Continuous positive airway pressure treatment in patients with OSA.pdf

8/14/2019 Continuous positive airway pressure treatment in patients with OSA.pdf

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Chapter 15

Continuous positive

airway pressuretreatment in patients

with OSAJ.M. Montserrat*,#, D. Navajas#,", O. Parra#,+ and R. Farre#,"

Summary

Obstructive sleep apnoea (OSA) is a common disorder thatincreases morbidity and even mortality. When the apnoea/hypopnoea index (AHI) is .30 and is accompanied bysymptoms, OSA must be treated. Although continuous positiveairway pressure (CPAP) is the most useful form of treatment, itshould always be complemented by the prescription of the

following: a weight loss programme, physical exercise, posi-tional therapy, sufficient sleep time, and an avoidance ofsedatives and alcohol. As each patient needs a different fixedCPAP, titration must be performed. When patients have nosevere associated comorbidity the fixed CPAP can be obtainedby using automatic devices. Training, educational sessions andclose follow-up, especially during the first months, are crucialfor obtaining adequate compliance. It is not clear whether non-sleepy OSA patients should be treated, although CPAP should

probably be prescribed for those with severe cardiovasculardisease or a very high AHI.

Keywords: Adaptive seroventilation, continuous positiveairway pressure, continuous airway pressure complications,continuous positive airway pressure titration, sleep apnoea,sleep apnoea treatment

*Servei Pneumologia, Hospital Clnic,Facultat de Medicina, IDIBAPS,"Unitat de Biofsica i Bioenginyeria,Facultat de Medicina, Universitat deBarcelona - IDIBAPS,+Hospital Universitari del SagratCor., Barcelona, and#CIBER Enfermedades Respiratorias,Bunyola, Spain

Correspondence: J.M. Montserrat,Sleep Laboratory. Hospital Clinic,Villarroel 170. 08036 Barcelona,Spain, Email [email protected]

Eur Respir Mon 2010. 50, 244266.Printed in UK all rights reserved.Copyright ERS 2010.European Respiratory Monograph;ISSN: 1025-448x.DOI: 10.1183/1025448x.00025109

Obstructive sleep apnoea (OSA) is characterised by recurrent upper airway collapse during

sleep caused by an abnormal increase in the collapsibility of the upper airway. The collapse ofthe upper airway can be caused by a variety of events, such as anatomical factors, abnormal bonyand soft tissue structures that tend to close the lumen of the upper airway and, more commonly,physiological factors, such as defects in the upper airway dilator muscles that are responsible forproducing the effort required to keep the upper airway lumen open. Under-performance by theupper airway muscles could be caused by neural and/or muscle dysfunction. When there is an

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imbalance between opening and collapsing forces, the upper airway muscles are unable to provideenough strength to keep the lumen open, resulting in partial or total upper airway occlusion(hypopnoea or apnoea, respectively) [1]. OSA affects 46% of the population [2, 3] and its mostcommon pathophysiological consequences are: periods of recurrent hypoxaemia, transient repeatedarousals, marked swings in negative intrathoracic pressure and increased sympathetic activity [4, 5].These injuries stimuli bring about biological consequences [6] that have subsequent clinical harmfuleffects, such as somnolence and inflammation, with associated metabolic, neurocognitive and

cardiovascular effects [5]. OSA also leads to higher mortality rates [7, 8]. Several studies havedemonstrated that treatment with continuous positive airway pressure (CPAP) reduces not only theabove mentioned harmful effects but also mortality in OSA patients [9, 10].

Pathophysiology

Collapsibility of the upper airway can be characterised by measuring the upper airway criticalpressure (Pcrit) [11, 12]. Figure 1 represents the upper airway as a simple tube with a collapsiblesegment. Pcrit is defined as the minimum intra-luminal airway pressure required to keep thiscollapsible segment open. Flow cannot occur until the pressure upstream of the collapsible segment

exceeds the pressure around it. As can be seen in figure 1, under normal conditions Pcritis negative[11, 12] and, therefore, the airways tend to remain open and stable, despite the negative intra-luminal pressure resulting from inspiration. This fact is explained by the upper airway musclesability to generate enough force to avoid occlusion. However, in patients with OSA, Pcritis positiveand there is a collapse, and occlusion, of the upper airway during sleep (fig. 1b). In patients with

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hypopnoea (fig. 1c), Pcrit is lessmarkedly negative than in normalsubjects and the airway is susceptibleto collapsing, especially when thesubject exerts a large negative inspira-tory pressure (PI).

CPAP is the most common treatment

for OSA [13, 14]. CPAP opens theupper airway pneumatically via con-stant pressure throughout the respira-tory cycle (fig. 2). A CPAP machine is adevice that generates a large quantity offlow [13], which passes through a tubeinto the nasal or oronasal mask (fig. 3).This mask incorporates a leakage thatinduces resistance and, therefore, posi-tive pressure in its interior. As a result,

the CPAP acts as a splint for the upperairway and thereby corrects all theharmful effects triggered by OSA [15].Nasal CPAP does not eliminate theunderlying causes of upper airwaycollapsibility in OSA but is a palliativetreatment that prevents upper airwayobstruction mechanically. The effec-tiveness of CPAP in preventing theupper airway from narrowing into OSA

is illustrated by the computed tomo-graphy scan of a patients pharyngealarea during sleep (fig. 4). The upperimages show two sections (fig. 4a andb) of the upper airway obtained whenthe patient was sleeping without CPAP.In the right section the lumen of theupper airway is extremely reduced,indicating that the airway is almostclosed. When the patient was subjected

to CPAP (fig. 4c and d) the upperairway lumen expanded considerably atthis point of obstruction. Some authorshave proposed that the increase in lungvolume found during CPAP could havea stabilising effect on the upper airwayby stiffening it [16], and therebytriggering a reflex that improves the

tone of the dilator muscle. However, this theory does not withstand close scrutiny, as a decrease in upperairway muscle activity has been clearly demonstrated during CPAP administration [17].

Efficacy of CPAP treatment on various disorders

As illustrated in figure 5, CPAP eliminates the symptoms typically found in OSA patients [5, 14,15]. The findings are clear concerning somnolence but not so conclusive with regard to otherassociated entities, such as cardiovascular or metabolic consequences associated with OSA [15].

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of this meta-analysis concludedthat CPAP induces only smallimprovements in subjective sleepi-ness and objective MWT in peoplewith mild-to-moderate OSA. Insummary, and in keeping with themore recent comments of MCDAID

et al.[23], in a systematic review ofCPAP for OSA, CPAP is an effec-tive treatment for moderate-to-severe symptomatic patients andmay also provide some benefitsfor mild symptoms.

There is also evidence that thesymptoms of daytime sleepinessand impaired concentration arisingfrom untreated OSA patients lead

to a significantly increased risk ofautomobile accidents [24, 25].Patients with untreated OSA oralcohol-intoxicated normal subjectsperformed significantly less well ina steering simulation test whencompared with CPAP-treated

patients or normal subjects [26]. In a recent systematic review of the OSA-related risk of crashin commercial motor vehicle drivers, TREGEAR et al. [27] analysed seven different electronicdatabases. The main conclusions were that individuals with OSA clearly have a greater risk of

crashing. The mean crash rate ratio associated with OSA is likely to be within the range of 1.214.89. The characteristics that make drivers with OSA prone to crashing include body mass index(BMI), AHI, oxygen saturation and, possibly, daytime sleepiness. The authors suggested the needfor annual relicensing in various cases such as: 1) patients with untreated OSA; 2) those who havehad a crash after falling asleep; 3) patients that have an AHI .20 before the application of CPAP;4) patients who have had surgery for OSA; and 5) subjects that have a high risk score according tothe Berlin Questionnaire.

GURUBHAGAVATULA et al. [28] considered three methods of dealing with OSA patients in apopulation of drivers: 1) polysomnography (PSG) in all drivers; 2) PSG for the high-risk group ofdrivers; and 3) no intervention. The costs of each of these three approaches were the sum of thecosts of testing and treating identified cases, plus the costs of the crashes themselves. If we assumethat treatment prevents OSA-related crashes, PSG in all the patients is not cost-effective, because itis more expensive than the costs generated by crashes. However, PSG performed only on high-riskdrivers was cost-effective, as long as a high proportion of the screened drivers accepted treatment.These findings indicate that strategies to reduce reliance on PSG may be more cost-effective thannot screening at all, and that treatment acceptance may need to be a condition of employment foraffected drivers. However, there is some controversy about the efficacy of CPAP treatment inpreventing OSA-related traffic accidents [25].

Patients with OSA who were treated with CPAP compared with placebo showed significant

improvement in general measurements of quality of life, using instruments such as the ShortForm-36 questionnaire, and in sleep-specific quality of life measurements in most [29, 30], but notall studies, especially in mild patients [31]. Two groups of patients merit specific attention. In onestudy, BARBE et al.[32] studied only non-sleepy patients and no significant changes were found inthe quality of life test after CPAP treatment, although the follow-up period was short. The elderlypopulation represents another special group. In this population MARTINEZ-GARCIAet al.[33] found

CPAPCardiovasculardisturbances

Other

Classical clinicalsymptoms

Somnolence

Cognitive defectsOthers OK

AgeGeneticsSexRace

LifestyleHypertensionSystemic inflammationObesityDiabetesLipid disordersHypercoagulabilityTobacco

Cardiac function

Treatment

?

?

Non-modifiable factors

Modifiable factors

Figure 5. In sleep apnoea patients the beneficial effects ofcontinuous positive airway pressure (CPAP) have been well

demonstrated on clinical symptoms but have not been fully

demonstrated in cardiovascular diseases or other circumstances,such as non-sleepy patients.

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that OSA in the elderly was not associated with a decrease in some quality of life tests whencompared with younger subjects. Based on these results, the authors believe that further studies areneeded to clarify the role of CPAP treatment for elderly patients with OSA. Of course, this doesnot mean that the aging population should not be treated with CPAP because other factors, suchas the cardiovascular or neurocognitive impact of OSA, also need to be considered. The positiveeffects of CPAP in these situations in the elderly have already been suggested. In summary,improvements in the quality of life for patients with OSA were observed after CPAP treatment,

particularly in somnolent subjects [3436].

Cardiovascular

In accordance withfigure 5, cardiovascular CPAP efficacy will be divided into modifiable factorsthat can prevent cardiovascular diseases, such as systemic hypertension (a major problem) ormetabolic syndrome, and intermediate mechanisms, as well as the effect of CPAP on myocardialfunction itself.

Systemic hypertension

OSA and systemic hypertension are associated diseases [37], although their causality and incidencehave yet to be fully studied. In two short follow-up studies, incidence was mainly demonstrated inobese patients with OSA [38, 39]. The evidence of the effect of CPAP on the reduction of bloodpressure (BP) has been analysed by two recent meta-analyses and a broad review of the topic [4042]. It should be noted that most published studies in this field have significant methodologicallimitations, making it difficult to analyse each study independently. These limitations include: 1)small sample size; 2) the fact that most of the studies are performed on males takingantihypertensive medication (or not taking it); 3) different ways of measuring BP or diagnosingand treating OSA; 4) the presence or absence of OSA symptoms, such as somnolence or associatedcomorbidity; 5) variations in the study design; and 6) different statistical analyses.

In the meta-analysis by ALAJMI et al. [40], the authors reviewed the literature in order to identifyrandomised, controlled trials with an appropriate control group. Systolic and diastolic BP (SBPand DBP, respectively) was measured before and after treatment with CPAP. On the whole, theeffects of CPAP were modest and not statistically significant; CPAP reduced SBP by 1.38 mmHgand DBP by 1.52 mmHg. However, in trials with more severe OSA (mean AHI .30), CPAPsignificantly reduced SBP and DBP by 3.03 mmHg and 2.03 mmHg, respectively. The meta-analysis of HAENTJENSet al.[41] covered only placebo-controlled randomised studies with data for24-h ambulatory blood pressure monitoring (ABPM). The effect of the CPAP interventionsignificantly decreased the 24-h mean BP by 1.69 mmHg. Both meta-analyses conclude that CPAP

reduces BP in patients, especially in those with a more severe degree of OSA.

To shed more light on this topic, two recent randomised studies were performed in Spain in anattempt to overcome the most significant limitations of the various studies published to date ( i.e.patients with chronic hypertension, no control group, no placebo and the role of CPAP treatmentin hypertensive OSA patients with no somnolence). BARBEet al.[43] analysed non-somnolent OSApatients. Overall, the SBP decreased by 1.89 mmHg (p50.06) and the DBP by 2.19 mmHg(p50.0008). However, when CPAP compliance was taken into account those patients with goodcompliance showed a more marked decrease in BP. In another study by DURAN-CANTOLLA et al.[44], OSA patients withde novohypertension were studied, to avoid the confounding effect of pre-existing chronic hypertension. CPAP significantly reduced both the mean 24-h BP (1.8 mmHg;p50.01) and the mean nocturnal BP (2.4 mmHg).

In the case of resistant hypertension (RH), however, the data are sparse. LOGANet al.[45] showed asignificant reduction in daytime, night-time and 24-h SBP (-1 mmHg) and night-time 24-h DBP(-7.8 mmHg) with CPAP treatment in 11 patients with ABPM-confirmed RH. MARTINEZ-GARCIAet al.[46] found a reduction in daytime and night-time SBP (-5.2 mmHg), but no effect on DBP,

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in 33 OSA patients with ABPM-confirmed RH when treated with nCPAP. In an observationalretrospective study on 42 OSA patients with RH, DERNAIKA et al. [47] found, on the basis ofconsulting room BP measurements, a significant decrease in mean daytime BP (-5.6 mmHg) in apatient with RH after 12 months of CPAP treatment, compared with 56 OSA patients withcontrolled hypertension (-0.8 mmHg). It can, therefore, be concluded from this data that CPAPimproves BP in OSA patients with RH.

All the data mentioned above have been exhaustively summarised by D URAN-CANTOLLAet al. [42]

in a very recent and detailed review. They analysed most of the controlled studies, as well as theaforementioned meta-analyses. The main findings of this review were that CPAP reduces 24-hmean BP by,2 mmHg, particularly in the night-time values. The effect is greater in patients withhigher BP levels and in those with more severe OSA. These authors concluded that treatment withCPAP should be considered in patients with severe OSA and hypertension, even in the absence ofsymptoms. The authors also pointed out the need to find markers to distinguish subjects in whomblood pressure will decrease with CPAP from those who will show no response.

Metabolic disturbances

There is evidence to suggest that OSA places patients at risk of developing metabolic syndrome,although no clear causality has yet been established. An overview of this topic has been undertakenby LEVY et al. [48] and TASALI and IP [49]. There are some discrepancies in the studies that haveexamined the effect of CPAP, mainly resulting from: the different lengths of the treatment period(1 day to 6 months), the absence of a control group, the diversity of the population groups, thedifferent parameters used, the lack of data on compliance and, probably most importantly, thepresence of associated comorbidity (particularly obesity). Such discrepancies can be demonstratedby, for instance, the findings of HARSCH et al. [50] and COUGHLIN et al. [51]. HARSCH et al. [50]analysed insulin sensitivity in 40 OSA patients who underwent CPAP treatment. Improvement wasobserved over a period of 3 months. In contrast, COUGHLINet al.[51] found no change in glucose,

lipids and insulin resistance but significant changes were observed in blood pressure values after6 weeks of CPAP in patients with OSA. LAMet al.[52] recently published a randomised controlledtrial on the effect of CPAP on insulin sensitivity in OSA patients. The main finding was that CPAPimproved insulin sensitivity in subjects after 12 weeks of treatment. Even though some studieshave demonstrated the short-term beneficial effect of CPAP on some metabolic values, there is stilla need for well-designed, long-term longitudinal and interventional studies [53].

Inflammatory and sympathetic changes in activity changes

The physiological changes that occur during apnoea episodes (hypoxia/normoxia, sustained

negative intrathoracic pressure) induce a series of biological changes, such as systemicinflammation, impairment of the vascular endothelial function, platelet activation, and activationof the sympathetic nervous system [5, 6]. Similar inflammatory changes can, however, also beinduced by obesity, a condition frequently associated with OSA [48]. These physiological andbiological changes translate into disease when the degree of injury outweighs the protectivefunction [5, 54]. This topic has been reviewed by several authors [5, 55, 56]. Most of the studies todate have demonstrated that CPAP therapy is associated with the reversal of various biologicalabnormalities (cytokines, adhesion molecules or nitric oxide) that occur in OSA patients [5763].It has also been demonstrated that sympathetic activation is reduced by CPAP treatment [64, 65].However, there is still some controversy surrounding this; KOHLERet al.[66] recently analysed 100

males with moderatesevere OSA who were randomised to therapeutic (n551) or subtherapeutic(n549) CPAP treatment for 4 weeks with the objective of investigating the effects of activetreatment on inflammatory markers, such as highly sensitive C-reactive protein (CRP), interleukin6, interferon-c, and anti-inflammatory adiponectin. Unlike other authors who have demonstratedimprovements in various biological markers in OSA patients, the authors found that, after4 weeks, no beneficial effects were observed on the blood markers of inflammation and

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adiponectin. In contrast, DRAGERet al.[67] randomly assigned 24 patients with severe OSA to eitherCPAP or no treatment, and they found a significant decrease in CRP after 4 months of CPAPtherapy. KOHLERet al. [66] suggested that associated comorbidity could be a possible explanationfor the conflicting findings. All patients included in the study by D RAGERet al.[67] were free of anycomorbidities, whereas the study by KOHLER et al. [66] included typical OSA patients, some ofwhom had arterial hypertension, diabetes and an increased cardiovascular risk score.

Heart function

The physiological and biological responses to repetitive upper airway closure in OSA may exertdeleterious effects on cardiac function. It therefore makes sense to consider whether CPAP isindicated in patients with cardiac disease and OSA, even in those without somnolence (the typicalsymptoms of OSA and the main indication for CPAP), because CPAP could improve the cardiacfunction, especially when the heart is already compromised. ARZT et al. [68] analysed the ESSscores of 155 consecutive patients with heart failure, compared them with controls and found thatpatients with heart failure have less subjective daytime sleepiness. This is one of the reasons whyCPAP indication is difficult in such patients. Furthermore, there is insufficient data available at

present to support the use of CPAP in non-symptomatic OSA patients with cardiac disease [69].Of course, these cardiac patients should be considered for OSA diagnosis and treatment when theypresent typical OSA symptoms. Clinical judgment and caution must ultimately be used to decidewhich non-symptomatic OSA patients and cardiovascular diseases should be considered for CPAPtreatment, especially in those with severe diseases. The coexistence of OSA with confoundingvariables, such as obesity, makes it difficult to prove that OSA is a direct participation in thetriggering or exacerbation of several cardiovascular diseases, although some authors havesuggested that CPAP reduces the classical physiological and biological changes even in minimallysymptomatic OSA patients [70]. Interestingly, DRAGERet al. [67] tested the effects of the use ofCPAP for a 4-month period versus no CPAP on early signs of atherosclerosis (carotid intima-

media thickness and arterial stiffness; evaluated by pulse-wave velocity) in 24 patients (12undergoing CPAP and 12 controls) with severe OSA. In the control group, the intima-mediathickness was similar at baseline and at 4 months, whereas the intima-media thickness significantlydecreased in the group randomised for CPAP therapy. The differences between the groups provedsignificant. The arterial stiffness in the control group was similar at baseline and at 4 months, butthe pulse-wave velocity decreased in all 12 subjects treated with CPAP and the mean decrease wassignificant. The differences between the groups were also significant. These data suggest that CPAPcan limit the progression of arteriosclerosis in OSA patients.

With regards to the effect of CPAP in patients with cardiac failure, only a few randomised trialshave been undertaken to analyse the effect of CPAP on OSA patients with cardiac failure, and allthese were conducted over a short period of time. In a randomised trial involving 24 patients withheart failure (mean left ventricular ejection fraction (LVEF)f45%) and moderate-to-severe OSA(mean AHIo20), KANEKOet al. [71] found that 30 days of CPAP lowered the daytime heart rateand SBP, and increased the LVEF by 9%. In contrast, there was no change in any of these variablesin the 12 patients in the control group. However, using the same type of patients and methods,EGEA et al. [72] and MANSFIELD et al. [73], found only a modest increase in the LVEF after3 months of CPAP treatment, mainly in those patients with less deteriorated LVEF. The study beSMITH et al. [74], found no improvement in any parameter of cardiovascular function in aplacebo-controlled crossover study of a population, with a similar degree of heart failure,undergoing automatic CPAP (A-CPAP), while KHAYATet al.[75] did find a marked improvementin heart function when using bilevel positive airway pressure (BiPAP) compared with CPAP. Moredata are therefore needed to definitively confirm or discount the role of CPAP in improving thecardiac function in patients with heart failure and OSA.

KHAYAT et al. [76] recently randomised patients with descompensated heart failure and OSA(diagnosed within 2 days of hospitalisation) into two groups: standard treatment plus CPAP (n523)

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or standard treatment alone (n523). The post-randomisation change in LVEF from baseline to3 days, in the intervention arm, was significantly superior to that of the control group [76]. Thisstudy raised an important issue: the probable impact of treatment on patients with acute heart failureand OSA.

CheyneStokes respiration (CSR) with central sleep apnoea (CSA), defined by CSR/CSA indexo15 events?h-1, was found in 40% of an unselected sample of 81 male patients with heart failure[77]. Various studies have shown higher rates of mortality in these patients. Improvements in

cardiac function, nocturnal oxygenotherapy, theophyline and acetazolamide have been used totreat these patients, albeit with limited success [7881]. CPAP treatment has also been considered[8284]. In a controlled trial conducted by SINet al.[84], 66 patients with cardiac failure and with(n529) or without (n537) CSR/CSA, were randomised to either a group that received CPAPnightly or to a control group. CPAP had no significant effect on LVEF in either group, but it wasassociated with a relative risk reduction of 60% in the mortality/cardiac transplantation rate inpatients who complied with CPAP therapy. The authors suggested that CPAP can reduce thecombined mortality/cardiac transplantation rate in those congestive heart failure patients whocomply with therapy. These data led to a large multicentre, randomised trial involving 258 patientswith heart failure and CSR/CSA which was known as the Canadian Positive Airway Pressure Trial

for Patients with Congestive Heart Failure and Central Sleep Apnoea, referred to as CANPAP [85].The application of CPAP reduced nocturnal desaturation and induced a modest but significantimprovement in the LVEF. The primary results of CANPAP did not, however, demonstrate theefficacy of CPAP and led to an early termination of CANPAP. The CANPAP researchersperformed a post hoc analysis and found a marked improvement in several variables in thosepatients in whom CSR/CSA was normalised. Thesepost hocobservations suggested that in patientswith heart failure, effective treatment might even improve their survival rates [86]. The potentialimplications of the post hocCANPAP findings have been addressed in a recent debate [87, 88].Moreover, as CPAP does not eliminate apnoea in all cardiac failure patients with CSA, new formsof ventilation,e.g.adaptive servoventilation (ASV), have been investigated. This type of ventilation

involves enhancing the ventilation when the flow is reduced by CSR/CSA. Preliminary studies haveshown that ASV is a promising treatment option in patients with CSR/CSA [8991], although itsefficacy has yet to be tested in large randomised multicentre trials.

Cardiac arrhythmias

The Sleep Heart Health Study has provided evidence of the association between OSAS andnocturnal cardiac arrhythmias, including atrial fibrillation and complex ventricular arrhythmias[92]. CPAP therapy has been reported to resolve pathological cardiac dysrhythmias [9395].Observational data suggests the presence of untreated OSA is associated with an 82% risk of the

recurrence of atrial fibrillation after an ablation procedure within 1 yr. This is roughly double therisk observed in effectively treated OSA patients [96]. Nevertheless, the data mentioned are stillinsufficient to clearly define the need for CPAP treatment in patients with OSA and arrhythmia,independently of the indication for treatment by the classical symptoms.

Stroke

OSA has been suggested as a modifiable and independent risk factor for stroke [97100], asdefined by international guidelines [101], and some studies have demonstrated that patients withstroke and OSA have an increased risk of death events [102, 103]. However, little is known about

the impact of CPAP treatment on patients with stroke and OSA. WESSENDORFet al.[104] observedthat CPAP was associated with improved well-being and decreased nocturnal blood pressure in thestable phase of the neurological event, while SANDBERGet al.[105] concluded that CPAP treatmentreduced post-stroke depressive symptoms. In a 5-yr prospective observational study in 166patients with an ischaemic stroke, MARTINEZ-GARCIA et al. [106] found that long-term CPAPtreatment of moderate-to-severe OSA and ischaemic stroke is associated with a reduction in the

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excess risk of mortality when compared with patients with an AHI .20 or an AHI ,20, or to non-compliant patients. The number of non-compliant patients was deemed high, as only 28 out of 96complied with the treatment [106]. PARRA et al. [107] have recently completed a large,randomised, controlled multicentre trial with 140 patients with an AHI o20; 71 were assigned toearly nCPAP plus conventional treatment and 69 to conventional treatment alone. The authorsconcluded that an early use of nCPAP in first-ever ischaemic stroke patients, who were followedup for 2 yrs, tended to improve some neurological outcomes [107]. A more precise selection of

patients and different tools for measuring improvement would also be desirable, as would longerfollow-up periods.

Mortality

Studies on long-term outcomes in patients with OSA and mortality have been reported. PEKERet al. [8] found an abnormally high level of cardiovascular disease in incompletely treated OSApatients, when compared with those efficiently treated over a 7-yr follow-up period. In aprospective cohort study, PUNJABI et al. [108] followed a large number of patients for 8.2 yrs andfound that OSA was associated with all causes of mortality, particularly coronary disease. Two

recent studies have analysed the long-term cardiovascular consequences in OSA patients [9, 10]. Inboth studies, the patients were free to accept or refuse CPAP treatment. The first study observed anincrease in cardiovascular mortality over a 10-yr follow-up in untreated or non-compliantpatients, when compared with patients with adequate compliance. The other study, however,suggested that untreated OSA may increase the severity rather than the prevalence ofcardiovascular disease. Furthermore, in mildmoderate OSA [109] or chronic obstructivepulmonary disease with OSA [110], CPAP improved the levels of morbidity and even mortality.More large-scale studies of treatment with CPAP are now urgently needed, especially in mild-moderate patients.

Others

Cognitive function

The information available is not clear, as demonstrated by three recent reviews. S AUNAMAKI andJEHKONEN [111] have analysed various neuropsychological functions, as covered by 55 articles.Depression and anxiety were evaluated most often, using the customary mood scales, but only afew studies provided any psychiatric diagnosis. The prevalence for depression was 763%, and foranxiety it was 1170%. The effect of CPAP on mood was inconsistent. The authors concluded thatvariations in the prevalence of depression and anxiety are affected by patient characteristics, mood

assessment methods, and the overlap between mood alterations and OSA-related symptoms.CPAP might improve mood alterations but more long-term data are needed to confirm this. Thesame authors also reviewed the recent research on OSA and the executive functions [112]. Theyreviewed 40 studies, in which most of the patient samples were heterogeneous in terms of OSAseverity. The executive functions were generally assessed with standardised test methods, and halfthe studies used only one or two tests. The most damaged fields of executive functions wereworking memory, phonological fluency, cognitive flexibility and planning. CPAP treatmentimproved performance times, cognitive flexibility and planning, but the deficits in workingmemory and phonological fluency persisted. The authors concluded that executive functions arethe cognitive domain most damaged by OSA. Once again, the authors pointed out that more

research is needed to ascertain the effectiveness of CPAP treatment on executive dysfunctions.Finally, and very recently, SANCHEZ et al. [113] performed an excellent and exhaustivebibliographic search in Medline, PsycINFO, and the Cochrane Database of Sytematic Reviews(19942007) for databases and selection of works that have evaluated the efficacy and/oreffectiveness of CPAPvis-a`-visdaytime somnolence, depression and cognitive functioning in OSApatients. The selected studies included randomised clinical trials in which CPAP was compared

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with more conservative measures,i.e.sham CPAP and oral placebo. The main conclusions were asfollows. 1) CPAP is effective in reducing subjective reports of daytime sleepiness. 2) It is estimatedthat depression occurs in 40% of OSA patients, but this is not related to OSA severity. Theeffectiveness of CPAP treatment varies from one study to the other. 3) Only some cognitivefunctions, particularly the executive functions, were improved with CPAP. 4) The diversity of theresults reflects differences in methodology, treatment duration, and severity of OSA, as well asdifferences in the cognitive functions under evaluation. The authors therefore conclude that

further research is needed to examine the efficacy of treatment that corresponds with the severityof OSA and thereby develop an adequate assessment protocol. Both medium- and long-termevaluations are also required.

Various

Other entities can also be considered when investigating the effects of CPAP, but in most casesassociated comorbidity makes the data difficult to evaluate. Furthermore, the literature is oftenuntrustworthy. The following comments should thus be approached with great caution. In OSA,increased negative intrathoracic pressure induces the secretion of atrial natriuretic peptide,

causing an increase in urine production, but CPAP markedly improves nocturia [114]. OSA isassociated with seizure exacerbation in older adults with epilepsy, and its treatment mayrepresent an important route for improvements in seizure control in this population [115].More data are needed, however, in order to accurately verify this hypothesis. OSA is verycommon in patients with end-stage renal disease. CPAP improves the classical symptoms ofOSA, reduces the high level of pressure and enhances glomerular hyperfiltration [116, 117].CPAP may also have a beneficial effect on the erectile dysfunction found in patients with sleepapnoea. It has been shown to improve symptoms, but significantly less so than sildenafil [118].In patients with morbid obesity, bariatric surgery is one treatment that should always beconsidered, but a diagnosis of OSA is a risk factor for potentially significant adverse effects for

this type of surgery. Problems with bariatic surgery are exacerbated by association with a historyof deep-vein thrombosis, OSA, pulmonary embolus or impaired functional status [119]. Ideally,therefore, such patients should be tested with a sleep study before surgery (at least in cases withclinical OSA symptoms) and treated with CPAP if OSA is diagnosed. However, the AmericanSociety of Anesthesiologists Task Force on perioperative management of patients with OSAsuggests, in the absence of any testing facilities, patients with a high clinical suspicion of OSAshould be treated with CPAP [120]. We suggest that A-CPAP devices that do not requiretitration could play an important role when diagnosis has not been confirmed by a sleep studyand patients have suggestive clinical symptoms. This could make CPAP treatment simpler.Finally, no adverse effects from bariatric surgery, e.g.anastomotic leaks, have been reported with

CPAP treatment [121].

CPAP treatment

Indications

The management of OSA must be tailored to individual patients, taking into account the severityof the OSA, the possible anatomical abnormalities and the coexisting medical problems, such asobesity and unfavourable lifestyle. It is essential to treat OSA once it has become severe, because ofthe aforementioned associated mortality and morbidity. A hallmark study by MARIN et al. [9]

showed that patients with an AHI .30 had more long-term cardiovascular morbidity andmortality, but that these were reduced by CPAP treatment. Even though CPAP is the most usefultreatment in most cases, weight loss programmes, physical exercise, positional therapy, sufficientsleep time and avoidance of sedatives or alcohol should always be considered. Upper airwaysurgery options are indicated in cases of obvious anatomical abnormalities, while bariatric surgeryshould be considered in cases of morbid obesity.

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With regard to CPAP, this is easy to indicate in patients with severe OSA (AHI .30 withmanifested secondary symptoms), but more difficult when patients have minor symptoms orwhen they have no symptoms but have a high AHI. The main reason for the absence of definitiveindications in such patients is the lack of any long-term outcome studies. The current indicationof treatment is based on the consensus of several sleep societies. For instance, the Spanish SleepSociety makes the following recommendations [122, 123]. 1) Patients with clear OSA, secondarysymptoms plus an AHI .30 undergo general treatment measures and CPAP. 2) Patients with mild

symptoms and an AHI,

30 undergo general treatment measures. 3) Patients with an AHI.

30with notable cardiovascular disorders, even with minor secondary symptoms to undergo generaltreatment measures plus CPAP. 4) Patients with a high AHI .30 but no symptoms orcardiovascular disorders undergo general treatment measures but with a close follow-up becauseCPAP is probably going to be indicated, especially in the non-aging population, if generalmeasures have failed. It should be mentioned that, when simplified diagnostic devices are used, theAHI is usually underestimated by 510 points. The recommendation of CPAP treatment in non-symptomatic patients is an important issue that has not been fully resolved. In a recent review ofthe topic, MONTSERRATet al.[124] emphasise the importance of well-designed randomised trials todetermine whether treating non-sleepy patients with OSA prevents cardiovascular disease and

whether treating OSA in patients with coexisting cardiovascular diseases reduces morbidity andmortality.

CPAP titration

Polysomnography

After a patient is diagnosed with OSA, the current standard practice involves performing attendedCPAP titration PSG, during which positive airway pressure is adjusted throughout the recordingperiod to determine the optimal pressure for maintaining upper airway patency. Titration is

usually undertaken on a trial-and-error basis by the technician operating the PSG, who adjusts theapplied pressure until those respiratory and sleep parameters that are considered to be clinicallyimportant are reduced to the degree considered acceptable by the clinician. One study hasreported that the presence of upper airway hysteresis in some patients means that the optimalCPAP value during the latter portion of the titration night is slightly lower than that requiredearlier in the night, suggesting that some individuals are prescribed unnecessarily high pressure asa result of the current criteria for titration [125]. The American Academy of Sleep Medicine(AASM) recently published clinical guidelines for the manual titration of positive airway pressurein patients with OSA [126]. These can be summarised as follows: 1) patients must receive CPAPtraining and educational sessions; 2) pressure should be increased from 4 cmH2O by,1 cmH2O

every 5 min until all the respiratory events and snoring are eliminated; 3) when the respiratoryevents have disappeared, the pressure should be maintained for 30 min to ensure that the pressureis adequate in supine and rapid eye movement (REM) sleep; 4) more CPAP should beadministered if required; and, finally, 5) when the pressure is sufficient, CPAP has to be reducedby 1 cmH2O until the events reappear. The pressure immediately prior to this reappearance ofevents is the optimal one. An acceptable titration is the pressure that normalises breathing or sleepor reduces the respiratory disturbance index to less than five, even in the REM and supine periods,with arterial oxygen saturation .90% with acceptable leakage. If the CPAP is higher than15 cmH2O BiPAP could be an option, although there are no definitive data to support it. WhenBiPAP titration is performed, the following points should be considered: 1) the CPAP is initially

increased until apnoeas and marked hypopnoeas disappear; 2) an increase in the inspiratorypressure, if desirable, must only be started in the presence of non-severe hypopnoeas; 3) therecommended initial pressure setting is 8/4 cmH2O and the suggested difference between the PIand expiratory pressure (PE) should be around 4 cmH2O (maximum 10 cmH2O; a trial-and-errorprocess is needed, combining PE and PI changes); and 4) the maximum PI should not exceed20 cmH2O. Central apnoeas may sometimes appear during titration when CPAP is increased;

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this is called complex sleep apnoea. The significance of this phenomenon is not clear, although itmay be precipitated by the sleep fragmentation associated with initial CPAP titration. Complexsleep apnoea usually disappears over the course of CPAP treatment [127, 128]. When it isrepetitive, however, some authors recommend using ASV [129], although we suggest treating thepatient with CPAP for a few weeks because the central apnoeas will probably disappear. SALLOUMet al. [130] recently induced hypocapnoea via nasal mechanical ventilation during sleep andcompared the apnoeic threshold, CO2 reserve and controller gain between subjects, with and

without OSA, and matched for age, sex and BMI. The controller gain was significantly increased inthe subjects with OSA when compared with the control. Controller gain decreased and CO2reserve increased in seven subjects, who were restudied after using CPAP for 1 month. Theauthors conclusions were that increased ventilatory instability in subjects with OSA, and itsreversibility with CPAP, is consistent with the notion that complex sleep apnoea may be caused bya reversible increase in chemoreflex sensitivity to hypocapnoea. CPAP therefore serves as rathermore than a mere splint that opens an upper airway.

Titration using A-CPAP to determine a fixed pressure

Traditional CPAP maintains an effective fixed pressure at all times. A number of A-CPAP deviceshave been developed for treatment to improve compliance, as they require less pressure to correctrespiratory events. When an obstructive event is detected, the device increases pressure until theevent is eliminated (fig. 6aand b). If no further events are detected during a set time period, thedevice will decrease pressure to a preset minimum. These devices incorporate sensors and softwareto detect and classify events automatically and reliably, and then increase the CPAP. No changes incompliance have been demonstrated when comparing fixed CPAP with A-CPAP treatment [131,132]. However, a few studies have suggested that some patients may benefit from A-CPAP. MASSIEet al.[133] found that patients who require higher fixed CPAP report greater benefits from the useof an A-CPAP device. Some important points need to be considered with respect to A-CPAP

including: 1) the A-CPAP device should be sufficiently robust to distinguish between sleep-disordered breathing events that require pressure adjustment (e.g. snoring, apnoeas, hypopnoeasand flow limitation) from common events (e.g. cough, sighs, swallowing, speaking, mouthbreathing, leaks and events associated with arousal from sleep) without triggering a modificationin the CPAP applied to the patient; 2) there is no consensus in the medical community as to whichsensors or pressure-increase strategies that need to be used; and finally, and very importantly; 3)almost all the A-CPAP devices are different from one another. The term A-CPAP is thus verygeneric and is of no use when discussing this type of treatment or device. Knowledge of different

Pressure in response

to clear events1 cmH2O,-5_10 min

Pressure (1 cmH2O) but

after analysing periods of30 min in responseto even mild events

Pressure in response

to 30 min ofnormal breathing,1 cmH2O

PressurecmH2O

a)

1 h 1 h 5 h

Pressure

Normal

OK

Hypopnoea

Little snoringor flowlimitation

Hypopnoea

Hypopnoea+ snoring

Apnoea

b)

Figure 6. Continuous positive airway pressure titration treatment: a) automatic or b) manual. Nasal pressure isincreased slowly, every 510 min in response to abnormal respiratory events until the breathing pattern is normal.

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types is needed and this factor, therefore, reinforces the need for bench testing with public accessto the results.

As mentioned above, A-CPAP was originally designed for treatment but was quickly adopted foruse in CPAP titration to determine the fixed CPAP required [134, 135]. MASAet al.[134], studiedpatients with severe OSA and reported that after 3 months of CPAP, there were no significantdifferences in the levels of improvement in AHI or subjective sleepiness when the fixed-pressureCPAP prescription was determined by the CPAP titration technician, during PSG in the sleep

laboratory, or was derived from examination of the profiles of the pressure applied duringA-CPAP. MULGREWet al. [135] also obtained similar results. It is important to note that, prior torandomisation, all participants had a personal instruction and interface-fitting session, as well asan opportunity to wear the CPAP device while awake in an effort to facilitate tolerance. A verysignificant point to be considered is that trials examining the use of A-CPAP to identify a single,fixed-pressure prescription generally excluded OSA patients with noteworthy medical andpsychiatric morbidities, such as severe nasal obstruction, even though they represented 20% of thepopulation [134]. Caution is required, therefore, as noted by MARRONEet al.[136] in their study,predictive equations obtained different pressure levels compared with A-CPAP 95th percentile,especially in the low and high range. Present day A-CPAP devices, and even regular CPAP devices,

make it possible to properly analyse the possible presence of residual events and leaks, as well asthe real compliance (time of adequate pressure). In patients who find difficulties with the fixedCPAP recommended by an A-CPAP, we suggest first performing a PSG, although it is also worthanalysing the parameters mentioned above, as in most cases, leaks and inadequate compliance areresponsible and so PSG titration is therefore unnecessary. The AASM published parameters for thepractice of A-CPAP titration [137]. It must be pointed out that A-CPAP titration has a number ofcontraindications: congestive heart failure; significant lung disease; the probability of nocturnalarterial oxyhaemoglobin desaturation, due to conditions other than OSA (e.g. obesityhypoventilation syndrome); absence of snoring (either naturally or as a result of palate surgery);and CSA syndromes in patients who are not currently candidates for A-CPAP titration or

treatment. Currently, A-CPAP devices are not recommended for split-night titration.

Split-night PSG titration

Split-night PSG titration is an attended, in-laboratory, overnight procedure during which sleepand breathing variables are recorded for diagnostic purposes during the first 23 h of the sleepperiod. After this period, if specific criteria are met, CPAP titration is performed for the remainderof the night. Split-night PSG titration may provide a pressure prescription that is comparable tothat of a full-night PSG titration in patients who demonstrate frequent obstructive events early inthe sleep period [138]. However, despite the recommendations of the AASM, there are insufficient

data to support the widespread use of split titration, except probably in severe patients. When it isused, it needs to be complemented by educational and training programmes. The technician needsto fully understand that if the number of events is not very high (,30) or if there are markedpostural or REM changes, then titration should not be performed and the diagnosis should becontinued with PSG.

CPAP treatment adherence and complications

CPAP treatment frequently has side-effects that impede compliance [139143] and thus limit itsbeneficial effects. Table 1 shows the most commonly reported adverse effects, which include:

rhinitis; nasal congestion and rhinorrhea with dryness or irritation of the nasal and pharyngealmembranes; leaks; skin lesions from contact with the mask; irritated eyes; claustrophobia; gastricand bowel distention; recurrent ear and sinus infections; and finally, negative social factors. Somepatients also show no improvement or find their mask slipping off uncontrollably. With adequatetraining, informative sessions and early treatment, most side-effects disappear or are controlledwithin a few weeks. The follow-up visit should generally be scheduled within 1 month of starting

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treatment with CPAP, and during this visit the parameters showed in table 2 should besystematically monitored. The most common side effects described are mouth leaks, rhinitis andpremature removal of the nCPAP mask [141143]. These three common side-effects have beenchristened by BALTZANet al.[142] as the side-effect syndrome. In addition to these side-effects, themotivation to use CPAP is associated with patients perceptions of the disease severity and outcomeexpectancies, rather than any objective measures of severity, such as the respiratory disturbanceindex or arousal index, and these are the most common facilitators of good compliance. It istherefore helpful to identify and act on the psychological predictors of adherence [143]. In fact,psychological support is at least as important as technical improvements in this field [140].

Nasal problems, particularly nasal congestion, rhinorrhea and sneezing, are the most importantelements of the side-effect syndrome. These problems may be caused by inflammation, resultingfrom reduced relative humidity derived from mouth leaks, which can lead to substantial

Table 1. The most commonly reported adverse effects of continuous positive airway pressure

Adverse effect Solution

Rhinitis See rhinitis protocol

Leaks, skin lesions, noise or conjunctivitis Try other masks

Avoid mouth leaks by using a chinstrap

Dry mouth Humidification

Oronasal maskLack of improvement Refer to table 3

Involuntary removal during the night Support measures

Explain that nothing will happen

Try a different mask

Anxiety, phobia, negative social aspects Psychotherapy

Other: thoracic or abdominal pain, aerophagia,

pressure sensation or cold air

Explain that most of them are transient; if cold air

is problem, offer humidification

Rare: maxillary, teeth, sinus or hearing

problems

Other diagnosis

Table 2. Recommended procedure at the control follow-up visit for a patients with obstructive sleep apnoeaundergoing treatment with continuous positive airway pressure (CPAP)

Clinical situation with regard to the main complaint before treatment

1. Better

2. Similar

3. Worse

Epworth Sleepiness Scale

Somnolence in opinion of the interviewer

1. No

2. Passive

3. Active

4. Driving

Compliance

CPAP device hours per day; from the counter and time of adequate pressure from CPAP

Check residual events and leaks from the CPAP device card

Measure the pressure in the maskEspecially if modifications, e.g. humidification, have been introduced

Check the swing of pressure during breathing

Ask for secondary effects

Measurement of blood pressure if the patient had hypertension

Check body weight if patient obese

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patient is unable to tolerate conventional nasal masks. A face mask cannot be recommended as afirst-line interface but it can be considered if nasal obstruction or dryness limits the use of a nasalmask [154]. In non-compliant patients, the C-Flex relief technology system could be useful [155].

Another component of the side-effect syndrome is the mouth leak, which represents a majorproblem during CPAP treatment and has yet to be satisfactorily resolved. A face mask is the bestoption in such cases but it is not always well tolerated [154]. We suggest that before using a facemask it could be worth trying a combination of chinstrap [156] plus humidification (to treat the

major symptom of oral leaks, which is a dry mouth) [157]. Once a patient has adapted to thissolution, the problem may be reduced within a few weeks.

Finally, the last component of the side-effect syndrome is the CPAP mask slipping off during sleep;this problem is not infrequent but is difficult to solve. There is no miraculous answer but the keysto success are finding a mask that is very comfortable, by solving local problems (leaks, nose anddry mouth) and treating nasal obstruction, and by educating patients and providing them withsupport, to prevent from feeling overwhelmed by this failure. Some authors have recommendedthe addition of a short course of sedative drugs at the beginning of CPAP treatment to improvecompliance [158]. A number of patients noted discomfort with the prescribed level of pressure

before they fall asleep and find it particularly difficult to exhale. A ramp function, which allowsthe pressure to increase gradually to the prescribed level over a set time (typically 20 min) as thepatient falls asleep, may also improve comfort and compliance.

CPAP treatment notwithstanding, many patients complain about persistent sleepiness. Ratherthan hastily attributing this to long-term intermittent hypoxia related to apnoeic events that coulddeteriorate the brain structures regulating alertness, such patients require a further precise anddefinitive analysis [159].Table 3shows the procedure recommended by the authors in these cases[159]. Associated disease, side-effects and inadequate compliance are usually the main reasons forthis phenomenon. If no cause is detected, then treatment with modafinil is needed. Some recentpapers have proposed that side effects must be treated quickly to improve compliance [160162].

Statement of Interest

None declared.

Acknowledgements

This work was supported in part by the Ministerio de Ciencia y Tecnolog a (SAF2008-02991 andPI08/0277) and SEPAR-FUCAP.

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