types of SDB conditions may respond poorly or even become worse.

The patients that actually develop or have worsening central apneas when exposed to CPAP, and who have mixed or apparent OSA alone on their diagnostic studies, have recently been described in more detail as CompSA patients.1,2 One review suggests CompSA may comprise more than 20% of patients presenting to a sleep laboratory, and these patients seem to require more attention when given CPAP therapy.2

Bilevel positive airway pressure (BLPAP) with a backup rate has been used with some success in CSA/CSR patients, but we found that the newly approved and released Adapt Servo Ventilator (ASV or VPAP Adapt SV) from ResMed Inc, Poway, Calif, was of particular value in these and other patients with non-OSA SDB.3 In our study, both BLPAP and VPAP Adapt were shown to be effective in the treatment of CSA, mixed apnea, and CompSA syndromes. However, the VPAP Adapt was the most effective in normalizing the SDB in these patients.

The case of one 68-year-old lifelong bachelor from Iowa who came to us for help with SDB presented one example of what we found in the study.

Patient Case
The 68-year-old man was retired from a high-school business education job and lived alone. He had a history of hypertension, hyperlipidemia, Barrett’s esophagus, and prior prostate adenocarcinoma. He had returned to his health care provider for general health maintenance and complained of frequent napping and fatigue. An oximetry display showed that he had a 4% desaturation index of about 40 per hour, which suggested that he might have a fairly significant sleep-related breathing disorder.

His usual bedtime was 9:30 pm, and he typically got up at 7:30 am. He had no difficulties with sleep initiation, but he did awaken two to three times during the night due to nocturia. There was no collateral history from a sleep partner, but he did report that he had snorted himself awake. There were no other known disturbances of sleep, but he remained quite fatigued on arising. He napped two or three times daily and could fall asleep somewhat inappropriately at other times. On his drive home from his last visit here several weeks ago, he fell asleep and found himself in the opposite lane.

In the past year, he had gained approximately 10 pounds. He did not consume alcohol and caffeine, or smoke tobacco. His Epworth Sleepiness Scale was 10. His medications included hydrochlorothiazide, fluticasone propionate (Flonase), desloratadine (Clarinex), fenofibrate (Tricor), and acetylsalicylic acid (aspirin).

Physical Examination
The patient was 187 cm tall and weighed 115.9 kg, which gave him a body mass index (BMI) of 33.3 kg/m2. This is considered obese. His blood pressure was 142/80 when measured on the left arm, and his pulse was 76.

Among the significant findings from the physical examination was that he had mild right septal deviation and slight nasal crowding. There was a very crowded posterior oropharynx with large uvula and posterior encroachment of the tongue. The neck was enlarged and redundant. He had a markedly protuberant abdomen.

A chest x-ray showed slight cardiac enlargement with ectatic aortic arch. Lung fields were clear without effusions or infiltrates. The electrocardiogram (ECG) demonstrated normal sinus rhythm with slight left axis deviation, but no conduction deficits. Laboratory assessment was notable for elevated lipids and glucose.

Our impression was that the abnormal oximetry likely represented significant OSA, so a split-night PSG study with CPAP was arranged. It showed the following:

• During the 198-minute diagnostic study, the sleep efficiency was 78% and all sleep stages were present.

• The overall apnea/hypopnea index (AHI) was 28 per hour, and sleep disordered breathing events consisted of central, mixed, and obstructive apneas. These were much more frequent when the patient slept on his back.

• 87% of 43 arousals per hour were breathing-related with a minimum oxygen saturation at 82%.

• Frequent periodic limb movements were present, but few led to an arousal. (See Figure 1.)

Subsequently, while utilizing nasal CPAP at a pressure setting of up to 10 cm H2O, obstructive sleep disordered breathing events were eliminated, but central sleep apneas increased during the titration phase, as did periodic breathing. The overall AHI remained high at 17 per hour, rising to 49 per hour when he was on his back in NREM sleep. However, the oxygen saturation normalized and the sleep efficiency remained stable. The periodic limb movements diminished to 12 per hour. The ECG tracing showed continuous premature ventricular complexes. (See Figure 2.)

The patient was willing to try CPAP and was provided with a prescription for the device. He was encouraged to come back in about a month for a repeat overnight oximetry to assess the central apneas and periodic breathing seen during the titration study. The role of obesity in the development of SDB was discussed with the patient, and a weight loss regimen was recommended. However, due to a motor vehicle accident, he was unable to return until a year later.

The repeat overnight oximetry showed nearly 50 oxygen desaturation events greater than 4% per hour. The minimum saturation was 78%. The pattern was most indicative of significant continuing events of mostly central apnea. (See Figure 3.)

He had struggled to maintain good compliance with the CPAP therapy and had not noticed a difference in how he felt during the daytime. He remained sleepy, and his Epworth Sleepiness Scale score was 13, which was actually worse from when we initially saw him last year, when it was 10. Given the findings on his recent overnight oximetry, he underwent a repeat overnight sleep study in order to see if his CompSA might be treatable with the newly available ASV.

The therapeutic trial of the ASV device showed that, during a total sleep time of 357 minutes, the sleep efficiency was 74% with an increased amount of REM sleep. The overall AHI was entirely normal on an end expiratory pressure (EEP) of 10 cm H2O with default pressure support. No snoring was heard. The oxygen saturation was entirely normal with resolution of the breathing-related arousals. Periodic limb movements of sleep occurred at a frequency of 62 per hour and led to arousals at 17%. (See Figure 4 )

His CompSA was entirely controlled with the ASV device. He was provided with a prescription specifying ASV with EEP of 10 cm H2O, default pressure support, and a new full-face mask with heated humidity. He was told that he needed to return in 61 to 90 days to verify his compliance and to ascertain that his sleep disordered breathing was, indeed, completely controlled with the new device.

The patient presented with classic features and findings of predominately OSA, but was found to have central and mixed apneas on the diagnostic study. Furthermore, the patient demonstrated a CompSA response with notably worse central apnea on CPAP. As seems to be common, the patient also had frequent periodic limb movements and predominance of apnea while sleeping on his back, with the exaggerated centrals on CPAP also in that position. At the time of his first diagnostic study, the only option was to proceed to a trial of CPAP and sleep in the side position as he did not meet current Medicare criteria for a trial of BLPAP with a backup rate. The hope was that the symptoms and complex apnea response would improve over time, but they did not. In the interim year, not only did the VPAP Adapt SV become available, but the Medicare criteria changed to recognize and allow treatment of CompSA with a BLPAP with a backup rate or the ASV device.

The Medicare criteria for central apnea now state4:
Central Sleep Apnea or Complex Sleep Apnea:
Prior to initiating therapy, a complete facility-based PSG must be performed documenting the following:

A) Diagnosis of central sleep apnea (CSA) or complex sleep apnea (CompSA); and
B) Rule out CPAP as effective therapy if either CSA or OSA is a component of initially observed sleep-associated hypoventilation; and
C) Significant improvement of the sleep-associated hypoventilation with the use of an E0470 or E0471 device on settings planned for initial use at home, while breathing the patient’s usual FIO2.

Central sleep apnea (CSA) is defined as:

1) An apnea hypopnea index > 5; and
2) Central apneas/hypopneas > 50% total apneas/hypopneas; and
(3) Central apneas or hypopneas > 5 times per hour; and
(4) Symptoms of either excessive sleepiness or disrupted sleep.

Complex sleep apnea (CompSA) is a form of central apnea specifically identified by the persistence or emergence of central apneas or hypopneas upon exposure to CPAP or an E0470 device when obstructive events have disappeared. These patients have predominately obstructive or mixed apneas during the diagnostic sleep study occurring at greater > 5 times per hour. With use of a CPAP or E0470, they show a pattern of apneas and hypopneas that meets the definition of CSA described above.

Most of the time OSA patients respond favorably to CPAP, but when CPAP initially exaggerates or produces CSA in patients identified as having primarily OSA, this is identified as CompSA. This is not a new disorder, but it is being increasingly recognized. In a recent consecutive series of 133 patients referred to a sleep laboratory for OSA, 34 (25.6%) were shown to be proven cases of CompSA.2 In this study, the mean age was 54.4 years with a total diagnostic AHI of 33.4, which was similar in both the CompSA group and the non-CompSA group.

There were a few differences between the patients with OSA vs those with CompSA. The CompSA patients were more commonly males, and the OSA patients tended to be slightly heavier. In another report that studied patients who were selected to undergo BLPAP for a variety of reasons, many showed a CompSA-like response to BLPAP (rarely was a backup rate added). However, it was not possible to discern an incidence estimate from the data provided.5

BLPAP and ASV have been shown to improve SDB in patients with CSA, particularly those with CSR.6 The best approach to treatment for CompSA or CSA/CSR patients remains controversial. A study that pursued this issue compared the response for both BLPAP and the ASV in a group of 21 adult patients (95% male) with CSA/CSR or CompSA who had undergone diagnostic PSG and then were titrated with PAP in a randomized crossover design.3 The entire group had a very elevated diagnostic AHI of 54.7 ± 23.8, with a mean age of 65 ± 12.4 years and a BMI of 31 kg/m2 ± 4.9 kg/m2. The preselected primary endpoints of reduced AHI and respiratory arousal index proved to be significantly superior when the ASV was used rather than the BLPAP (P <0.02). Although the BLPAP and ASV seem to be effective in the acute setting for treatment of SDB in patients with CompSA and far more efficacious than CPAP alone, particularly the CompSA patients seemed to respond optimally to ASV as suggested by the patient described above.

Peter C. Gay, MD, is an associate professor of pulmonary, critical care, and sleep medicine at the Mayo Clinic, Rochester, Minn. He has special interests in treating patients with noninvasive ventilation and those with neuromuscular disease or other more complicated sleep disordered breathing problems. He has an extensive bibliography in these and other areas of pulmonary medicine. He is president-elect of the National Association for the Medical Direction of Medical Care (NAMDRC) and the incoming vice-chair of the Home Care Network and a delegate of the Sleep Institute for the American College of Chest Physicians (ACCP).

1. Gilmartin GS, Daly RW, Thomas RJ. Recognition and management of complex sleep-disordered breathing. Curr Opin Pulm Med. 2005;11:485-93.

2. Pusalavidyasagar S, Olson EJ, Gay PC, Morgenthaler TI. Treatment of complex sleep apnea syndrome: a retrospective comparative review. J Clin Sleep Med. 2006. In press.

3. Morgenthaler TI, Gay PC, Brown LK. Adaptive servo-ventilation versus noninvasive positive pressure ventilation for central, mixed, and complex sleep apnea syndromes. Sleep. 2006. In press.

4. Palmetto GBA. Respiratory Assist Device (RAD). Chapter 40 of online publication. Available at: [removed][/removed]. Accessed August 15, 2006.

5. Johnson KG, Johnson DC. Bilevel positive airway pressure worsens central apneas during sleep. Chest. 2005;128:2141-2150.

6. Teschler H, Dohring J, Wang YM, Berthon-Jones M. Adaptive pressure support servo-ventilation: a novel treatment for Cheyne-Stokes respiration in heart failure. Am J Resp Crit Care Med. 2001;164: 614-9.