Chapter 15

Continuous positive airway pressure treatment in patients with OSA

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

Summary
Obstructive sleep apnoea (OSA) is a common disorder that increases morbidity and even mortality. When the apnoea/ hypopnoea index (AHI) is .30 and is accompanied by symptoms, OSA must be treated. Although continuous positive airway pressure (CPAP) is the most useful form of treatment, it should always be complemented by the prescription of the following: a weight loss programme, physical exercise, positional therapy, sufficient sleep time, and an avoidance of sedatives and alcohol. As each patient needs a different fixed CPAP, titration must be performed. When patients have no severe associated comorbidity the fixed CPAP can be obtained by using automatic devices. Training, educational sessions and close follow-up, especially during the first months, are crucial for obtaining adequate compliance. It is not clear whether nonsleepy OSA patients should be treated, although CPAP should probably be prescribed for those with severe cardiovascular disease or a very high AHI. Keywords: Adaptive seroventilation, continuous positive airway pressure, continuous airway pressure complications, continuous positive airway pressure titration, sleep apnoea, sleep apnoea treatment
nic, *Servei Pneumologia, Hospital Cl Facultat de Medicina, IDIBAPS, " sica i Bioenginyeria, Unitat de Biof Facultat de Medicina, Universitat de Barcelona - IDIBAPS, + Hospital Universitari del Sagrat Cor., Barcelona, and # CIBER Enfermedades Respiratorias, Bunyola, Spain Correspondence: J.M. Montserrat, Sleep Laboratory. Hospital Clinic, Villarroel 170. 08036 Barcelona, Spain, Email jmmontserrat@ub.edu

CPAP IN OSA

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

bstructive 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 of the upper airway can be caused by a variety of events, such as anatomical factors, abnormal bony and 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 for producing the effort required to keep the upper airway lumen open. Under-performance by the upper 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 provide enough 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 most common pathophysiological consequences are: periods of recurrent hypoxaemia, transient repeated arousals, marked swings in negative intrathoracic pressure and increased sympathetic activity [4, 5]. These injuries stimuli bring about biological consequences [6] that have subsequent clinical harmful effects, such as somnolence and inflammation, with associated metabolic, neurocognitive and cardiovascular effects [5]. OSA also leads to higher mortality rates [7, 8]. Several studies have demonstrated that treatment with continuous positive airway pressure (CPAP) reduces not only the above 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 critical pressure (Pcrit) [11, 12]. Figure 1 represents the upper airway as a simple tube with a collapsible segment. Pcrit is defined as the minimum intra-luminal airway pressure required to keep this collapsible 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 Pcrit is negative [11, 12] and, therefore, the airways tend to remain open and stable, despite the negative intraluminal pressure resulting from inspiration. This fact is explained by the upper airway muscles ability to generate enough force to avoid occlusion. However, in patients with OSA, Pcrit is positive and there is a collapse, and occlusion, of the upper airway during sleep (fig. 1b). In patients with
a)

b)

c)
J.M. MONTSERRAT ET AL.

Pcrit<0 P tr<0 (-4)# P N=0 P tr<0 (-30)

Pcrit>0 P N=0 P tr<0 (-30)

Pcrit _ +0 P N=0

Flow Poes

Figure 1. Respiratory model based on a Starling resistor for the collapsible upper airway. a) When critical
pressure (Pcrit) is lower than zero there is no airway collapse and the breathing pattern is normal, as shown in the normal flow and oesophageal pressure (Poes). b) When Pcrit is positive this results in an airway closure, apnoea, inducing a progressive decrease in intratracheal pressure (Ptr) as the patient tries to breathe against a collapsed airway. c) When Pcrit is slightly negative the upper airway partially collapses and a hypopnoea occurs as the Ptr progressively decreases along with inspiration. PN: upstream (nasal) pressure. #: -4 cmH2O; ": -30 cmH2O.

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hypopnoea (fig. 1c), Pcrit is less markedly negative than in normal subjects and the airway is susceptible to collapsing, especially when the subject exerts a large negative inspiratory pressure (PI). CPAP is the most common treatment for OSA [13, 14]. CPAP opens the upper airway pneumatically via constant pressure throughout the respiratory cycle (fig. 2). A CPAP machine is a device that generates a large quantity of flow [13], which passes through a tube into the nasal or oronasal mask (fig. 3). This mask incorporates a leakage that induces resistance and, therefore, positive pressure in its interior. As a result, the CPAP acts as a splint for the upper airway and thereby corrects all the harmful effects triggered by OSA [15]. Nasal CPAP does not eliminate the underlying causes of upper airway collapsibility in OSA but is a palliative P tr <0 CPAP P N= +10 (+6) treatment that prevents upper airway obstruction mechanically. The effectiveness of CPAP in preventing the upper airway from narrowing into OSA is illustrated by the computed tomography scan of a patients pharyngeal area during sleep (fig. 4). The upper images show two sections (fig. 4a and b) of the upper airway obtained when Flow the patient was sleeping without CPAP. In the right section the lumen of the upper airway is extremely reduced, Poes indicating that the airway is almost closed. When the patient was subjected to CPAP (fig. 4c and d) the upper airway lumen expanded considerably at this point of obstruction. Some authors Figure 2. Respiratory model based on a Starling resistor for the collapsible upper airway when nasal continuous positive airway have proposed that the increase in lung pressure (CPAP) is applied. CPAP increases the intraluminal volume found during CPAP could have pressure preventing the upper airway from collapsing. Ptr: a stabilising effect on the upper airway intratracheal pressure; PN: upstream (nasal) pressure; Poes: by stiffening it [16], and thereby oesophageal pressure. triggering a reflex that improves the tone of the dilator muscle. However, this theory does not withstand close scrutiny, as a decrease in upper airway muscle activity has been clearly demonstrated during CPAP administration [17].

CPAP IN OSA

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 other associated entities, such as cardiovascular or metabolic consequences associated with OSA [15].

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Symptoms and quality of life

Blower

Air filter

Leak orifice Patients with OSA have daytime Inspiratory airflow somnolence, along with complaints of impaired memory, concentraLeak airflow Blower airflow tion and irritability. These sympP+ toms lower the quality of life and CPAP tube CPAP device Humidifier exacerbate the risk of automobile Mask accidents. Three meta-analyses studied the efficacy of CPAP treatFigure 3. Diagram of nasal continuous positive airway pressure (CPAP) system used to treat patients with obstructive sleep apnoea. ment on the classical symptoms of P+: mask pressure. sleep apnoea [1820]. PATEL et al. [18] analysed 12 trials of CPAP with a larger number of patients (n5706) and found that CPAP significantly reduced the Epworth Sleepiness Scale (ESS) by an average of 2.94 points more than the placebo. When the authors analysed severe OSA patients, i.e. patients with an apnoea/hypopnoea index (AHI) .30 and a mean ESS .11, there was an even greater decrease in the ESS score [18]. In another meta-analysis, GILES et al. [19] used a Cochrane Database of Systematic Reviews to analyse 36 trials involving a large number of patients (n51,718). Compared with the control, CPAP showed significant improvements in objective and subjective sleepiness, as well as in measurements of quality of life and cognitive function. However, GILES et al. [19], suggested that long-term data are required for all outcomes in order to determine whether the initial benefits seen in a) b) short-term clinical trials persist. In this regard, some studies have suggested that compliance is low in a significant number of patients, especially on a long-term basis [21, 22]. Therefore, the main conclusions of the studies mentioned were that CPAP clearly improves measurements of both sleepiness and the quality of life in OSA patients with moderate-to-severe sleep disease, although more supc) d) port and care are needed to improve compliance, especially on a long-term basis. Finally, in the third meta-analysis, MARSHALL et al. [20] focused on the impact of CPAP on mild-to-moderate daytime sleepiness in seven randomised, controlled trials. CPAP was compared with either a placebo or with conservative management in the treatment of mild-to-moderate Figure 4. Axial computed tomography scans of the upper airway OSA (AHI 530). CPAP signifiobtained during sleep from a patient with obstructive sleep cantly reduced the ESS by 1.2 apnoea. a, b) Head sections taken of the patient breathing points and improved objective spontaneously without continuous positive airway pressure daytime wakefulness (MWT) by (CPAP). c, d) The same two head sections taken whilst the patient is undergoing the application of CPAP device. The arrows indicate 2.1 min, but it did not affect the upper airway lumen, which as shown increased with the use of objective daytime sleepiness (mean CPAP. benefit -0.2 min) [20]. The authors

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Treatment Other Classical clinical symptoms Somnolence Cognitive defects Others OK ? CPAP ?

Non-modifiable factors Age Genetics Sex Race Cardiovascular disturbances Modifiable factors Lifestyle Hypertension Systemic inflammation Obesity Diabetes Lipid disorders Hypercoagulability Tobacco

of this meta-analysis concluded that CPAP induces only small improvements in subjective sleepiness and objective MWT in people with mild-to-moderate OSA. In summary, and in keeping with the more recent comments of MCDAID et al. [23], in a systematic review of CPAP for OSA, CPAP is an effective treatment for moderate-tosevere symptomatic patients and may also provide some benefits for mild symptoms.

There is also evidence that the symptoms of daytime sleepiness and impaired concentration arising from untreated OSA patients lead to a significantly increased risk of Cardiac function automobile accidents [24, 25]. Figure 5. In sleep apnoea patients the beneficial effects of Patients with untreated OSA or continuous positive airway pressure (CPAP) have been well alcohol-intoxicated normal subjects demonstrated on clinical symptoms but have not been fully performed significantly less well in demonstrated in cardiovascular diseases or other circumstances, a steering simulation test when such as non-sleepy patients. compared with CPAP-treated patients or normal subjects [26]. In a recent systematic review of the OSA-related risk of crash in commercial motor vehicle drivers, TREGEAR et al. [27] analysed seven different electronic databases. 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 1.21 4.89. 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 need for annual relicensing in various cases such as: 1) patients with untreated OSA; 2) those who have had 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 to the Berlin Questionnaire. GURUBHAGAVATULA et al. [28] considered three methods of dealing with OSA patients in a population of drivers: 1) polysomnography (PSG) in all drivers; 2) PSG for the high-risk group of drivers; and 3) no intervention. The costs of each of these three approaches were the sum of the costs of testing and treating identified cases, plus the costs of the crashes themselves. If we assume that treatment prevents OSA-related crashes, PSG in all the patients is not cost-effective, because it is more expensive than the costs generated by crashes. However, PSG performed only on high-risk drivers 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 than not screening at all, and that treatment acceptance may need to be a condition of employment for affected drivers. However, there is some controversy about the efficacy of CPAP treatment in preventing 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 Short Form-36 questionnaire, and in sleep-specific quality of life measurements in most [29, 30], but not all studies, especially in mild patients [31]. Two groups of patients merit specific attention. In one et al. [32] studied only non-sleepy patients and no significant changes were found in study, BARBE the quality of life test after CPAP treatment, although the follow-up period was short. The elderly NEZ-GARCI A et al. [33] found population represents another special group. In this population MARTI

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that OSA in the elderly was not associated with a decrease in some quality of life tests when compared with younger subjects. Based on these results, the authors believe that further studies are needed to clarify the role of CPAP treatment for elderly patients with OSA. Of course, this does not mean that the aging population should not be treated with CPAP because other factors, such as the cardiovascular or neurocognitive impact of OSA, also need to be considered. The positive effects 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 with figure 5, cardiovascular CPAP efficacy will be divided into modifiable factors that can prevent cardiovascular diseases, such as systemic hypertension (a major problem) or metabolic syndrome, and intermediate mechanisms, as well as the effect of CPAP on myocardial function itself.

Systemic hypertension
OSA and systemic hypertension are associated diseases [37], although their causality and incidence have yet to be fully studied. In two short follow-up studies, incidence was mainly demonstrated in obese patients with OSA [38, 39]. The evidence of the effect of CPAP on the reduction of blood pressure (BP) has been analysed by two recent meta-analyses and a broad review of the topic [40 42]. It should be noted that most published studies in this field have significant methodological limitations, 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 taking antihypertensive medication (or not taking it); 3) different ways of measuring BP or diagnosing and treating OSA; 4) the presence or absence of OSA symptoms, such as somnolence or associated comorbidity; 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 identify randomised, controlled trials with an appropriate control group. Systolic and diastolic BP (SBP and DBP, respectively) was measured before and after treatment with CPAP. On the whole, the effects of CPAP were modest and not statistically significant; CPAP reduced SBP by 1.38 mmHg and DBP by 1.52 mmHg. However, in trials with more severe OSA (mean AHI .30), CPAP significantly reduced SBP and DBP by 3.03 mmHg and 2.03 mmHg, respectively. The metaanalysis of HAENTJENS et al. [41] covered only placebo-controlled randomised studies with data for 24-h ambulatory blood pressure monitoring (ABPM). The effect of the CPAP intervention significantly 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 an attempt 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 treatment in hypertensive OSA patients with no somnolence). BARBE et al. [43] analysed non-somnolent OSA patients. 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 good N-CANTOLLA et al. compliance showed a more marked decrease in BP. In another study by DURA [44], OSA patients with de novo hypertension were studied, to avoid the confounding effect of preexisting 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. LOGAN et al. [45] showed a significant reduction in daytime, night-time and 24-h SBP (-1 mmHg) and night-time 24-h DBP NEZ-GARCI A (-7.8 mmHg) with CPAP treatment in 11 patients with ABPM-confirmed RH. MARTI et 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 observational retrospective study on 42 OSA patients with RH, DERNAIKA et al. [47] found, on the basis of consulting room BP measurements, a significant decrease in mean daytime BP (-5.6 mmHg) in a patient with RH after 12 months of CPAP treatment, compared with 56 OSA patients with controlled hypertension (-0.8 mmHg). It can, therefore, be concluded from this data that CPAP improves BP in OSA patients with RH.
N-CANTOLLA et al. [42] All the data mentioned above have been exhaustively summarised by DURA in a very recent and detailed review. They analysed most of the controlled studies, as well as the aforementioned meta-analyses. The main findings of this review were that CPAP reduces 24-h mean BP by ,2 mmHg, particularly in the night-time values. The effect is greater in patients with higher BP levels and in those with more severe OSA. These authors concluded that treatment with CPAP should be considered in patients with severe OSA and hypertension, even in the absence of symptoms. The authors also pointed out the need to find markers to distinguish subjects in whom blood 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 undertaken by LEVY et al. [48] and TASALI and IP [49]. There are some discrepancies in the studies that have examined 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, the different parameters used, the lack of data on compliance and, probably most importantly, the presence of associated comorbidity (particularly obesity). Such discrepancies can be demonstrated by, 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 was observed over a period of 3 months. In contrast, COUGHLIN et al. [51] found no change in glucose, lipids and insulin resistance but significant changes were observed in blood pressure values after 6 weeks of CPAP in patients with OSA. LAM et al. [52] recently published a randomised controlled trial on the effect of CPAP on insulin sensitivity in OSA patients. The main finding was that CPAP improved insulin sensitivity in subjects after 12 weeks of treatment. Even though some studies have demonstrated the short-term beneficial effect of CPAP on some metabolic values, there is still a need for well-designed, long-term longitudinal and interventional studies [53].

CPAP IN OSA

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 systemic inflammation, impairment of the vascular endothelial function, platelet activation, and activation of the sympathetic nervous system [5, 6]. Similar inflammatory changes can, however, also be induced by obesity, a condition frequently associated with OSA [48]. These physiological and biological changes translate into disease when the degree of injury outweighs the protective function [5, 54]. This topic has been reviewed by several authors [5, 55, 56]. Most of the studies to date have demonstrated that CPAP therapy is associated with the reversal of various biological abnormalities (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; KOHLER et 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 active treatment on inflammatory markers, such as highly sensitive C-reactive protein (CRP), interleukin 6, interferon-c, and anti-inflammatory adiponectin. Unlike other authors who have demonstrated improvements in various biological markers in OSA patients, the authors found that, after 4 weeks, no beneficial effects were observed on the blood markers of inflammation and

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adiponectin. In contrast, DRAGER et al. [67] randomly assigned 24 patients with severe OSA to either CPAP or no treatment, and they found a significant decrease in CRP after 4 months of CPAP therapy. KOHLER et al. [66] suggested that associated comorbidity could be a possible explanation for the conflicting findings. All patients included in the study by DRAGER et al. [67] were free of any comorbidities, whereas the study by KOHLER et al. [66] included typical OSA patients, some of whom 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 exert deleterious effects on cardiac function. It therefore makes sense to consider whether CPAP is indicated in patients with cardiac disease and OSA, even in those without somnolence (the typical symptoms of OSA and the main indication for CPAP), because CPAP could improve the cardiac function, especially when the heart is already compromised. ARZT et al. [68] analysed the ESS scores of 155 consecutive patients with heart failure, compared them with controls and found that patients with heart failure have less subjective daytime sleepiness. This is one of the reasons why CPAP 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 they present typical OSA symptoms. Clinical judgment and caution must ultimately be used to decide which non-symptomatic OSA patients and cardiovascular diseases should be considered for CPAP treatment, especially in those with severe diseases. The coexistence of OSA with confounding variables, such as obesity, makes it difficult to prove that OSA is a direct participation in the triggering or exacerbation of several cardiovascular diseases, although some authors have suggested that CPAP reduces the classical physiological and biological changes even in minimally symptomatic OSA patients [70]. Interestingly, DRAGER et al. [67] tested the effects of the use of CPAP for a 4-month period versus no CPAP on early signs of atherosclerosis (carotid intimamedia thickness and arterial stiffness; evaluated by pulse-wave velocity) in 24 patients (12 undergoing CPAP and 12 controls) with severe OSA. In the control group, the intima-media thickness was similar at baseline and at 4 months, whereas the intima-media thickness significantly decreased in the group randomised for CPAP therapy. The differences between the groups proved significant. The arterial stiffness in the control group was similar at baseline and at 4 months, but the pulse-wave velocity decreased in all 12 subjects treated with CPAP and the mean decrease was significant. The differences between the groups were also significant. These data suggest that CPAP can limit the progression of arteriosclerosis in OSA patients. With regards to the effect of CPAP in patients with cardiac failure, only a few randomised trials have been undertaken to analyse the effect of CPAP on OSA patients with cardiac failure, and all these were conducted over a short period of time. In a randomised trial involving 24 patients with heart failure (mean left ventricular ejection fraction (LVEF) f45%) and moderate-to-severe OSA (mean AHI o20), KANEKO et al. [71] found that 30 days of CPAP lowered the daytime heart rate and SBP, and increased the LVEF by 9%. In contrast, there was no change in any of these variables in 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 after 3 months of CPAP treatment, mainly in those patients with less deteriorated LVEF. The study be SMITH et al. [74], found no improvement in any parameter of cardiovascular function in a placebo-controlled crossover study of a population, with a similar degree of heart failure, undergoing automatic CPAP (A-CPAP), while KHAYAT et al. [75] did find a marked improvement in heart function when using bilevel positive airway pressure (BiPAP) compared with CPAP. More data are therefore needed to definitively confirm or discount the role of CPAP in improving the cardiac 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 to 3 days, in the intervention arm, was significantly superior to that of the control group [76]. This study raised an important issue: the probable impact of treatment on patients with acute heart failure and OSA. CheyneStokes respiration (CSR) with central sleep apnoea (CSA), defined by CSR/CSA index o15 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 to treat these patients, albeit with limited success [7881]. CPAP treatment has also been considered [8284]. In a controlled trial conducted by SIN et al. [84], 66 patients with cardiac failure and with (n529) or without (n537) CSR/CSA, were randomised to either a group that received CPAP nightly or to a control group. CPAP had no significant effect on LVEF in either group, but it was associated with a relative risk reduction of 60% in the mortality/cardiac transplantation rate in patients who complied with CPAP therapy. The authors suggested that CPAP can reduce the combined mortality/cardiac transplantation rate in those congestive heart failure patients who comply with therapy. These data led to a large multicentre, randomised trial involving 258 patients with 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 significant improvement in the LVEF. The primary results of CANPAP did not, however, demonstrate the efficacy of CPAP and led to an early termination of CANPAP. The CANPAP researchers performed a post hoc analysis and found a marked improvement in several variables in those patients in whom CSR/CSA was normalised. These post hoc observations suggested that in patients with heart failure, effective treatment might even improve their survival rates [86]. The potential implications of the post hoc CANPAP 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 forms of 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 have shown that ASV is a promising treatment option in patients with CSR/CSA [8991], although its efficacy has yet to be tested in large randomised multicentre trials.

CPAP IN OSA

Cardiac arrhythmias
The Sleep Heart Health Study has provided evidence of the association between OSAS and nocturnal 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 the risk observed in effectively treated OSA patients [96]. Nevertheless, the data mentioned are still insufficient 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], as defined by international guidelines [101], and some studies have demonstrated that patients with stroke 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. WESSENDORF et al. [104] observed that CPAP was associated with improved well-being and decreased nocturnal blood pressure in the stable phase of the neurological event, while SANDBERG et al. [105] concluded that CPAP treatment reduced post-stroke depressive symptoms. In a 5-yr prospective observational study in 166 NEZ-GARCIA et al. [106] found that long-term CPAP patients with an ischaemic stroke, MARTI treatment 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 noncompliant patients. The number of non-compliant patients was deemed high, as only 28 out of 96 complied 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 to early nCPAP plus conventional treatment and 69 to conventional treatment alone. The authors concluded that an early use of nCPAP in first-ever ischaemic stroke patients, who were followed up 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 longer follow-up periods.

Mortality
Studies on long-term outcomes in patients with OSA and mortality have been reported. PEKER et al. [8] found an abnormally high level of cardiovascular disease in incompletely treated OSA patients, when compared with those efficiently treated over a 7-yr follow-up period. In a prospective cohort study, PUNJABI et al. [108] followed a large number of patients for 8.2 yrs and found 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]. In both studies, the patients were free to accept or refuse CPAP treatment. The first study observed an increase in cardiovascular mortality over a 10-yr follow-up in untreated or non-compliant patients, when compared with patients with adequate compliance. The other study, however, suggested that untreated OSA may increase the severity rather than the prevalence of cardiovascular disease. Furthermore, in mildmoderate OSA [109] or chronic obstructive pulmonary 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 mildmoderate patients.

Others Cognitive function

KI and The information available is not clear, as demonstrated by three recent reviews. SAUNAMA JEHKONEN [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 a few studies provided any psychiatric diagnosis. The prevalence for depression was 763%, and for anxiety it was 1170%. The effect of CPAP on mood was inconsistent. The authors concluded that variations 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. The same authors also reviewed the recent research on OSA and the executive functions [112]. They reviewed 40 studies, in which most of the patient samples were heterogeneous in terms of OSA severity. The executive functions were generally assessed with standardised test methods, and half the studies used only one or two tests. The most damaged fields of executive functions were working memory, phonological fluency, cognitive flexibility and planning. CPAP treatment improved performance times, cognitive flexibility and planning, but the deficits in working memory and phonological fluency persisted. The authors concluded that executive functions are the 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. NCHEZ et al. [113] performed an excellent and exhaustive Finally, and very recently, SA bibliographic search in Medline, PsycINFO, and the Cochrane Database of Sytematic Reviews (19942007) for databases and selection of works that have evaluated the efficacy and/or ` -vis daytime somnolence, depression and cognitive functioning in OSA effectiveness of CPAP vis-a patients. 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 as follows. 1) CPAP is effective in reducing subjective reports of daytime sleepiness. 2) It is estimated that depression occurs in 40% of OSA patients, but this is not related to OSA severity. The effectiveness of CPAP treatment varies from one study to the other. 3) Only some cognitive functions, particularly the executive functions, were improved with CPAP. 4) The diversity of the results reflects differences in methodology, treatment duration, and severity of OSA, as well as differences 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 severity of OSA and thereby develop an adequate assessment protocol. Both medium- and long-term evaluations are also required.

Various
Other entities can also be considered when investigating the effects of CPAP, but in most cases associated comorbidity makes the data difficult to evaluate. Furthermore, the literature is often untrustworthy. 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 is associated with seizure exacerbation in older adults with epilepsy, and its treatment may represent 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 very common in patients with end-stage renal disease. CPAP improves the classical symptoms of OSA, 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 sleep apnoea. 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 be considered, 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 history of 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 with clinical OSA symptoms) and treated with CPAP if OSA is diagnosed. However, the American Society of Anesthesiologists Task Force on perioperative management of patients with OSA suggests, in the absence of any testing facilities, patients with a high clinical suspicion of OSA should be treated with CPAP [120]. We suggest that A-CPAP devices that do not require titration could play an important role when diagnosis has not been confirmed by a sleep study and 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].

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CPAP treatment
Indications
The management of OSA must be tailored to individual patients, taking into account the severity of the OSA, the possible anatomical abnormalities and the coexisting medical problems, such as obesity and unfavourable lifestyle. It is essential to treat OSA once it has become severe, because of the 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 and mortality, but that these were reduced by CPAP treatment. Even though CPAP is the most useful treatment in most cases, weight loss programmes, physical exercise, positional therapy, sufficient sleep time and avoidance of sedatives or alcohol should always be considered. Upper airway surgery options are indicated in cases of obvious anatomical abnormalities, while bariatric surgery should 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 with manifested secondary symptoms), but more difficult when patients have minor symptoms or when they have no symptoms but have a high AHI. The main reason for the absence of definitive indications in such patients is the lack of any long-term outcome studies. The current indication of treatment is based on the consensus of several sleep societies. For instance, the Spanish Sleep Society makes the following recommendations [122, 123]. 1) Patients with clear OSA, secondary symptoms 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 .30 with notable cardiovascular disorders, even with minor secondary symptoms to undergo general treatment measures plus CPAP. 4) Patients with a high AHI .30 but no symptoms or cardiovascular disorders undergo general treatment measures but with a close follow-up because CPAP is probably going to be indicated, especially in the non-aging population, if general measures have failed. It should be mentioned that, when simplified diagnostic devices are used, the AHI is usually underestimated by 510 points. The recommendation of CPAP treatment in nonsymptomatic patients is an important issue that has not been fully resolved. In a recent review of the topic, MONTSERRAT et al. [124] emphasise the importance of well-designed randomised trials to determine whether treating non-sleepy patients with OSA prevents cardiovascular disease and whether treating OSA in patients with coexisting cardiovascular diseases reduces morbidity and mortality.

CPAP titration Polysomnography

After a patient is diagnosed with OSA, the current standard practice involves performing attended CPAP titration PSG, during which positive airway pressure is adjusted throughout the recording period 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 the applied pressure until those respiratory and sleep parameters that are considered to be clinically important are reduced to the degree considered acceptable by the clinician. One study has reported that the presence of upper airway hysteresis in some patients means that the optimal CPAP value during the latter portion of the titration night is slightly lower than that required earlier in the night, suggesting that some individuals are prescribed unnecessarily high pressure as a 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 pressure in patients with OSA [126]. These can be summarised as follows: 1) patients must receive CPAP training 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 respiratory events have disappeared, the pressure should be maintained for 30 min to ensure that the pressure is adequate in supine and rapid eye movement (REM) sleep; 4) more CPAP should be administered if required; and, finally, 5) when the pressure is sufficient, CPAP has to be reduced by 1 cmH2O until the events reappear. The pressure immediately prior to this reappearance of events is the optimal one. An acceptable titration is the pressure that normalises breathing or sleep or 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 than 15 cmH2O BiPAP could be an option, although there are no definitive data to support it. When BiPAP 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 inspiratory pressure, if desirable, must only be started in the presence of non-severe hypopnoeas; 3) the recommended initial pressure setting is 8/4 cmH2O and the suggested difference between the PI and expiratory pressure (PE) should be around 4 cmH2O (maximum 10 cmH2O; a trial-and-error process is needed, combining PE and PI changes); and 4) the maximum PI should not exceed 20 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 it may be precipitated by the sleep fragmentation associated with initial CPAP titration. Complex sleep apnoea usually disappears over the course of CPAP treatment [127, 128]. When it is repetitive, however, some authors recommend using ASV [129], although we suggest treating the patient with CPAP for a few weeks because the central apnoeas will probably disappear. SALLOUM et al. [130] recently induced hypocapnoea via nasal mechanical ventilation during sleep and compared 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 in the subjects with OSA when compared with the control. Controller gain decreased and CO2 reserve increased in seven subjects, who were restudied after using CPAP for 1 month. The authors conclusions were that increased ventilatory instability in subjects with OSA, and its reversibility with CPAP, is consistent with the notion that complex sleep apnoea may be caused by a reversible increase in chemoreflex sensitivity to hypocapnoea. CPAP therefore serves as rather more 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 devices have been developed for treatment to improve compliance, as they require less pressure to correct respiratory events. When an obstructive event is detected, the device increases pressure until the event is eliminated (fig. 6a and b). If no further events are detected during a set time period, the device will decrease pressure to a preset minimum. These devices incorporate sensors and software to detect and classify events automatically and reliably, and then increase the CPAP. No changes in compliance 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. MASSIE et al. [133] found that patients who require higher fixed CPAP report greater benefits from the use of 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 sleepdisordered breathing events that require pressure adjustment (e.g. snoring, apnoeas, hypopnoeas and flow limitation) from common events (e.g. cough, sighs, swallowing, speaking, mouth breathing, leaks and events associated with arousal from sleep) without triggering a modification in the CPAP applied to the patient; 2) there is no consensus in the medical community as to which sensors 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 very generic and is of no use when discussing this type of treatment or device. Knowledge of different
a) b)
OK

CPAP IN OSA

Normal Little snoring or flow limitation Hypopnoea Hypopnoea

Pressure cmH2O

1h Pressure in response to clear events 1 cmH2O, -5_10 min

5h Pressure (1 cmH2O) but after analysing periods of 30 min in response to even mild events

1h Pressure in response to 30 min of normal breathing, Pressure 1 cmH2O

Hypopnoea + snoring Apnoea

Figure 6. Continuous positive airway pressure titration treatment: a) automatic or b) manual. Nasal pressure is
increased 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 access to the results. As mentioned above, A-CPAP was originally designed for treatment but was quickly adopted for use in CPAP titration to determine the fixed CPAP required [134, 135]. MASA et al. [134], studied patients with severe OSA and reported that after 3 months of CPAP, there were no significant differences in the levels of improvement in AHI or subjective sleepiness when the fixed-pressure CPAP 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 during A-CPAP. MULGREW et al. [135] also obtained similar results. It is important to note that, prior to randomisation, all participants had a personal instruction and interface-fitting session, as well as an opportunity to wear the CPAP device while awake in an effort to facilitate tolerance. A very significant 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 and psychiatric morbidities, such as severe nasal obstruction, even though they represented 20% of the population [134]. Caution is required, therefore, as noted by MARRONE et 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 as the real compliance (time of adequate pressure). In patients who find difficulties with the fixed CPAP recommended by an A-CPAP, we suggest first performing a PSG, although it is also worth analysing the parameters mentioned above, as in most cases, leaks and inadequate compliance are responsible and so PSG titration is therefore unnecessary. The AASM published parameters for the practice of A-CPAP titration [137]. It must be pointed out that A-CPAP titration has a number of contraindications: congestive heart failure; significant lung disease; the probability of nocturnal arterial oxyhaemoglobin desaturation, due to conditions other than OSA (e.g. obesity hypoventilation 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 sleep and breathing variables are recorded for diagnostic purposes during the first 23 h of the sleep period. After this period, if specific criteria are met, CPAP titration is performed for the remainder of the night. Split-night PSG titration may provide a pressure prescription that is comparable to that of a full-night PSG titration in patients who demonstrate frequent obstructive events early in the 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 is used, it needs to be complemented by educational and training programmes. The technician needs to fully understand that if the number of events is not very high (,30) or if there are marked postural or REM changes, then titration should not be performed and the diagnosis should be continued with PSG.

CPAP treatment adherence and complications

CPAP treatment frequently has side-effects that impede compliance [139143] and thus limit its beneficial 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 pharyngeal membranes; leaks; skin lesions from contact with the mask; irritated eyes; claustrophobia; gastric and bowel distention; recurrent ear and sinus infections; and finally, negative social factors. Some patients also show no improvement or find their mask slipping off uncontrollably. With adequate training, informative sessions and early treatment, most side-effects disappear or are controlled within a few weeks. The follow-up visit should generally be scheduled within 1 month of starting

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Table 1. The most commonly reported adverse effects of continuous positive airway pressure Adverse effect Rhinitis Leaks, skin lesions, noise or conjunctivitis Solution

See rhinitis protocol Try other masks Avoid mouth leaks by using a chinstrap Dry mouth Humidification Oronasal mask Lack 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, Explain that most of them are transient; if cold air pressure sensation or cold air is problem, offer humidification Rare: maxillary, teeth, sinus or hearing Other diagnosis problems

CPAP IN OSA

treatment with CPAP, and during this visit the parameters showed in table 2 should be systematically monitored. The most common side effects described are mouth leaks, rhinitis and premature removal of the nCPAP mask [141143]. These three common side-effects have been christened by BALTZAN et al. [142] as the side-effect syndrome. In addition to these side-effects, the motivation to use CPAP is associated with patients perceptions of the disease severity and outcome expectancies, rather than any objective measures of severity, such as the respiratory disturbance index or arousal index, and these are the most common facilitators of good compliance. It is therefore 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 important elements of the side-effect syndrome. These problems may be caused by inflammation, resulting from reduced relative humidity derived from mouth leaks, which can lead to substantial
Table 2. Recommended procedure at the control follow-up visit for a patients with obstructive sleep apnoea
undergoing 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 mask Especially 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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Mask interface is at least partially responsible for most issues related to side-effects and it can be an important determinant of adherence to CPAP therapy [150]. Anxiety disorder has been described as interfering with CPAP adherence in both females and males [151] and claustrophobia is another major factor [152]. A nasal pillow circuit may help as it induces reduced claustrophobia and anxiety. Most of todays masks and nasal pillows use silicone rubber that may lead to contact allergic dermatitis, as well as a host of irritations. These conditions can range from a mild rash along the perimeter of the masks edge to the complete breakdown of the skin, especially on the bridge of the nose, leading to an ulcerated condition. Some patients find relief with one particular model of mask. CHAI et al. [153] compared the efficacy of the various interfaces available in a Cochrane Database of Systematic Reviews. Their main conclusion was that the limited number of studies comparing various interface types made it difficult to establish the optimal CPAP delivery interface. In addition, some results suggest that nasal pillows or the OracleTM oral mask (Fisher and Paykel Healthcare Ltd, Panmure, Aukland, New Zealand) may be useful alternatives when a
Table 3. Recommended procedures during the follw-up visit for patients with persistent sleepiness Ensure that the duration of the sleep is adequate Confirm diagnosis of OSA Confirm adequate titration Ensure adequate compliance Measure CPAP efficacy from the device (card) to detect leaks and pressure compliance Exclude comorbid conditions (depression, narcolepsy and poor sleep hygiene) Some patients may have an unrealistic degree of improvement
OSA: obstructive sleep apnoea; CPAP: continuous positive airway pressure.

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Rhinitis unidirectional airflow across the Previous No previous nasal and oral mucosa [144]. This flow of cold air through the nose Study and treat possible oral leaks dries up the mucosa and increases Increase treatment intensity nasal airway resistance. This also Analyse intensity and persistency Allergic: stimulates the local nerves and of symptoms Inhaled steroids leads to the release of inflammatory Antihistamines inhaled Allergic tests and rhinomanometry mediator cells. CPAP has also been or systemic considered a cause of nose inflamSome times very short course mation [145]. Figure 7 shows of oral steroids 2 weeks of follow-up with inhaled guidelines to follow in CPAP treatsteroids and/or ipatropium bromide Vasomotor: ment on patients with nasal problems. Any previous treatment for Some times inhaled steroids Adequate interface even with a strep Ipatropium bromide rhinitis should be intensified, while any leaks must be monitored and If no improvement: rectified in those patients with no No improvement Improvemnt previous history of rhinitis (suitable Follow the same way as non-previous mask, oronasal mask, mandibular Humidification Rhinitis and rhinomanometry, straps). The next option is pharmaENT. Possible allergic test cological treatment or humidificaNo improvement Naso-bucal mask tion. Humidification results in a better control of nose symptoms, Figure 7. Recommended procedure for follow-up in patients with rhinitis during continuous positive airway pressure treatment. ENT: when compared with nasal steroids, ear, nose and throat. but neither of these approaches improve compliance or the quality of life [146]. However, it must also be borne in mind that on occasions humidification has failed to result in better compliance [147] and may indeed trigger problems, such as an inability to maintain the set pressure dynamically [148], depending on the device being used [149].

patient is unable to tolerate conventional nasal masks. A face mask cannot be recommended as a first-line interface but it can be considered if nasal obstruction or dryness limits the use of a nasal mask [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 major problem during CPAP treatment and has yet to be satisfactorily resolved. A face mask is the best option in such cases but it is not always well tolerated [154]. We suggest that before using a face mask 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 this solution, 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 keys to success are finding a mask that is very comfortable, by solving local problems (leaks, nose and dry mouth) and treating nasal obstruction, and by educating patients and providing them with support, to prevent from feeling overwhelmed by this failure. Some authors have recommended the addition of a short course of sedative drugs at the beginning of CPAP treatment to improve compliance [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 allows the pressure to increase gradually to the prescribed level over a set time (typically 20 min) as the patient falls asleep, may also improve comfort and compliance. CPAP treatment notwithstanding, many patients complain about persistent sleepiness. Rather than hastily attributing this to long-term intermittent hypoxia related to apnoeic events that could deteriorate the brain structures regulating alertness, such patients require a further precise and definitive analysis [159]. Table 3 shows the procedure recommended by the authors in these cases [159]. Associated disease, side-effects and inadequate compliance are usually the main reasons for this phenomenon. If no cause is detected, then treatment with modafinil is needed. Some recent papers have proposed that side effects must be treated quickly to improve compliance [160162].

CPAP IN OSA

Statement of Interest
None declared.

Acknowledgements
a (SAF2008-02991 and This work was supported in part by the Ministerio de Ciencia y Tecnolog PI08/0277) and SEPAR-FUCAP.

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