hypopnea

Sleep Medicine Reviews, Vol. 5, No. 1, pp 7–23, 2001

SLEEP MEDICINE

doi:10.1053/smrv.2000.0131, available online at http://www.idealibrary.com on

reviews

CLINICAL REVIEW

Optimal continuous positive airway pressure for the treatment of obstructive sleep apnea/hypopnea William Beninati1 and Mark H. Sanders2 1

Pulmonary and Critical Care Medicine, Wilford Hall USAF Medical Center and Uniformed Services University of the Health Sciences, 2Pulmonary Sleep Disorders Program, Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh School of Medicine, Pulmonary Service, Veterans Affairs Health Care System of Pittsburgh, USA KEYWORDS obstructive sleep apnea-hypopnea syndrome, continuous positive airway pressure, polysomnogram

Summary The obstructive sleep apnea/hypopnea syndrome (OSA/H) is characterised by repetitive obstruction of the upper airway during sleep. The consequences of OSA/H include excessive daytime sleepiness, reduced perceived health quality and an increased risk of driving accidents. There is evidence that treatment with nasal continuous positive airway pressure (CPAP) is effective in eliminating these consequences. In addition, OSA/H may also be associated with hypertension and an increased risk of vascular disease, and although there is no clear evidence in this regard, CPAP may be effective alleviating these consequences as well. Nasal CPAP is considered the treatment of choice for clinically significant OSA/H. The optimal CPAP prescription is that which is most effective in eliminating the adverse consequences of OSA/H. Patients should be initially treated with standard CPAP. For those in whom standard CPAP is unsuccessful or intolerable bi-level or self-adjusting modes may be attempted. The nasal CPAP pressure level can be titrated to eliminate apnea, hypopnea, snoring, respiratory arousal and inspiratory flow limitation as a means of predicting successful long-term therapy. The reliability of these physiologic parameters in predicting the optimal long-term CPAP pressure is eroded by the tendency of CPAP pressure-level requirement to decrease with chronic CPAP use, and by other factors that may increase the CPAP pressure requirement. The split-night polysomnogram and unattended auto-CPAP titration have been proposed as efficient means of determining the optimal CPAP pressure, but for patients with subtle OSA/H, underlying cardiopulmonary disease or other forms of sleep-disordered breathing a full-night polysomnogram may be required. The CPAP prescription must include a comfortable well-fitting interface. When CPAP is prescribed it is essential that the patient undergo clinical re-evaluation to ensure that treatment goals are being met.  2001 Harcourt Publishers Ltd

INTRODUCTION Correspondence should be addressed to: Lt Col William Beninati, Pulmonary/Critical Care Medicine Division, 2200 Berquist Drive, Lackland AFB, TX 78236-5300, USA. The views expressed in this article are those of the authors and do not reflect the official policy of the Department of Defense or the US Government. 1087–0792/01/010007+17 $35.00/0

The obstructive sleep apnea/hypopnea syndrome (OSA/H) is characterised by repetitive obstruction, or partial obstruction, of the upper airway during sleep. This obstruction results in physiologic and  2001 Harcourt Publishers Ltd

8

clinical abnormalities. Although not well standardised in the literature, the obstructive sleep apnea/ hypopnea syndrome may be defined as a disorder in which subjects have five or more obstructive breathing events per hour of sleep in association with symptoms, such as daytime sleepiness or fatigue, that are not explained by other factors [1]. A caveat to interpreting the literature on OSA/H is that multiple definitions have been used. Accordingly, this review will use the term OSA/H to include work done with a range of definitions as set by the studies’ authors. Obstructive sleep apnea/hypopnea is common. The Wisconsin Sleep Cohort Study evaluated working age adults and estimated an OSA/H prevalence of 4% among men and 2% among women, using a definition that required both an apnea/hypopnea index (AHI) of 5 and symptoms of OSA/H [2]. Employing a broader definition to include an AHI of 5 with or without symptoms, they observed a prevalence of 9% among women and 24% among men. Although it is clear that OSA/H is common, the significance of this condition is less clear. This remains a notable issue because the initial decision that must be made by the clinician is if the patient’s OSA/H warrants more than conservative therapy (e.g. recommendation for weight loss, avoidance of alcohol and agents that increase upper airway collapsibility, etc.). Multiple consequences of OSA/ H have been described including increased risk of driving accidents, other alertness-related social and occupational consequences, daytime hypertension and cardiovascular events such as myocardial infarction and stroke. Brief consideration of these consequences helps to place the decision to treat OSA/H in proper perspective. The best-established consequences of OSA/H are daytime sleepiness and reduced perceived health status. Convincing evidence of this relationship comes from clinical trials in which excessive sleepiness and perceived health status improved significantly when OSA/H was successfully treated with CPAP [3–7]. The excessive sleepiness in OSA/H is largely a consequence of the repetitive arousals from sleep that often accompany the termination of an obstructive breathing event [8,9]. The sleepiness can, in turn, lead to impaired psychomotor performance during alertness-critical tasks such as driving. In a casecontrol study Teran-Santos et al. evaluated 102 drivers who received emergency treatment following an accident, and 154 age-matched controls

W. BENINATI AND M. H. SANDERS

[10]. They tested both populations for the presence of OSA/H, defined as an AHI of 10 and found that subjects with OSA/H had a relative risk of 6.3 for experiencing an automobile accident. The risk was not related to the severity of OSA/H as defined by AHI. A larger study by George and Smiley in London, Ontario, used Provincial driving records to provide accident statistics, and polysomnography (PSG) for diagnosis and characterisation of OSA/H [11]. This study confirmed that individuals with OSA/H have an increased risk of driving accidents. However, in contrast to Teran-Santos et al., these investigators did find a relationship between OSA/H severity and accident risk, with an increased risk only in those individuals with AHI >40. Obstructive sleep apnea/ hypopnea causes daytime sleepiness and an increased risk of accidents. The degree of risk to which a given patient is exposed should be an important factor in the treatment decision-making process. A compelling notion is that OSA/H can cause hypertension and cardiovascular complications including mortality. Data from the Wisconsin Sleep Cohort Study disclosed an association between OSA/H and systemic hypertension that was independent of other known confounding factors such as age, sex and obesity [12]. In addition this study also demonstrated a dose-response relationship between OSA/H and the AHI. Among subjects with an AHI of 30, the odds-ratio for hypertension was 3 relative to subjects with an AHI of 0. It has been proposed, but not proven, that OSA/H is not simply associated with systemic hypertension but actually causes it. Evidence for a causal relationship comes from a study by Brooks et al., who developed a canine model of OSA by intermittently occluding a tracheotomy during sleep [13]. Independent of confounding variables, the dogs developed sustained daytime hypertension over a period of 1–3 months. This daytime hypertension resolved over 1–3 weeks after the OSA was corrected. As systemic hypertension is known to cause vascular disease, it has been postulated that OSA causes vascular disease, mediated by hypertension. In 1988 a retrospective review of 198 patients with OSA/H found an elevated vascular mortality among patients treated conservatively compared with those treated with tracheotomy [14]. That same year another retrospective study also found an increased mortality among patients with untreated OSA/H, and although the cause of death was not

OPTIMAL CPAP THERAPY FOR OBSTRUCTIVE SLEEP APNEA

specified vascular complications are the likely explanation [15]. The National Institutes of Health has sponsored a multi-center, prospective cohort study, Sleep Heart Health Study (SHSS) [16], to determine whether OSA/H actually is an independent risk factor for the development of cardiovascular and cerebrovascular disease. There is mounting evidence that OSA/H is a significant risk factor for the development of vascular disease and more definitive evidence is expected to come from the SHSS. Whether or not the presence of hypertension or other cardiovascular illness should be a determinant of the level of therapeutic aggressiveness is uncertain and more work is required in this regard. It is intuitive however, that tolerance for sleep-related hypoxemia should be less among patients with known coronary artery disease. On the basis of data linking OSA/H with sleepiness, an increased risk of driving accidents, and possibly with vascular complications, many clinicians elect to treat patients with OSA/H. There is a range of treatments available for OSA/H including a variety of conservative therapies (CT), surgical therapies, dental orthotic devices and nasal continuous positive airway pressure (CPAP). Nasal CPAP is widely considered to be the treatment of choice for clinically important OSA/H [17]. This review will focus on the factors that constitute an optimal prescription for nasal CPAP.

CPAP OVERVIEW The first reported use of nasal CPAP for OSA/H in adults was by Sullivan and colleagues in 1981 [18]. Their device consisted of a blower unit attached to intranasal tubes. Using this device they successfully abolished OSA in five patients with severe disease, while in the laboratory, and correctly predicted that this treatment would be accepted for home use. Subsequently others reported the successful outpatient use of nasal CPAP delivered via an external nasal mask, similar to those in widespread use today [19]. When a therapeutic level of CPAP is applied to the pharynx of a patient with OSA/H there is an immediate relief in the upper airway obstruction. It has been demonstrated that CPAP produces this benefit by functioning as a pneumatic splint for the upper airway [20]. In addition CPAP produces other sustained physiologic benefits, including improvements in the function of pharyngeal dilator muscles [21], ventilatory drive [22] and upper airway

9

morphology [23]. Serious side-effecs of nasal CPAP therapy are rare, but approximately 25% of patients develop nasal congestion with chronic use [24]. Patient adherence with a nasal CPAP prescription is problematic. A recent study using a covert adherence monitor found that only 6% of patients used CPAP for at least 7 h on at least 70% of days prescribed [25]. Recognising the demonstrated efficacy of nasal CPAP for the management of OSA/H, several professional organisations have issued guidelines regarding its use for this indication [26,27]. Despite this, the benefit of nasal CPAP use remains controversial. In 1997, Wright et al. published a controversial systematic review which concluded that the relevance of OSA/H to public health had been exaggerated and that the effectiveness of CPAP in improving health outcomes had been poorly evaluated [28]. The authors cited only one randomised, controlled trial of CPAP. Since that time additional randomised controlled trials have been published, all of which have shown a benefit from treatment of OSA/H with CPAP. Ballester et al. evaluated 105 subjects with moderate to severe OSA/H who were assigned at random to receive either CPAP+CT or CT alone [3]. After 3 months, the group treated with CPAP had an odds-ratio of 6.52 for experiencing improvement in sleepiness and perceived health status. Redline et al. performed a similar trial, recruiting 111 volunteers with mild to moderate OSA/H (AHI 5–30) for randomisation to receive either CPAP or CT [4]. In this non-sleepclinic population 49% of those assigned to CPAP experienced an improvement in OSA/H symptoms. This equates to a lower odds ratio than the previous study, but the findings are perhaps more significant as these subjects had never presented to a sleep clinic seeking relief of symptoms. In Edinburgh, Engleman et al. performed a crossover trial using CPAP and an oral placebo tablet in a subject population with a mean AHI of 46 [5]. Using this unique study design the authors detected not only a significant improvement in subjective slepiness, but also a significant improvement in daytime sleep propensity as assessed by the multiple sleep latency test (MSLT). This group of investigators extended this observation to a population with mild OSA/ H (AHI 5–15) [6]. They again found a significant improvement in symptoms with CPAP use, as compared with an oral placebo. In the latter study they replaced the MSLT with a maintenance-ofwakefulness test (MWT), and found no significant

10

difference between the CPAP and placebo groups. This was likely due to the small sample size and the variability inherent in the MWT. More recently, Jenkinson et al. studied the effects of nasal CPAP on 107 patients with OSA/H who were assigned at random to receive 1 month of either therapeutic CPAP or subtherapeutic CPAP [7]. Therapeutic CPAP was superior to subtherapeutic CPAP in reducing subjective sleepiness (final Epworth scores of 7.0 vs 13.0, P<0.0001), objective sleepiness (final mean MWT times of 32.9 vs 23.5 min, P<0.005) and perceived health status (as assessed with the SF-36). The benefit of nasal CPAP to treat the sleepiness associated with OSA/H is now well established. Studies have also been conducted to assess the benefit of CPAP in controlling other important OSA/H outcomes. Perceived quality of life (QoL) is increasingly being used in healthcare research to determine the benefit of a given intervention, including the uses of CPAP for OSA/H. The only randomised, controlled trials of CPAP in OSA/H that used QoL endpoints were those mentioned above [3–7]. In four of these studies the subjects in the active/CPAP arm experienced significantly greater subjective health benefits than those in the control arm, the exception being the relatively small study of Engleman et al. [5] in which neither improvement nor deterioration of perceived health/ QoL was reported. A recent study in Austria assessed quality of life in 67 patients on chronic CPAP for OSA/H, and the results were compared with untreated patients with OSA/H and with randomly selected on-patient hospital visitors [29]. The perceived QoL of patients treated for OSA/H with at least 3 months of CPAP did not differ significantly from the presumed-healthy control group, but was significantly better than untreated OSA/H patients, in all categories that were measured. Despite the limitations of this study design, primarily the lack of medical data on the control group, the results suggest an important benefit of using CPAP to treat OSA/H, further extending the results of the randomised clinical trials mentioned above. The risk of having an automobile accident is of major concern among patients with OSA/H. A prospective, randomised controlled trial of CPAP as a means of accident reduction in a population with OSA/H has not yet been reported. A large uncontrolled study, however, assessed a population of 893 French patients with OSA/H

W. BENINATI AND M. H. SANDERS

who were surveyed about the frequency of accidents in the year prior to initiating treatment and the year following treatment [30]. The authors found a marked, and statistically significant, reduction in the total number of accidents (from 60 to 36) and the number of accidents per patient (from 1.6 to 1.1), with similar reductions in the rates of near-miss accidents. This data suggests a strong benefit from CPAP in driving accident reduction. In addition to placing the individual OSA/H sufferer at risk of medical complications and accidents, the snoring and sleep disruption associated with OSA/H may also impair the sleep of the patient’s bed partner, and could potentially result in daytime consequences for the bed partner [31]. This complication, if present, is potentially amenable to correction with CPAP. In a preliminary study using a split-night methodology, applying CPAP to patients with OSA/H improved both sleep efficiency and arousal index among their spouses [32]. The clinical significance of this observation is not clear yet, but it suggests another potential benefit of CPAP on QoL, in this case for the bed partner. There is limited evidence, to date, that CPAP is useful in reducing cardiovascular consequences of OSA. No study has directly shown that CPAP directly reduces major cardiovascular consequences, but several recent studies have shown that CPAP improves potential surrogate markers for cardiovascular mortality including 24-h blood pressure [33], endogenous catecholamine levels [34] and muscle sympathetic neural activity [35]. In the study by Hedner et al. [34] it is interesting to note that blood pressure did not fall, despite a reduction in catecholamine levels. At this time is has not been firmly established that OSA/ H causes an increased risk of cardiovascular complications, including mortality. It is even more uncertain whether CPAP can decrease cardiovascular risk. This remains a major unanswered question, as many patients with OSA/H and many sleep clinicians wish to pursue the goal of cardiovascular risk reduction. In summary, nasal CPAP has been in use for nearly 20 years as a treatment for OSA/H. In that time period nasal CPAP use has become widespread. It has been established that nasal CPAP is a safe and effective means of eliminating upper airway obstruction due to OSA/H. It has also been firmly established that among patients with OSA/H, nasal

OPTIMAL CPAP THERAPY FOR OBSTRUCTIVE SLEEP APNEA

11

Table 1 CPAP prescription Elements of a CPAP prescription 1. Type of titration study

Major variables Full night PSG Split-night PSG Unattended auto-CPAP titration Clinical prediction

2. Endpoints for pressure level titration

Apneas and hypopneas Esophageal pressure nadir Excessive arousals Snoring Inspiratory flow limitation

3. PAP mode

Fixed CPAP Bi-level PAP Auto CPAP

4. Patient interface

Nasal mask Oronasal mask Nasal pillows

5. Frequency and duration of use

During all major sleep periods Nightly use for as long as tolerated

6. Humidification

None Passover humidifier Heated humidifier

CPAP is superior to placebo or conventional therapies in correcting daytime sleepiness and in improving perceived health status. There is some evidence that CPAP may also be able to reduce mortality from driving accidents and from cardiovascular disease. The challenge for the practicing sleep physician is to transate this potential benefit into an actual benefit through a CPAP prescription.

POSITIVE AIRWAY PRESSURE PRESCRIPTION AND GOALS OF TREATMENT The optimal prescription for positive airway pressure therapy in a patient with OSA/H is that which most effectively prevents the adverse consequences of OSA/H, while causing the least patient discomfort and the lowest risk of complications. This seemingly simple concept overlies substantial complexity due to the many variables involved in prescribing CPAP for OSA/H. The elements in a prescription for positive airway pressure are summarised in Table 1. A central element of the CPAP prescription is

the pressure level, which is typically derived through a titration study. When a decision is made to prescribe CPAP, the patient and physician both need to understand the consequences of OSA/H that are being addressed with this prescription. As discussed above, it has been established that OSA/H can cause sleepiness, a reduced QoL, and an increased risk of driving accidents. There is strong evidence that CPAP effectively treats these consequences. Continuous positive airway pressure is clearly indicated for the treatment of sleepiness and reduced quality of life caused by OSA/H. There is also growing evidence that OSA/H causes hypertension and an increased risk of cardiovascular disease. However, it remains to be established that this is definitely the case, what the level of risk is for any given severity of OSA/H, or that CPAP can abolish this risk. Given this uncertainty the decision to treat OSA/H with the sole goal of cardiovascular risk reduction should be undertaken with the patient’s full knowledge that this is an unproven treatment. In the future there may be sufficient data to justify treating OSA/H with CPAP in the otherwise asymptomatic patient.

12

Until that time patients, physicians, and third-party payers must weigh the available evidence before investing effort and money in CPAP therapy. A caveat must be observed for those patients with known, or highly suspected, vascular disease and OSA/H manifesting with significant hypoxemia. In this setting hypoxemia can lead to malignant ventricular dysrhythmia [36], and CPAP should be prescribed if it is successful in abolishing the hypoxemia. The reality that many patients with significant obstructive sleep-disordered breathing also have treatable symptoms, for which CPAP is clearly indicated, reduces the complexity of this decision. The final OSA/H consequence to consider eliminating is that of bed partner sleep disruption. Pending further data this should be considered a subjective problem, the significance of which varies from couple to couple. Some couples do rate the problem as highly significant and report habitually altering their sleeping arrangements due to the snoring noise. Continuous positive airway pressure appears to be effective in controlling bed partner sleep disturbance. Having selected target consequences for a given patient the clinician must translate them into measurable treatment goals. To be practical these treatment goals should include both physiological and clinical parameters. The physiological goals can be assessed at the time of CPAP titration and will allow the clinician to predict how successful a given level of CPAP will be at eliminating target consequences in that individual patient. These physiologic parameters will be addressed below. Clinical goals are required because physiological parameters may not be totally predictive of clinical success. In addition, factors such as body position, nasal congestion and alcohol use may differ between the sleep lab and the patient’s home, further eroding the predictive value of the physiological goals. Table 2 summarises the major consequences of OSA/H, and their clinical and physiologic counterparts.

Clinical goals The clinical goals of CPAP therapy, when it is directed at the consequences of daytime sleepiness, reduced QoL, and bed partner sleep disturbance are generally obvious. They reflect the patient’s symptoms and meeting these goals is essentially equivalent to eliminating the target consequence.

W. BENINATI AND M. H. SANDERS

With regard to sleepiness, there is insufficient evidence that the results of MSLT, MWT or neuropsychiatric tests are more accurate than symptoms in predicting complications. These tests cannot be recommended for routine use in assessing the efficacy of CPAP therapy. The science of using CPAP to reduce the risk of driving accidents or the risk of developing cardiovascular disease has not advanced to the point that any particular clinical goals are known to be predictive of success. Common sense suggests that the elimination of subjective sleepiness will reduce the risk of driving accidents, but that has yet to be proven. Controlling systemic hypertension, without medications, is a logical clinical goal when CPAP is used for cardiovascular risk reduction. Hypertension may result from OSA/H in some individuals and it can respond to treatment in a reasonable time period [13,33]. Hypertension unrelated to OSA/H however, is sufficiently common that persistently elevated blood pressure while on CPAP may not indicate a treatment failure. The primary advantage of the above clinical goals is their simplicity. As a patient undergoes CPAP therapy these goals can be periodically reassessed and the prescription adjusted until optimal control of OSA/ H is achieved.

Physiologic aspects of CPAP titration During a CPAP titration study the CPAP pressure level is adjusted in response to physiological indices of obstructed breathing, with the goal of finding the lowest pressure that normalises respiratory and sleep physiology. Several caveats are in order before discussing the specific physiological markers of airflow obstruction. First, this approach assumes that there is a trade-off: using sufficient pressure to eliminate all obstructive breathing will abolish the consequences of OSA/H, but excessive pressure will lead to poor adherence and possibly sideeffects. Unfortunately, the threshold at which OSA/ H becomes a disease (reducing longevity or the QoL) is not known. Similarly it is not known with certainty how much residual OSA/H is problematic. Furthermore, the extent to which poor adherence and side-effects are related to excessive pressure is controversial. Second, the required pressure level changes with both body position and stage of sleep, with the highest pressure levels occurring during stage REM in the supine position [37]. A CPAP titration study should include assessment in supine

OPTIMAL CPAP THERAPY FOR OBSTRUCTIVE SLEEP APNEA

13

Table 2 Clinical and physiologic treatment goals in the management of OSA/H Consequences of OSA/H

Excessive daytime sleepiness

Reduced quality of life

Increased risk of driving accidents

Evidence that CPAP is effective in eliminating this consequence

Randomised, controlled trials

Randomised, controlled trials

Uncontrolled prospective trial

Increased risk of cardiovascular complications Indirect clinical and physiologic studies

Retrospective review Clinical correlates to consequence

Physiologic correlates to consequence

Inappropriate daytime sleeping

Reduced sense of wellbeing

Increased Epworth Score

Score on survey instrument (SF36, Nottingham Health Questionnaire, and others)

Increased arousals

Increased arousals

Increased AHI

Increased AHI

Driving simulator performance

stage REM, although this may be difficult to achieve during the course of a sleep study. Finally, the pressure level that is required at the time CPAP is first applied decreases with continued use of nasal CPAP [38,39]. These data raise the question of whether CPAP pressure should be reduced over time to avoid over treating the patient. Results from the latter of these studies suggest that this is the case [39]. Given these considerations, a foundation of uncertainty underlies the entire concept of a CPAP titration – is it possible, or even necessary to find the optimal pressure during the initial titration? Despite these considerations, a clinically useful CPAP titration can be performed with careful attention to the conditions of the study. When a CPAP titration study is performed, the pressure level is either manually or automatically adjusted in response physiological indices of obstructive breathing. The most obvious physiologic manifestations of OSA/H are apnea, hypopnea and oscillations in oxyhemoglobin saturation. Eliminating these is a useful goal of CPAP titration, as discussed

Reports of nodding while driving Near miss accidents

Bed partner sleep disturbance Bed partner reports

Un-randomised physiologic study Bed partner sleep complaints Frequency of couple sleeping separately due to snoring noise

Increased AHI

Snoring amplitude and frequency

below. Guilleminault et al. recognised that partially obstructed breathing with increased esophageal pressure swings and increased arousals, even in the absence of apnea or hypopnea, could lead to daytime sleepiness [40]. This is consistent with the findings that respiratory effort and mechanoreceptor stimulation is the primary determinant of arousal during obstructive apneas [41], and that arousals are the primary determinant of sleepiness [8]. This suggests that eliminating excessive respiratory effort, as assessed by esophageal pressure swings, would be a useful physiologic goal during CPAP titration. Esophageal manometry is cumbersome to perform though, and is not widely used. Condos et al. have proposed analysing the flow signal provided by some CPAP machines as a non-invasive alternative to esophageal manometry [42]. They found that with low CPAP/high airway resistance the inspiratory flow contour developed a plateau representing flow limitation, and that flow contour normalised with increasing the CPAP pressure, which decreased upper airway resistance. As respiratory arousals

14

are related to daytime sleepiness, their elimination and subsequent improvement in sleep continuity is another goal during CPAP titration. There are several important limitations to this approach though. Measuring arousals requires electroencephalography, which greatly increases the expense and complexity of the titration study. In addition, it has been shown that obstructive breathing events that terminate with an arousal do not differ with regard to respiratory effort from those events ending without an arousal [43]. The significance of this finding is uncertain without further study, but it suggests that arousals may not be useful in breath-by-breath determinations of the adequacy of CPAP level. Evidence of subcortical, or autonomic, arousal may be more cost-effective than using electroencephalography to measure cortical arousal. However, this strategy has not been prospectively validated yet in a study with important clinical and economic endpoints. Snoring is an additional parameter that is easily monitored during a CPAP titration. Snoring has the advantage of being a non-invasive indicator of residual airway obstruction, and titration to eliminate snoring is in itself a treatment goal in those cases in which bed partner sleep disturbance is a major part of the clinical presentation. Several studies have been performed to evaluate the relationship between different physiologic variables during the course of a CPAP titration. Montserrat et al. titrated CPAP in a small population of patients with severe OSA/H while monitoring respiratory pattern, inspiratory flow contour, oximetry, sleep architecture, and esophageal manometry [44]. They found that even after apneas, hypopneas and respiratory arousals were eliminated there was persistence of inspiratory flow limitation and elevated esophageal pressure. Inspiratory flow limitation was the parameter that correlated best with excessive esophageal pressure swings. In a study by Ayappa et al. a self-adjusting CPAP device (auto-CPAP) was used to assess the occurrence of flow limitation and snoring during decreases from a therapeutic CPAP level [45]. Of the 2177 events assessed, flow limitation occurred in 86% of the events, snoring occurred in 30% of the events; both occurred in 22% of events. The results again confirm that among the commonly available parameters during CPAP titration, inspiratory flow limitation has the highest sensitivity for detecting residual upper airway obstruction.

W. BENINATI AND M. H. SANDERS

The clinician, faced with the above information, is left to choose the optimal set of parameters for CPAP titration in their own laboratory. The ideal level of evidence would be a prospective study that randomised patients to CPAP pressure levels on the basis of different sets of titration parameters. The study population would then be assessed for differences in the control of target consequences such as daytime sleepiness, driving accidents or cardiovascular mortality. Our review of the Englishlanguage literature uncovered one such study. A group of 18 patients with newly diagnosed OSA/H were assigned at random to treatment with CPAP adjusted either to eliminate flow limitation or to eliminate apnea, hypopnea and snoring [46]. The subjects were treated for 3 weeks and re-assessed for adherence, subjective and objective sleepiness, and with a simple test of neuropsychiatric function. Patients from both groups improved significantly by all measures. The only significant differences between the groups were greater adherence in the group titrated on the basis of flow limitation (7.6 vs 6.0 h of use/day), and a greater variation in the MWT scores among the group titrated to eliminate apnea, hypopnea and snoring. The results of this study suggest that titrating CPAP to eliminate flow limitation is warranted, but this is still insufficient data for a definitive recommendation that this approach is superior. Despite these results, it is still possible that the generally higher pressure-level used when CPAP is titrated to relieve inspiratory flow limitation represents over-treatment. This study will hopefully be the first of many to use the methodology of a randomised clinical trial to provide the information needed to prescribe CPAP therapy that is not merely better than placebo, but truly optimal. Pending further such studies additional insight into CPAP titration can be gleaned from the randomised controlled trials which demonstrated that CPAP is superior to either placebo or conservative therapy. In three of these trials, CPAP was manually adjusted to eliminate apneas, hypopneas, and arousals [5,6], or snoring and the majority of respiratory events [4]. In the other two trials, CPAP pressure was determined using auto-CPAP devices that titrate to eliminate apneas, hypopneas, snoring and flow limitation [3] or apneas, hypopneas and snoring [7]. These results do not indicate that one approach to titration is superior to another, but they do demonstrate which methods of CPAP titration have

OPTIMAL CPAP THERAPY FOR OBSTRUCTIVE SLEEP APNEA

been successful in improving sleepiness and/or QoL. Until more data accumulates CPAP should be titrated to eliminate apneas, hypopneas, snoring, respiratory arousals and probably inspiratory flow limitation. There is currently insufficient data to comment on a relationship between methods of CPAP titration and elimination of driving accidents or cardiovascular disease. In the absence of such data it seems prudent, when treating for these consequences of OSA/H, to use the techniques that have been shown to be successful for controlling excessive sleepiness. To summarise, among patients with OSA/H, CPAP pressure can be titrated to find a level that is likely to provide successful long-term therapy. The available data show that titration to eliminate apneas, hypopneas, snoring, and respiratory arousal is clearly useful. Inspiratory flow limitation is a more sensitive measure of residual upper airway obstruction during CPAP titration. Titration to eliminate inspiratory flow limitation can yield a pressure that is more successful than CT, and possibly more successful than CPAP, at a pressure-level based on titration to eliminate apnea, hypopnea, and snoring. In an individual patient though, optimal CPAP is a moving target. This pressure is likely to decrease with chronic CPAP use and to increase with factors outside of the sleep laboratory such as weight gain, nasal congestion, change in body position, or alcohol use. As such, a highly accurate determination of optimal CPAP pressure at the time of titration may result in either over or under-treatment. To avoid either of these situations the clinician must follow up with the patient to reassess the course of the CPAP treatment and change the CPAP prescription if treatment goals are not being met.

CPAP titration studies The traditional approach to diagnosing OSA and prescribing CPAP is to devote a full night of PSG to both the diagnostic study and the CPAP titration. The major drawback to this approach is that it is highly resource intensive. Polysomnography requires space, expensive equipment and the time of highly trained technicians. The high prevalence of OSA [2] and the demonstrated benefit of CPAP suggest that a substantial portion of the population might benefit from CPAP titration and therapy. For this to be practical the cost of CPAP titration needs to be decreased and the availability increased. A

15

number of alternative approaches have been developed, including split-night PSG and unattended home titration using an auto-CPAP device. This section will review some of the issues involving these approaches. In a split-night PSG the patient begins a standard diagnostic PSG. When the technician performing the study detects significant OSA the patient is awakened to apply CPAP, and the remainder of the night is spent with the technician titrating CPAP as per the laboratory’s protocol. This technique has been in use since 1991 [47]. The primary rationale of this approach is that many patients with significant OSA/H can be identified within several hours of sleep. Continuing to record their OSA/H does not add further information. With the time remaining in the night a well-trained technician can often accomplish an adequate CPAP titration. Compared with 2-night PSG this approach has a lower cost, increases the availability of this service and reduces waiting times for those patients who have critical sleepiness. In addition, this approach preserves the benefits of having an attended study, in which a technician can respond to problems such as mask leaks. The practice of performing split-night PSG raises several concerns though, primarily that the accuracy of the titration may not be adequate and that patient acceptance and adherence will suffer. Several studies address the issue of the accuracy of CPAP titration by comparing the results of a split-night titration with those of a full-night titration in the same patient. In one such study 50 patients who had undergone split-night PSG had a full-night PSG on a subsequent night, initially employing the positive pressure prescription derived from the split-night titration. The need for adjustment of the split-night positive pressure prescription was assessed [48]. In this study changes in pressure level, interface and pressure mode were considered during the full-night titration. Of the 41 patients who remained on CPAP 19 remained on the same pressure, 20 had a pressure increase (2.5 cm H2O or more in 11 patients), and two had a pressure decrease. In a subsequent study, 107 patients with OSA/H all underwent a split-night PSG followed by a full-night CPAP titration starting at a minimal pressure [49]. In this study final CPAP levels were again generally higher after the full-night PSG, however this effect was only statistically significant in those patients with AHI <20. These results raise some question about the validity of split-night studies, particularly in mild patients, but there are two

16

factors which tend to minimise the significance of this effect. First, a clinician who finds that the CPAP titration was clearly inadequate, at the time of interpretation of a split-night, can order a repeat CPAP titration. This will still result in less expense than ordering 2-night studies in every patient undergoing CPAP titration. The second factor is that required CPAP pressure declines with long-term CPAP use [38,39], such that the optimal pressure at the time of titration becomes over-treatment. It is not clear whether initial under-treatment is worse than long-term over-treatment. Series et al. reported on 13 patients who were initially given subtherapeutic CPAP (residual AHI >10) due to intolerance of higher pressures [38]. This treatment was continued, as sleep architecture improved and the patients experienced a dramatic improvement in sleepiness. At 2 months of follow-up, the AHI was normalised on CPAP in 11/13 patients, and in 7/13 patients this occurred at a pressure level 2–4 cm H2O lower than the initial suboptimal level. Split-night CPAP titrations are not generally as accurate as full-night titrations, but this is of unclear significance. In clinical practice the accuracy of a split-night should be improved by insisting on a minimum duration for the CPAP titration phase of the study. Studies have also addressed the issue of CPAP acceptance and adherence following a split-night study. A cohort of 31 patients was followed after receiving a split-night PSG to diagnose OSA/H and titrate CPAP [50]. Of this cohort 27 received an adequate CPAP titration, 21 of these accepted CPAP therapy and 16 used it long term. In this group the average nightly use was 6.7 h as determined by reading time counters on the CPAP units. There was no control group in this study, but this level of adherence is considered excellent. A more recent study evaluated these same factors in 24 patients who underwent split-night PSG and a group of 24 controls, matched for age, AHI and gender [51]. Among the split-night group 86% of patients accepted positive airway pressure therapy, and over the first 6 weeks of use, the daily adherence did not differ significantly between the split-night group (4.8 h) and the 2-night group (4.8 h). Based on this data fear about poor CPAP acceptance and adherence following split-night PSG appears to be unfounded. Another approach to reducing the cost of CPAP titration might be the use of auto-CPAP devices to

W. BENINATI AND M. H. SANDERS

perform the titration. A group of 20 patients with OSA/H all underwent both full-night manual CPAP titration and titration with an auto-CPAP device in random order [52]. The device performed well technically, in that the final pressures and the sleep quality did not differ on the manual and automatictitration studies. The auto-CPAP nights took place on a hospital ward where adjustments to the mask could be made by a nurse, as required. Another trial was conducted in which 122 patients with OSA/H were assigned at random to have their inlab titration performed either manually or with an auto-CPAP device [53]. The authors did not report any problems with the use of the auto-CPAP device, and found that patients who had been titrated with this device had CPAP acceptance and symptom relief that was at least as good as those who underwent manual titration. A natural extension of this work is to perform unattended titrations. This was attempted in an unselected group of 21 patients who underwent unattended auto-CPAP in a sleep laboratory followed by attended manual CPAP titration [54]. A full night of auto-CPAP titration was completed in 19 patients and the final pressure correlated closely with that from manual titration. In 15 of the patients the device was well tolerated. In the remaining six patients, who all had underlying cardiopulmonary disease, complications developed including insomnia, significant central apneas, sustained hypoxemia and high-grade arrhythmia. In general, auto-CPAP devices hold promise as a means of performing unattended CPAP titration, but there is currently insufficient data to recommend their use in that mode. If they are used it should only be for patients without underlying cardiopulmonary disease.

Positive airway pressure mode The most commonly employed mode for delivery of positive airway pressure (PAP) in OSA/H is CPAP mode. In this mode a flow generation unit, equipped with a pressure feedback system, varies delivered flow during changes in the respiratory cycle to maintain constant pressure. Many CPAP units have a ramp feature that allows the user to program a gradual increase in delivered pressure in order to allow sleep onset before therapeutic pressure is reached. There are two major variations of CPAP: bi-level PAP, and auto-CPAP. Each of these alternate modes has theoretical advantages over CPAP that

OPTIMAL CPAP THERAPY FOR OBSTRUCTIVE SLEEP APNEA

must be considered when choosing the optimal mode for a given patient. The major potential advantage of both of these devices is control of upper airway obstruction at a lower mean airway pressure. This should then lead to a reduction in pressurerelated side-effects such as mask leak and discomfort from exhaling against pressure, and in turn lead to higher adherence. A study by Sanders et al., employing sensitive measurement of airflow during mixed apneas, disclosed evidence of expiratory upper airway obstruction [55]. This finding has subsequently been confirmed by investigators using dynamic upper airway imaging [56]. This passive upper airway collapse during end-expiration, occurring without the negative intraluminal pressure that accompanies inspiration, is potentially correctable with a lower PAP level than that required during the active airway obstruction that occurs with inspiration. This hypothesis was tested with the application of a device (BiPAP) that allows independent adjustment of inspiratory and expiratory pressures [57]. This study confirmed that the pressure level required to maintain airway patency during expiration is less than that required during inspiration. The clinical implications of this finding are that bi-level PAP can control OSA/H at a lower mean airway pressure than CPAP, and that patients will not have to expire against as high a pressure. These factors may increase the tolerance of bi-level PAP over that of CPAP, leading to better acceptance and adherence. This hypothesis was tested in a study that randomised patients to CPAP or BiPAP and followed their adherence objectively over 12 months of use [58]. There was a significantly higher dropout rate in the CPAP group, suggesting greater acceptance in the bi-level group but among those that completed the study there was no difference in usage between the CPAP and BiPAP users. Bi-level PAP has also been evaluated as a salvage therapy in a group of 92 patients in whom CPAP was either ineffective or not tolerated [59]. In this study bilevel PAP was accepted by 75% of those who failed CPAP, and adherence was 48% at 6 months, indicating that in OSA/H patients who fail CPAP half of them can be effectively treated long-term with bi-level PAP. Bi-level PAP devices have been widely used to provide non-invasive pressure support ventilation for patients with acute or chronic respiratory failure. In some cases complicated OSA/ H is an integral part of respiratory failure, but this

17

condition is beyond the scope of the current review. Pending more definitive data the most prudent course of action in uncomplicated OSA/H is to reserve bi-level PAP as a salvage therapy for those individuals in whom CPAP is ineffective, who refuse to accept CPAP, or who are unable to tolerate CPAP. A different approach to reducing mean airway pressure is to use a device that continuously adjusts applied pressure as airway resistance changes over the course of the night. There are several such devices available, and for the purposes of this review this class of devices will be termed auto-CPAP. The rationale for auto-CPAP is that multiple factors affect the pressure level required to maintain airway patency. Some of these factors are prone to change both over the course of a single night, and from one night to another. These factors include body position, sleep stage, degree of sleep deprivation, presence of nasal obstruction and the presence of alcohol or sedative medications. Standard CPAP is typically adjusted to provide sufficient pressure to overcome the greatest airway collapsibility encountered during a titration study. During subsequent use of CPAP at home this pressure will be excessive in some circumstances and insufficient in others. The former situation may lead to excessive pressure-related side-effects and poorer adherence, while in the latter situation efficacy will suffer. An early study demonstrated the potential advantages of auto-CPAP in a short-term comparison study with fixed-pressure CPAP. Meurice et al. randomised 16 patients with newly diagnosed OSA/H to 3 weeks of therapy with either CPAP or auto-CPAP [60]. They employed the Morphe´e Plus (Laboratoire Pierre Me´dical, Verrie`res Le Buisson, France) autoCPAP device. This device tracks the patient’s ventilation through the flow provided by the CPAP compressor, and automatically compensates for changes in flow by varying the applied pressure. The subjects were assessed with PSG, MWT, Epworth Sleepiness Scale and trail-making tests at baseline, and following 3 weeks of therapy. The auto-CPAP device was as effective as CPAP in controlling disordered-breathing events, normalising sleep architecture, improving sleepiness and improving a measure of neuropsychiatric function. In addition, the nightly CPAP use was slightly better in the autoCPAP group. It has been proposed that auto-CPAP devices will provide more effective long-term treatment

18

of OSA/H than standard CPAP. This hypothesis has been examined in two published studies that compare the efficacy of an auto-CPAP device to standard CPAP in the outpatient management of OSA/H. Boudewyns et al. randomly selected 15 patients on chronic CPAP therapy for severe OSA/H, and subjected them to 2 months of treatment with an auto-CPAP device (REM+ Auto, Version 1.6, Sefam, Villers Les Nancy, France) that adjusts itself based on respiratory pauses and acoustic vibrations [61]. The standard CPAP had been titrated to eliminate respiratory events and snoring during REM and NREM sleep. The endpoints of this study were subjective sleepiness, CPAP-related side-effects, and severity of OSA/H as assessed by PSG. Assessments were made before and after the 2-month trial, on both auto-CPAP and standard CPAP. The severity of residual OSA/H was no different on auto-CPAP or standard CPAP, and both were superior to baseline sleep. There was no overall change in Epworth Sleepiness Scores, although four patients complained of increased daytime fatigue on autoCPAP, compared with their previous treatment with standard CPAP. The authors concluded that auto-CPAP is as effective as standard CPAP, but do not claim any better efficacy. A larger study used 50 patients with OSA/H randomised to therapy with either auto-CPAP or standard CPAP in a single blind fashion [62]. The CPAP was provided, in both groups, by a device that can be set to deliver fixed pressure or to selfadjust (Horizon, DeVilbiss, Langen, Germany). The standard CPAP was titrated during PSG to eliminate apneas and arousals. The auto-CPAP mode adjusted pressure to eliminate evidence of obstructive breathing based on airway pressure and flow oscillations. The therapy was continued for 3–6 months, during which time a portable screening device was used to assess adherence. At the end of this time period PSG was repeated. A total of 48 subjects completed the study, with two dropouts in the standard CPAP arm due to intolerance. The auto-CPAP device provided essentially identical control of OSA/H, but did so at a slightly lower mean mask pressure (6.5 vs 8.1 cm H2O). Subjects in the auto-CPAP group also had a greater improvement in percentage slow-wave sleep. The average hours of use did not differ significantly between the groups, although the auto-CPAP group used the treatment significantly

W. BENINATI AND M. H. SANDERS

more often (6.5 vs 5.7 days/week). In this study the auto-CPAP appeared to be slightly superior in several aspects, but data is not provided about meaningful endpoints such as control of sleepiness or elimination of systemic hypertension. Standard CPAP has been shown to be superior to placebo or CT in treating OSA/H [3–7], and this treatment has been compared with both bilevel PAP and auto-CPAP. On the basis of these comparisons it is justifiable to use either bi-level PAP or auto-CPAP to manage OSA/H. Pending further safety data though, auto-CPAP should be reserved for patients with uncomplicated OSA/H and for those unable to tolerate standard CPAP. Both of these alternative modes appear to have advantages over fixed-pressure CPAP, most notably better patient acceptance and adherence. However, neither of these modes has yet been shown to be superior with regard to elimination of meaningful OSA/H consequences such as daytime sleepiness, driving accidents, or cardiovascular complications. As such bi-level PAP and autoCPAP are best reserved for OA/H patients who do not accept or tolerate standard CPAP.

CPAP frequency and duration of use When CPAP is used to treat OSA/H it is generally prescribed that it be used all night, every night. However, there is no definitive guidance on what frequency and duration of CPAP use are required to optimally control the consequences of OSA/ H. It has been demonstrated in patients on chronic CPAP for OSA/H that when therapy is stopped the AHI and degree of oxyhemoglobin desaturation are nearly as abnormal on the first night off CPAP as at baseline, and that severe objective, but not subjective, daytime sleepiness returns after just one night off CPAP [63]. This suggests that nightly use is required. Insight into duration of use comes from a study by Hers et al. in which patients with OSA/H underwent a full-night diagnostic PSG and subsequently a PSG with an initial half-night of effective CPAP followed by a return to baseline sleep [64]. The authors found that the oxyhemoglobin desaturation index and movement arousal index were both significantly lower following a half-night of effective CPAP than at baseline. Taken together these studies suggest a powerful residual effect of CPAP that lasts for at least 3–4 h, but not 16–24 h.

OPTIMAL CPAP THERAPY FOR OBSTRUCTIVE SLEEP APNEA

Information on how reduced CPAP use affects daytime function comes from a placebo-controlled trial of CPAP involving 32 patients with OSA/H [65]. In the active treatment arm the mean daily time at effective mask pressure was 3.4 h, over a 4-week period. Despite this limited use of CPAP the patients on active therapy had significant improvements in symptoms, objective sleepiness and cognitive performance. On the basis of these studies, and until more definitive data is available, it is prudent to recommend nightly use of CPAP for as much of the night as tolerated, preferably the entire night.

Patient interface and CPAP humidification An easily overlooked element of a CPAP prescription is selecting a proper patient interface. The major types of interface are nasal mask, nasal pillows and oronasal mask. In general the interface of first choice is either a nasal mask or nasal pillows, with the choice depending on patient comfort and preference. Achieving proper fit can increase the stability of the interface on the patient’s face and prevent leaks, which can cause discomfort and which may diminish the effectiveness of the therapy. When a properly fitting nasal mask is worn, the seal should come from the circuit pressure inflating the mask material against the skin rather than by tightening the headgear to force a seal. This latter practice can lead to skin breakdown and to potentially serious facial infections. When mouth-opening occurs with patients using CPAP through a nasal mask a bothersome high-flow leak can develop through the mouth, causing excessive mucosal drying. Chinstraps are available to correct this, but they should be easily removable to prevent asphyxiation. An alternative to nasal CPAP is oronasal CPAP. The primary advantages of an oronasal mask are more effective delivery of pressure in the presence of nasal obstruction or mouth opening, and potentially greater comfort. There are several potential problems though, including a risk of aspiration if vomiting should occur, retropositioning of the mandible if the mask is applied too tightly, asphyxiation if the CPAP unit fails and mouth opening is inhibited and worsened airway obstruction from differential pressurisation of the oropharyngeal and nasopharyngeal spaces. These

19

concerns have failed to materialise in several studies that evaluated their efficacy in a total of 40 patients [66,67]. A randomised trial was also conducted in which 20 newly diagnosed patients with OSA/H were assigned to therapy with either a nasal or an oronasal mask [68]. In this study adherence and comfort rating were both higher with nasal masks. The oronasal mask should not be considered a first-line interface for delivery of CPAP to patients with OSA/H, but it is a reasonable alternative for selected patients. Humidifiers can be added to CPAP systems as an accessory intended to increase patient comfort and decrease vasomotor rhinitis. The two basic models of humidification available for CPAP are heated humidifiers, and cold passover humidifiers which are simpler and substantially less expensive. To evaluate their relative efficacy a randomised crossover trial was conducted in 38 patients beginning CPAP treatment for OSA/H [69]. The subjects spent 3 weeks using each type of humidifier with an intervening 2-week washout period. During the heated humidity period mean duration of CPAP usage was 0.59 h higher than the period with no humidification, and 0.37 h higher than the period with cold passover humidification. Patients also felt significantly more refreshed upon awakening after sleeping with heated humidification. These changes were statistically significant, but probably do not justify the routine use of heated humidification.

SUMMARY The use of nasal CPAP has increased dramatically since its introduction nearly 20 years ago. There are multiple parameters that a clinician can specify in a prescription for CPAP including the pressure mode, the endpoints for CPAP titration, the type of study used to determine these endpoints, the frequency and duration of CPAP use, the use of humidification and the patient interface. The ultimate answer of what constitutes optimal CPAP is that combination of the above factors which is most effective in eliminating the adverse consequences of OSA/H. To minimise the consequences optimal CPAP needs to strike the proper balance between physiologic success and tolerability. As recently as 1997 it was controversial whether OSA/H even caused significant adverse consequences [28]. Since that time a number of

20

well-designed studies have demonstrated that OSA/H causes, or is associated with, adverse neuropsychiatric and cardiovascular consequences [3–7,10–13]. Furthermore convincing evidence has demonstrated that CPAP is effective in eliminating important consequences of OSA/H [3–7]. With the effectiveness of CPAP now firmly established through randomised controlled trials the next generation of studies will need to compare the variables mentioned above using, as endpoints, well-accepted consequences of OSA/H. At this point the only pressure mode that has been shown to be superior to placebo is standard CPAP. This mode is the least expensive, but adherence with therapy is often poor. Patients should be initially treated with standard CPAP. For those in whom standard CPAP is unsuccessful or intolerable, bi-level or auto-CPAP modes should be attempted. Among the many physiologic variables that can be used to titrate CPAP, prescriptions based on elimination of apnea, hypopnea, snoring, respiratory arousal and inspiratory flow limitation have been shown to be superior to CT or placebo. Of these parameters inspiratory flow limitation is the most sensitive non-invasive marker of residual upper airway obstruction during CPAP titration but its use may result in over-treatment. The reliability of these physiologic parameters in predicting the optimal long-term CPAP pressure is eroded by the tendency of CPAP pressure-level requirement to decrease with chronic CPAP use. A number of strategies have been developed for arriving at the optimal CPAP pressure including full-night CPAP titration with PSG, split-night PSG and out-of-lab titration using auto-CPAP. The available evidence shows that for patients with moderate or severe OSA/H a split-night PSG is usually adequate. Patients without severe underlying cardiopulmonary disease are candidates for unattended auto-CPAP titration, although this strategy remains unproven in longterm clinical studies. For more complex patients such as those with subtle OSA/H, those with severe underlying cardiopulmonary disease, and those in whom CPAP is not adequately titrated on an initial split-night study, a full-night attended PSG is indicated. Pending further evidence, the choice of patient interface is primarily based on fit and comfort, as no particular interface has been show to be superior. There is growing evidence that heated humidification is potentially beneficial in all patients. Humidification may increase adherence, and its use

W. BENINATI AND M. H. SANDERS

should be considered at the time of the initial CPAP prescription. At the start of the new millennium the science of treating OSA/H with positive pressure is still in its infancy. Many fundamental questions about optimal CPAP therapy remain unanswered, and a great deal is left to clinical judgement. For many patients the simple principles outlined above will produce excellent results. However as yet there is not a set of clinical or physiologic parameters that reliably predict successful CPAP therapy in all patients. The most important element of a CPAP prescription remains the follow up visit to ensure that treatment goals are being reached. Practice Points 1. Continuous positive airway pressure (CPAP) is the only treatment for obstructive sleep apnea/hypopnea (OSA/H) that has been shown to be superior to placebo. 2. The initial mode of choice is fixed-level CPAP. Consider transition to bi-level positive airway presure (PAP) or auto-CPAP if CPAP is not tolerated. 3. In the majority of patients, split-night polysomnography (PSG) is an effective, economical means of determining appropriate pressure. 4. Nasal CPAP can be titrated to eliminate apneas and hypopneas, snoring, excessive arousals, or inspiratory flow limitation. None of these parameters is clearly superior. 5. Identify individualised goals of CPAP therapy and reassess at the time of follow-up. Adjust therapy if these goals are not being met.

Research Agenda 1. Determine whether CPAP is effective in eliminating cardiovascular complications of OSA/ H. 2. Determine whether a CPAP prescription, with the pressure level determined on the basis of an unattended titration with auto-CPAP, is effective in eliminating consequences of OSA/ H. 3. Compare different endpoints for CPAP titration for their effectiveness in predicting successful long-term therapy.

OPTIMAL CPAP THERAPY FOR OBSTRUCTIVE SLEEP APNEA

REFERENCES 1. American Academy of Sleep Medicine Task Force. Sleep-related breathing disorders in adults: recommendations for syndrome definition and measurement techniques in clinical research. Sleep 1999; 22: 667–689. 2. Young T, Palta M, Dempsey J, Skatrud J, Weber S, Badr S. The occurrence of sleep disordered breathing among middle-aged adults. N Engl J Med 1993; 328: 1230–1230. 3. Ballester E, Badia JR, Hernandez L et al. Evidence of the effectiveness of continuous positive airway pressure in the treatment of sleep apnea/hypopnea syndrome. Am J Respir Crit Care Med 1999; 159: 495–501. 4. Redline S, Adams N, Strauss ME, Roebuck T, Winters M, Rosenberg C. Improvement of mild sleepdisordered breathing with CPAP compared with conservative therapy. Am J Respir Crit Care Med 1998; 157: 858–865. ∗5. Engleman HM, Martin SE, Kingshott RN, Mackay TW, Deary IJ, Douglas NJ. Randomised placebo controlled trial of daytime function after continuous positive airway pressure (CPAP) therapy for the sleep apnoea/hypopnoea syndrome. Thorax 1998; 53: 341–345. 6. Engleman HM, Kingshott RN, Wraith PK, Mackay TW, Deary IJ, Douglas NJ. Randomized placebocontrolled crossover trial of continuous positive airway pressure for mild sleep apnea/hypopnea syndrome. Am J Respir Crit Care Med 1999; 159: 461–467. ∗7. Jenkinson C, Davies RJO, Mullins R, Stradling JR. Comparison of therapeutic and subtherapeutic nasal continuous positive airway pressure for abstructive sleep apnoea: a randomised prospective parallel trial. Lancet 1999; 353: 2100–2105. 8. Guilleminault C, Partinen M, Quera-Salve MA, Hayes B, Dement WC, Nino-Murcia G. Determinants of daytime sleepiness in obstructive sleep apnea. Chest 1988; 94: 32–37. 9. Colt HG, Haas H, Rich GB. Hypoxemia vs sleep fragmentation as cause of excessive daytime sleepiness in obstructive sleep apnea. Chest 1991; 100: 1542–1548. 10. Teran-Santos J, Jimenez-Gomez A, Cordero-Guevara J. The association between sleep apnea and the risk of traffic accidents. N Engl J Med 1999; 340: 847–851. 11. George CFP, Smiley A. Sleep apnea and automobile crashes. Sleep 1999; 22: 790–795.

∗ The most important references are denoted by an asterisk.

21

12. Young T, Peppard P, Palta M, Hla KM, Finn L, Morgan B, Skatrud J. Population-based study of sleep-disordered breathing as a risk factor for hypertension. Arch Intern Med 1997; 157: 1746–1752. 13. Brooks D, Horner RL, Kozar LF, Render-Teixeira CL, Phillipson EA. Obstructive sleep apnea as a cause of systemic hypertension: evidence from a canine model. J Clin Invest 1997; 99: 106–109. 14. Partinen M, Jamieson A, Guilleminault C. Long-term outcome for obstructive sleep apnea syndrome patients: mortality. Chest 1988; 94: 1200–1204. 15. He J, Kryger MH, Zorick FJ, Conway W, Roth T. Mortality and apnea index in obstructive sleep apnea. Experience in 385 male patients. Chest 1988; 94: 9–14. 16. Quan SF, Howard BV, Iber C et al. The Sleep Heart Health Study: design, rationale, and methods. Sleep 1997; 20: 1077–1085. 17. Strollo PJ, Roberts RM. Obstructive sleep apnea. N Engl J Med 1996; 334: 99–104. 18. Sullivan CE, Issa FG, Berthon-Jones M, Eves L. Reversal of obstructive sleep apnoea by continuous positive airway pressure applied through the nares. Lancet 1981; 1(8225): 862–865. 19. Sanders MH, Moore SE, Eveslage J. CPAP via nasal mask: a treatment for occlusive sleep apnea. Chest 1983; 83: 144–145. 20. Abbey NC, Cooper KR, Kwentus JA. Benefit of nasal CPAP in obstructive sleep apnea is due to positive pharyngeal pressure. Sleep 1989; 12: 420– 422. 21. Mortimore IL, Douglas NJ. Palatal muscle EMG response to negative pressure in awake sleep apneic and control subjects. Am J Respir Crit Care Med 1997; 156: 867–873. 22. Lin CC. Effect of nasal CPAP on ventilatory drive in normocapnic and hypercapnic patients with obstructive sleep apnoea syndrome. Euro Respir J 1994; 7: 2005–2010. 23. Ryan CF, Lowe AA, Li D, Fleetham JA. Magnetic resonance imaging of the upper airway in obstructive sleep apnea before and after chronic nasal continuous positive airway pressure therapy. Am Rev Respir Dis 1991; 144: 939–944. 24. Pepin JL, Leger P, Veale D, Langevin B, Robert D, Levy P. Side effects of nasal continuous positive airway pressure in sleep apnea syndrome: study of 193 patients in two French sleep centers. Chest 1995; 107: 375–381. 25. Kribbs NB, Pack AI, Kline LR et al. Objective measurement of patterns of nasal CPAP use by patients with obstructive sleep apnea. Am Rev Respir Dis 1993; 147: 887–895. 26. American Thoracic Soociety. Indications and standards for use of nasal continuous positive airway

W. BENINATI AND M. H. SANDERS

22

27.

28.

29.

30.

31.

32.

33.

34.

35.

36.

37.

pressure (CPAP) in sleep apnea syndromes. Official statement. Am J Respir Crit Care Med 1994; 150: 1738–1745. Loube DI, Gay PC, Strohl KP, Pack AI, White DP, Collop NA. Indications for positive airway pressure treatment of adult obstructive sleep apnea patients: a consensus statement. Chest 1999; 115: 863–866. Wright J, Johns R, Watt I, Melville A, Sheldon T. Health effects of obstructive sleep apnoea and the effectiveness of continuous positive airways pressure: a systematic review of the research evidence. Br Med J 1997; 314: 851–860. Bolitschek J, Schmeiser-Rieder A, Schobersberger R, Rosenberger A, Kunze M, Aigner K. Impact of nasal continuous positive airway pressure treatment on quality of life in patients with obstructive sleep apnoea. Eur Respir J 1998; 11: 890–894. Krieger J, Meslier N, Lebrun T, Levy P, Phillip-Joet F, Sailly JC, Racineux JL. Accidents in obstructive sleep apnea patients treated with nasal continuous positive airway pressure: a prospective study. Chest 1997; 112: 1561–1566. Dement WC, Kushida C. Snoring and sleep quality: everyone deserves a good night’s rest. Mayo Clinic Proceedings 1999; 74: 1049–1050. Beninati W, Harris CD, Herold D, Shepard JW Jr. The effect of snoring and obstructive sleep apnea on the sleep quality of bed partners: the spousal arousal syndrome. Mayo Clinic Proceedings 1999; 74: 955–958. Wilcox I, Grunstein RR, Hedner JA, Doyle J, Collins FL, Fletcher PJ, Kelly DT, Sullivan CE. Effect of nasal continuous positive airway pressure during sleep on 24-hour blood pressure in obstructive sleep apnea. Sleep 1993; 16: 539–544. Hedner J, Darpo B, Ejnell H, Carlson J, Caidahl K. Reduction in sympathetic activity after long-term CPAP treatment in sleep apnoea: cardiovascular implications. Eur Respir J 1995; 8: 222–229. Waradekar NV, Sinoway LI, Zwillich CW, Leuenberger UA. Influence of treatment on muscle sympathetic nerve activity in sleep apnea. Am J Respir Crit Care Med 1996; 153: 1333–1338. Shepard JW Jr. Cardiorespiratory changes in obstructive sleep apnea. In: Kryger MH, Roth T, Dement WC (eds). Principles and Practice of Sleep Medicine, 2nd edition. London: WB Saunders 1994; 657–666. Oksenberg A, Silverberg DS, Arons E, Radwan H. The sleep supine position has a major effect on optimal nasal continuous positive airway pressure: relationship with rapid eye movements and nonrapid eye movements sleep, body mass index, respiratory disturbance, and age. Chest 1999; 116: 1000–1006.

∗38. Series F, Marc I, Cormier Y, La Forge J. Required levels of nasal continuous positive airway pressure during treatment of obstructive sleep apnea. Eur Respir J 1994; 7: 1776–1781. 39. Jokic R, Klimaszewski A, Guruswamy S, Fitzpatrick MF. Continuous positive airway pressure requirements during the first month of treatment in patients with severe obstructive sleep apnea. Chest 1998; 114: 1061–1069. 40. Guilleminault C, Stoohs R, Clerk M, Cetel M, Maistros P. A cause of excessive daytime sleepiness: the upper airway resistance syndrome. Chest 1993; 104: 781–787. 41. Kimoff RJ, Cheong TH, Olha AE, Charbonneau M, Levy RD, Cosio MG, Gottfried SB. Mechanisms of apnea termination in obstructive sleep apnea. Role of chemoreceptor and mechanoreceptor stimuli. Am J Respir Crit Care Med 1994; 149: 707–714. 42. Condos R, Norman RG, Krishnasamy I, Peduzzi N, Goldring RM, Rapoport DM. Flow limitation as a noninvasive assessment of residual upper-airway resistance during continuous positive airway pressure therapy of obstructive sleep apnea. Am J Respir Crit Care Med 1994; 150: 475–480. 43. Rees K, Spence DP, Earis JE, Calverley PM. Arousal responses from apneic events during non-rapideye-movement sleep. Am J Respir Crit Care Med 1995; 152: 1016–1021. ∗44. Montserrat JM, Ballester E, Olivi H, Reolid A, Lloberes P, Morello A, Rodriguez-Roisin R. Time-course of stepwise CPAP titration: behavior of respiratory and neurological variables. Am J Respir Crit Care Med 1995; 152: 1854–1859. 45. Ayappa I, Norman RG, Hosselet JJ, Gruenke RA, Walsleben JA, Rapoport DM. Relative occurrence of flow limitation and snoring during continuous positive airway pressure titration. Chest 1998; 114: 685–690. 46. Meurice JC, Paquereau J, Denjean A, Patte F, Series F. Influence of correction of flow limitation on continuous positive airway pressure efficiency in sleep apnoea/hypopnoea syndrome. Eur Respir J 1998; 11: 1121–1127. 47. Sanders MH, Black J, Constantino JP, Kern N, Studnicki K, Coates J. Diagnosis of sleep-disordered breathing by half-night polysomnography. Am Rev Respir Dis 1991; 144: 1256–1261. ∗48. Sanders MH, Kern NB, Costantino JP, Stiller RA, Studnicki K, Coates J, Orris S, Schimerman S. Adequacy of prescribing positive airway pressure therapy by mask for sleep apnea on the basis of a partial night trial. Am Rev Respir Dis 1993; 147: 1169–1174. ∗49. Yamashiro Y, Kryger MH. CPAP titration for sleep apnea using a split-night protocol. Chest 1995; 107: 62–66.

OPTIMAL CPAP THERAPY FOR OBSTRUCTIVE SLEEP APNEA 50. Fleury B, Rakotonanahary D, Tehindrazanarivelo AD, Hausser-Hauw C, Lebeau B. Long-term compliance to continuous positive airway pressure therapy (nCPAP) set up during a split-night polysomnography. Sleep 1994; 17: 512–515. ∗51. Sanders MH, Costantino JP, Strollo PJ, Studnicki K, Atwood CW. The impact of split-night Polysomnography for diagnosis and positive pressure therapy titration on treatment acceptance and adherence in sleep apnea/hypopnea. Sleep 2000; 23: 17–24. 52. Lloberes P, Ballester E, Montserrat JM, Botifoll E, Ramirez A, Reolid A, Gistau C, Rodriguez-Roisin R. Comparison of manual and automatic CPAP titration in patients with sleep apnea/hypopnea syndrome. Am J Respir Crit Care Med 1996; 154: 1755– 1758. 53. Stradling JR, Barbour C, Pitson DJ, Davies RJ. Automatic nasal continuous positive airway pressure titration in the laboratory: patient outcomes. Thorax 1997; 52: 72–75. ∗54. Juhasz J, Schillen J, Urbigkeit A, Ploch T, Penzel T, Peter JH. Unattended continuous positive irway pressure titration. Clinical relevance and cardiorespiratory hazards of the method. Am J Respir Crit Care Med 1996 154: 359–365. 55. Sanders MH, Rogers RM, Pennock BE. Prolonged expiratory phase in sleep apnea: a unifying hypothesis. Am Rev Respir Dis 1985; 131: 401–408. 56. Schwab RJ, Gefter WB, Hoffman EA, Gupta KB, Pack AI. Dynamic upper airway imaging during awake respiration in normal subjects and patients with sleep disordered breathing. Am Rev Respir Dis 1993; 148: 1385–1400. ∗57. Sanders MH, Kern N. Obstructive sleep apnea treated by independently adjusted inspiratory and expiratory positive airway pressures via nasal mask: physiologic and clinical implications. Chest 1990; 98: 317–324. 58. Reeves-Hoche MK, Hudgel DW, Meck R, Witteman R, Ross A, Zwillich CW. Continuous versus bilevel positive airway pressure for obstructive sleep apnea. Am J Respir Crit Care Med 1995; 151: 443–449. 59. Szumstein S, Atwood CW, Strollo PJ, Sanders MH. Is bilevel positive airway pressure (BPAP) an effective

60.

61.

∗62.

63.

64.

65.

66.

67.

68.

69.

23

salvage therapy for obstructive sleep apnea (OSA) patients who fail CPAP therapy? Am J Respir Crit Care Med 1999; 159: A250. Meurice JC, Marc I, Series F. Efficacy of autoCPAP in the treatment of obstructive sleep apnea/ hypopnea syndrome. Am J Respir Crit Care Med 1996; 153: 794–798. Boudewyns A, Grillier-Lanoir V, Willemen MJ, De Cock WA, Van de Heyning PH, De Backer WA. Two months follow up of auto-CPAP treatment in patients with obstructive sleep apnea. Thorax 1999; 54: 147–149. Konnerman M, Sanner BM, Vylets M, Laschewski F, Groetz J, Sturm A, Zidek W. Use of conventional and self-adjusting nasal continuous positive airway pressure for the treatment of severe obstructive sleep apnea: a comparative study. Chest 1998; 113: 714–718. Sforza E, Lugaresi E. Daytime sleepiness and nasal continuous positive airway pressure therapy in obstructive sleep apnea syndrome patients: effects of chronic treatment and I-night therapy withdrawal. Sleep 1995; 18: 195–201. Hers V, Liistro G, Dury M, Collard P, Aubert G, Rodenstein DO. Residual effect of nCPAP applied for part of the night in patients with obstructive sleep apnoea. Eur Respir J 1997; 10: 973–976. Engleman HM, Martin SE, Deary IJ, Douglas NJ. Effect of continuous positive airway pressure treatment on daytime function in sleep apnoea/hypopnoea syndrome. Lancet 1994; 343: 572–575. Sanders MH, Kern NB, Stiller RA, Strollo PJ Jr, Martin TJ, Atwood CW Jr. CPAP therapy via oronasal mask for obstructive sleep apnea. Chest 1994; 106: 774–779. Prosise GL, Berry RB. Oral-nasal continuous positive airway pressure as a treatment for obstructive sleep apnea. Chest 1994; 106: 180–186. Mortimore IL, Whittle AT, Douglas NJ. Comparison of nose and face mask CPAP therapy for sleep apnoea. Thorax 1998; 53: 290–292. Massie CA, Hart RW, Peralez K, Richards GN. Effects of humidification on nasal symptoms and compliance in sleep apnea patients using continuous positive airway pressure. Chest 1999; 116: 403–408.