CLINICAL EFFECTS OF CONTINUOUS POSITIVE AIRWAY PRESSURE THERAPY

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3 RESPIRATORY RESEARCH ADVANCES CLINICAL EFFECTS OF CONTINUOUS POSITIVE AIRWAY PRESSURE THERAPY FOR OBSTRUCTIVE SLEEP APNOEA (OSAS) AND/OR CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) PATIENTS: IMPLICATIONS FOR CARE The exclusive license for this PDF is limited to personal website use only. No part of this digital document may be reproduced, stored in a retrieval system or transmitted commercially in any form or by any means. The publisher has taken reasonable care in the preparation of this digital document, but makes no expressed or implied warranty of any kind and assumes no responsibility for any errors or omissions. No liability is assumed for incidental or consequential damages in connection with or arising out of information contained herein. This digital document is sold with the clear understanding that the publisher is not engaged in rendering legal, medical or any other professional services.

4 RESPIRATORY RESEARCH ADVANCES Additional E-books in this series can be found on Nova s website under the E-book tab.

5 RESPIRATORY RESEARCH ADVANCES CLINICAL EFFECTS OF CONTINUOUS POSITIVE AIRWAY PRESSURE THERAPY FOR OBSTRUCTIVE SLEEP APNOEA (OSAS) AND/OR CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) PATIENTS: IMPLICATIONS FOR CARE DOMENICO MAURIZIO TORALDO Nova Science Publishers, Inc. New York

6 Copyright 2012 by Nova Science Publishers, Inc. All rights reserved. No part of this book may be reproduced, stored in a retrieval system or transmitted in any form or by any means: electronic, electrostatic, magnetic, tape, mechanical photocopying, recording or otherwise without the written permission of the Publisher. For permission to use material from this book please contact us: Telephone ; Fax Web Site: NOTICE TO THE READER The Publisher has taken reasonable care in the preparation of this book, but makes no expressed or implied warranty of any kind and assumes no responsibility for any errors or omissions. No liability is assumed for incidental or consequential damages in connection with or arising out of information contained in this book. The Publisher shall not be liable for any special, consequential, or exemplary damages resulting, in whole or in part, from the readers use of, or reliance upon, this material. Any parts of this book based on government reports are so indicated and copyright is claimed for those parts to the extent applicable to compilations of such works. Independent verification should be sought for any data, advice or recommendations contained in this book. In addition, no responsibility is assumed by the publisher for any injury and/or damage to persons or property arising from any methods, products, instructions, ideas or otherwise contained in this publication. This publication is designed to provide accurate and authoritative information with regard to the subject matter covered herein. It is sold with the clear understanding that the Publisher is not engaged in rendering legal or any other professional services. If legal or any other expert assistance is required, the services of a competent person should be sought. FROM A DECLARATION OF PARTICIPANTS JOINTLY ADOPTED BY A COMMITTEE OF THE AMERICAN BAR ASSOCIATION AND A COMMITTEE OF PUBLISHERS. LIBRARY OF CONGRESS CATALOGING-IN-PUBLICATION DATA ISBN: Published by Nova Science Publishers, Inc. New York

7 CONTENTS Preface Guest Editor 1 List of Terms 3 Target Audience 5 Part I. Part II. Impact of Continuous Positive Airway Pressure on Cardiovascular Metabolic & Respiratory Effects 7 Chronic Obstructive Pulmonary Disease (COPD) with Nocturnal Oxygen Desaturation 23 Acknowledgment 35 Disclosure 37 References 39 Index 51 vii

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9 PREFACE The view on treatment with continuous positive airway pressure (CPAP) of patients with severe chronic obstructive pulmonary disease (COPD) and Obstructive Sleep Apnea Syndrome (OSAS) has changed during the past decades. COPD and OSAS represent two of the most prevalent chronic respiratory disorders in clinical practice and the term of overlap syndrome is commonly used to describe the two disorders, when coexisting OSAS and COPD. In part this deficiency reflects the lack of a standardized definition, and a lack of a unique diagnostic code. Additionally, both OSAS and COPD have undergone revisions in diagnostic techniques and/or criteria in the last 25 years. The first part of the book introduces the importance of the CPAP in the treatment of OSAS; the second part introduces the treatment instead with CPAP/BiPAP in the overlap syndrome (OSAS+COPD). It also introduces the newer technologies, such as APAP, which show promise as alternative options in the diagnosis and long-term treatment of OSAS. In a selected population, a CPAP trial may help to diagnose OSAS, to identify patients who might benefit from CPAP, and to reduce the need for polysomnography. Newer modalities such as C-Flex and A-Flex also show promise as treatment options for the future. However, standard CPAP therapy should continue as the mainstay of OSAS management. Currently, CPAP with oxygen therapy as needed is the treatment of choice for overlap syndrome. Domenico M. Toraldo MD, FCCP

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11 GUEST EDITOR Domenico Maurizio Toraldo MD, FCCP Address: via A. C. Casetti n.2, Lecce (Italy); Telephone: ; Date of Birth: 08/05/1958; Employment history: Pneumologist at A. Galateo Lung Disease Hospital, ASL Lecce, regional service Puglia, Italy from 05/1988 to present; Academic positions: teaching at the medical school for nurses at the University of Bari, Italy from 2000 to 2008; Professional credentials: graduate school specialization in Pulmonary Diseases, University of Modena, Italy; Publications: 46 publications in Italian and English; Associations: Gold Member of the European Respiratory Society since 2002 and Fellow of the College of Chest Physicians since He has a special interest in chronic mechanical ventilation in COPD and OSAS and sleep studies. The Author has taken great care to ensure that medical information presented in this book is accurate and in accordance with professional standards in effect at the time of publication. However, readers are advised to always check the manufacturer s product information sheet packaged with the respective products to be fully informed of changes in technical recommendations before prescribing or administering therapeutic treatments.

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13 LIST OF TERMS AHI - apnea-hypopnea index; adherence CPAP therapy - is measured through self-report measures, including diaries and verbal recall, over reporting of CPAP use; AECOPD - acute exacerbations of COPD; Auto adjusting CPAP - A-PAP; BMI (Kg/m 2 ) - body mass index; COPD - chronic obstructive pulmonary disease; BiPAP - bilevel positive airway pressure; BDI - beck depression inventory; CBT - cognitive behavioural therapy; CPAP - continuous positive airway pressure; OSAS - obstructive sleep apnea syndrome; Compliance CPAP therapy - has been defined as the use of CPAP therapy for more than 4-5 hrs per night; C-Flex & A-Flex - is an advanced technological option to CPAP therapy; COPD Desaturator - T 90 of 30% and nadir SatO 2 85% and mean nocturnal SatO 2 90% were defined as Desaturators (D); DE - doppler echocardiography; FEV1 % - forced expiratory volume in one second; ESS (0-10) - epworth sleepiness scale; FEV 1 /FVC ration is the FEV 1 expressed as a percentage of the FVC (or VC if that is greater) i.e. the proportion of the vital capacity inhaled in the first second; FOSQ - functional outcomes of sleep questionnaire;

14 4 Domenico Maurizio Toraldo IH - intermittent hypoxaemia; LTOT - long term oxygen therapy; MPAP mmhg - mean pulmonary artery pressure; Mean SaO 2 % - mean nocturnal SatO 2 ; Nadir SaO 2 % - nadir nocturnal SatO 2 Nocturnal hypoxaemia - hypoventilation during sleep; Oxygen desaturation - a fall of SatO 2 5% with SatO 2 90% and a nadir SatO 2 value of at least 85%, during quiet breathing ; NIV - non-invasive ventilation; Non REM sleep - non rapid eye movement during sleep the first four consisting of non-rem sleep; PaCO 2 mmhg - arterial carbon dioxide tension; PAP - positive airway pressure; PaO 2 mmhg - arterial oxygen partial pressure; PH - pulmonary hypertension; PSG - polysomnography SatO 2 - arterial oxygen saturation ; Overlap syndrome - OSAS + COPD; REM sleep - rapid eye movement during sleep, is the fifth of the five stages of sleep; SDB - sleep-disordered breathing; SatO 2 % - arterial oxygen saturation TRT - total polygraphic recording time ; VFA - visceral fat accumulation;

15 TARGET AUDIENCE Physicians in pulmonary medicine Respiratory therapists Nurses Physicians assistants

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17 PART I. IMPACT OF CONTINUOUS POSITIVE AIRWAY PRESSURE ON CARDIOVASCULAR METABOLIC & RESPIRATORY EFFECTS EDUCATIONAL AIMS 1) Nasal CPAP is the definite treatment of choice of OSAS. 2) Observational studies have shown a reduction in the risk of cardiovascular events in OSAS patients treated with CPAP compared with untreated patients. 3) CPAP is not tolerated by all patients with OSAS and alternative modes of pressure delivery have been developed to overcome pressure intolerance, thereby improving patient comfort and adherence. 4) Ensure adequate compliance and measure efficacy from the device (card) to detect leaks and pressure compliance. 5) CPAP compliance is improved by systematic education and heated humidification 6) Newer technologies such as auto-adjusting CPAP show promise as alternative options in the diagnosis and long term treatment of OSAS. 7) Newer modalities such as C-Flex and A-Flex also show promise as treatment options in the future.

18 8 Domenico Maurizio Toraldo Continuous positive airway pressure (CPAP) has become the treatment of choice for the obstructive sleep apnea syndrome (OSAS) and has been demonstrated to resolve sleep-disordered breathing events and improve several clinical outcomes. [1] Acute application of CPAP results in the elimination of obstructive disordered breathing events and associated consequences, such as oxygen oxyhemoglobin desaturation [2]. Randomized controlled trials [3-4]. have shown CPAP therapy to be superior to the placebo at improving stages 3 and 4 sleep and REM sleep. As CPAP eliminates OSAS and the large negative swings in juxtacardiac pressure that occur during upper airway occlusion, CPAP decreases the transmural pressure and wall tension across the right and left ventricles. This results in a decrease in after load, which, in turn, should decrease myocardial oxygen consumption and increase stroke volume. As CPAP eliminates arterial oxyhemoglobin desaturation and hypercapnia, there should also be a decrease in sympathetic activity, neurohormonal activation, oxidative stress and inflammation. Some studies suggest that CPAP may reduce morbidity and mortality [5],and cardiovascular morbidity.[6] Treatment with CPAP reduces sympathetic activity [7],diminishes platelet activation and aggregation, and normalizes oxidation of low-density lipoprotein particles [8], as well as decreasing the production of reactive oxygen species in neutrophils and monocytes [9].Circulating levels of C-reactive protein (CRP fibrinogen and IL-6 are elevated in apneic patients and decrease significantly with CPAP [10].However, some clinical data strongly indicate that IL-6 levels are elevated in patients with OSAS, but not in patients where obesity is present [11].The baseline level of CRP in large-scale prospective studies is an independent predictive marker for future myocardial infarction, stroke, cardiovascular death and incidence of peripheral arterial disease [12, 13].Therefore, CRP level is a risk factor for atherosclerosis as well as an active pathogenic agent. That decrease [14, 15] in CRP levels in OSAS patients becomes evident when CPAP has been used for more than 4 h per night. However, the authors concluded that CRP levels are OSAS independent and may be associated with obesity. The baseline level of CRP in large-scale prospective studies is an independent predictive marker for future myocardial infarction, stroke, cardiovascular death and incidence of peripheral arterial disease. [16, 17] Therefore, CRP level is a risk factor for atherosclerosis as well as an active pathogenic agent. The decrease [18, 19] in CRP levels in OSAS

19 Part I 9 patients becomes evident when CPAP has been used for more than 4 h per night. However, the authors concluded that CRP levels are OSAS independent and may be associated with obesity. Recently, patients with newly diagnosed non smoking OSAS without comorbidities or medication in use have been studied at baseline and during the follow-up period [20]. Serum cardiovascular risk factors (i.e., high-sensitivity CRP, homocysteine, total cholesterol, triglycerides, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, Apo lipoprotein A-I and Apo lipoprotein B) have been measured at baseline and 6 months after CPAP application. Patients were classified into the following three groups according to CPAP use: group 1 (n = 20), good compliance ( 4 h use per night); group 2 (n = 19), poor compliance ( 4 h use per night); and group 3 (n = 14), refusal of CPAP treatment. Results showed that in the good compliance to CPAP treatment patient group, there were lower serum levels of cardiovascular risk factors, indicating a beneficial effect on the overall cardiovascular risk. In some cases, CPAP reduces serum levels of inflammatory cytokines (TNF-a and IL-6), probably reducing the atherosclerosis risk. [21] Recent studies suggests that long-term CPAP treatment in moderate-to-severe OSAS and ischemic stroke is associated with a reduction in risk of mortality and a longer survival rate. [22,23] One study [24] to explore further the relationship between vascular regulation and OSAS. Vascular responses were reassessed in a subset of patients with OSAS after CPAP therapy. Cerebral and forearm blood flow were measured by tran cranial doppler and venous occlusion plethysmography, respectively. The cerebral and forearm vasodilator responses were significantly smaller in patients with OSAS, and 12 weeks of CPAP therapy reversed some of these impairments. The results confirm the previously reported alterations in endothelial dysfunction and demonstrate that impaired vascular responsiveness can be reversed in a short period of time with CPAP therapy. A study examined both the relationship between the changes in the brain tissue, haemoglobin indices and oxygen saturation during sleep in patients with OSAS and the effect of CPAP treatment on haemoglobin indices. [25] Matsuo et al have demonstrated that the fluctuations in these cerebral haemoglobin indices during sleep were significantly larger in the OSAS group than in the control group. In the OSAS group, these changes also correlated strongly with the change in SatO 2.[25]

20 10 Domenico Maurizio Toraldo Martinez-Garcia et al performed an observational prospective study that included 5 years of follow-up in 166 patients with ischemic stroke. [26] The authors concluded that long-term CPAP therapy in patients with moderate to severe OSAS and ischemic stroke is associated with improved mortality. OSAS is a prevalent disorder particularly among middle-aged, obese men. Several features of OSAS suggest that sleep apnea is a manifestation of metabolic syndrome.[27-28] Indeed, there is a strong association of OSAS with obesity, male gender, hypertension and diabetes[29-30] which are also found in patients with metabolic syndrome. Visceral fat accumulation (VFA) correlates with the severity of OSAS and is a key factor for the development of metabolic syndrome. [31-32] Punjabi et al performed frequently sampled intravenous glucose tolerance tests on 118 no diabetic patients to assess whether OSAS alters in vivo kinetics of glucose and insulin. [33] Compared with patients without OSAS, those with mild, moderate, and severe OSAS had a 26.7%, 36.5%, and 43.7% reduction in insulin sensitivity, respectively, after adjusting for age, sex, race, and percent of body fat measured by dual-energy X-ray absorptiometry. The authors concluded that obstructive respiratory events associated with either oxygen desaturation or micro-arousals are associated with impaired insulin sensitivity and pancreatic b-cell dysfunction independent of adiposity, and that these metabolic alterations may increase the risk of glucose intolerance and type 2 diabetes in patients with OSAS. Continuous positive airway pressure treatment improves insulin sensitivity in patients with OSAS within a few days before any possible changes in body weight or lifestyle. [34]Taken together, these findings suggest that independent of sleep duration, both the frequency of micro arousals and the severity of intermittent hypoxemia during sleep can adversely modify glucose homeostasis. The results of a retrospective cohort study investigating the effect of CPAP therapy on blood gas, specifically hypercapnia and hypoxia, have demonstrated that in hypercapnic patients with OSAS, adherence to positive airway pressure is an important modifiable predictor of improvements in the partial pressure of carbon dioxide (PaCO 2 ) and oxygen (PaO 2 ) in the arterial blood, and its benefit plateaus between 5 and 7 hrs of daily therapy [35].In a randomized study, nocturnal oxygen

21 Part I 11 supplementation and CPAP treatment have improved psychological symptoms, using a three-arm, placebo-controlled design. OSAS patients (n = 38) were monitored for two nights with polysomnography and then randomized to 2-week therapeutic CPAP, placebo CPAP or oxygen supplementation [36]. Because CPAP normalizes both sleep disruption and oxyhemoglobin desaturation, the mechanism of psychological symptom improvement is unclear. Finally, long-term CPAP treatment reestablishes a physiological relationship between chronic lack of sleep and metabolic disorders and can improve nocturnal melatonin plasma levels that play a crucial role as a mediator between the thermoregulatory, arousal systems and sleep-promoting properties [37]. Daytime hypercapnia and hypoxia is common in morbidly obese patients with obstructive sleep apnea and is associated with serious complications. Some studies showed that the therapeutic effects of CPAP treatment on neurocognitive function, mood and quality of life are also variable and inconsistent, with most randomized trials demonstrating no clear benefit from CPAP therapy, compared with placebo or conservative treatments. [38, 39] One possible explanation for the inconsistent effect of CPAP in improving these outcomes is the use of multiple measures of function to assess similar parameters. MORTALITY Studies on long-term outcomes in patients with OSAS and mortality have been reported. Two studies have analysed the long-term cardiovascular consequences in OSAS patients. [40, 41].The first study observed an increase in cardiovascular mortality in untreated or noncompliant patients when compared with patients with compliance at treatment. The data of the second study supports a protective effect of CPAP therapy against death from cardiovascular disease in patients with OSAS. Besides, in mild-moderate OSAS [42] or chronic obstructive pulmonary disease with OSAS [43]; the present observational study indicates that CPAP treatment was associated with higher survival in patients with moderate-to-severe OSAS and hypoxaemic COPD receiving long term oxygen therapy (LTOT).

22 12 Domenico Maurizio Toraldo VARIOUS Other entities can be considered when investigating the effects of CPAP, but in most cases, the data is difficult to evaluate. The effect of recurrent changes in intrathoracic pressure has been little studied and is often neglected in models of the pathogenetic mechanisms for the consequences of OSAS. In OSAS increased negative intrathoracic pressure induces secretion of atrial natriuretic peptyde (ANP) a volumeregulating hormone that functions to decrease the volume within the vascular system as a result of fluid overload, that caused an increase in urine production and decreased with CPAP treatment. [44] CPAP may also, have a beneficial effect on erectile dysfunction found in patients with sleep apnoea, but sildenafil was superior to CPAP in the treatment in men with OSAS. This paper concludes that new therapeutic agents or a combination of the two methods should be studied further. [45] OSAS is associated with epilepsy and the treatment with CPAP may represent an important route for improvements in seizure control of epilepsy in these patients.[46] Patients with OSAS demonstrate renal signs such as proteinuria, glomerular hypertrophy and focal glomerular sclerosis with end-stage renal disease. In the study, CPAP improved and enhanced glomerular hyper filtrating and symptoms of OSAS. EFFECTS ON DRIVING ABILITY Performance impairment in OSAS is characterised by being sleepy, with micro-sleep attacks, attention lapses and increased reaction times interfering with driving ability. There is evidence linking sleep apnoea and daytime sleepiness with an increased risk of vehicle accidents, with enough evidence to suggest that CPAP treatment can counter the accident risk. [47] However, patients with OSAS who are successfully treated do not pose an accident risk. Therefore, the OSAS patients should be evaluated at the time of diagnosis, after treatment initiation and during regular follow-up visits. It is not yet clear whether in-laboratory testing results truly reflect a patient s fitness to drive and can thus be used to recommend that subjects who perform poorly should not drive until results normalise. Alternatively, the development of new sensors for cars, such as camera-based sensors for the detection of eye blinks, with

23 Part I 13 feedback of sleepiness to the driver, could be the ultimate solution for determining fitness to drive. ADHERENCE & COMPLIANCE The compliance with CPAP therapy has been defined as the use of CPAP therapy for more than 4 hrs per night on 70% of the observed nights, and objective CPAP compliance is estimated to be between 50 68%.[49] The short-term follow-up of OSAS patients demonstrates that CPAP usage patterns fall into the following two groups of patients: first, those with an average usage time greater than 6 hrs per night; and second, those with an average usage time of less than 3 5 hrs per night [50]. Long-term follow-up has demonstrated that approximately 68% of OSAS patients continue to use their CPAP therapy after 5 years. [51] Nursing support and intensive education programs improve compliance. Simple interventions such as weekly phone calls and mailings may improve compliance, especially when they are performed in the initial weeks of therapy. In general, increased intensity of patient education or frequency of healthcare-provider contact improve CPAP therapy adherence. Typical problems that may lead to reduced compliance of CPAP include claustrophobia, nasal congestion and poor mask fit, leading to leaks and skin irritation. Some studies have demonstrated that the addition of heated humidification improves the symptoms of nasal congestion and increases objective CPAP use. [52, 53] Another study demonstrated that improved adherence to CPAP treatment in participants with OSAS encourages a better cognitive behavioural therapy (CBT) intervention. [54] All patients carried out 1-h CBT interventions (including a video of real CPAP users) in addition to the usual treatment (mask fitting and information), or usual treatment only. Questionnaires measuring self-efficacy, social support and expectancy (mediators of adherence) were given after intervention or after usual treatment. A higher adherence to CPAP therapy was found in the CBT group relative to usual treatment at 28 days. The CBT group had significantly higher scores for self-efficacy and social support but not for expectancy. The CBT intervention resulted in both increased adherence and uptake of CPAP and therefore it would be expected to reduce the social, economic and health-related consequences of untreated OSAS. However, when

24 14 Domenico Maurizio Toraldo combined with real-time assessment of CPAP use and support for problem-solving or troubleshooting difficulties with CPAP, supportive interventions may be useful in promoting adherence to CPAP. One study [55]. has examined that if reported OSAS-symptom improvement, baseline depressive symptoms, or polysomnographically measured sleep parameters are associated with adherence to CPAP. Low adherence to CPAP therapy is common and poorly understood. Depression and lack of perceived benefits from CPAP are possible reasons for low adherence. A total of 78 patients evaluated for OSAS at a sleep medicine center agreed to participate in the study; 54 patients completed all study assessments. The beck depression inventory (BDI) and the functional outcomes of sleep questionnaire (FOSQ) were administered before polysomnography evaluation. A card embedded in the CPAP device electronically recorded adherence. The BDI and FOSQ were administered 1 2 months after the baseline measurements were obtained. This study has demonstrated that patients with the greatest level of CPAP adherence also reported the greatest improvement in OSAS symptoms. Patients who continued to experience OSAS symptoms after CPAP treatment also tended to have more depressive symptoms after CPAP treatment. Long-term adherence to CPAP therapy can be predicted as early as 3 days following CPAP initiation. The study also demonstrates that younger age and African American race are independently associated with lower CPAP adherence.[56] The aim of these systematic reviews is to compare the efficacy of the various CPAP delivery interfaces available for the treatment of OSAS. [57] There are many different CPAP interfaces now available for the treatment of OSAS. The type of CPAP delivery interface is likely to influence a patient s acceptance of CPAP therapy and long-term compliance. Owing to the limited number of studies available comparing various interface types, the optimum form of CPAP delivery interface remains unclear. The results of our review suggest that nasal pillows or the Oracle oral mask may be useful alternatives when a patient is unable to tolerate conventional nasal masks. The face mask cannot be recommended as a first-line interface, but may be considered if nasal obstruction or dryness limits the use of a nasal mask. Our current understanding of CPAP adherence suggests that adherence is a multi-factorial, complex clinical problem that requires similarly designed approaches to effectively

25 Part I 15 address poor CPAP adherence in the OSAS population (see Table 1 and 2). EFFECT OF FIXED VERSUS AUTO ADJUSTING CPAP TREATMENTS Auto adjusting CPAP (A-PAP) devices are a recent alternative treatment to traditional CPAP and are able to improve symptoms while reducing the high costs of CPAP titration [58].However, conversely to CPAP, the impact of A-PAP therapy on cardiovascular and metabolic outcomes in OSAS patients remains unknown, and a study has reported that A-PAP therapy may not be able to reduce diurnal arterial blood pressure. [59] In OSAS treatment, the use of A-PAP devices is progressively becoming more common, mainly due to the reduced cost of sleep laboratory titration in comparison with CPAP, despite achieving similar reductions in hyper somnolence and hypoxemia [60] and similar compliance rates. [61] A-PAP devices are based on the delivery of a positive airway pressure that is not fixed but variable during sleep, depending on the degree of upper airway obstruction occurring during the different sleep stages and body positions. The American Academy of Sleep Medicine has published an evaluation of the effects of A-PAP on sleep, OSAS symptoms and compliance, whereas no data is available on the effects of long-term treatment with A-PAP on the cardiovascular outcomes and practice parameters, and recommendations for using A-PAP to determine the need for or to provide treatment for OSAS. [62] All studies showed that the two treatments, despite significant effects on OSAS indexes and symptoms, do not appear to act on cardiovascular risk factors in the same fashion. This is important in clinical practice when prescribing A-PAP for OSAS treatment because it should be taken into account that there is still no solid and conclusive evidence that A-PAP is as efficient as CPAP in the intervention on major cardiovascular risk factors. Not all A-PAP devices are the same. A-PAP represents a group of technologies that monitor, assess and respond in different ways by using different algorithms. Therefore, results from one A-PAP study are specific to that device and cannot be generalized to all A-PAP devices. In a laboratory situation, A-PAP titration may be used on patients with uncomplicated

26 16 Domenico Maurizio Toraldo moderate-to-severe OSAS to determine an effective conventional CPAP pressure setting. A-PAP results is similar, but not better, improvements in apnea-hypopnea index and compliance compared with conventionally titrated CPAP therapy. A-PAP use is indicated for patients with uncomplicated moderate-to-severe OSAS and without concomitant disease states such as chronic obstructive pulmonary disease, chronic heart failure and obesity hypoventilation syndrome. Previous studies have addressed the efficacy of A-PAP devices in home therapy of OSAS over several weeks. A randomized study [63] including eight patients treated for 3 weeks with the A-PAP device in automatic mode and eight patients in constant mode revealed a better compliance in the A-PAP group of 6.5 hrs per night vs. 5.1 hrs per night in the fixed CPAP group. Another study, [64] concluded that patients with OSAS preferred A- PAP over fixed CPAP in the initial phase of therapy. The effectiveness A-PAP in improving major outcomes was equivalent to fixed CPAP. Since A-PAP does not require initial titration, it is a simple and promising modality for sleep apnea home therapy. Therefore, A-PAP is a promising alternative to conventional CPAP treatment with fixed mask pressure. USE OF A-PAP TO DIAGNOSE AND TREATMENT IN PATIENTS WITH OSAS The American College Chest Physicians (ACCP) Medicine Review guidelines currently do not recommend the use of A-PAP devices for diagnostic purposes [65]. Only a few studies have examined the use of A-PAP in diagnosing OSAS. Most studies have directly compared A- PAP with concomitant PSG and have lacked uniformity in terms of patient selection across studies. [66] It should also be noted that PSG expresses apnoea-hypopnoea index (AHI) in terms of time spent asleep, excluding intervening periods of wakefulness, and thus provides a more precise assessment of sleep apnoea severity. Although A-PAP devices can diagnose severe OSAS effectively, their utility in the diagnosis of milder disease remains questionable. Senn et al have described a novel approach to the diagnosis of patients with clinically suspected OSAS [67]. Treatment of OSAS is often delayed because polysomnography, the recommended standard diagnostic test, is not readily available. The

27 Part I 17 authors evaluated whether the diagnosis of sleep apnea could be inferred from the response to a treatment trial with CPAP. This approach is based on observing the response to an CPAP. Industrial companies have designed a CPAP device that includes a flow and pressure sensor and that can store raw data of these parameters on a long-term basis. Specific software allows home care providers or clinicians to download these data onto a personal computer. [68] Downloaded data devices can be separated into three categories. The first is a synthesis report: compliance, settings, mean level of leaks, tidal volume respiratory frequency. The second category is detailed data analysis. Raw data of a given parameter could be analyzed cycle by cycle. The third category provides polygraphic data analysis. In this situation, by adding an external module connected to the machine, physiological parameters such as oxygen saturation, heart rate and respiratory effort can be recorded and displayed, in addition to the signals already stored by the CPAP devices. [69] Although the role of A-PAP in the treatment of OSAS is still not well defined, it has the potential to improve the delivery of positive airway pressure therapy by reducing the current sleep laboratory. Finally, A-PAP use is strongly indicated for patients with uncomplicated moderate-to-severe OSAS without concomitant diseases such as chronic obstructive pulmonary disease, obesity hypoventilation syndrome and chronic heart failure. The differences between various APAP devices are acknowledged in the current AASM practice parameters [65].Further studies are required to compare A-PAP devices in varying patient cohorts, with particular attention to cost-effectiveness and their effects on cardiovascular outcomes. In conclusion, in a selected population, CPAP may help to diagnose OSAS, to identify patients who could benefit from CPAP and to reduce the need for polysomnography. C-FLEX & A-FLEX C-Flex is an advanced technological option to CPAP therapy in which the positive airway pressure is reduced in the initial phase of expiration on a breath-by-breath basis in proportion to the patient s expiratory flow rate. The first such device was developed by Respironics (C-Flex ; Respironics; Murraysville, PA, USA) and has three comfort

28 18 Domenico Maurizio Toraldo levels, allowing differential levels of flexible pressure. It is hypothesized that C-Flex may improve treatment adherence and clinical outcomes by increasing comfort during exhalation. [70] A number of studies have compared C-Flex to CPAP. In a non randomized study, Aloia et al demonstrated an average of 1.7 h/night greater usage in the C-Flex-treated group compared with CPAP (p < 0.001) [71]. In a randomized controlled trial by Marshall et al, initial compliance was greater with C-Flex than CPAP in severe OSAS patients, but CPAP provided a greater improvement in subjective sleep propensity as measured by the Epworth Sleepiness Score. [72] Further studies are required to assess the role of C-Flex in milder disease, where compliance rates are lower and the impact of periods of lower positive airway pressure during exhalation may have a greater influence on patient comfort and adherence to therapy. The only controlled study evaluating the C-Flex technology evaluated 52 CPAP-naive patients who recently received a diagnosis of OSAS and allocated them to either fixed CPAP or C-Flex therapy. After 7 weeks of treatment, both CPAP and C-Flex groups demonstrated equal improvements in subjective compliance (5.2 vs. 5.3 h) and daytime sleepiness, and reduction in the apnea-hypopnea index. Finally, C-Flex therapy offered no significant benefits in the subgroup of patients who required pressures of 9 cm or more of water. According to the limited data available, C-Flex therapy offers no significant benefits over fixed CPAP therapy in patients requiring CPAP 9 cm or more of water or experiencing dry mouth with CPAP. Further studies should be done to investigate the effects of C-Flex in these patients as well as in low-compliance patients. [73] A-Flex is a further modification of C-Flex technology by Respironics. During the expiratory phase of the respiratory cycle, A-Flex works in exactly the same way as C-Flex. However, A-Flex also softens the pressure transition from inhalation to exhalation by increasing the pressure delivered more gradually to better mirror the normal breathing rhythm of the CPAP user. APAP devices are significantly more expensive than standard CPAP devices A-Flex also helps to prevent the CPAP machine from delivering a pressure that is too high. Studies are required to validate the role of A- Flex devices in the treatment of OSAS. [68]

29 Part I 19 CPAP FUTURE We propose that various features be incorporated into new-generation CPAP devices, including ramps, automatic leak compensation and humidification, and that the choice and sophistication of CPAP accessories, such as masks, increase as efforts are made to improve patient compliance. In 5 years time, further studies are required to validate the roles of A-PAP, C-Flex and A-Flex. We propose [74] that the optimal strategy of CPAP treatment is to evaluate the temporal changes in biomarkers pathways and to assess the molecular signature in obstructive events.. (see Table 3) New approaches include the assessment of change in gene expression or protein expression of specific molecules in populations of cells or tissue before and after CPAP treatment, and discovering a strategy to assess OSAS severity and individual differences in the effects of CPAP treatment. Table 1. troubleshooting for CPAP therapy Problem Dry mouth /throat Nasal congestion Conjunctivitis Skin irritation Solution Install a humidifier connected to the CPAP machine Check for leaks Increase temperature of the bedroom Acute rhinitis when not to use the CPAP machine for 5-6 days Use nasal decongestants in the short term Check for leaks and consider using a humidifier If you wake up with water in you mask / tubing, Your humidifier is set too high: start at the 1st setting (1) and gradually increase as necessary each night Disappears with appropriate adjustment of the mask by the patient in the first weeks, protect your eye patches Disappears with appropriate adjustment of the mask by the patient in the first weeks, protect your eye patches

30 20 Domenico Maurizio Toraldo Table 2. face mask options: choosing the right size of the mask Selecting the right CPAP mask is integral in obtaining effective CPAP therapy 1) Nasal mask: these are the most common type of the mask. It is a triangular-shaped mask that fits over the nose which is snugly held in place by straps. It uses a headgear to maintain it snugly in place. 2) Full face mask: this covers the whole face. It does not irritate the nose or cause skin breakdown. These are useful for patients who only breathe through their mouth or whose breathing regularly alternates between their nose and their mouth. 3) Nasal cushions and nasal pillows: this type uses two small cone pillows made of silicon placed under the nose near the edge of the nostrils. They offer a useful alternative to the other types of mask, especially for patients who feel claustrophobic with a face mask or who cannot find a mask that suits them Table 3. management options for CPAP in OSAS Moderate and severe OSAS 1. Nasal CPAP is the definite treatment of choice. 2. CPAP therapy may be used to treat OSAS with (AHI) 15 with the most consistent improvements being seen in those patients with severe disease AHI Aside from improvements in AHI, there is little data to support the use of CPAP in patients with mild disease AHI 5 to If CPAP no compliance can be used, other interventions, including masks, ramp mechanisms and newer technologies. such as A-PAP, bilevel, and C-Flex. A range of CPAP masks are available. To check CPAP accessories and humidifier 5. C-Flex and Bilevel therapy, result in objective compliance that is similar to but not better than conventional CPAP therapy. 6. A-PAP indicated for patient s uncomplicated moderate to severe OSAS. 7. Attended in-laboratory A-PAP titrations may be used in patients with uncomplicated moderate to severe OSAS to determine an effective conventional CPAP pressure setting. 8. BiPAP pressure for CPAP non-compliance.

31 Part I 21 EXPERT COMMENTARY The studies presented in this article have demonstrated that increased CPAP therapy improved alertness, neurobehavioral outcomes in cognitive processing, memory and executive function and decreased sleep disruption, and had a positive effect on cardiac and respiratory metabolic function, including vascular resistance, platelet coagulability, metabolic profiling and other aspects of cardiovascular health. One approach to understanding the clinical variability in the consequences of OSAS in different subjects is to evaluate the molecular signatures of the disorder. Differences between individuals with OSAS may be directly related to the nature of their sleep disordered breathing events. Thus, we believe that the optimal molecular signature for OSAS is likely to be changed in relevant biomarkers across the sleep period; that is to measure the change from pre-sleep to post-sleep. Recent study [75] have demonstrated that homocysteine (Hcy) and cysteine (Cys) are correlated as cardiovascular risk factors in OSAS patients and is reduced after effective OSAS treatment with CPAP. and they can provide a molecular signatures for OSAS that could potentially be used diagnostically and to predict who is likely to develop different OSAS-related co morbidities. Several cross-sectional studies have shown consistently that OSAS is independently associated with surrogate markers of premature atherosclerosis. These studies are not at present at the stage of clinical application but the experimental approaches outlined here are likely to lead in the future to new approaches to diagnose and therapy as well as providing prognostic information. The future clinical utility in routine practice will of course be determined by the results of such studies. We propose that the optimal strategy is to evaluate the temporal changes in relevant molecular pathways during sleep in OSAS patients and believe and after CPAP treatment, in particular, the alterations from before to after sleep when assessed in blood and/or urine. More research is needed to fully understand the path physiological significance of molecular signatures of OSAS and their relationship with OSAS comorbidities.

32

33 PART II. CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) WITH NOCTURNAL OXYGEN DESATURATION EDUCATIONAL AIMS 1) To provide a comprehensive, up-to-date review of the aetiology and path physiology of nocturnal oxygen desaturation in COPD patients. 2) COPD patients with daytime PaO 2 levels in the mildly hypoxemic range can also develop clinically significant nocturnal oxygen desaturation. 3) COPD patients that show a nocturnal polygraphic recording the following values: T 90 30% and a nadir SatO 2 85% and mean nocturnal SatO 2 90% were defined as Desaturators (D) and the others as Non-Desaturators (ND). 4) Nocturnal oxygen desaturation caused pulmonary hypertension and various arrhythmias and right-heart failure. 5) COPD and OSAS (overlap syndrom) are both common diseases affecting respectively 10 and 5% of the adult population over 40 years of age. 6) Low-grade systemic inflammation is considered a hallmark of COPD that potentially links COPD to an increased rate of systemic manifestations of the disease.

34 24 Domenico Maurizio Toraldo 7) CPAP/BiPAP therapy for overlap syndrome in addition to LTOT 2 L min -1 if hypoxaemic during daytime, PaO 2 55 mmhg. COPD WITH NOCTURNAL OXYGEN DESATURATION COPD is defined by the presence of airflow limitation that is not fully reversible, and its treatment is mostly guided by the severity of this limitation. [76] The sleep-related disturbances in gas exchange in COPD are a consequence of the disease itself and are separate and distinct from sleep apnoea. [77] In COPD patients, the hypoventilation during REM sleep is more pronounced than in normal subjects due to a number of factors : airway obstruction, hyperinflation, respiratory muscle dysfunction, blunted ventilatory responses to hypercapnia and/or hypoxia, and medications can all contribute to this nocturnal hypoventilation. The most significant sleep abnormality associated with COPD is nocturnal oxygen desaturation. [78-79] Several studies have reported that 27 70% of patients with COPD with daytime oxygen saturation of 90 95% can experience substantial desaturation at night, particularly during REM sleep. [80-81] Nocturnal hypoxemia was defined as a SatO 2 of 90% for at least 5 min with a nadir SatO 2 of 85%. Time in bed was defined as the time from the start to the end of the recording. The percentage of total recording time (TRT) was defined as the time spent in bed -- sleep latency + intrasleep wakefulness. The TRT spent in bed with a SatO 2 of 90% was defined as the T 90. COPD patients with a T 90 30% and a nadir SatO 2 85% were defined as Desaturators (D) and the others as Non-Desaturators (ND). [82] Daytime oxygen saturation has the greatest predictive value, although it imperfectly predicts nocturnal desaturation. [83-84] Daytime PaCO 2 has also been found to be predictive. Perhaps most clinically relevant, nocturnal oxygen desaturation is a marker of increased mortality in COPD. [85] Three mechanisms have been identified that might contribute to nocturnal oxygen desaturation: alveolar hypoventilation, decreased ventilation-perfusion matching, and decreased end-expiratory lung volume. The greater drop in minute ventilation in subjects with COPD may reflect increased dependence on accessory muscles that become

35 Part II 25 hypotonic during sleep, particularly during REM sleep. Hypoventilation cannot explain all of the observed desaturation since, while there appears to be a uniform rise in carbon dioxide, PaO 2 falls a variable amount. Although never directly measured, this suggests that ventilation and perfusion matching is altered during sleep, perhaps due to changes in lung volume that occur with sleep onset and/or REM sleep. An alternative explanation comes from the work by O Donoghue et al, who found an even greater drop in minute ventilation during non-rem sleep in hypercapnic COPD patients. [86] However, there is evidence that some patients with daytime PaO 2 levels in the mildly hypoxaemic range can also develop clinically significant nocturnal oxygen desaturation, which may predispose them to pulmonary hypertension. [87] CONSEQUENCES OF NOCTURNAL OXYGEN DESATURATION IN COPD A review of the normal changes in respiration that occur with sleep onset is helpful to understand the changes that occur during sleep in those with COPD. Nocturnal oxygen desaturation causes surges in both systemic and pulmonary blood pressure.[88] It now seems likely that repetitive, transient oxygen desaturation can cause pulmonary hypertension.[89] Systemic inflammation is considered a hallmark of COPD and one of the key mechanisms that may be responsible for the increased rate of co-morbidities, including cardiovascular complications in COPD. Various arrhythmias are also reported during episodes of nocturnal desaturation.[90] These consequences might help explain why nocturnal oxygen desaturation is a marker of increased mortality, and why COPD patients are reported to die more frequently at night than expected.[91] Patients with COPD have also been reported to have an increase in premature ventricular contractions during sleep, which decrease in frequency with supplemental oxygen.[92] Two studies have demonstrated a significant relationship between nocturnal desaturation and long-term survival, although it is not clear whether this relationship is independent of other factors such as lung function or daytime blood gases.[93,94] Furthermore, there is no evidence to demonstrate that correction of nocturnal oxygen desaturation improves survival.[94]

36 26 Domenico Maurizio Toraldo OVERLAP SYNDROME: OBSTRUCTIVE SLEEP APNEA IN PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE The combination of chronic obstructive pulmonary disease and sleep apnea syndrome has been denominated overlap syndrome by the late Flenley.[95] COPD is presently defined by the presence of an obstructive ventilatory defect characterized by an FEV 1 /FVC ratio of less than 70% in patients not exhibiting any other chronic respiratory disease.[96] OSAS was defined as an apnea-hypopnea index (AHI) of 5/h; patients with OSAS were divided into mild (AHI 5/h and 15/h), moderate (AHI 15/h and 30/h) and severe OSAS (AHI 30/h) and the presence of symptoms (daytime sleepiness, poor quality of sleep, etc.) were required. [97] Previous studies have suggested that the prevalence of OSAS in patients with COPD, and of COPD in patients with OSAS, was high.. [98, 99,100,101] The prevalence of OSAS among patients with mild COPD equals that among the general middle-aged population (22% vs. 29%). [102] An additional quarter of COPD patients with mild daytime hypoxemia suffer from nocturnal oxyhemoglobin desaturation even in the absence of OSAS.[88] A progressive decline in FEV 1 and a forced vital capacity (FVC) ratio of less than 65% is associated with an accelerated increase in the risk of oxyhemoglobin desaturation during sleep. [102] Taken together, these epidemiological data suggest that nocturnal oxyhemoglobin desaturation, either related or unrelated to OSAS, is present in at least a half of COPD patients without significant daytime hypoxemia. Overlap patients develop more pronounced nocturnal oxygen desaturation than patients with COPD or OSAS alone, which predisposes them to pulmonary hypertension. If the overlap syndrome is observed in a relatively high number of subjects (or patients), it is simply because COPD and OSAS are both frequent conditions. [103] If COPD is present in about 10% of the adult population 40 years of age or older, and if the prevalence of OSAS in the same population is in the range of 5 to 10% [104], overlap syndrome can be expected to be present in 0.5 to 1% of the population over 40 years of age, which is far from being negligible. Epidemiological studies indicate a prevalence of approximately 1% of the overlap syndrome in adult

37 Part II 27 males, but the co-existence of asymptomatic lower airway obstruction with sleep-disordered breathing is considerably higher. [104] Current guidelines for evaluation of nocturnal oxyhemoglobin saturation in COPD patients without significant daytime hypoxemia are somewhat restrictive. Measuring nocturnal oxyhemoglobin saturation in COPD patients who have daytime arterial partial pressure of oxygen (PaO 2 ) of mm Hg is not recommended, except in patients with unexplained polycythemia or cor pulmonale.[105] Nocturnal polysomnography is recommended in COPD patients whose symptoms suggest co-existent OSAS. This includes COPD patients who have daytime hypercapnia with only moderately reduced FEV 1, those who are obese snorers, or those who develop headache after nocturnal oxygen therapy. [105] In conclusion, considering that approximately half of patients with COPD who have nocturnal hypoxemia have coexistent OSAS, clinicians should be careful in establishing the diagnosis of OSAS in these patients. Readily available and inexpensive nocturnal oxymetry should be performed in COPD patients with mild daytime hypoxemia and/or an FEV 1 /FVC ratio below 65%. Patients with COPD who are diagnosed with nocturnal hypoxemia by nocturnal oxymetry should undergo attended nocturnal polysomnography to exclude co-existent OSAS as a treatable cause of nocturnal hypoxemia. EFFECTS OF CPAP ON LUNG FUNCTION IN THE OVERLAP SYNDROME CPAP remains the accepted standard treatment for OSAS, and is currently the accepted standard for overlap syndrome. Prospective studies of long-term CPAP therapy reported reduction in airway obstruction and improvement in gas exchange and respiratory muscle strength in patients with COPD and OSAS. [106,107,108] CPAP therapy for 24 months reduces daytime arterial PaCO 2 and increases daytime PaO 2 and FVC and FEV 1 in these patients.[108] Improvement in spirometry and gas exchange persisted after 18 months of CPAP therapy.[110] Possible mechanisms responsible for CPAP-mediated improvement in lung function in patients with overlap syndrome includes counteraction of auto-positive end-expiratory pressure, decreasing