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Bilevel Positive Airway Pressure Worsens Central Apneas During Sleep^*

^* From the Rhode Island Hospital (Dr. K. Johnson), Providence, RI; and Spaulding Rehabilitation Hospital (Dr. D. Johnson), Boston, MA.

Correspondence to: Douglas C. Johnson, MD, Spaulding Rehabilitation Hospital, 125 Nashua St, Boston, MA 02114; e-mail: djohnson5{at}partners.org

	Abstract

TOP Abstract Introduction Materials and Methods Results Discussion References

 
Study objectives: While most patients with sleep-disordered breathing are treated with continuous positive airway pressure (CPAP), bilevel positive airway pressure (BLPAP) is often used. Having observed that BLPAP therapy increased central apneas in some of our patients undergoing sleep studies, we conducted this study to evaluate the effects of BLPAP.

Design: Retrospective analysis of all sleep studies performed in an outpatient sleep center that used BLPAP over a 2-year period. We assessed the incidence and frequency of events during rapid eye movement (REM) sleep and non-REM sleep during baseline conditions, CPAP, and BLPAP. Desaturations, hypopneas, obstructive apneas, and central events, including periodic breathing (PB), Cheyne-Stokes respiration (CSR), and non-CSR central apneas were evaluated.

Patients: Ninety-five of the 719 patients who underwent sleep studies met inclusion criteria. Eighty of the 95 patients treated with BLPAP were also treated with CPAP.

Results: BLPAP was more likely to worsen than improve CSR (p = 0.002), non-CSR central apneas (p < 0.001), and CSR or PB (p < 0.001). CSR (p = 0.03) and non-CSR central apneas (p = 0.01) were more likely to worsen with BLPAP (24% and 23%, respectively) than with CPAP (11% and 8%). Central events (p = 0.04) and CSR (p = 0.009) were more likely to worsen during BLPAP in patients with baseline CSR or PB (62% and 48%, respectively) than develop in those without baseline CSR or PB (34% and 18%). Higher BLPAP differences worsened central events in 28% of patients, while 7% improved (p = 0.02). During REM sleep, central apneas improved, while hypopneas and obstructive apneas worsened (p < 0.001).

Conclusions: BLPAP often increases the frequency of CSR and non-CSR central apneas during sleep. Since CSR has adverse effects on cardiac function and sleep, it is important to consider this possible adverse effect of BLPAP.

Key Words: bilevel positive airways pressure • Cheyne-Stokes respiration • continuous positive airways pressure • periodic respiration • polysomnography • positive pressure respiration • sleep, rapid eye movement • sleep apnea, central • sleep apnea syndromes

	Introduction

TOP Abstract Introduction Materials and Methods Results Discussion References

 
Sleep disordered breathing (SDB), which includes both obstructive and central apneas and hypopneas, is very common and is associated with morbidity and mortality. Approximately 7% of adults have moderate-to-severe obstructive sleep apnea (OSA), 20% have mild OSA, and 5% > 65 years old have central sleep apnea.¹ Nearly 50% of patients with congestive heart failure (CHF) have SDB.² SDB is usually treated with continuous positive airway pressure (CPAP). An alternative treatment is bilevel positive airway pressure (BLPAP), which detects the patient’s inspiration to "trigger" the change to the higher pressure (inspiration positive airway pressure [IPAP]), and switches to the lower pressure (expiratory positive airway pressure [EPAP]) when inspiration ends. BLPAP can be set to provide a backup rate, which changes to the higher pressure if the patient does not initiate a breath within a specified time. We observed that many patients referred for outpatient sleep studies acquired or had more frequent central apneas during BLPAP.

Central apneas occur when there is an absence of central ventilatory motor output. Central apneas during sleep cause repetitive arousals, increase catecholamine levels, increase BP, disrupt sleep, worsen CHF, and are associated with increased mortality in patients with CHF.³ Cheyne-Stokes respiration (CSR) is a subset of central apneas in which there is a gradual decrease in breath size followed by an apnea, then a gradual increase in breath size. CSR is common among patients with CHF and stroke. Central apneas also include non-CSR central apneas that often occur following arousals or with sleep onset or changes in sleep state.

The standard treatment of both OSA⁴ and CSR⁵ is CPAP, which improves OSA by holding the airway open and improves CSR by several mechanisms. BLPAP has been reported as effective as CPAP for treating OSA⁶ and central apneas.⁷ We were concerned that BLPAP could worsen central apnea in many patients.

Although there has been at least one case report⁸ of more frequent central apneas with BLPAP, we are unaware of any large studies. This retrospective study evaluates patients who received BLPAP to manage their SDB.

	Materials and Methods

TOP Abstract Introduction Materials and Methods Results Discussion References

 
All sleep studies performed in the sleep center from January 2002 to December 2003 were reviewed. The review included 852 studies on 719 subjects. Each study began by evaluating tolerance of an interface using CPAP while awake. If sufficient respiratory events were present after a 2-h baseline period, then CPAP was begun and titrated to eliminate the respiratory events. If the patient did not tolerate CPAP because of difficulty breathing against the pressure or had persistent respiratory events with CPAP, then BLPAP was attempted. If hypoxia developed (oxygen saturation 4% below awake baseline) that did not improve with CPAP, BLPAP was then attempted prior to adding supplemental oxygen. BLPAP was also used for patients with known respiratory muscle weakness or previously determined to need BLPAP. If there were significant central apneas with BLPAP, then a back-up rate of 10/min was begun or CPAP resumed. Near the end of the study period, an exhalation pressure relief device (C-Flex; Respironics; Murrysville, PA) was used if there were significant central events with BLPAP. Our current practice is to use the pressure relief device prior to BLPAP. The pressure relief device detects the patient’s exhalation, and makes it easier to breathe out than CPAP by lowering the pressure for approximately one third of a second at the start of exhalation. The C-flex device has three "comfort settings," which allows one to adjust the amount of pressure drop.

Our protocol for setting BLPAP pressures was to set EPAP at the level found during CPAP titration that eliminated obstructive apneas, or to 4 cm H₂O if there were no obstructive apneas, and then increase EPAP if the inspiratory efforts did not consistently trigger IPAP. The protocol for setting IPAP pressure was to start 3 cm H₂O or 4 cm H₂O higher than EPAP, and then titrate higher to eliminate hypopneas or improve saturations.

Standard criteria were used to stage sleep⁹ and identify apneas and hypopneas.⁴ For periods of BLPAP with a backup rate, apneas were identified by the chest and abdominal signal. The central and obstructive apnea indexes are the number of respective apneas per hour of sleep, with mixed apneas counted in both indexes.

Each study was reviewed for diagnosis. OSA had more than five obstructive apneas or hypopneas per hour. CSR had crescendo-decrescendo alterations in respiratory effort and tidal volume separated by periods of central apnea (Fig 1 ). Periodic breathing (PB) had periodic increases and decreases in respiratory effort without central apneas (Fig 2 ). Non-CSR central apneas were central apneas that were not associated with crescendo-decrescendo alterations in respiratory effort, and often occurred with sleep onset or after arousal (Fig 3 )

View larger version (66K): [in this window] [in a new window] [Download PPT slide]   Figure 1. CSR, with crescendo-decrescendo alterations in respiratory effort and airflow, separated by periods of central apnea. There were no arousals during this period. Oxygen saturations (O2 Sat) are highest during the periods of apnea.

View larger version (76K): [in this window] [in a new window] [Download PPT slide]   Figure 2. Periodic breathing, with crescendo-decrescendo alterations in respiratory effort and airflow without central apneas. There were no arousals during this period. Oxygen saturations are highest during the periods of hypopnea. See Figure 1 legend for expansion of abbreviation.

View larger version (64K): [in this window] [in a new window] [Download PPT slide]   Figure 3. Non-CSR central apnea, with postarousal central apneas. There are two arousals (shaded on EEG tracing) related to obstructive hypopneas, then a central apnea, then two closely timed arousals related to the central apnea, and then a second central apnea. The arousals were associated with increased heart rate. See Figure 1 legend for expansion of abbreviation.

Of the study group, 10 patients were treated with BLPAP with only a backup rate, and 3 patients were treated with BLPAP both with and without a backup rate. CPAP data were absent for 15 patients, and 1 patient had no baseline data.

The study group was evaluated for respiratory events during baseline, CPAP, and BLPAP. The indexes of obstructive apneas, central apneas, mixed apneas, hypopneas, and desaturations were determined for each condition using the periods with the highest CPAP or IPAP levels that totaled 1 h. Our analysis proceeded as follows: (1) The period with highest CPAP was identified. If the sleep time was > 1 h, this was the only period included in the analysis. (2) If the sleep time was < 1 h, the period with the next highest CPAP was also included. (3) This process continued until there was at least 1 h of sleep time or until all the CPAP periods were included. For BLPAP, we used a similar analysis to determine the periods with the highest IPAP to a total of 1 h of sleep. BLPAP periods with a pressure difference of < 4 cm H₂O were excluded because we wanted there to be a clear difference between CPAP and BLPAP. We also determined the periods with the highest pressure difference (IPAP minus EPAP) with at least 10 min of sleep so we could test the hypothesis that higher pressure differences worsened central events. The studies were reviewed to determine the presence and effect of treatment on respiratory events. Each study was evaluated for presence of rapid eye movement (REM) periods during baseline, CPAP, and BLPAP, and whether there were no events, an increase, no change, or a decrease in obstructive apneas, central apneas, and hypopneas in REM vs non-REM sleep.

Statistical Analysis
Mean ± SD values are reported. A two-tailed Fisher Exact Test was used to compare events between groups with or without baseline CSR or PB. ² test was used to determine if the numbers of patients’ improving vs worsening respiratory events differed.

	Results

TOP Abstract Introduction Materials and Methods Results Discussion References

 
Of the 719 patients, 638 patients had primary OSA, including 14 patients with CSR and 47 patients with non-CSR central apneas. Eighteen patients had OSA and CSR as co-equal diagnoses; 14 patients had primary CSR, including 9 patients with OSA.

The 95 patients treated with BLPAP included 77 patients with primary OSA, including 2 patients with CSR and 1 patient with non-CSR central apnea. Six patients had OSA and CSR as co-equal diagnoses. Six patients had primary CSR, including four patients with OSA. Two patients had OSA and non-CSR central apnea as co-equal diagnoses. Two patients had periodic limb movements with OSA, one patient had non-CSR central apnea with OSA, and one patient had amyotrophic lateral sclerosis. Thirty-nine patients had periodic limb movements, including 10 patients with periodic limb movements as a primary diagnosis. Medical conditions included hypertension (n = 47), obstructive lung disease (n = 29), diabetes (n = 19), irregular heart rate (n = 16), CHF (n = 11),stroke (n = 6), and pulmonary hypertension (n = 3). Their mean age was 57.8 ± 13.8 years, and mean body mass index was 36.0 ± 9.0. There were 54 men and 41 women. Oxygen saturation was < 90% for 17.5 ± 21.6% of the time.

For the periods analyzed, the average CPAP was 11.0 ± 3.6 cm H₂O, IPAP was 15.9 ± 4.8 cm H₂O, EPAP was 9.4 ± 4.4, and IPAP minus EPAP was 5.9 ± 3.1 cm H₂O. For the period with the greatest IPAP minus EPAP value, the IPAP was 15.8 ± 4.2 cm H₂O, EPAP was 8.3 ± 4.0 cm H₂O, and IPAP minus EPAP was 8.0 ± 2.4 cm H₂O. Reasons for using BLPAP included difficulty tolerating CPAP (n = 28, 3 with backup), hypoxia persisting with CPAP (n = 22), persistent respiratory events with CPAP (n = 17, 1 with backup), hypoxia and events continuing on CPAP (n = 9, 1 with backup), central apneas on CPAP (n = 13, 6 with backup), BLPAP at home (n = 6), and known respiratory muscle weakness (n = 1).

At baseline, 14 patients had CSR, 18 patients had PB, 21 patients had either CSR or PB, and 3 patients had non-CSR central apnea without CSR or PB. At baseline, 23 patients had a central apnea index > 5/h, and 15 patients had a central apnea index > 10/h. These baseline characteristics did not differ based on reported medical condition.

Central apneas, including both CSR and non-CSR central apneas, and PB were more frequent (worse) during BLPAP than during baseline. Twenty-three patients had worse CSR, 65 patients were unchanged, and 6 patients improved (p = 0.002). Twenty-two patients had worse non-CSR central apneas, 71 patients were unchanged, and 1 patient improved (p < 0.001). Twenty-seven patients had worsening of either CSR or PB, 61 patients were unchanged, and 6 patients improved (p < 0.001). Patients with CSR or PB at baseline were more likely to acquire or have worsened central events, in particular CSR, with BLPAP (Table 1 ).

View larger version (17K): [in this window] [in a new window] [Download PPT slide]   Figure 4. Effect of BLPAP (n = 94) and of CPAP (n = 80) on CSR and non-CSR central apnea, compared to baseline.

View larger version (16K): [in this window] [in a new window] [Download PPT slide]   Figure 5. Effect of treatment on central apnea index. Groups include BLPAP vs baseline (n = 93), CPAP vs baseline (n = 78), and BLPAP vs CPAP (n = 69). *Patients improved compared to those who worsened.

Two patients were treated with the exhalation pressure relief device. Both patients had OSA and CSR at baseline, had worse CSR on BLPAP, and improved with exhalation pressure relief.

During REM sleep compared to non-REM sleep, central apneas improved (decreased) [p < 0.001] in most patients, while hypopneas and obstructive apneas worsened (increased) [p < 0.001; Fig 6 , Table 2 ]. The only patient with more central apneas during REM sleep had worse obstructive apneas leading to more postarousal central apneas.

View larger version (12K): [in this window] [in a new window] [Download PPT slide]   Figure 6. Effect of REM compared to non-REM sleep on central apneas (n = 27), obstructive apneas (n = 35), and hypopneas (n = 109) among patients with events. Central apneas improved during REM, while obstructive apneas and hypopneas worsened. This combines the data from baseline, CPAP, and BLPAP conditions.

Recommended treatment included 57 patients for BLPAP (25 patients with BLPAP only, 14 patients with BLPAP and oxygen, 18 patients for BLPAP and a backup rate [9 patients with oxygen]); 35 patients for CPAP (26 patients with CPAP only, 9 patients also with oxygen); and 3 patients for exhalation pressure relief. Of the 92 patients with OSA, BLPAP was recommended for 54 patients. Thus, of the entire group of 666 OSA patients, BLPAP was recommended for 8%.

	Discussion

TOP Abstract Introduction Materials and Methods Results Discussion References

 
While CPAP is the standard treatment for OSA and CSR, BLPAP is often used. This study was undertaken to address our concern that BLPAP may cause adverse effects in some patients. We found that BLPAP increased central apneas including CSR and non-CSR central apneas compared to baseline and CPAP.

CSR occurs when instability of the ventilatory control system leads to oscillations in PCO₂, PO₂, and breathing. The onset of CSR often occurs with sleep onset or following an arousal. This is probably due to a lower respiratory drive with a higher apneic threshold during sleep than when awake, or during sleep than arousal. When PCO₂ drops below the "apneic threshold," central apnea occurs,¹⁰ resulting in a delayed increase in PCO₂, which increases the drive to breathe, which in turn decreases the PCO₂, resulting in another apnea. A central apnea may also cause an arousal, which can result in deeper breaths and subsequent fall in PCO₂, resulting in another central apnea. CSR is more common during sleep than when awake. During sleep, the ventilatory response to carbon dioxide changes, with hypocapnia having a more potent inhibitory effect on ventilation during non-REM sleep.¹¹ Reduction in lung volumes in the supine position lowers gas stores, which contributes to PB because each apnea and respiration leads to a larger change in alveolar PCO₂.

CSR is associated with CHF, stroke, and ascent to high altitude. CSR occurs in approximately 50% of patients with CHF,²¹²¹³ and is associated with an increased morbidity and mortality.¹⁴ CHF often results in delayed circulation time, increased respiratory drive secondary to interstitial edema, and lower lung volume, factors that make CSR more likely. Treatment of CSR with CPAP in patients with CHF improves heart function and transplant-free mortality.³ Patients with stroke often have CSR,¹⁵ likely related to increased respiratory drive due to reduced cortical inhibition of the central respiratory center. High altitude increases respiratory drive due to hypoxia.¹⁶ We are unaware of much literature on non-CSR central apnea.

We found that worse CSR with BLPAP was more common among patients with baseline CSR or PB. Patients who start with an unstable respiratory system are particularly prone to become more unstable during BLPAP.

There are several mechanisms by which BLPAP could increase the incidence and severity of central apneas. BLPAP increases tidal volume for a given respiratory effort, contributing to instability of ventilation and making it more likely that PCO₂ will fall below the apneic threshold. The finding that inhalation of carbon dioxide improves CSR¹⁷ supports this hypothesis. Large tidal volumes can also cause central apnea through neurochemical inhibition even if normocapnia is maintained.¹⁸ Morrell et al¹⁹ studied the effects of BLPAP on six normal subjects during sleep and found that one patient had PB and another patient had CSR. Both CPAP and BLPAP could unmask CSR by improving obstructive respiratory events.

Pressure support ventilation (PSV) is often used in the hospital setting to treat patients with respiratory distress. Since PSV is comparable to BLPAP, providing a higher inspiratory pressure with patient-initiated breaths, we would expect PSV to have the same worsening of CSR and non-CSR central apnea during sleep. Meza et al²⁰ showed that most healthy subjects have PB during sleep and PSV of 5 to 10 cm H₂O, which is similar to our IPAP minus EPAP values. Parthasarathy and Tobin²¹ found that central apneas occur frequently among patients with respiratory failure treated with PSV, particularly those with CHF.

During BLPAP treatment with larger pressure differences, we found that central apneas and PB were more likely to increase than decrease. Larger BLPAP pressure differences lead to larger tidal volumes, which lower PCO₂, thus worsening central apneas. Hommura et al⁸ reported a case of worsening number and duration of apneas as the pressure difference increased in a patient with central sleep apnea. Our results and others are consistent with the worsening of central apneas with BLPAP caused by the pressure difference, and not simply the IPAP setting.

Both CPAP and BLPAP effectively reduced obstructive apneas and hypopneas during non-REM and REM sleep. Our finding that BLPAP was somewhat more effective than CPAP for improving obstructive events was probably due to having higher IPAP than CPAP settings for the periods analyzed. Our finding that REM sleep consistently worsened obstructive apneas during baseline and during positive airway pressure was expected. Reduced muscle tone during REM sleep increases upper airway obstruction.

Central apneas and periodic respiration occur rarely during REM sleep at baseline.¹⁴²² We found that BLPAP did not worsen central apneas during REM sleep as it did during non-REM sleep. This is likely due to sleep state-related differences in ventilatory control. During REM sleep, ventilatory control is largely independent of the usual chemoreceptor drive to breathe,²² with significantly reduced respiratory drive to carbon dioxide,²³ absence of an apneic threshold,²⁴ and nonchemoreceptor activation of respiratory neurons.²⁵ The difference in response to BLPAP during non-REM and REM sleep supports our hypothesis that BLPAP worsens central apneas during non-REM sleep by lowering PCO₂ below the apneic threshold.

We found that CPAP was effective treatment for OSA, less likely to worsen or induce CSR or PB than BLPAP, and more likely to improve CSR or PB than BLPAP. CPAP improves CSR by several mechanisms. By increasing dead space²⁶ and carbon dioxide lung volume, CPAP helps keep carbon dioxide above the apneic threshold and reduce fluctuations in PCO₂. By increasing lung volume, CPAP increases lung oxygen stores reducing fluctuations in PO₂. By improving OSA, CPAP reduces the number of postarousal central apneas. By reducing cardiac afterload and preload, CPAP leads to improved cardiac function and decreased circulation time in patients with CHF. By reducing interstitial edema in patients with CHF, CPAP could reduce pulmonary vagal efferent stimulation leading to reduced ventilatory drive.²⁷

Nocturnal BLPAP is a well-established treatment for patients with chronic respiratory failure, improving daytime dyspnea, sleepiness, and PCO₂.²⁸ BLPAP with a backup rate is effective treatment for patients with primary central sleep apnea. Kohnlein et al⁷ report equivalent effects of CPAP and BLPAP with a backup rate for treating patients with CHF and CSR. Willson et al²⁹ found that BLPAP with a backup rate set to eliminate respiratory efforts effectively treated CSR in patients with CHF. Teschler et al³⁰ studied patients with CHF and found comparable improvements in central apnea and arousal indexes with oxygen and CPAP, further improvements with BLPAP with a backup rate two below the baseline respiratory rate, and further improvements with adoptive servoventilation. We found, however, that CSR often persists during BLPAP with a backup rate. The backup rate and pressure settings we used were probably not sufficient to maintain PCO₂ below the apneic threshold. It is important to note that our findings were on the initial night of positive airway pressure therapy. It is possible there might be different responses to long-term therapy.

BLPAP is often recommended for treatment of OSA in patients who have difficulty tolerating CPAP, and find it more comfortable to breathe against a lower expiratory pressure.³¹ Our current practice is to use exhalation pressure relief for patients with difficulty exhaling with CPAP, prior to attempting BLPAP. In both patients included in this study, exhalation pressure relief effectively managed central apneas that were worsened on BLPAP. Another reason for treating OSA patients with BLPAP is the need for higher tidal volumes in patients with elevated PCO₂.

BLPAP is also used at home for the treatment of OSA and other SDB, with Resta et al³² reporting starting 18% of their OSA patients on BLPAP. Among our patients with OSA, we recommended BLPAP therapy for 8%, and expect this will drop now that the exhalation pressure relief device is available.

It is important to recognize that BLPAP and PSV worsen central sleep apneas in some patients, placing them at risk for adverse cardiac effects and sleep disturbance. Based on our results and current literature, we believe that CPAP should be the primary treatment for OSA and CSR. For patients who cannot tolerate CPAP due to difficulty with exhalation, exhalation pressure relief should be tried first, then BLPAP. BLPAP without a backup rate may be effective for patients with OSA, but should not be used to treat CSR. BLPAP with a high backup rate (ie, more than or equal to the patient’s baseline respiratory rate) or adoptive servoventilation are options to treat CSR, but have not been as fully studied as CPAP. Hospitalized patients receiving BLPAP or PSV should be observed for central sleep apneas. Our findings support Medicare guidelines that BLPAP should only be used to treat sleep apnea if the patient has failed to respond to CPAP. Our findings do not affect the standard practice of using BLPAP with a backup rate for patients with primary central sleep apneas with hypercapnia.

In summary, we found that many patients acquired or had worsened CSR and non-CSR central apneas when treated with BLPAP. Patients with baseline CSR or PB are more likely to have worsened CSR with BLPAP than those without baseline CSR or PB. CSR often persisted despite using a backup rate with BLPAP. Central apneas consistently improved during REM sleep. Since CSR has detrimental health effects, by the principle of "do no harm," it is important to ensure that treatment for SDB does not create more problems. BLPAP should be used with caution to treat OSA, particularly if there is periodic respiration or CSR at baseline.

	Footnotes

 
Abbreviations: BLPAP = bilevel positive airway pressure; CHF = congestive heart failure; CPAP = continuous positive airway pressure; CSR = Cheyne-Stokes respiration; EPAP = expiratory positive airway pressure; IPAP = inspiration positive airway pressure; OSA = obstructive sleep apnea; PB = periodic breathing; PSV = pressure support ventilation; REM = rapid eye movement; SDB = sleep-disordered breathing

This work was performed at the Spaulding Rehabilitation Hospital.

Received for publication November 17, 2004. Accepted for publication March 28, 2005.

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