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Definition, discrimination, diagnosis, and treatment of central breathing disturbances during sleep.

An ERS Statement

Randerath W*#1, Verbraecken J*#2, Andreas S3, Arzt M4, Bloch KE5, Brack T6, Buyse B7, De Backer W2, Eckert DJ8, Grote L9, Hagmeyer L1, Hedner J9, Jennum P10, La Rovere MT11, Miltz C1, McNicholas WT12, Montserrat J13, Naughton M14, Pepin J-L15, Pevernagie D16, Sanner B17, Testelmans D7, Tonia T18, Vrijsen B7, Wijkstra P19, Levy P#15

*contributed equally as first authors #co-chaired the Task Force

1 Bethanien Hospital, Institute of Pneumology, Solingen, Germany 2 Dept of Pulmonary Medicine, Antwerp University Hospital and University of Antwerp, Edegem, Belgium 3 Cardiology and Pneumology, University Medical Center Göttingen, Germany and Lung Clinic Immenhausen, Krs. Kassel, Germany 4 Department of Internal Medicine II University Hospital Regensburg, Germany 5 University Hospital Zurich, Department of Pulmonology and Sleep Disorders Center, Zurich, Switzerland 6 Department of Internal and Pulmonary Medicine, Kantonsspital Glarus, Switzerland 7 Department of Pulmonary Medicine – KU Leuven, Leuven, Belgium 8 8 Neuroscience Research Australia (NeuRA) and the University of New South Wales, Sydney, New South Wales, Australia 9 Sleep Disorders Center, Dept. of Pulmonary Medicine, Sahlgrenska University Hospital, Göteborg, Sweden 10 Center for Healthy Aging and Danish Center for Sleep Medicine, Faculty of Health Sciences, University of Copenhagen, Denmark

11 Department of Cardiology, Fondazione S. Maugeri, IRCCS, Istituto Scientifico di Montescano (Pavia), Italy 12 Pulmonary and Sleep Disorders Unit, St. Vincent’s University Hospital and University College Dublin, Dublin, Ireland 13 Laboratori del Son, Hospital Clínic, Universitat de Barcelona, Barcelona, Spain. 14 General Respiratory and Transplantation, Alfred Hospital and Monash University, Melbourne, Victoria, Australia 15 Laboratoire du sommeil explorations fonct. respire. Centre Hospitalier Universitaire Grenoble, France 16 Dept. of Respiratory Diseases and Sleep Medicine Centre Ghent University Hospital, Belgium 17 Department of Internal Medicine, Agaplesion Bethesda Hospital Wuppertal, Germany 18 ERS Methodologist, Institute of Social and Preventive Medicine Universtity of Bern, Switzerland 19 Department of Pulmonology/Home Mechanical Ventilation, University Mecical Center Groningen, University of Groningen, Netherlands

Address correspondence to: Winfried J. Randerath, M.D., FCCP, Professor of Medicine University of Cologne, Clinic for Pneumology and Allergology, Centre of Sleep Medicine and Respiratory Care, Bethanien Hospital Aufderhöherstraße 169-175, 42699 Solingen, Germany E-mail: [email protected]

Table of contents

I. Abbreviations II. Criteria and results of the literature search III. Additional information IV. Figures V. Tables VI. References

I. Abbreviations

A Areas AASM American Academy Scoring Manual AAV Adeno-associated virus ABD Abdomen ABG Arterial blood gases ACZ Acetazolamide AD Alzheimer Disease ADL’s Activities of Daily Living AHI Apnoea-Hypopnoea-Index AHRF Acute Hypercapnic Respiratory Failure AI Arousal Indices ALS Amyotrophic Lateral Sclerosis AM Acromegaly AMS Acute Mountain Sickness AN Autonomic Neuropathy ANN Artificial Neural Network ANP Atrial Natriuretic peptide APCV Assisted Pressure Control Ventilation ARF Acute Respiratory Failure ASV Adaptive Servo Ventilation AVAPS Average Volume Assured Ventilation BMI Body Mass Index BNP Brain Natriuretic Peptide BP Blood Pressure BPAP Bilevel Positive Airway Pressure BPAP-S Bilevel Positive Airway Pressure in Spontaneous Mode BPAP-ST Bilevel Positive Airway Pressure in Spontaneous Timed Mode BURR Backup Respiratory Rate CAD Coronary artery disease CAH central apnoea/hypopnoea CAHI Central Apnoea-Hypopnoea Index

CAI Central Apnoea Index CGBPS Cardiac Gated Blood Pool Scan CHF Chronic Heart Failure CI Confidence Interval CMS Chronic Mountain Sickness CMV Controlled Mechanical Ventilation CNIV Chronic noninvasive ventilation therapy CompSAS Complex Sleep Apnoea syndrome COPD Chronic Obstructive Pulmonary Disease CPAP Continuous Positive Airway Pressure CPC Cardiopulmonary coupling CPX Cardio-pulmonary exercise testing CRDQ Chronic Respiratory Disease Questionnaire CRQ Chronic Respiratory Disease Questionnaire CRT Cardiac Resynchronisation Therapy CSA Central Sleep Apnoea CSAS Central Sleep Apnoea Syndrome CSB Cheyne Stokes Breathing CSR Cheyne Stokes Respiration

CT<90% Cumulative Time SpO2<90% Ctrl Control CV Cardiovascular CWD Chest Wall Disease d Day DCMAP Diaphragmatic compound muscle action potential DIAST-CHF Diastolic Chronic Heart Failure DM Diabetes mellitus DMD Duchenne Mycotrophic Dystrophy DMD Duchenne Muscular Dystrophy DP Diaphragmatic pacing DWT Discrete Wavelet Transforms ECG Electrocardiography EDR ECG-derived Respiration

EE Excessive Erythropoiesis EEG Electroencephalogram EF Ejection Fraction eGFR Cyst C Glomerular filtration rate estimating formulae based upon Cystatin C EK “Egen Klassifikation” e-LFC Elevated Low-Frequency Coupling EMG Electromyography EMGdi Diaphragmatic Electromyography eNB-LFC Elevated Narrow Band Low-Frequency Cardiopulmonary Coupling EPAP Expiratory Positive Airway Pressure EPM Name of a company ESRD Endstage Renal Disease ESS Epworth Sleepiness Scale ET Exercise Training EWL Excessive weight loss F Female FDA Food and Drug Administration FLI Flow Limitation Index FOT Forced Oscillation Technique FSS Fatigue Severity Scale FVP Forehead Venous Pressure GAA Acid alpha-glucosidase gFR Glomerular Filtration Rate GH Growth Factor/Growth Hormone GRADE Grading of Recommendations Assessment Development and Evaluation H Hour HAPE High Altitude Pulmonary Oedema HCVR Hypercapnic Ventilatory Response HF Heart Failure HFJV High Frequency Jet Ventilation HFpEF Heart Failure with Preserved Ejection Fraction HI Hypopnoea index

HMV Home Mechanical Ventilation HR Hazard Ratio HRQL/HRQoL Health Related Quality of Life HRrEF Heart Failure with Reduced Ejection Fraction HRV Heart Rate Variability HTx Heart Transplantation HVR Hypoxic Ventilatory Response IBW Ideal Body Weight ICC Intra Class Correlation ICD Implanted Cardioverter Defibrillator I-CSA Idiopathic Central Sleep Apnoea ICU Intensive Care Unit IEE Inspiratory Efforts during Expiration IFLI Inspiratory Flow Limitation Index IGF Insuline Like Growth Factor IHD ischemic heart disease IK Idiopathic kyphoscoliosis IPAP Inspiratory Positive Airway Pressure IQR Interquartile Range IV Intravenous K Kappa (Inter Rater Agreement) L Self-Inductance LGMD Limb Girdle Muscular Dystrophy LnBNP Logarithmic BNP (Brain Natriuretic Peptide) LSQ Least Squares Method LTOT Long Term Oxygen Therapy LVEF Left Ventricular Ejection Fraction LVESD Left Ventricular End-Systolic Diameter m Meter M Month MA Mixed Apnoea MD Myotonic Dystrophy MD Mean Difference // Myotonic Dystrophy

MDRS Muscular disability rating scale MEP Maximal Expiratory Pressure MEP Maximal Expiratory Pressure METS Metabolic Equivalent Task Score Min Minute MIP Maximal Inspiratory Pressure MIP Maximal Inspiratory Pressure MIPPV Mouthpiece intermittent positive pressure ventilation MIRS Muscular Impairment Rating Scale MMSD Mean Magnitude of the Second Derivatives MMT Methadone Maintenance Treatment MPV Mouth piece ventilation MR Mitral Regurgitation MRF Mitral Regurgitation Flow ms Milliseconds MSNA Muscle Sympathetic Nerve Activity MTIF Mean Tidal Inspiratory Flow MV Mechanical Ventilation MV Mechanical Ventilation N Number N.S. Non-Significant NA Not Applicable NAF Nasal Air Flow nCPAP Nasal Continuous Positive Airway Pressure NIHSS National Institutes of Health Stroke Scale nIPPV Non Invasive Positive Pressure Ventilation NIV Non Invasive Ventilation NIV-PS Non-Invasive Ventilation-Pressure Support NOT Nocturnal Oxygen Therapy NP Nasal Pressure NPPV Non-Invasive Positive Pressure Ventilation NPV Negative Pressure Ventilation nREM Non Rapid Eye Movement

NT-proBNP N-terminal Brain Natriuretic Peptide NYHA New York Heart Association OA Obstructive Apnoea OAH Obstructive Apnoea/Hypopnoea OAHI Obstructive Apnoea-Hypopnoea Index OAI Obstructive Apnoea Index O-CSA Opioid-related Central Sleep Apnoea ODI Oxygen Desaturation Index ODI Oxygen Desaturation Index OHS Obesity Hypoventilation Syndrome OLV One Lung Ventilation OSA Obstructive Sleep Apnoea p p-Value for Statistical Significance PAV Proportional Assist Ventilation PB Periodic Breathing PC Pulmonary Comorbidity PCF Peak Cough Flow pCPAP Placebo Continuous Positive Airway Pressure PCWP Pulmonary Capillary Wedge Pressure PD Parkinson Disease PDS Portable Diagnostic System PE Piezoelectric PEF Peak expiratory flow PEG Percutaneous endoscopic gastrostomy

PetCO2 Endtidal CO2 PHYS Physiological PIFMF Peak Inspiratory Flow to Mean Inspiratory Flow ratio PIR Passive Infrared PNE Plasma Norepinephrine PNT Nasal Oral Pneumotachygraphy Poes Oesophageal Pressure PP Post-Polio PR Pulmonary Rehabilitation

Pred Predicted PSG Polysomnography PSQI Pittsburgh Sleep Quality Index PSQI Pittsburgh Sleep Quality Inventory Pst Suprasternal Pressure Transducer PSV Pressure Support Ventilation PSV-VTG volume guaranteed pressure support ventilation

PtcCO2 Transcutaneous CO2 PTIF Peak Tidal Inspiratory Flow PTPdi Diaphragmatic Pressure Time Product Pts Patients PTT Pulse Transit Time PVA Patient-Ventilator Asynchrony PVDF Polyvinylidene Fluoride PVDFb Polyvinylidene Fluoride Belts QDL Qualitative Diagnostic Calibration QoL Quality of Life r Correlation Coefficient RAI Respiratory Arousal Index RC Ribcage RCT Randomised Controlled Trial RDI Respiratory Disturbance Index REM Rapid Eye Movement RERA’s Respiratory Effort Related Arousals Resp.-EZ Trademark of respiratory polygraph RIP Respiratory Inductive Plethysmography RIPsum Sum of thoracic and abdominal signal during respiratory Inductive plethysmography RMS Respiratory Muscle Strength ROC Receiver Operating Characteristics RP Respiratory Polygraphy RR Blood Pressure RR Relative Risk

S Seconds SA Sleep Apnoea SAPS2 Simplified Acute Physiology Score SAQLI Sleep Apnoea Quality of Life Inventory SBP Systolic Blood Pressure SD Mean/Standard Deviation SDB Sleep Disordered Breathing SE Standard Error SEI Sleep efficiency index SEM Standard Error of Mean SEQ Simultaneous Equation Method SF Short Form Health Survey SHHS Sleep Heart Health Study SMA Spinal Muscular Atrophy SNIP Sniff Inspiratory Pressure SOFA Sequential Organ Failure Assessment Score SP Spirometry

SpO2 (peripheral) Oxygen Saturation SRBD Sleep Related Breathing Disorder SRI Severity Respiratory Insufficiency Questionnaire SWS Slow Wave Sleep tCPAP Therapeutic Continuous Positive Airway Pressure Th Thermistor Ti Inspiration Time TIA Transient Ischemic Attack TINA-TCM3 Trademark of capnograph TIV Tracheal Invasive Ventilation TLV Total Lung Ventilation TMV Tracheal mechanical ventilation TOSCA Trademark of capnograph TST Total Sleep Time TTdi Tension Time Index of the diaphragma TTI Transthoracic Impedance

UA Upper Airway UARS Upper Airway Resistance Syndrome UNE Urinary norepinephrine US Usual VA Veterans Affairs VAS Visual Analogue Scale VC Vital Capacity S. 21?

VE/VCO2 Minute Ventilation − Carbon Dioxide Production Relationship VPAP Trademark of ventilator Vs Versus VT Tidal Volume WASO Wake After Sleep Onset Wks Weeks Yrs Years Zrs Respiratory Impedance

II. Criteria and results of the literature search

Chapter 1.3. Measurement techniques

Keywords and keyword combinations Polysomnography/instrumentation and sleep apnoea, central/diagnosis or sleep apnoea, central or sleep apnoea, obstructive and polysomnography/instrumentation or sleep apnoea syndromes/classification and polysomnography/instrumentation or polysomnography/methods or polysomnography/utilization or sleep apnoea, central/diagnosis and polysomnography or sleep apnoea, central and sleep apnoea, obstructive or capnography and polysomnography or PaCO2 and end-tidal CO2 or transcutaneous CO2

A personal archive was also reviewed.

Results of the literature search The total number of retrieved papers was 138. Of these, 29 papers included data on thermistors, thermocouples, nasal prongs and polyvinylidene fluoride (PVDF) sensors; 64 papers reported on studies evaluating respiratory effort sensors (10 papers on oesophageal manometry; 19 papers on piezo-electric bands, respiratory inductive plethysmography, PVDF belts and magnetometry; 6 papers on pulse transit time (PTT); 4 papers on electromyography; 4 papers on forced oscillation technique; 13 papers on complex algorithms; 8 papers on miscellaneous techniques). 3 papers reported on nocturnal capnography as an adjunct signal for detection of sleep apnoea, based on changes in the shape of the capnogram. 42 papers were selected on measurement techniques in hypoventilation.

Chapter 2.2. Primary CSA, drug induced CSA

Keywords and keyword combinations Central sleep apnoea or sleep apnoea, central or sleep and apnoea and central or central sleep apnoea or central and sleep and apnoea and opioid and analgesic

Results of the literature search The search yielded 73 references. 20 studies were included in the analysis. Nine studies used a prospective, combined or retrospective design to address the prevalence of sleep related breathing disorder (SRBD) in patients with addiction, chronic pain or sleep apnoea [1-9]. One study [10] was randomised and addressed a single ramifentanil infusion in patients with sleep apnoea. Four studies were case series comprising patients on methadone programs [11] or chronic opioid therapy [12-14]. Four studies investigated the effectiveness of various forms of positive airway pressure (PAP) therapy on opioid-induced CSA [15-18]. There is a lack of randomised controlled trials (RCTs) in this area of research.

Chapter 2.3. CSA in high altitude

Keywords and keyword combinations Altitude and apnoea or altitude and periodic and respiration or altitude and periodic and breathing or altitude or apnoea or altitude or respiration or breathing

Results of the literature search Total number of retrieved papers: 235; of these, 44 papers included data on high altitude periodic breathing (HAPB) or central sleep apnoea (CSA) at altitude in at

14 least 5 participants; 31 papers reported on prevalence and clinical characteristics of high altitude periodic breathing, 13 papers reported on studies evaluating treatment of high altitude periodic breathing

Chapter 2.4.1. CSA in heart failure

Keywords and keyword combinations Heart failure and sleep-disordered breathing or central sleep apnoea or Cheyne Stokes respiration or continuous positive airway pressure or oxygen or adaptive servo-ventilation or auto servo-ventilation or bilevel positive airway pressure or coronary artery disease and sleep-disordered breathing or central sleep apnoea or Cheyne Stokes respiration or arrhythmias and sleep-disordered breathing or central sleep apnoea and Cheyne Stokes respiration“.

Results of the literature search 74 studies on treatment were included in the further analysis. One randomised controlled study, 33 randomised controlled studies, 2 systematic reviews, 3 “Outcomes” research and 35 case series, cohort studies or case-control studies [19](table 1 main text).

2.4.2. CSA in stroke patients

Keywords and keyword combinations: Epidemiology of sleep disordered breathing and stroke or stroke and central sleep apnea

15 or cerebro-vascular disease and Cheyne Stokes Respiration or CPAP and stroke or NIV and stroke or Cerebro-vascular disease and sleep-disordered breathing or Treatment of sleep apnea after stroke or Sleep apnea and stroke/cerebrovascular disease

2.5.1. CSA in other internal diseases

Keywords and keyword combinations CSA or HCSB or Acromegaly or diabetes mellitus or end stage renal disease or dialysis or CPAP or Bi Level or complex sleep apnoea

Chapter 2.5.2. CSA and hypoventilation in interstitial lung disease

Keywords and keyword combinations Sleep apnoea or hypoxemia orinterstitial lung disease or idiopathic pulmonary fibrosis or sarcoidosis or scleroderma

Chapter 2.5.3. CSA and pulmonary hypertension

Keywords and keyword combinations Central sleep apnoea or Cheyne-Stokes respiration or periodic breathing and pulmonary hypertension

Chapter 2.5.4. CSA in neurological diseases other than stroke

Keywords and keyword combinations CSA or HCSB or (Morbus) Parkinson Disease or (Morbus) Alzheimer disease or CPAP or BiLevel and treatment

Chapter 2.6. Treatment-Emergent Central Sleep Apnoea

Keywords and keyword combinations CompSAS or CPAP-emerging CSA or CPAP-persistent CSA or CPAP-resistant CSA or co-existing obstructive and CSA.

Results of the literature search Of 52 studies, 15 were included in further analysis: 3 randomised controlled studies [20-22], 3 compared cohorts or were cross-sectional analyses [23-25], 9 case series or retrospective analyses [26-34].

Chapter 2.7. Idiopathic Central Sleep Apnoea

Keywords and keyword combinations Idiopathic central sleep apnoea or primary central sleep apnoea or essential central sleep apnoea or protopathic central sleep apnoea or genuine central sleep apnoea.

Results of the literature search The search brought 16 references. 10 studies were excluded, 5 were case reports, 5 studied patients with several underlying diseases or treatment associated central sleep apnoea. One of the remaining 6 studies investigated the relevance of hyperventilation and arousals from sleep in the pathophysiology of idiopathic central sleep apnoea [19].

Chapter 3.1.

Keywords and keyword combinations Polysomnography and obesity hypoventilation syndrome or hypoventilation or hypoventilation or obesity hypoventilation syndrome and capnography or capnography and polysomnography or oximetry and polysomnography or polysomnography and asynchronies or non-invasive ventilation or NIV and polysomnography or asynchronies and polysomnography or leaks and polysomnography or leaks and polysomnography and NIV or leaks and polysomnography and noninvasive ventilation or noninvasive ventilation and titration or NIV and titration

Chapter 3.2.

Keywords and keyword combinations Congenital hypoventilation or congenital hypoventilation syndrome oridopathic congenital hypoventilation or idopathic congenital hypoventilation syndrome or central congenital hypoventilation or central congenital hypoventilation syndrome or Ondine Curse.

Results of the literature search Total number of retrieved papers: 613; of these, 88 papers included data on congenital hypoventilation in at least 3 participants. 70 papers reported on prevalence and clinical characteristics of congenital hypoventilation, 18 papers reported on studies evaluating treatment of congenital hypoventilation. Studies on genetics were not included.

Chapter 3.3. Hypoventilation in Neuromuscular Disorders

Keywords and keyword combinations Neuromuscular or amyotrophic lateral sclerosis or myotonic or Steinert or Duchenne or Pompe or neuropathy and ventilation and neuromuscular or neuropathy and hypoventilation

Chapter 3.4. Kyphoscoliosis

Keywords and keyword combinations

(Kypho)scoliosis and sleep or apnoea or (kypho)scoliosis and Hypoventilation or (kypho)scoliosis and Polysomnography or (kypho)scoliosis and ventilation

Chapter 3.5. Obesity hypoventilation syndrome

Keywords and keyword combinations Obesity or obesity hypoventilation or sleep related breathing disturbances or respiratory drive or upper airway obstruction or pulmonary compliance or leptin or restrictive disease or obstruction or hypercapnia or chemoresponsiveness or respiratory failure or chronic hypoxia or polyglobulia and heart failure or pulmonary hypertension or corpulmonale or metabolic syndrome and CPAP or mechanical ventilation or weight loss or surgery

Results of the literature search 29 interventional studies: 7 RCT´s[35-40], 4 cohort or cross-sectional analyses [41- 43], the others case series or retrospective analyses (4) [44-55].

Chapter 3.6. Chronic NIV in chronic hypercapnic COPD

Keywords and keyword combinations Lung diseases, obstructive or pulmonary disease, chronic obstructive or emphysema or chronic and bronchitis or obstruct* and pulmonary or lung* or airway* or airflow* or bronchi* or broncho* or respirat* or COPD or COAD or COBD or AECB and clinical trial or drug therapy or nose or mechanical or noninvasive or non-invasive or positive or intermittent or bi-level or airway or pressure or pressure support and ventilat* or NIPPV

III. Additional information

Additional information on chapter 1.3. Measurement techniques

A. Summary

1. Full PSG with oesophageal pressure measurement is the optimal procedure to diagnose central sleep apnoea. However, as oesophageal manometry is an invasive technique, different surrogates are used. 2. Although misleading in some cases the most common surrogates used are the thoracoabdominal bands, especially the inductive plethysmography bands and the shape of the inspiratory flow detected by a nasal prongs pressure. Pulse transit time that estimates changes in pleural pressure and detects autonomic arousals is a capable tool to distinguish central and obstructive events, although some expertise is needed to perform it. 3. New developments, combining different simple variables analyses by artificial intelligence or mathematical procedures, are promising. 4. Brand new sensors are needed to be developed, which could substitute classical and older ones that have been used in PSG for many years. 5. The daytime hallmark feature of hypoventilation is diurnal hypercapnia. Nocturnal sleep study monitoring, using the classical variables of a polysomnography (PSG)

in addition to monitoring the gas exchange (SaO2 and especially CO2) and respiratory effort are the optimal way to assess night time hypoventilation.

6. As both PaCO2 and oesophageal pressure are invasive techniques, surrogates

are used: PaCO2 can be estimated by transcutaneous CO2 and end-tidal CO2. Oesophageal pressure can be evaluated by thoracoabdominal bands, flow limitation, EMG of the thoracic muscles or PTT. 7. During non-invasive ventilation (NIV) titration, more sensors are required: minute ventilation, pressures, leak sensors and procedures to detect asynchronies. 8. Non-invasive mechanical ventilation reverses the clinical consequences of hypoventilation in most of the patients. However, this is not so clear in COPD patients. It is of paramount importance to understand the functioning of the different non-invasive mechanical ventilators to manage these patients properly.

B. Background The study of the sleep apnoea-hypopnoea syndrome (SAHS) has made considerable advances in the last decade. These are at least partly due to the development and refinement of non-invasive sensors and techniques, unobtrusive technology, combination of different techniques or sensors as well as better procedures or strategies [56-64]. SAHS are divided into two groups: obstructive and central. During polysomnography (PSG), central sleep apnoea is scored when a cessation of airflow (or ≥ 90%) is detected for 10 seconds or more, without any identifiable respiratory effort. In contrast, an obstructive apnoea has the same definition, but with an associated ventilatory effort. No oxygen desaturation criteria are needed in either case. Hypopnoea is scored when there is a discernible flow drop (by ≈ 30%) from the pre-event baseline value associated with either ≥ 3% arterial oxygen desaturation or an arousal. When respiratory effort is not present in the first part of a respiratory event, but is present in the second part, the event is considered mixed.

Hypoventilation occurs when alveolar ventilation is reduced. The most important marker is the rise of arterial CO2 (PaCO2). Ventilation depends on three major elements: the respiratory muscles, the load placed on them and the central ventilatory control, such as the afferent pathways [65-73]. During sleep, especially during REM sleep, there is a reduction in basic tone of the respiratory muscles and the drive to breathe, as well as an increase in upper airway resistance. Therefore, when a patient has a problem with the thoracic pump, the respiratory centres or the efferent pathways, there is a risk of developing sleep disturbances [65-66, 68]. It is important to detect these patients as soon as possible by some daytime tests [67, 74- 77] and, if needed, to perform an adequate sleep study [56-57, 78-79].

Box e1 shows the update of the AASM Manual for the Scoring of Sleep and Associated Events for the definition of hypopnoea [57, 80].

Box e2 shows a classification of the different sensors used during sleep, including those measuring flow, effort and the surrogates of blood gases.

Box e3 shows the standard techniques for routine PSG.

Box e4 shows the main daytime tests and disorders that can be associated with nocturnal hypoventilation (from cortex to the thoracic pump). This chapter will review the various sensors used to analyse sleep breathing disorders, especially those that allow us to distinguish between central and obstructive sleep apnoea, and those used to detect hypoventilation.

C. Description of measurement techniques in central sleep apnoea

C.1. Flow sensors

C.1.1. Pneumotachograph (PNT) This is the gold-standard device for measuring flow. It quantifies airflow by measuring the pressure drop across a linear (constant) resistance [81-82]. Therefore, the flow measurement is very precise. However, PNT is not used for routine diagnosis. The PNT not only quantifies the flow signal, but also assesses the morphology and flow limitation, which is a surrogate of respiratory effort. The PNT is the only sensor able to detect changes in the percentage of ventilation, as thermal sensors and nasal prongs do not make quantitative measurements. However, since it cannot be used in diagnostic sleep studies, surrogates are needed. It has to be mentioned that neither thermal nor nasal prongs sensors are quantitative.

C.1.2 Thermistors and Thermocouples Thermal devices were the first to be used to monitor airflow in clinical sleep studies [81-83]. These sensors have electrical characteristics (resistance and voltage) that depend on their temperature. To assess breathing flow, the device is placed close to the airway opening, either the nose or the mouth. The flow is monitored by measuring variations in temperature when the patient inspires or expires. The signal is merely semi-quantitative [56-57, 81-83], but their main limitation is the slowness of their dynamic response. Therefore, the relationship between the electrical signal and the airflow is not linear [82]. Accordingly, thermistors and thermocouples are not suitable for accurately quantifying the magnitude of flow [81-83] (hypopnoea) or the morphology of the flow signal (flow limitation). In other words, they are inadequate for scoring hypopnoeas, because they underestimate the flow reduction, but adequate for detecting apnoeas (Figure e1).

C.1.3 Nasal prongs Thermal devices measure both oral and nasal flow, while the pressure swing of the nasal prongs only estimates nasal flow. When conventional nasal prongs (NP), similar to those designed for long-term oxygen therapy, are inserted in the nostrils and connected to a pressure transducer, they measure the pressure fluctuations that occur during breathing. These oscillations are used as a surrogate of the nasal flow [84-86]. Nasal prongs work as follows: because the tip of the cannula is inside the nostrils and the other side of the pressure transducer is open to the atmosphere, there is a drop in the pressure between the cannula tip inside the nostril and the atmospheric pressure during breathing, due to the resistance of the nostrils. As the flow is turbulent, the relationship between the pressure change, flow and resistance is non-linear, and therefore, the flow estimated by the NP is only qualitative, but unlike the thermistor, they overestimate flow reduction, due to the quadratic pressure-flow relationship [87]. Nevertheless, the nasal-prongs signal can be linearized [87] to obtain an excellent surrogate flow signal (Figure e2). It has to be mentioned that the NP signal does not provide an absolutely accurate reading of total airflow over the entire night (e.g. due to changes in the position of the cannula, among others) [84-85]. As with thermal sensors, the changes in breathing pattern detected in a given sleep event should be compared with the signal in the previous

27 normal cycles. The major advantage of NP is their fast response. This permits the detection of a dynamic obstruction (obstructive hypopnoeas, or the inspiratory waveform contour), particularly if the signal is linearized (Figure e2). The AASM scoring manual recommends nasal-oral thermal sensors for the detection of apnoea and NP sensors (with or without square root transformation of the signal) for the detection of hypopnoea. The simultaneous use of both NP and nasal-oral thermal sensors is recommended, providing the additional advantage of a backup sensor, if one of the airflow detection devices fails. The Table e1 shows more information of the studies mentioned above as well as others related to the measurement of respiratory airflow [88-109]. Table e2 shows information about the two papers that analyse the respiratory flow by using polyvinylidenefluoride (PVDF). This sensor is more sensitive to detect changes in airflow during sleep compared with traditional thermal devices [58, 110].

C.2. Respiratory effort sensors Oesophageal manometry is the gold standard for the detection of respiratory effort and provides an estimate of the magnitude of effort [56, 79]. However, this procedure does require an invasive oesophageal balloon or catheter, so it is not appropriate for routine practice. Indirect methods are used at present to estimate inspiratory effort non-invasively (flow limitation, thoracoabdominal bands, thoracic EMG or pulse transit time among others).

C.2.1. Oesophageal manometry The measurement of oesophageal pressure, which reflects pleural pressure, is the gold standard for the detection of respiratory effort and for distinguishing central apnoeas from obstructive events [79, 111-114]. A catheter needs to be placed in the oesophagus to obtain a corresponding pressure curve (Figure e3). As it is an invasive procedure, it is not useful in routine practice, and may create problems [115]. Instead, different surrogates are employed. Table e1.3.C. and e1.3.K show more information on the studies mentioned above, as well as others related to the measurement of the oesophageal pressure [115-120].

C.2.2. Thoraco-abdominal bands

These sensors measure thoraco-abdominal excursions, although the magnitude of these excursions is not exactly proportional to swings in oesophageal pressure (Figure e4). They are semi-quantitative and may sometimes misclassify obstructive events as central. The bands analyse the amplitude of the thoracic and abdominal compartments, as well as the synchrony between the movements of both compartments [121]. Piezo-electric bands [122] are frequently used, although at present, the AASM recommends respiratory inductive plethysmograph (RIP) bands. Other options are polyvinylidene fluoride (PVDF) sensors (excellent but still no fully incorporated) and pneumatic bands, which have been used in the past with acceptable – and more economical – results in most cases.

C.2.3. Piezo-electric bands Quartz crystals and some manufactured ceramics have the characteristic of inducing an electric charge when they are stretched, and if they are connected to an amplifier, they can reflect respiratory movement (without any battery being required). A small, thin piezo-electric crystal is usually placed on one elastic band on the thorax and another one on the abdomen. Piezo-electric sensors are very easy to use in sleep studies. The sensory element is located on only a very small section of the band’s length, usually near the nipple line (or mid-chest) and just above the belly button. The expansion of thorax and abdomen during breathing stretches the piezo-electric sensors and the changes in the electric charge allow to estimate the thoracoabdominal movement [122-123]. However, problems may occur when a patient lies on top of the piezo crystal or in morbidly obese patients, and the signal may be inadequate.

C.2.2.1. Respiratory inductive plethysmography (RIP) This system involves insulated copper-wire sensors placed on elastics bands around the rib cage and abdomen to measure changes in their cross-sectional area [124- 125]. The sensors, inserted into bands surrounding the thorax and abdomen, consist of arrays of sinusoidal wires that are stimulated continuously by a very low current from a high-frequency electrical oscillatory circuit. When movement occurs in the rib cage or the abdomen, this is reflected by changes in the voltage generated by the sensors. Both the bands and the sensors can be extended without any significant mechanical resistance when the bands are stretched. Theoretically, when the RIP is

29 correctly calibrated, it permits the measurement of the volume of the breathing cycle [126]. However, as calibration is impaired during sleep, it has to be considered that RIP does not measure ventilation quantitatively. The RIP bands are the optimal method for detecting the sum of the thoracoabdominal motion. When the expansion and contraction of the chest and abdomen are completely out of phase, it means that an upper airway occlusion occurs and the sum channel tends to be flat [127]. Figure e4 shows the comparison between oesophageal pressure, bands and the shape of the inspiratory flow (nasal prongs). Table e4 shows more information of the studies mentioned above as well as others related to the thoraco-abdominal bands [122, 128-141].

C.2.3. Electromyography (EMG) An increased diaphragmatic or intercostal EMG signal occurs during each inspiration and so, measurement of the EMG could be a useful tool for detecting respiratory effort and thus, distinguishing central and obstructive apnoeas [142]. An EMG recording uses two electrodes set horizontally, about 2 cm apart, in the intercostal (2nd or 3rd intercostal spaces in the mid-axillary line) or diaphragmatic area (7th intercostal space in the right anterior axillary line). Both electrodes are placed on the right side to reduce ECG artefact. Despite the scant literature available, the AASM recommends EMG as an alternative sensor for the detection of respiratory effort. Table e5 shows more information on the studies mentioned above as well as others related to the EMG measurement [143-145].

C.2.4. Pulse transit time (PTT) This method is considered effective, as it is a useful marker of respiratory effort. It calculates changes in pleural pressure and detects autonomic arousals, although some expertise is needed to perform it. The PTT is the time taken for the arterial- pulse pressure wave to travel from the aortic valve to the vessels in the finger, as detected by a pulse-oximeter sensor [146]. Stiffness and tension in the arterial walls are the main factors determining the speed of the transmission of the pulse wave, which in turn largely depends on blood pressure. The progressive rise in blood pressure, which occurs during an apnoea, increases arterial wall tension and stiffness, thus shortening the PTT. Conversely, a drop in blood pressure reduces this stiffness and tension, thus lengthening the PTT. The extent of the drops in systolic

30 blood pressure occurring with inspiration (pulsus paradoxus) has been shown to correlate well with the degree of inspiratory effort, allowing the PPT to differentiate between central and obstructive apnoeas [147-148]. It is also useful during noninvasive mechanical ventilation [149]. Furthermore, the PTT strikingly decreases during apnoea and hypopnoea, as a result of increased blood pressure at the apnoea termination PTT, and its variations are therefore considered as a marker of autonomic arousal [146]. Table e6 shows more information of the studies mentioned above as well as others related to the PTT measurement [150-151].

C.2.5. Others The following techniques can also help to distinguish between obstructive vs central sleep apnoea: the forced oscillation technique (FOT), snoring, and changes in the ECG during apnoeas and others.

C.2.5.1. FOT This technique provides a non-invasive method for assessing and quantifying airway obstruction. It involves superimposing a small pressure oscillation (5-Hz) on spontaneous breathing via a nasal mask [152-154]. Respiratory impedance (Z) is calculated online from pressure and flow signals recorded from the nasal mask. In an open airway, FOT measures total respiratory impedance, whereas in the case of a closed airway, FOT measures the effective impedance of the airway segment from the mask to the site of collapse. During apnoeas, the impedance is high, while during hypopnoea, the impedance increases intermittently, because there is an inspiratory obstruction (dynamic obstruction), while during the normal breathing, the impedance is at normal values. Table e7 shows more information of the studies mentioned above as well as others related to the measurement of FOT 105.

C.2.5.2 Snoring and other measurements of respiratory effort

C.2.5.2.1. Snoring The evidence-based literature indicates that snoring may not be a trivial symptom, but should be considered in any medical assessment. It also helps us to differentiate between central and obstructive events. Surprisingly, the AASM Task Force stated that the monitoring of snoring is at the discretion of clinicians [57, 80]. Although there

31 is no sensor available to quantify the degree of snoring, there are sensors that substantially help the assessment of whether a patient snores or not during a PSG. The most commonly used are microphones or piezo electric sensors applied to the neck near the larynx [155-157]. Snoring can also be seen in the NP signal as rapid oscillations [155].

C.2.5.2.2. Other measurements of respiratory effort Measurement of cardiac oscillations [158], the analysis of suprasternal pressure traducer [159] or midsagittal jaw movement are useful techniques to detect respiratory effort [160]. Table e8 shows more information of the studies mentioned above as well as others related to the measurement of respiratory effort [161-165].

C.2.5.2.3. Electrocardiogram (ECG)-based method As there is a need for simple diagnostic devices with documented accuracy for the differentiated classification of sleep apnoeas (central vs. obstructive), one approach focuses on analysing the ECG, with or without other sensors [166-169]. A novel algorithm, using an oximeter-based finger plethysmographic signal in combination with a nasal cannula, has been shown to accurately distinguish obstructive and central apnoeic events during sleep [166]. Its simplicity has the potential to improve ambulatory home testing.

C.2.5.2.4. Other techniques A prolongation of the inspiratory time has been considered a good non-invasive predictor of high/low upper airway resistance [170]. Therefore, it can classify respiratory events as central or obstructive, especially in combination with flow limitation and the presence of cardiogenic oscillations in the flow signal. Interestingly, one recent paper used a combination of different variables (flattening, paradoxical breathing, arousal position, hypopnoea termination, REM/NREM), which together allow us to define most hypopnoeas as central or obstructive 7. A single automatic analysis of nasal airflow allows to the different ion of obstructive and central hypopneas [171-174]. Finally, there are various computer methods that use artificial intelligence or mathematical procedures to identify apnoeas as central or obstructive [175-177]. Table e9 shows more information of the studies mentioned above as well as others related to the measurement of the sleep disorders of breathing [157, 178].

C.3. Blood gases C.3.1 Arterial oxygen desaturation

An arterial oxygen desaturation during sleep is defined as a decrease in the SaO2 of 3-4% or more from the baseline that commonly occurs up to approximately 10-15 seconds after a respiratory event. The more specific measurement of SaO2 in sleep apnoea patients is the oxygen desaturation index (ODI), the number of oxygen desaturations per hour of sleep. Oxygen desaturation is considered when the SaO2 decreases 3% from the pre-event baseline value. The ODI tends to correlate with the apnoea-hypopnoea index. Other measurements that are not so specific but estimate the total degree of hypoxaemia are the time with a SaO2 < 90% (CT90%), the mean

SaO2 throughout the night and the minimum SaO2 during oxygen desaturations [179]. It is important to know the characteristics of the oximeters used, e.g. the average time [180].

C.3.2 Measurement of PaCO2 during sleep

Measurement of the PaCO2 during sleep in patients with CSA is less often performed, but can be of interest, especially in patients in which hypoventilation needs to be assessed. It has to be said that the assessment of the PaCO2 during the night is not as easy as that of SaO2 and sometimes no precise values are obtained

[181-182]. Clinical judgement is always needed. The measurement of both PetCO2 and TcPCO2 requires a visual analysis of the graphical recording. Nocturnal hypoventilation is defined as an increase in the PaCO2 during sleep ≥ 10 mm Hg compared with a wakeful period. PaCO2 is almost never assessed directly during

PSG. Instead, surrogates, such as the end-tidal CO2 (PetCO2) or transcutaneous

CO2 (TcPCO2), are used. Sometimes, a blood gas test is performed on awakening, on the assumption of hypoventilation. If hypercapnia is present, then night-time hypoventilation is highly probable. Also high daytime bicarbonate (>27mmol/L) is suggestive for nocturnal hypoventilation). TcPCO2 is a good instrument for recording trends in the PaCO2 during the night. The TcCO2 is higher than the PaCO2. The range of agreement for PtcCO2 vs. PaCO2 is ± 7.5 mm Hg. The manufacturer's recommendations should be followed [181]. Sometimes, the signal is inadequate and experience with the technique is needed. During the initial exhalation, PetCO2 is

0 mmHg (the dead space). Then, the PetCO2 increases until a plateau occurs as a 33 result of air exhaled from alveoli. If a clear plateau is reached, the difference between the PaCO2 and PetCO2 is usually no more than 5 mmHg and is considered useful to estimate the PaCO2 [183]. When the plateau is not reached, the PetCO2 is not useful. Table e10 shows the most significant studies about the relationship between

PaCO2, and transcutaneous CO2 and end-tidal CO2 [184-204]. Transcutaneous CO2 is the optimal surrogate of PaCO2 in the adult population.

Several studies compared the AHI calculated from the PetCO2 waves and the corresponding polysomnographic data and demonstrated that a capnography-based AHI significantly correlates with the AHI as measured by traditional PSG. However, classification of apnoeas (as obstructive, central, or mixed) and hypopnoeas is not well validated [205-207].

D. Description of measurement techniques in hypoventilation

D.1. Daytime measurements Box e5 shows the criteria for hypoventilation. The cardinal criterion is daytime hypercapnia (PaCO > 45 mmHg). A FVC < 50%, blood bicarbonate (>27mmol/L) and 2 a CT90% > 30 % are good predictors of daytime hypercapnia, as well as some symptoms like morning headache, somnolence, cor pulmonale or polyglobulia. [208]

D.2. Nighttime measurements

Nighttime Hypoventilation is defined when PaCO2 increases > 10 mmHg with respect to daytime PaCO2, with a duration of at least 10 minutes, based on consensus. However, if reporting hypoventilation, the duration of hypoventilation as a percentage of the total sleep time should be reported. Ten minutes is probably not long enough, since some surrogates of PaCO2 require more time for stabilisation, and measuring hypoventilation by surrogates of PaCO2 is not an easy task and requires experience. Nocturnal sleep monitoring, using the classical variables of PSG in addition to monitoring the gas exchange (SaO2 and especially CO2) and respiratory effort are the optimal way to assess night time hypoventilation. As both PaCO2 and oesophageal pressure are invasive, surrogates are used: PaCO2 could be estimated by transcutaneous CO2 and end-tidal CO2. Oesophageal pressure could be evaluated by thoraco-abdominal bands, flow limitation, EMG of the thoracic muscles or PTT.

During non-invasive ventilation (NIV) titration, more sensors are required: minute ventilation, pressures, leaks sensors and procedures to detect asynchronies (ASY) (Box e6).

NIV reverses the clinical consequences in most of the patients with the above mentioned diseases. However, it is not so clear in COPD patients. It is of paramount importance to understand the functioning of the different non-invasive ventilators to manage these patients properly [209-215].

D.2.1 Understand the NIV device D.2.1.1 Devices Management of nocturnal NIV is difficult and different problems may occur throughout the night, such as a) physiological variations of different variables, b) clinical problems (pain and secretions, among others) or c) sleep disturbances. In addition, almost all ventilators are different, and having knowledge on most of them is impossible, which may generate difficulties or even mistakes. Marked differences can occur in the ventilatory performance, mode of triggering, pressurisation slope and type of exhalation. In addition, leaks and upper airway resistance variations may, in turn, modify these patterns. Technicians require a lot of experience to work with 36 them, which is not easy to acquire. It is not rare, that during the first night, not all events are corrected. To obtain an adequate interaction between the patient and the ventilator, sometimes new studies or refinements are required. Attempting to correct all the events during the first night may be not recommended in a number of patients, because it is important that patients feel well (no pain nor sleep disruption among others) in the morning (pleasant night - key point for an adequate future compliance). In addition to the sensors mentioned, flow and pressure curves should be analysed in one way or another to recognise leaks and ASY. However, in the case of ASY, the experts in this field have a lack of concordance in a significate number of cases.

NIV devices can be divided in two groups, volume or pressure-targeted ventilators. However, other modalities exist, such as synchronised intermittent mandatory ventilation, and various others that combine features of volume or pressure targeted ventilators with other characteristics or that use a neural adjusted ventilatory. The volume ventilators deliver a fixed volume during a given time and generate any pressure to achieve this, regardless of the patient contribution to ventilation. Therefore, airway pressure is not constant, and results from the interaction between ventilator settings and patient characteristics. The main problems of these ventilators are that 1) the airway pressure can harmfully increase, hence a pressure alarm is needed, 2) the fixed ventilatory assistance does not allow taking into account patient’s varying requirements and finally, 3) if a leak occurs, there will be no compensatory increase in flow rate to maintain ventilation. Pressure ventilators deliver airflow by generating a predefined positive pressure in the airways for a given time. Therefore, airflow is adjusted in order to establish and maintain a constant airway pressure. The major problem is that the volume delivered is not fixed and will depend on the interaction with the patient's characteristics or underlying disease. Therefore, volume varies, and in some cases hypoventilation may occur. Hence, a volume alarm is required. The major advantage of this type of ventilation is that leaks can be compensated. At present, this is the most common type of ventilator used. Also, a combination of both systems exists (assured volume mode).

D.2.1.2. Ventilator settings The settings of the ventilators must be adjusted, depending on the disease and patients' characteristics to optimise ventilation with an adequate synchrony between

37 patient and ventilator, without leaks. It is of vital importance to thoroughly understand ventilation and its features. Ventilators must always be adapted to the patient and not the other way around. Figure e5 shows the different characteristics and settings of the ventilators that need to be adjusted to achieve patient’s comfort and adequate ventilation.

The inspiratory trigger initiates the ventilator support. There are two types of triggering: Inspiratory triggers: negative pressure or negative flow ones (the most common) to initiate ventilation. When a very negative flow is needed to be reached to initiate ventilation or when a minimum pressure or flow is required to start ventilation, discomfort may occur [216] (Figure e5, part A). The pattern of flow delivery (Figure e5, part B/C) is also an important point of the ventilatory support. A fast increase unloads the respiratory system. A slow increase may increase the inspiratory work, so the underlying disease and its characteristics will determine the setting of this parameter [217]. Switching from inspiration to expiration (Expiratory trigger or cycling) (Figure e5, part D) can be time-cycled or flow-cycled. In time-cycled modes, ventilators use time criteria chosen by the clinician. In flow-cycled modes, cycling occurs as inspiratory flow decreases to a predetermined percentage of the peak inspiratory flow which is supposed to indicate the end of the inspiration [218].

Due to different types of ventilators as well as their features, Rabec et al. suggested three really basic questions to characterise ventilators: 1) What is the ventilatory mode (pressure or volume)?, 2) How is inspiration triggered (assisted, assisted/controlled, or controlled)?, and 3) How is switching from inspiration to expiration (cycling) managed (flow or timed) [211]? The goal of these questions is to make NIV management easier in clinical practice. Despite these comments, other characteristics of ventilators, such as an easy way to detect leak, the backup respiratory rates or an optimal knowledge of the devices is highly recommended to avoid simple but important mistakes [219-221] . Also, Rabec et al. showed in a landmark paper the most important technical characteristics of pressure ventilators and their influence during NIV [210].

D.2.1.3 Ventilator asynchronies and leaks

Box e7 shows the ASY discussed before. It has to be mentioned that this issue is extremely difficult and in addition, curves or concepts are different, depending of the type of ventilator used or its invasive or noninvasive nature.

The use of pressure and flow curves together with bands are the best way to check ASY. The most important types of ASY are: 1) Inspiratory trigger asynchronies: a) ineffective efforts: the patient cannot trigger the ventilator, because the sensitivity is high or the patient cannot generate sufficient force (e.g. myopathies), b) auto triggering, defined as the occurrence of a rapid successions of pressurisation, clearly above that of the patient’s respiratory rate. This is usually due to very low trigger sensitivity. 2) Pressurisation asynchronies: the most important are inadequate or excessive support. 3) Expiratory trigger asynchronies: appear when the coupling between the ventilator time and the patient’s neural time is inadequate. If the ventilator time is less than the neural time, the ventilator flow stops earlier, while in the opposite case, the patient's inspiratory effort stops earlier. No doubt that asynchronies and leaks represent the most important problem during NIV that always has to be detected and corrected [219, 222-233]. Leaks lower the effectiveness of ventilation through pressure loss, poor inspiratory triggering, and prolonged inspiratory time. The quality of sleep is affected, and adverse effects and treatment intolerance may arise. 39

In general, a leak of<24 L.min-1 is considered as normal [228]. A larger leak with oxygen desaturation or with a decrease in minute ventilation has to be considered as really abnormal. Different portable ventilators allow leaks to be estimated, but the performance of their algorithms is variable [228]. Solutions for reducing leaks include chin straps or using mouth interface (the choice of an adequate interface is a key point to perform efficient ventilation). Clinically, the most common symptoms of leakage are: dry mouth, conjunctivitis or a perception of leakage by the patient himself. In addition, other findings could be an increased respiratory rate, asynchronies with discomfort, periods of hypoventilation and periods of SaO2 reduction.

D.2.2 Measurement of PaCO2 during sleep

Measurement of PaCO2 during sleep is important in those patients that need assessment of hypoventilation [181-182]. Nocturnal hypoventilation is defined as an increase in PaCO2 during sleep ≥ 10 mm Hg compared with a wakeful period. PaCO2 is almost never assessed directly during PSG. Instead, surrogates, such as the end- tidal CO2 (PetCO2) or transcutaneous CO2 (PtcCO2) are used (table e6).

Transcutaneous CO2 is more reliable than end-tidal CO2 [181-182, 185, 192, 200,

224, 234-238]. In addition, two approaches are also applicable: PaCO2 when wakening or bicarbonate levels. Measurement of PaCO2 by arterial puncture at the end of the night, in order to document night-to-morning increases in PaCO2, could be an option but rarely used. Blood is usually sampled after arousal and thus after a short period of appropriate ventilation. In this condition, a normal morning PaCO2 175 does not actually reflect the abnormal time course of PaCO2 at night . It has to be said that the assessment of PaCO2 surrogates at night is not as easy as for SaO2, and sometimes, imprecise values are obtained. Clinical judgment is always needed.

Measurement of both PetCO2 and PtcCO2 requires a visual analysis of the graph recorded [181-182, 236].

D.2.2.1 PetCO2

PetCO2 measures the fraction of CO2 in exhaled gas [182]. During expiration, PetCO2 increases until a plateau occurs as a result of air exhaled from the alveoli. If a clear plateau is reached, the difference between PaCO2 and PetCO2 is usually no more 40 than 5 mmHg. However, when a plateau has not been reached, PetCO2 is not useful for estimating PCO2. This can occur in COPD patients, for example, because the alveoli do not exhale at the same time when a bronchial disease is present. Table e12 shows the relationship between PaCO2 and the different surrogates used. Some discrepancies exist between the different studies.

D.2.2.2 TcPCO2

Measurement of TcPCO2 depends on the fact that heating the skin causes increased capillary blood flow and makes the skin permeable to the diffusion of CO2. The CO2 in the capillaries diffuses through the skin and is measured by an electrode on its surface. The collar of the sensor heats the skin, which induces a local hyperaemia, improving the permeability of the skin to gas diffusion and ‘arterialises’ the capillary blood to obtain PtcCO2 readings closer to PaCO2 values. Typically, PtcCO2 electrodes are calibrated with a reference gas. PtcCO2 can be a good instrument for recording trends in PCO2 at night. PtcCO2 is higher than PaCO2. The range of agreement for PtcCO2 vs. PCO2 is 2,9±1,9 mmH [235] (drift corrected). The manufacturer's recommendations should be followed [181]. Sometimes, the signal is inadequate and hence, experience with the technique is needed [236]. When comparing or correlating values for PCO2, PtcCO2 proves to be a good surrogate and may provide a much better estimation of PaCO2 than PetCO2. However, the AASM scoring manual from the respiratory scoring rules for adults states that there is insufficient evidence to recommend a specific method for detecting hypoventilation, although it adds that PtcCO2 may be acceptable if validated and calibrated [182,

236]. PtcCO2 sensor drift has also been reported during overnight recordings.

Summarising, assessing PtcCO2 overnight is highly recommended to evaluate correction of nocturnal hypoventilation by NIV or for identifying periods of hyperventilation leading to ventilatory instability.

D.2.3 Electromyography (EMG) An increased diaphragmatic or intercostals EMG signal occurs during each inspiration and so, measurement of EMG could be a useful tool for detecting respiratory effort and thus, distinguishing central and obstructive apnoeas [142-143]. An EMG recording uses two electrodes set horizontally, about 2 cm apart, in the intercostal (2nd or 3rd) spaces in the mid-axillary line) or diaphragmatic area (7th

41 intercostal spaces in the right anterior axillary line). Both electrodes are placed on the right side to reduce ECG artefact. Despite the scant literature available, the AASM recommends EMG as an alternative sensor for the detection of respiratory effort.

D.2.4 Oximetry See paragraph 1.3.

E. Titration of mechanical ventilation during PSG in chronic hypoventilation Despite different recommendations [239], NIV titration is a very complex task, and therefore, experience is extremely important. Broadly speaking, there are three well defined steps, which are all equally important. These are training and adaptation, the titration itself and the follow-up during the next one or two weeks in order to refine the parameters if needed.

E.1. Adaptation and training Adaptation and training are mandatory. The patient must adapt to the device and accessories. Also, the choice of an adequate mask is crucial, and it is important that the patient is trained for as long as needed to reach an adequate result (sometimes time is needed). The ventilator must always be adapted to the patient and never the other way round (triggers, frequency or pressure among others). Furthermore, during the training, it is of uttermost importance to check leaks and asynchronies. Training usually starts at low pressures, with an inspiratory positive pressure (IPAP) of 8 cmH2O and expiratory positive pressure (EPAP) of 4 cm H2O. Both are gradually increased. In the first training sessions, no more than IPAP 12 cm H2O/EPAP 6 to 8 cm H2O should be reached. Sometimes, it may even be advisable to leave the patient for a few days with the ventilator at low pressures.

E.2. Titration itself Titration in patients with hypoventilation represents a difficult task. Despite the recommendations, it has to be said that at least in part, titration for mechanical ventilation represents an art. Figure e6 summarises the recommended steps. It is necessary to mention that these patients are very hard to titrate, since almost each patient is different. Sometimes, in morbid obesity, hypoxemia may persist. Autotitrating noninvasive ventilation is a promising method [240].

E.3. Follow-up period Follow-up period is also essential. Sometimes compliance may depend on how the initial side effects, disturbances or doubts are solved. Refinement of the parameters might also be needed to improve levels of adaptation, which, as mentioned, is a key point. After a few weeks, the different settings and major outcomes should be checked, especially when improvement is less than expected. However, it has to be emphasised that in some cases, improvement can take more time.

An acceptable titration requires the normalisation of the neurological variables, to obtain a mean SaO2 > 90% during al at least 90% of the recording time with absence -1 of leaks (<24 l/min ) and asynchronies and improvement of transcutaneous CO2.

Normalisation of daytime PaCO2 is the final objective. During mechanical ventilation, the standard definitions for respiratory events cannot easily be applied. The following has been recommended: 1) apnoea/ hypopnoea events, 2) hypoventilation periods,

3) SaO2 indices, 4) periodic breathing, 5) asynchrony index (at present only manual scoring), 6) leaks and 7) periods of upper airway obstruction [241] (Box e8).

F. Control of NIV at home At present, integrated modules or information from the ventilators allow an accurate recording of multiple parameters that are very useful, such as leaks, flow, pressure and tidal volume. Sandoz et al. summarised this point in a recent paper [242]. 43

Downloaded ventilator data can help to identify causes of hypoventilation. Keeping in mind that such data do not provide direct evidence of hypoventilation, the data should be reviewed in parallel with the patient's signs and symptoms when making adjustments, to improve tidal volume, minute ventilation, comfort, and adherence.

Additional information on chapter 2.4.2. CSA in stroke patients

Since the first description of periodic breathing by Cheyne 200 years ago, Cheyne- Stokes respiration (CSR) has been regarded as a characteristic sequel of an extensive cerebro-vascular stroke and also as a sign of the luring death [19]. After Cheyne’s keen observation, many investigators have analysed the breathing pattern during sleep of stroke patients and regularly found an elevated incidence of CSR immediately after the stroke, while CSR declined markedly 3 and 6 months into recovery. Depending on the methodology of the sleep studies and the time that had passed after the acute stroke, reports of CSR vary widely ranging from incidences of 3% up to 72% [57-59]. On one hand, sleep studies that were based solely on the measurement of nasal air flow or on the displacement of a single thoracic respiratory inductive plethysmograph were not sufficiently suited to recognize central sleep apnoea and on the other hand, authors defined and quantified CSR quite differently. And in contrast to patients with heart failure and CSR, the pathophysiology responsible for the development of CSR in stroke is poorly researched and understood. The influence of CSR on the recovery of stroke patients remains to be unclear and CPAP therapy for either CSR or OSA is only tolerated by a minority of patients.

Obstructive sleep apnoea (OSA) has been studied more extensively than CSR in stroke patients. Many stroke patients suffer from clinically relevant OSA. OSA seems to be a risk factor for both the occurrence of the first stroke and a recurrent stroke. OSA often worsens after a stroke, but also improves during neurologic recovery. CPAP therapy for OSA is associated with better neurologic and functional recovery and CPAP probably decreases the risk of a recurrent stroke and other cardiovascular events, albeit only few stroke patients are able to appropriately tolerate long term CPAP therapy [80].

Additional information on chapter 2.7. Idiopathic Central Sleep Apnoea

There was an association of the duration of the central apnoea with the intensity of arousals. The EEG arousals and even more movement arousals increased the length

45 of the event. Arousals were associated with the minute ventilation during the ventilatory phase of periodic breathing, and central apnoea was triggered by hyperventilation during nREM-2 sleep[243].

The same group studied the effect of inhaled CO2 or dead space on ICSA [244]. The authors measured end-tidal CO2 and transcutaneous pCO2 during breathing of room air, alternating breathing of room air and CO2, breathing of CO2 throughout the whole night and addition of dead space by a face mask all night. They included 6 patients without underlying diseases predisposing to CSA. They found reductions of the end- tidal CO2 preceding central apnoeas. The events were eliminated by application of

CO2 or addition of dead space. The study showed that a reduction of the pCO2 below the apnoea threshold induces CSA and that the elevation of the CO2 above the threshold eliminates CSA.

A case series of 20 patients who were treated with zolpidem at bedtime for 9 weeks showed a reduction of the CAHI from 26.0±17.2 to 7.1±11.8 (p<0,001). The improvement of the CAHI was accompanied by a reduction of the arousal index. However, obstructive events did not change in mean. These effects were accompanied by reduction of sleep latency and a shift from nREM stage 1 to nREM stage 2. Daytime sleepiness as measured by the Epworth Sleepiness Scale decreased [245].

The efficacy of acetazolamide (ACT) was investigated in 14 patients with CSA. After one night and one month of treatment, the administration of ACT was associated with a significant improvement of CSA, a decrease of the pH and the PaCO2 and an increase of the PaO2. The hypercapnic ventilatory response did not change. In addition, daytime symptoms improved under treatment. Paraesthesia was described as side effect[246].

CPAP and oxygen trial had failed in a small series of 3 patients [247] so that adaptive servoventilation (ASV) was applied. ASV reduced the number of breathing disturbances from 35.2 to 3.5/h associated with a reduction of arousals and improvement in daytime sleepiness and mood. Treatment showed a continuous efficacy during follow up of 6 to 12 months.

Additional information on chapter 3.2.Treatment of congenital central hypoventilation syndrome

Overview of the evidence The term congenital hypoventilation is used to describe a reduction of minute ventilation without a prevailing underlying cause of hypoventilation, in the presence of a PHOX2B gene mutation. Its prevalence is not well known, but probably underestimated [248-249]. The literature in this field is growing since a mutation in the PHOX2B-gene (“PARM” mutation) was described, which accounts for 90% of the cases. PHOX2B-gene directly regulate expression of thyrosine hydroxylase and dopamine beta hydroxylase, two enzymes involved in the catecholamine biosynthesis [250-251]. The remaining 10% of cases have a non-PARM missense, nonsense or frameshift mutation. Hypoventilation is its most apparent and potentially debilitating phenotypic feature, and is most severe in deep non-REM sleep, during which automatic or homeostatic control of breathing normally predominates [252]. Ventilation can also be abnormal during REM sleep and wakefulness, although to a milder degree [252]. This may be due to increased excitatory inputs to the respiratory system during REM sleep and is an important differential point from patients with other causes of hypoventilation in whom hypoventilation worsens in REM sleep [253]. At the end of the spectrum, patients have complete apnoea during sleep and severe hypoventilation during wakefulness. Most often, hypoventilation starts in childhood, with deterioration during sleep. Only the more severely affected individuals, about 15% of the cases, also hypoventilate while awake [254-256]. In some cases, the disease may manifest during adulthood after severe respiratory illness, general anaesthesia, or respiratory depressants [257]. All patients with diagnosis after the neonatal period would be considered as later-onset CCHS. Phenotypes with many extra alanines are more often accompanied with neuroblastoma, cardiac arrhythmias and Hirschsprung’s disease, and have an increased number of symptoms of imbalance of the autonomic system [258-259]. The 20/24 genotype is likely underdiagnosed because of the subtle hypoventilation and potential need for environmental cofactors [256]. Typical traits in individuals with congenital hypoventilation are a lack of responsiveness to endogenous challenges

(hypoxaemia and hypercapnia) in terms of ventilation and arousal during sleep and a lack of perception of asphyxia during wakefulness, even during exertion. CCHS is also associated with a more global autonomic nervous system dysfunction [260]. Symptoms reflecting autonomic nervous system dysregulation include abnormal responsives to light (diminished pupillary light reflex), strabism, miosis, anisocoria, abnormal irides, lack of tears, oesophageal dysmotility and impaired swallowing, breath-holding spells, cardiac variability and arrhythmia, bradycardia, vagally mediated syncope or asystole, non-dipping blood pressure profile, hypotonia, profuse sweating, reduced basal body temperature (with absence of fever with infection), altered pain and anxiety perception, constipation (even in the absence of Hirschsprung’s disease), urinary retention, and recurrent pneumonia [261]. A significant association has been observed between PARM length and number of ANSD symptoms, but not with the number of ANSD-affected systems [249]. There are indications that integration of afferent activity with respiratory motor output is deficient in CCHS, rather than chemoreceptor failure [262]. Functional MRI and physiologic studies have shown widespread cerebral abnormalities in response to stimuli such as hypercapnia. The lesion occurs in the lower brainstem and involves the lateral portion of the medulla. Typically, this lesion causes a selective interruption of the descending anterolateral medullocervical pathways, which in turn are responsible for automatic breathing. Reduced expression of brain-derived neurotrophic factor in the cerebrospinal fluid was found in a preliminary small series of infants, indicating dysregulation of the maturation and differentiation of respiratory neurons [263]. Consequences include hypoglycaemia, mental retardation or severe neurocognitive disturbances, growth failure, seizures, cor pulmonale and pulmonary hypertension, and severe constipation. Once the diagnosis is considered, blood should be sent for the PHOX2B Screening test, or for the PHOX2B Sequencing Test if the screening test is negative. Causative gross anatomic brainstem/brain lesions should be ruled out with an MRI and/or CT scan. A metabolic screen should be performed as well to check for inborn errors of metabolism [261]. Echocardiograms, haematocrit levels, and erythrocyte counts performed each 12 months provide information regarding polycythaemia and cor pulmonale, with testing performed more often if clinically indicated and warranted. Treatment aims to compensate for the altered or absent ventilatory responses to hypoxaemia and hypercapnia during wakefulness and sleep. Approximately a third of patients require ventilatory support

24 h per day [264]. Modalities of home mechanical ventilation include positive pressure ventilation via tracheostomy, non-invasive positive pressure ventilation (bilevel ventilation), AVAPS mode ventilation, rarely negative pressure ventilation by body chamber or cuirass and occasionally diaphragmatic pacers [265]. During early infancy and childhood, patients with CCHS typically require more ventilatory support than older children and adults, related to longer sleep periods and overall more immature respiratory systems. Patients with CCHS are unlikely to trigger the ventilatory adequately during sleep, and ventilatory support should be used in ST mode. Supplemental oxygen alone is not indicated, but can be used safely if combined with ventilatory support [266]. Tracheostomy and home ventilator is offered to individuals requiring ventilatory support 24 h per day and for children/adults requiring ventilatory support during sleep only. Mask ventilation is a consideration in cooperative older children and in adults requiring ventilatory support during sleep. Because mask ventilation has been associated with mid-face hypoplasia when introduced from infancy or early childhood, mask ventilation should be used with extreme caution [267]. Close longitudinal follow up by specialists with dental and craniofacial expertise is essential due to the risk of facial deformation. Older patients with CCHS can be successfully switched from tracheostomy to non-invasive mask ventilation, preventing restrictions in social life [267]. The typical transition to noninvasive ventilation occurs between the age 6-11 years. These subjects may require interim endotracheal intubation to allow for optimal oxygenation and ventilation during acute illness that requires a more aggressive approach. With modern home ventilators, most patients with CCHS can have prolonged survival with a good quality of life [268]. There are no systematic studies but only small case series and abundant case reports on the application of PAP in CCHS. Owing to the small number of reported paediatric patients with CCHS, it is not clear whether PAP can stimulate respiratory activity in these subjects. Prognosis has improved with early recognition and care. There is a relationship between the genotype for PARMs and the need for continuous ventilatory support [269-270]. Those individuals with the 20/25 genotype (and a small subset of NPARMs) rarely require 24-h per day ventilatory support, while individuals with the 20/26 genotype demonstrate variable awake needs depending upon the level of activity. Those with genotypes from 20/27 to 20/33 typically require continuous support. Late-onset cases with the 20/24 or 20/25 genotype have the mildest hypoventilation and only need nocturnal ventilatory

49 support. Individuals with NPARMs require continuous ventilatory support. Physiologic studies should include continuous recording of RIP, ECG, oximetry, pulse waveform, capnography, sleep stages, blood pressure, and temperature. Mortality is largely related to complications of long-term ventilatory support or from complications of bowel disease if Hirschsprung’s disease is present [261]. Diaphragm pacers offer a modality of ventilatory support and are indicated for full- time ventilatory patients, and may allow for a more normal lifestyle [271-278]. About 40% uses their pacer only at night as their sole source of ventilatory support. Others use diaphragmatic pacers during daytime and receive mechanical ventilation via tracheostomy or mask at night. They may permit tracheostomy decannulation in subjects requiring only support during sleep. Drug treatment with the respiratory stimulant almitrine was not effective [279].

Statements 1. There is insufficient evidence on the prevalence of CCHS, since population based studies in caucasions are lacking (A). 2. Evidence suggests to determine the specific PHOX2B genotype or mutation to assess specific clinical abnormalities or risks (A). 3. A clear relationship has been observed between the alanine expansion length and phenotype severity, and with the likelihood to hypoventilate awake (A). 4. The members of the Task Force assess symptoms of autonomic dysfunction in addition to hypoventilation (A). 5. There is limited evidence suggesting that in CCHS, hypoventilation is most severe during non-REM sleep. Central apnoeas only occur occasionally (C). 6. Abnormalities in CCHS do not ameliorate over time and patients may require lifelong ventilatory support (D).

IV. Figures

Figure e1. Thermistor. Bench study. On the top, flow measured by a PNT according three situation. Baseline flow, 50% decrease and with a modified shape. At the bottom, flow measurements by a thermistor that does not measure properly the flow neither the shape. Flow measured by a thermistor that does not evaluate the shape nor the amplitude. European Respiratory Journal Jan 1998, 11 (1) 179-182; DOI: 10.1183/09031936.98.11010179 [83]

Figure e2. Flow measured by a PNT, nasal prongs and by a square root transformation of the nasal prongs. The nasal prongs flow measurement exaggerates the flow reduction that is corrected by the square root transformation. Nasal prongs exaggerate the reduction in flow. Reprinted with permission of the American Thoracic Society. Copyright © 2016 American Thoracic Society. [87]

Figure e3. During an apnoea, there is a progressive increase of oesophageal pressure. Reproduced with permission of the European Respiratory Society ©: European Respiratory Journal Dec 2004, 24 (6) 1052-1060; DOI: 10.1183/09031936.04.00072304 [82].

Figure e4. Right side. Inspiratory flow contour and thoracoabdominal (T-A) band motion. A progressive T-A band incoordination and flow limitation occurs. Left side. Flow and T-A band morphology score with respect to the oesophageal pressure measurement. There is an acceptable relationship between the pressure and incoordination of the thoracoabdominal bands and especially with the shape of the flow signal. Reprinted with permission of the American Thoracic Society. Copyright © 2016 American Thoracic Society [89]

Figure e5. Different characteristics and setting of the ventilator setup to properly achieve adequate ventilation. (See text) [210]

Figure e6. Non-invasive mechanical ventilation titration as applied by most of the TF members: 1) Diurnal training with an adequate interface and 2) PSG titration. Use the pre-selected daytime pressure at the beginning of the sleep study. Eliminate the obstructive events progressively, by progressively increasing both the inspiratory pressure (IPAP) and the expiratory pressure (EPAP) with 1 cmH2O, 3) Once all obstructive events have been corrected, if hypoventilation is present (CO2 increase, oxygen desaturation and low minute ventilation), increase the IPAP until reaching an adequate minute ventilation (6-8 cc /weight) and a normal CO2 level, 4) IPAP values more than 25 cm H2O are not recommended and 5) if still abnormal levels of CO2 and SaO2 are present add O2. When it is not possible to correct all the physiological abnormalities, it is better to wait for a new sleep study.

List of Tables

Tables of chapter 1.3. Measurement Techniques e1.3.A. Measurement of respiratory airflow: thermistors and nasal cannulae e1.3.B. Measurement of respiratory airflow: PVDF flow sensors e1.3.C. Measurement of respiratory effort: oesophageal pressure e1.3.D. Measurement of respiratory effort: Abdominal belts e1.3.E. Measurement of respiratory effort: EMG e1.3.F. Measurement of respiratory effort: PTT e1.3.G. Measurement of respiratory effort: FOT e1.3.H. Measurement of respiratory effort: miscellaneous methods e1.3.I. Measurement of flow and respiratory effort: complex algorithms e1.3.J. Capnography as an adjunct signal for the detection of sleep apnoea e1.3.K. Representative studies on capnography e1.3.L. Capnography for the detection of hypoventilation: Relationship between

PaCO2, transcutaneous CO2 (PtcCO2) and end-tidal CO2 (Pet CO2 ) e1.3.M. Predictors of hypoventilation e1.3.N. PAP Titration e1.3.O. Leaks e1.3.P. Asynchronies

Table of chapter 2.1. Pathophysiology e2.1.A. Pathophysiology

Table of chapter 2.2. Drug induced e2.2.A Studies in patients with chronic pain e2.2.B Studies in patients treated for opioid dependency, and e2.2.C Miscellaneous studies (this will only be one experimental study in patients with known respiratory failure).

Table of chapter 2.3. CSA in high Altitude e2.3.A. CSA at altitude (high altitude periodic breathing) e2.3.B. CSA at altitude, therapy

Table of chapter 2.4. CSA in in cardiovascular diseases e2.4.1.A. CSA in Heart Failure e2.4.2.A . CSA/CSR in Patients after Stroke or TIA

Tables of chapter 2.5. CSA in other internal or neurological diseases, other than cardiovascular diseases e2.5.A. Acromegaly e2.5.B. Diabetes mellitus e2.5.C. End Stage Renal Disease e2.5.D. CSA and Pulmonary Hypertension e2.5.E. Parkinson’s Disease e2.5.F. Alzheimer´s Disease

Tables of chapter 2.6. Treatment emergent CSA e2.6.A. Treatment-Emergent CSA

Table of chapter 2.7. Idiopathic Central Sleep Apnoea e3.1.A. Idiopathic Central Sleep Apnoea

Tables of chapter 3.2. Treatment of congenital central hypoventilation syndrome e3.2.A. Mechanical ventilation e3.2.B. Diaphragmatic pacing e3.2.C Respiratory stimulants

Tables of chapter 3.3. Hypoventilation/hypoxic diseases secondary to internal or neurological disorders e3.3.A. Amyotrophic Lateral Sclerosis e3.3.B. Duchenne Muscular Dystrophy e3.3.C. Myotonic Dystrophy e3.3.D. Acid Maltase Deficiency e3.3.F. Mixed NMD Studies

Tables of chapter 3.4. Kyphoscoliosis e3.4. A. Articles on sleep(breathing) e3.4.B. Articles on impact of NIV on sleep(breathing) e3.4.C. Articles on impact of NIV on daytime blood gases, respiratory muscle force, vital capacity, respiratory drive and dyspnoea e3.4.D. Articles on impact of NIV on hospitalisations for acute problems (unless stated otherwise) e3.4.E. Articles on impact of NIV on survival

Tables of chapter 3.5. Obesity Hypoventilation Syndrome e3.5.A. Obesity Hypoventilation Syndrome

Tables of chapter 3.6. Chronic NIV in COPD e3.6.A. Chronic NIV after acute respiratory failure e3.6.B. Chronic NIV in COPD patients with stable hypercapnic respiratory failure e3.6.C. Chronic NIV in COPD patients in combination with rehabilitation

Tables of Chapter 1.3. Measurement Techniques e1.3.A. Measurement of respiratory airflow: thermistors and nasal cannulae

Author Design EBM Patient population Results Comments Condos et al, Case series 4 Study in respiratory At high CPAP, resistance was low and When respiration is 1994 [88] model and in N=8 inspiratory flow contour was found to be stable, the contour of (all male) OSA rounded. inspiratory flow patients, age 34 (21- At low CPAP, resistance was high and flow tracing from a CPAP 49) yrs, BMI 41 (35- contour developed a plateau suggesting system can be used 53) kg/m2, AHI 60 flow limitation. to infer the presence (42-100). of elevated upper- airway resistance and flow limitation. Montserrat et Case series 4 N=9 (8 male) OSA The usefulness of the thoracoabdominal The contour of al, 1995 [89] patients, age 49±13 bands output morphology and the inspiratory flow yrs, BMI 32±5 kg/m2, inspiratory flow measured by appears as the

AHI 67±19, FEV1 pneumotachography were evaluated to simplest variable that 83±12 % Pred. identify upper airway resistance during best correlates with CPAP titration. If the end point was the lowest disappearance of arousals, most patients oesophageal

with SAHS would still exhibit periods of high pressure during intrathoracic pressures with limited CPAP titration. inspiratory flow. Alternatively, if the end point to be reached was the lowest oesophageal pressure, higher CPAP levels would be needed. Both methods identified well episodes of increased upper airway resistance, although the inspiratory flow behaviour from pneumotachography was better than that of the bands. Bradley et al, Case series 4 31 (26 male) Autoset gave a sensitivity of 100%, 1995 [90] consecutive patients, specificity of 92%, positive predictive value age 46±2 (SE) yrs, of 92%, and negative predictive value of BMI 30±1 (SE) 100%. kg/m2, ESS 12±1 (SE) assessed by PSG had simultaneous monitoring of their respiratory pattern using the Autoset

system (detection of episodes of flattening of the flow/time profile using nasal cannula). Kiely et al, Case series 4 N=36 patients with The diagnostic capabilities of one limited 1996 [91] suspicion of OSA: diagnostic system (ResCare Autoset ™) 27 males, age 45±13 were compared with full PSG. There were yrs, BMI 28.0±5.3 highly significant correlations between the kg/m2, ESS 10±6; Autoset AHI and the AHI scored by the 9 females, age manual PSG scoring method (r=0.92; 41±10 yrs, BMI p<0.001). The positive predictive value for 28.3±5.0 kg/m2, ESS diagnosis of OSA for the Autoset was 86% 10±6. when compared with manual PSG scoring, PSG with thermistors based on an AHI threshold for OSA of 15 and respiratory events/h (sensitivity 100%, specificity 92%). inductive However, the agreement between Autoset plethysmography and PSG was poor in severe cases of OSA, (RIP), AutoSet with although not sufficiently so as to result in nasal cannula. mistaken diagnosis in any of these cases. Fleury et al, Case series 4 N=44 (34 male) The Autoset overestimated the number of Useful technique for

1996 [92] heavy snorers, age apnoeas. Oral breathing or displacement identifying significant 52± 11 (29-75) yrs, of the nasal prongs partially explained OSA, but less useful BMI 28.5±4.4 kg/m2. these differences. A significant correlation in patients with mild PSG with was found between the apnoea indices (AI) to moderate SRBD. pneumotachography assessed by the two methods (r = 0.98). and thermistors. For an AI of 20/h, the Autoset was 100% AutoSet with nasal sensitive and 88% specific. The Autoset cannula. significantly underestimated the number of hypopnoeas compared to the PSG with pneumotachography (63± 5 vs. 86±73, p= 0.04), although for an AHI of 20, Autoset was 100% sensitive and 88% specific. Berg et al, Case series 4 N=not reported, Comparison between indirect methods for Measurements 1997 [81] healthy, non-obese, measuring respiratory airflow with direct performed awake in adults male measurement of minute ventilation (body seated position volunteers, no plethysmography). The poorest agreement during sequences of characteristics was for the thermistor method, and the best different levels of reported. agreement was obtained when a voluntary combination of thoraco-abdominal hypoventilations at movements and nasal respiratory-airflow 20 breaths/minute.

pressure was employed. 3 different brands of thermistors were tested. Norman et al, Case series 4 N= 11 OSA patients 1873 events were detected by thermistors. 1997 [84] and 9 with UARS (no 3541 events were detected by nasal other characteristics cannula, 52% were detected by definite specified) thermistor criteria. Nasal cannula reliably detected respiratory events seen by thermistor. Montserrat et Case series 4 N= 6 (5 male) The square root of the flow signal Short observations al, 1997 [85] healthy subjects, age measured with nasal cannula is the during 60 s 28-45 yrs, in good simplest method for correcting for the health, without a nonlinear pressure-flow relationship. history of sleep disturbances and with a normal spirometry Rees et al, Case series 4 N=20 (all male) All apnoeas were scored by both systems, This study shows that 1998 [94] consecutive patients but 41% more hypopnoeas were scored the AutoSet and the with suspicion of on PSG and these were clinically standard PSG OSA, age 48±11 (29- significant, with 78% ending in cortical approach

70) yrs, BMI 31±5 arousal. 20% of apnoeas and hypopnoeas differ in their kg/m2, AHI 39±26 (8- scored by the AutoSet occurred during detection of 114). PSG with wakefulness. Large breaths, defined as a hypopnoeas. thermistors and RIP, two-third increase in ventilation, marked AutoSet with nasal 77% of respiratory-associated but only 9% cannula. of spontaneous arousals. Large breaths also marked 48% of "autonomic" arousals following respiratory events without visible EEG changes. 27% of large breaths occurred during wakefulness. Mayer et al, Case series 4 N=95 (79 male) Correlation between AHI assessed by If a high pretest 1998 [95] patients with AutoSet and PSG was r=0.87 for total sleep probability and a suspicion of OSA, time (TST), p<0.0001. A Bland and Altman negative Autoset age53±11 yrs, BMI plot gave an agreement between the two result, PSG should 30.7±7.3 kg/m2, ESS methods of ±40%. For a threshold of AHI be performed. 12±5. PSG with >15 events/h to diagnose OSAS, AutoSet pneumotachography had a sensitivity of 92%, specificity of 79%, and thermistors. positive predictive value of 93% and AutoSet with nasal negative predictive value of 76%. With a cannula. pretest probability 80%, sensitivity and positive predictive value were 98 and 100%

respectively. Farré et al, Respiratory 4 No living subjects Thermistor/thermocouples are inaccurate 1998 [83] model flow-measuring devices when used at the airflow conditions typical of sleep studies. Use of these sensors may result in considerable under detection of hypopnoeas. Hosselet et al, Case-control 4 N=10 symptomatic Resistance in all stages of sleep was In patients with 1998 [96] series subjects, with increased for breaths with flattened (387 symptoms of suspicion of OSA, ±188%) or intermediate (292 ±163%) flow excessive daytime age 47 (29-69) yrs, contour. In combination with apnoea– somnolence and low BMI 30 (23-42) hypopnoea index (AHI), identification of AHI, where standard kg/m2, AHI 29 (6-72). “respiratory events,” consisting of thermistors do not 5 patients were consecutive breaths with a flattened reliably detect the diagnosed with OSA, contour, allowed differentiation of characteristic airway 4 with UARS, and 1 symptomatic from asymptomatic subjects. events, this approach with snoring. Control may help diagnose group consisted of 4 the upper airway asymptomatic resistance syndrome subjects, age 31 (24- and separate it from 47) yrs, BMI 22 (18- non-respiratory

24) kg/m2, AHI 4 (2- causes of sleep 5). fragmentation. Ballester et al, Case series 4 N=8 OSA patients, 877 sleep episodes were observed (805 Only 3% mouth 1998 [97] age 53±12 yrs, BMI true respiratory events). When compared breathing respiration 29±6 kg/m2, AHI to single or combined thermistor and bands was detected. This 27±20. approach, nasal pressure had the highest limitation of the respiratory events detection rate, 779 technique is clearly (96.8%) versus 673 events (83.6%). counter-balanced by a more accurate overall event detection rate. Clark et al, Case series 4 N=7 (5 male) healthy A flow limitation index (FLI) was derived 1998 [98] habitual snorers, age from the time profile (“shape”) of three non- 19-25 yrs. invasive estimates of flow rate (pneumotachograph, RIP, nasal pressure). FLI is effective in differentiating severe types of inspiratory flow limitation (sensitivity/specificity>80%), but is not able to consistently detect mild levels of flow limitation (sensitivity/specificity 62-72%). Nasal pressure is the recommended

technique. Sériès et al, Case series 4 N=212 consecutive Three different methods of analysis 1999 [99] patients with (thermistry, inductive plethysmography, and suspicion of OSA, nasal pressure tracing) were compared. age 50±11 yrs, BMI The AHI was significantly higher with nasal 32.1±6.1 kg/m2, neck pressure scoring than with the conventional circumference 42±4 method (thermistors combined with RIP) cm. 19 subjects (mean difference 4.5, p<0.0001). The mean were excluded from difference in apnoea index between analysis due to conventional and nasal pressure scoring impaired nasal was -7.5/h. In 78 patients who did not have ventilation. OSA according to the conventional method of analysis, 17 of them had an AHI of >15/h by the nasal pressure method of analysis. Ayappa et al, Case series. 4 N=10 patients with There was good agreement (ICC=0.91) The nasal cannula is 2000 [100] Nasal cannula UARS/OSA and 5 between the number of events detected by the tool of choice for vs oesophageal normal subjects. nasal cannula and oesophageal manometry monitoring manometry. with a slight bias towards the nasal cannula respiratory airflow (4.5 events/hr). There was no statistically during sleep in significant difference (bias 0.9/hr, 95%CI – both clinical and 0.3-2.0) between the number of nasal research sleep

cannula flow limitation events terminated by studies, especially if arousal and manometry events terminated one wishes to detect by arousal (RERAs). both apnoea/hypopnoea and milder sleep disordered breathing events. Akre et al, Case series 4 N=50 (41 male) OSA AHI was 50±23 (PSG), 48±25 (internal External thermistors 2000 [101] patients, age 50 yrs thermistors) and 32±22 (external miss an overage of (46-53), BMI 27.5 thermistors). almost 20 respiratory (26.2-28.8) kg/m2. events/h. Epstein et al, Case series 4 N=50 consecutive, Mean respiratory arousal index (RAI) (nasal 2000 [102] non-selected cannula) was greater than the mean RAI- patients with thermistors by 25%, 302%, and 500% in suspicion of OSA: OSA, UARS, and primary snoring, N=20 (15 male) OSA respectively. RAI-nasal cannula was > 14 patients, age 48 (28- (mean, 25.2) in UARS and < 14 (mean, 9) 66) yrs, BMI 35.9 in PS.Nasal cannula is more sensitive than (25-58) kg/m2, ESS thermistors in detecting respiratory events 14 (2-23). during PSG and may represent a simple, N=25 (14 male) objective means to identify UARS among

UARS patients, age patients with a range of SRBD. 48 (28-81) yrs, BMI 32.9 (22-55) kg/m2, ESS 11 (2-21). N=5 (3 male) primary snorers, age 42 (35- 55) yrs, BMI 29.4 (22-34) kg/m2, ESS 7 (5-10). Farré et al, Case series 4 N= 6 severe OSA Square-root linearization of nasal pressure A total of 21 2001 [87] (no other greatly increases the accuracy of representative characteristics quantifying hypopnoeas and flow limitation. inspiratory patterns reported) were selected from six patients. Thurnheer et Case series 4 N=20 (17 male) with Compared with facemask al, 2001 [86] suspicion of OSA, pneumotachography, nasal pressure age 52 (33-73) yrs, monitoring provides accurate AHI for BMI 27.3 (20.3-50.5) clinical purposes even in patients kg/m2, AHI 24±5 (1- perceiving nasal obstruction. Square-root 72). transformation provides near linear nasal pressure/airflow relationships over a short

time but is not essential for estimation of AHI. Hernandez et Case series 4 N=27 (16 male) The AHI was significantly higher with the Under recognition of al, 2001 [103] patients, age 49±14 nasal prongs (18 vs 11) in the general global obstructive yrs, BMI 27±4 kg/m2. population and 37 vs 27 in the group with events by the 15 (8 males) suspicion of OSA. The CAI was thermistor. The recruited from the comparable with the nasal prongs (3 vs 4) presence of mouth general population in the general population and 3 vs 2 in the breathing is not a (age 48±13 yrs, BMI group with suspicion of OSA. significant drawback 27.4±5.0 kg/m2), 12 in the analysis of (8 males) with nasal prongs. suspicion of OSA (age 51±15 yrs, BMI 27.3±4.0 kg/m2). Heitman et al, Case series 4 N=11 (8 male) OSA, Intermeasurement agreements were 0.76, Nasal pressure is a 2002 [104] RDI 49 (10-143). 0.73, and 0.50. Inter- and intrarater valid device for 550 of the events agreements were 0.68 and 0.60 for the identifying identified were pneumotachograph, 0.66 and 0.82 for nasal apnoeas/hypopnoeas randomly selected pressure, 0.61 and 0.78 for square root during sleep. for analysis. nasal pressure, and 0.47 and 0.76 for Agreement was RIPsum.

evaluated between pneumotachography and nasal pressure, square root nasal pressure, and RIPsum signals. Guilleminault et Case series 4 N=45 (39 male) The arousal index was a mean of 3±2/h in The scoring of these al, 2002 [105] subjects: 15 (13 patients with OSA, 17.9±4/h in patients with short events showed male) controls (age UARS, and 2±1.5/h in control subjects. that patients with 41±3 yrs, BMI 24±1 UARS responded kg/m2, RDI 0±0, 15 very quickly with an (13 male) OSA arousal to breathing patients (age 42±3 abnormalities, such yrs, BMI 25±1 kg/m2, as an abnormal RDI 33±5) and 15 increase in breathing (13 male) UARS effort or minor flow patients (age 42±3 limitation without yrs, BMI 25±1 kg/m2, development of RDI 2±1). apnoea or hypopnoea. Teichtahl et al, Case series 4 N=30 consecutive In severe SRBD (AHI >50), nasal pressure It was suggested to

2003 [106] PSG’s. No other (NP) + thermistor (Th), NP alone and Th use both NP and Th criteria reported. alone have similar ability to detect signal analysis for respiratory events. When AHI <50, NP + Th routine diagnostic appears better for detecting respiratory PSG’s, and that both events than NP or Th alone. If only one signals should be measure of airflow is used, NP detects used for analysis of more events than Th. PSG respiratory events. BaHamman, Case series 4 N=40 (26 male) More events were nearly always detected Nasal pressure 2004 [107] subjects with using nasal cannula compared to measurements were suspicion of OSA, thermistors (AHI 44±37 vs 35±31). CAI was superior to age 46±15 yrs, BMI 0.69±1.4 and 0.67±1.4 respectively. Sleep thermistors for 36.2±11.9 kg/m2, position had no effect on either detecting obstructive ESS 10±6. 26 (17 measurement method. respiratory events male) patients had during sleep. No OSA (age 49±11 yrs, difference in the CAI BMI 38±12 kg/m2, between the two ESS 11±5), 10 (6 methods could be male) patients had detected. UARS (age 46±17 yrs, BMI 30±7 kg/m2,

ESS 12±3) and 4 (3 male) had habitual snoring (age 35±15 yrs, BMI 33.8±3.7 kg/m2, ESS 4±2). Johnson et al, Case series 4 N=10 (5 male) Flattening of the nasal flow profile preceded Nasal cannula is the 2005 [108] normal healthy all 227 arousals. In contrast, only 40% of most reliable method volunteers, age 43±9 arousals were preceded by an increase in to detect increased (29-59) yrs, BMI the size of the stretch sensor signal, 22% upper airway 24.9±3.3 (20-32) by more-negative resistance. kg/m2, all women deflection of the oesophageal pressure premenopausal. All signal and 21% by increase in the signal subjects had 1 to 3 size of RIP. glasses of red wine. 227 EEG arousals were assessed. 4 methods to detect the presence of increased upper airway resistance were evaluated:

oesophageal pressure manometry, RIP, a piezoelectrically treated strech sensor adhered to the supraclavicular fossa, and nasal cannula. Calero et al, Case series 4 N=14 (all male) OSA Prolonged periods of flow limitation induce Flow limitation should 2006 [109] patients requiring significant physiological changes: swings of be considered and

CPAP treatment, age blood pressure, lower baseline SaO2, normalised.

52±8 yrs, BMI 33±6 higher end-tidal CO2, more negative kg/m2, AHI 59±8, oesophageal pressures, and longer ESS 16±5. inspiratory time. e1.3.B. Measurement of respiratory airflow: PVDF flow sensors

Author Design EBM Patient population Results Comments Berry et al, Case series 4 N=10 (all male) mild The AHI was 29±27 (mean±SD) with the The PVDF sensor 2005 [58] to very severe OSA, pneumotachograph and 26±26 with the compared favourably

age 5511 (SD) yrs, polyvinylidene fluoride (PVDF) thermal with a “gold standard” weight 21754 lb. sensor. method of detecting respiratory events during sleep in patients with OSA. PVDF sensor is likely to be a more sensitive instrument for detecting changes in airflow during sleep compared with traditional thermal devices. Nakano et al, Case series 4 N=100 (80 male) A PVDF flow thermal sensor and a novel The airflow sensor 2008 [110] consecutive patients algorithm were prospectively validated. was designed to with suspicion of The sensitivity and specificity of the in- detect both nasal and OSA, age 45±10 yrs, laboratory flow-RDI to diagnose SDB were oral breathing. BMI 26.9±4.3 kg/m2, 0.96 and 0.82, 0.91 and 0.82, and 0.89 and Results are thought AHI 30 (9-65) 0.96, for apnoea/hypopnoea index (AHI) ≥5, to be due to the high- ≥15 and ≥30 events/h, respectively. performance sensor and the robust

analytical algorithm.

e1.3.C. Measurement of respiratory effort: oesophageal pressure

Author Design EBM Patient population Results Comments Tvinnereim et Case series 4 N= 10 (9 male) OSA Excellent agreement between the 2 al, 1995 [111] patients, age 50±13 methods: K=0.89. AI was 22±23 (PSG) and (24-68) yrs, BMI 22±22 (Poes). HI was 12±7 (PSG) and 32.5±10.1 (20-52) 10±6 (Poes). CAI was equally: 3±4 (PSG) kg/m2. Efficacy of a vs 3±4 (Poes). Only 1 single central apnoea portable was reclassified as mixed apnoea. oesophageal Sensitivity was 95% and specificity 99%. pressure catheter vs PSG was evaluated. 200 respiratory events were assessed. Boudewyns et Case series 4 N=22 (21 male) OSA Strain gauges were compared with Flow was measured al, 1997 [112] patients, age 49±10 oesophageal pressure measurements. with thermistors. yrs, BMI 28.1±5.1 Based on strain gauges, 422 central Measurement of

kg/m2, AHI 37±6. apnoeas were scored. After rescoring, 266 respiratory effort by central apnoeas were found. After means of strain rescoring, the number of central apnoeas gauges is sufficiently (initially scored by strain gauges) reliable decreased from 10 (3-25) to 6 (2-16). The for characterisation of number of mixed apnoeas increased from 4 apnoeas in most (0-20) to 6 (1-21). In only 3 patients the (86%) patients. Only difference in the absolute number of central in a few patients apnoeas was more than 4. When all (14%), an patients were considered, the mean overestimation of difference in the absolute number of central central apnoeas was apnoeas was -7 (-37%). found, and not reaching clinical relevance. Akre et al, Case series 4 N=124 (110 male) Aim was to determine whether the flow and Silicon tube was use 1999 [116] patients with pressure sensors located in the epipharynx, containing both suspicion of OSA, oropharynx and hypopharynx could simple pressure age 50 yrs, BMI 27.9 differentiate between nasal and oral sensors and kg/m2. breathing. The internal thermistors showed thermistors if the patient was breathing through the (incorporated into the nose or mouth. sensors used for

The mean reduction in nasal flow signals measuring pressure) when changing from nasal to oral breathing located in the upper was 83.7% (p<0.0001). The same was airways. The study seen in a lateral position, 82.2% (p<0.000l). showed that it is possible to differentiate between nasal and oral breathing using internal thermistors. Watanabe et Case series 4 N= 34 OSA, No significant correlation between the AHI AI does not reflect al, 2000 [113] AHI>50: n=8; and Poes indices. the severity of the AHI 15-50: n=18; increase in negative AHI 5-15, n=9; Poes. UARS n=7. No other characteristics reported. Watanabe et Case series 4 N= 17 OSA, No significant correlation between the AHI AI does not reflect al, 2000 [114] AHI>30: n=5 (age 43 and Peso indices. the severity of the yrs, BMI 28.4 kg/m2, increase in negative AHI 49); Poes. AHI <30: n=6 (age

54 yrs, BMI 26.4 kg/m2, AHI 15); UARS n=6 (age 44 yrs, BMI 25.6 kg/m2, AHI 3) Reda et al, Case series 4 N=59 snoring Simultaneous pharyngoesophageal 2001 [117] patients, no other manometry and PSG were performed. The characteristics AHIs measured by the 2 methods were reported. highly correlated (r=0.971). Manometry was 100% sensitive and specific in excluding OSA and identifying severe OSA. It was 90% sensitive in identifying moderate OSA and 80% sensitive in identifying mild OSA. Coursey et al, Case series 4 N=5 (all male) The mean calculated pleural pressure at 2011 [118] healthy subjects. No flow limitation with the stop-flow method characteristics was 2.7 times and 1.6 times that via the reported. oesophageal-balloon method at 25% of VC and 50% of VC, respectively. The maximum flow at flow-limitation with the stop-flow technique was 0.7 times and 0.6 times that

via the oesophageal-balloon method at 25% of VC and 50% of VC, respectively. Morgenstern et Case series 4 N=20 (17 male) OSA Nasal pressure and oesophageal pressures al, 2011 [119] patients, age 48±16 were analysed. The peak-Poes (23-77) yrs, BMI measurement method obtained the highest 28.1±4.3 (22-38) separation index, followed by the area kg/m2, AHI 11±10 (1- index and the peak-flow methods. 43). 109.955 breaths were automatically extracted and assessed. Clarenbach et Case series 4 N=10 patients The oesophageal pressure median al, 2013 [120] referred for cardiac decreased significantly during inspiration catheterisation, age through a threshold load, bud not during an- 64 (46-75) yrs, BMI expiratory central apnoea. 28.3 (23.9-34.8) kg/m2. Chervin et al, Case-control 3b N=155 patients who Oesophageal manometry was associated 1997 [115] series slept with Poes with small but statistically significant catheter during PSG (p<0.05) decrements in total recording time,

vs 155 matched total sleep time, sleep efficiency, percent patients who slept Stage 2 sleep, and percent REM sleep, and without Poes with increases in latency to REM sleep, catheter. No latency to persistent sleep, and percent characteristics Stage 3/4 sleep. The differences were of reported. such small magnitude that their clinical significance is doubtful. The number of awakenings per hour of sleep, latency to sleep onset, and percent Stage 1 sleep were not different when oesophageal manometry was used. AHI with Poes was 10±12 and without Poes 10±12 (completely the same, p=0.85).

e1.3.D. Measurement of respiratory effort: Abdominal belts

Author Design EBM Patient population Results Comments Sharp et al, Case series 4 N=17 (all male) Oesophageal pressure was measured 1980 [128] sleep apnoea simultaneously with respiratory patients (9 OSA and magnetometer records of rib cage and

8 OSA+CSA). 3 abdominal motion. The magnetometer were asymptomic, 2 records alone permitted distinction between patients were obstructive and central apnoea. hypercapnic.12 patients were moderately to severe obese. AI 41 (29- 54). No other characteristics reported. Cohn et al, Case series 4 N=33 young, healthy Changes of lung volumes measured with Volume equivalency 1982 [124] subjects: RIP were compared with simultaneous of RIP to spirometry 15 (9 male) healthy spirometry. Tidal volumes: 88% is present over a non-smokers, age agreement. Vital capacity: 80% agreement, wide range of body 24±3 (17-28) yrs, max voluntary ventilation: 80% agreement. postures and spinal weight 69± 12 kg. attitudes, at the 18 (8 male) expense of variable asymptomatic errors in smokers, age 30±7 determination of the (19-42) yrs, weight rib cage to abdominal 62±13 kg. contributions to tidal

volume. Chadha et al, Case series 4 N=20 (12 male) Two calibration methods for RIP were 1982 [125] healthy subjects, age compared: least squares method (LSQ) vs 26 (21-37) yrs. No simultaneous equation method (SEQ). The other characteristics optimal calibration procedure for RIP in reported. terms of accuracy and ease of subject performance is the LSQ procedure. Staats et al, Case series 4 N=54 (48 male) Obstructive apnoea occurred to a variable Ribcage and 1984 [129] symptomatic patients extent in all patients and was characterised abdominal motion with suspicion of by stereotyped paradoxical motion of the can adequately OSA, age 51 (23-7) RC or ABD or both in 49 patients (91%). characterise apnoea yrs. No other There was no paradox in 2 patients with in most patients and characteristics "feeble" inspiratory effort during thus avoid invasive reported. obstructions and in 3 patients with normal monitoring inspiratory effort during obstructed breaths. techniques that can Paradox did not occur in central apnoea or adversely affect in the central component of mixed apnoea. sleep. Obstructive hypopnoea was characterised by paradox during part of the breath. Brouillette et al, Case series 4 N=28 patients The RIP and the impedance monitor

1987 [130] (among them: 7 with detected 99.6 ±0.6% and 98.3±3.0% of normal breathing, 7 breaths, respectively. The impedance with OSA, 3 with monitor, but not the RIP, missed breaths borderline OSA, 11 following sighs in 16 of 29 studies. Both with chronic lung monitors detected all 60 episodes of central disease of apnoea. neurological disease), age 41±38 (1-180) M. No other characteristics reported. Whyte et al, Case series 4 N=22 (18 male) The need to record flow as well as 1992 [133] symptomatic OSA thoracoabdominal movement was patients, age 22-70 assessed. Thermocouples and calibrated yrs, body weight thoracoabdominal movement by respiratory 133% (105-174) of inductance plethysmography was used. ideal body weight, There was also close agreement between AHI>15, apnoeas 1- the total number of respiratory events 81/h, hypopnoeas scored with and without reference to the 12-83/h. flow signal (r = 0.99; mean difference 1.4%) with a maximum under-recognition of

18 events per night in a subject with 237 apnoeas per night. Cantineau et Case series 4 N= 13 (10 male) Study to assess the accuracy of RIP during al, 1992 [134] OSA patients, age sleep in obese patients with OSA. The 55±10 (33-69) yrs, mean error in tidal volume measurement body weight 99±19 was -0.7% during wakefulness and 2.1% (70-129) kg, BMI during sleep. Precision was less during 34±9 kg/m2, AI sleep than wakefulness. Precision was 28±10 (15-53) least during REM sleep. Errors in all subjects’ respiratory cycles during sleep showed no correlation with BMI. Adams et al, Case series 4 N=21 healthy full- Regression coefficient of RIP Tidal Volume Qualitative diagnostic 1993 [126] term newborns. and Pneumotachyography Tidal Volume calibration (QDC) is was 0.91 (supine) and 1.00 (prone). based on the Weighted mean difference was -0.05 ml equations of the (supine) and -0.32 ml (prone). isovolume manoeuvre, carried out during a 5-min period of natural breathing without subject cooperation.

Drummond et Case series 4 N=10 (5 male) Transthoracic impedance (TTI) and rib cage al, 1998 [135] patients after major inductance bands were compared in a abdominal surgery, postoperative setting. The correspondence age 68 yrs, weight between TTI and rib cage inductance band 89% ideal. No other signals was very good, even when there characteristics were transient changes in the pattern of reported. respiration or episodes of severe airway obstruction. Loube et al, Case series 4 N=14 patients with Measurement of peak inspiratory flow to RIP can accurately 1999 [136] suspected UARS, 9 mean inspiratory flow ratio (PIFMF) was distinguish UARS with UARS (age performed during quite wakefulness and from non-UARS 38±6 yrs, BMI with 40 randomly selected breaths in the patients using the 27.3±1.7 kg/m2, ESS supine position for two conditions: stage 2 analysis of PIFMF 14±4), 5 without sleep, immediately prior to arousals. (wake-sleep) for UARS (age 35±10 The greatest diagnostic accuracy for stage breaths randomly yrs, BMI 27.1±3.1 2 sleep occurs at a cut-off of 0.1 PIFMF selected immediately kg/m2, ESS 11±3). (wake-sleep) with a sensitivity of 67% and prior to an arousal in Assessment of RIP specificity of 80%. For breaths occurring the supine position. in the diagnosis of immediately prior to arousals, PIFMF UARS. (wake-sleep) had a greater diagnostic accuracy, with a sensitivity and specificity of

100%. Kaplan et al, Case series 4 Learning session: Computer assisted RIP for detection of 2000 [137] N=16 (all male) inspiratory flow limitation was tested. Three OSA, age 49 (35-62) of various computerised RIP derived yrs, BMI 31 (22-53) parameters were identified that help to kg/m2, AHI 42 (10- predict inspiratory flow limitation: 116). 1) fractional inspiratory time Validation session: 2) peak tidal inspiratory to mean tidal N=10 (9 male) OSA, inspiratory flow ration (PTIF/MTIF) age 56 (41-71) yrs, 3) rib cage contribution to tidal volume. BMI 30 (24-38) They were combined to an inspiratory flow kg/m2, AHI 56 (49- limitation index (IFLI). The sensitivity and 65). specificity of the IFLI was 80%. Changes in body position did not affect accuracy. Masa et al, Case series 4 Group with The correlation between RERA index RIP can be used as 2003 [121] sleepiness: N=52 (39 determined by oesophageal pressure and the usual method to male) subjects, age bands was 0.98. Sensitivity was 94% and detect respiratory 47±9 yrs, BMI specificity 94% versus the oesophageal effort-related 29.0±4.2 kg/m2, AHI pressure measurement. arousals. 6±7. Group without

sleepiness: N=42 (37 male) subjects, age 42±10 yrs, BMI 27.0±3.9 kg/m2, AHI 3±5. 14.617 arousals were analysed. Ishida et al, Technical 4 System using a Detects sleep apnoea from the amplitude 2004 [139] description piezoelectric sensor, and frequency components of the timed a microcontroller, a thoracic body movement changes. compact flash memory and a laptop computer. Masa et al, Case series 4 N=90 (73 male) AHI, based on thermistor signal, was 4±5. The addition of an 2009 [140] patients with RDI, based on thoracoabdominal bands arousal to obstructive suspicion of OSA, (with oxygen desaturation criterion), was non-apnoeic events, age 44±10 yrs, BMI 3.3±4.3. RDI, based on thoracoabdominal with only oxygen 28±4 kg/m2. bands (with oxygen desaturation or desaturation, Comparison of arousal), was 11±11. markedly increased thermistors, RDI, based on oesophageal pressure with RDI, with probable thoracoabdominal oxygen desaturation criterion, was 3±4. therapeutic

bands and RDI, based on oesophageal pressure with implications. oesophageal oxygen desaturation or arousal criterion, pressure was 13±13. measurement. Koo et al, 2011 Case series 4 N=50 (23 male) OSA The respiratory event detection by PVDF [141] patients, age not impedance belts (PVDFb), RIP, and nasal- reported, BMI oral pneumotachography (PNT) was 36.2±8.2 kg/m2, AHI compared. PVDFb was less sensitive than 26 (16-53). PNT but not different compared to RIP in detecting decreased breathing amplitude. The overall levels of agreement for scoring obstructive apnoeas, central apnoeas, hypopnoeas, and total events all exceeded 0.95. Martinot- Technical X Experimental and L-A relationships vary not only with shape Lagarde et al, description computed or ellipticity of the cross section, but also 1988 [131] relationships with the wave pattern shape. When the between self- configuration shape is constant, the inductance (L) of correspondence between delta L and delta coils and areas (A) A is almost linear. When the shape is included inside. nearly circular, the relative error in delta A

estimation is <5%. Pennock, 1990 Model X Model comparing During normal ventilation, 68 and 95% of [132] piezoelectric belts the peak flows measured with the belts fall with a within ±10 and 20% of the flows measured pneumotachograph. with a screen pneumotachometer. De Groote et Respiratory X RIP was compared Both sensors can provide different phase The complex al, 2000 [138] model with strain gauges information for identical cross section dependence of RIP for several cross deformations, and hence, can estimate on perimeter and section thoracoabdominal asynchrony differently. area warns against deformations. this sensor for the evaluation of thoracoabdominal asynchrony. Vaughn et al, Model X 10 RIP belts and 10 All RIP belts performed well at all Results suggest 2012 [122] piezoelectric (PE) distraction lengths and demonstrated linear that PE belts perform belts stretched by performance. Eight of 10 PE belts similarly to RIP belts mechanical performed well through all measures, at distraction distraction across 6 whereas 2 showed nonlinear increase in distances up to 10 distances (2.5 to 15 signal on stretch of greater than 12.5 cm. cm. The lack of cm) and replicated Signals from PE belts highly correlated with uniform results in the 10 times for each the distance of distraction (r=0.96 to 0.99) range (12.5-15 cm)

belt. and the RIP belts (r=0.98 to 0.99). may be more related to the fabric characteristics than to the PE sensor itself. Minimal distance change <2.5 cm was not investigated, and thus minimal change may not correlate between the 2 sensor types. Further testing on biological models is needed to determine if PE belts are a suitable alternative for RIP belts in PSG.

e1.3.E. Measurement of respiratory effort: EMG

Author Design EBM Patient population Results Comments Bradley et al, Case series 4 N=18 (14 male) CSA To distinguish central and obstructive 1986 [144] patients, age 39-59 apnoeas, diaphragmatic EMG was yrs, weight 101-142 recorded in 6 patients, in addition to % ideal, AHI 14-56. respiratory inductive plethysmography. BMI not reported. Surface electrodes were positioned below the costal margin. Vincken et al, Case series 4 N=4 male OSA With each occluded inspiratory effort, the 1987 [145] patients, age 55±15 tension time index of the diaphragm (38-75) yrs, BMI (TTdi) increased progressively to reach or 29.83±5.46 (24-35) slightly exceed the fatigue threshold, 0.15 kg/m2. to 0.18. Stoohs et al, Case series N=9 (7 male) OSA, Increase in Poes, apnoea: 118±118%, Diaphragmatic EMG 2005 [143] age 54±13 yrs, BMI hypopnoea 76±74%. Increase in may be clinically 27.4±2.6 kg/m2, RDI diaphragmatic EMG, apnoea 123±132%, useful to reliably 28±8. hypopnoea 73±74%. dissociate central from obstructive events. However, central events were not studied. Luo et al, 2009 Case series 4 N=19 (18 male) CSA About 1/3rd of CSA events diagnosed by Conventional PSG

[142] patients, age 53±16 uncalibrated RIP could not be confirmed by overestimates the yrs, BMI 27.4±3.8 Poes or EMGdi: the number of central proportion of central kg/m2, AHI 55±21. apnoeas was 97±84 (RIP), 69±87 (Poes), apnoeas, because it 7 patients had 68±85 (EMGdi). No difference was found in depends on detecting chronic heart failure. the number of CSAs diagnosed by Poes neural respiratory (1,319) vs EMGdi (1,293; p > 0.01). drive with RIP. Poes and EMGdi are both much more sensitive than RIP in distinguishing central from obstructive respiratory events.

e1.3.F. Measurement of respiratory effort: PTT

Author Design EBM Patient population Results Comments

Pitson et al, Case series 4 N=8 (all male) OSA The mean regression value of pulse transit Measurement of the 1995 [151] patients, age 44 (34- time (ms) oscillations against intra- inspiratory change in

58) yrs, ODI 43 (13- oesophageal pressure (Poes) (cmH2O) PTT may be a useful 68) oscillations was 0.94. part of a respiratory sleep study, since it is able to provide quantitative information about inspiratory effort in patients with SRBD. Pitson et al, Case series 4 N=40 (34 male) Inspiratory blood pressure falls were 9 (8- The measurement of 1998 [146] patients with 12), 11 (9–15), 18 (13–21) and 8 (6–10) for indirect beat-to-beat suspicion of OSA, the same groups. Both BP arousals and blood pressure by age 48 (23-66) yrs, inspiratory BP falls therefore show a clear using pulse transit BMI 31 (24-50) progression from normal to severe that time may be a useful kg/m2. returns to the normal level on treatment. addition to a portable monitoring system for the management of OSA. Argod et al, Case series 4 N=13 (all male) 177 events were detected by Poes and 167 1998 [147] sleep apnoea by PTT. PTT was highly specific (93%) and

patients, age 47±14 sensitive (100%) in recognising 40 central yrs, BMI 27.1±4.5 apnoeas. It was less sensitive (84.6%) in kg/m2, AHI 25±17. the detection of 26 central hypopnoeas as 177 respiratory compared with apnoeas, but remained events were highly specific (98.6%). Misclassifications of classified as respiratory episodes were due to baseline obstructive or variations or artefacts in the PTT signal in central. 57% (i.e., eight of 14) cases. Discrepancies between Poes and PTT often occurred in REM sleep (six of 14 of the false classifications). Overall sensitivity was 91- 94%, specificity was 95-97% (two observers). Argod et al, Case series 4 N=9 (all male) OSA, PTT had a sensitivity of 79.9% and a Its ability to detect 2000 [148] age 49±10 yrs, BMI positive predictive value of 91.2% (using autonomic arousal 25.9±3.5 kg/m2, AHI Poes as the gold standard). gives the PTT signal 25±11. added clinical 340 hypopnoeas and usefulness. RERA’s were randomly selected for scoring.

Yin et al, 2004 Case series 4 N=16 patients with PTT was much more sensitive for Only 2% of the [280] suspicion of OSA. obstructive events than for central events respiratory events No other criteria (or central components). A very poor were central. specified. sensitivity (0% of the observations) was reported. Contal et al, Case-control 4 N= 10 (6 male) The total number of events and the The ability of PTT to 2013 [149] series patients with obesity percentage of central events scored when estimate respiratory hypoventilation, age using PTT alone or Poes alone were highly effort under NIV 56±12 yrs, BMI 35±5 significantly correlated (r=0.98 and r=0.86, should be kg/m2. N=11 (6 respectively; p=0.001). Bias was only 5 established in other male) healthy events or -3.4%. The ICCs between Poes patient populations, controls, age 31±9 and PTT were 0.97 for total number of such as COPD and yrs, BMI 22.3±2.5 events and 0.97 for percentage of central thoracic cage kg/m2. events restrictive diseases as well.

97 e1.3.G. Measurement of respiratory effort: FOT

Author Design EBM Patient population Results Comments Farré et al, Respiratory 4 No living subjects Respiratory impedance decreased from 508 The amplitude of

1997 [154] model cm H2O.s/L (at CPAP 0 mbar) to 57 cm airway impedance

H2O.s/L (at CPAP 6 mbar) and to 14 measured by FOT

H2O.s/L (at CPAP 14 mbar). was a suitable index to detect obstruction in the collapsible segments. Navajas et al, Case series 4 N=6 (all male) OSA, Midinspiratory resistance decreased from FOT can be used as

1998 [152] age 44±3 yrs old, 36±4 H2O.s/L (at CPAP 4 mbar) to 13±3 an alternative to the 2 BMI 34.7±2 kg/m , H2O.s/L (at CPAP 11 mbar) oesophageal balloon AHI 70±4 for assessing airway (mean±SE) obstruction in patients with SRBD. Vanderveken Case series 4 N=8 (all male) OSA, Complete UA closure was indicated by et al, 2005 age 50±8 yrs, BMI Zrs(OA) values of 35.9 ± 8.0 hPa/l/s. In 4 [153] 27±3 kg/m2, AHI out of the 22 analysed central apnoeas, a 38±27 definite occlusion of the UA occurred as demonstrated by Zrs values of 35–57

hPa/l/s. During two other central apnoeas, Zrs increased by >200%, reaching a value of 22–23 hPa/l/s. In 16 central apnoeas, only a partial occlusion or no change at all in airway patency occurred, with Zrs <17. Jobin et al, Case series 4 N=9 males with Baseline impedance values during stable 2012 [281] compensated heart breathing in stage 2 sleep were 11±1

failure (left cmH2O.s/L. Mean impedance increased to

ventricular ejection 32±7 cmH2O.s/L during obstructive fraction 28±5 %) and apnoeas (7% of events, n=46). Increases predominant central in impedance consistent with upper airway CSR (AHI 44±4), age narrowing (more than two-fold baseline) 66±3 yrs, BMI were common during central apnoeas 29.5±2.7 kg/m2, AHI (50±12 % of events) 46±4. Mean number of central apnoeas was 40 (10-110) and mean number of central hypopnoeas 27 (2-97). PSG with pneumotachography,

RIP or oesophageal pressure and FOT- derived impedance.

e1.3.H. Measurement of respiratory effort: miscellaneous methods

Author Design EBM Patient population Results Comments Ayappa et al, Case series 4 648 apnoeas in 52 Cardiac oscillations were present: in 60% The transmission of 1999 [158] (40 male) OSA (210/351) of central apnoeas and in 0% these cardiac- patients, age 48 ± 12 (0/297) of obstructive apnoeas. induced oscillations yrs, BMI 36±10 Cardiogenic oscillations were also seen may relate to the kg/m2, AHI 65±40. intermittently during quiet exhalation in relaxation of thoracic apnoea-free periods. muscles during central apnoea and is impeded by high muscle tone during obstructive apnoea. Meslier et al, Case series 4 N=26 (25 male) There were 2556 obstructive apnoeas, 347 2002 [159] sleep apnoea mixed apnoeas and 358 central apnoeas. patients, age 55±10 The concordance between the two methods

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yrs, BMI 32.1±6.7 was very good, with a sensitivity of (23-52) kg/m2. 3261 suprasternal pressure transducer (Pst) of episodes of apnoea 99.4% for the detection of apnoeas with were present. respiratory efforts and a specificity of Suprasternal 93.6%. Only 18 apnoeas were incorrectly pressure transducer classified as central apnoeas. The was placed over the sensitivity of this transducer to detect trachea above the respiratory efforts during apnoeas appears sternal notch. to be greater than that of thoracoabdominal Comparison was strain gauges. made to the reference method (oesophageal pressure).

Popovic et al, Case series 4 N=14 (9 male) Only 7 of the 14 patients exhibited central Although the 2009 [162] patients with or mixed events, all with <5/h. FVP was behaviour of FVP is suspicion of OSA, superior to effort belts in the detection of different than effort age 48±7 yrs, BMI obstructive apnoeas and hypopnoeas belts during central 29.3±4.1 kg/m2, ESS (100% vs 89-95%), similar in the detection events, with 11±5, RDI 12±13. of persistent flow limitation (100% vs 100%) proper orientation as

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200 respiratory and physiological changes in ventilation to the behaviour of events were (89% vs 69-93%) and inferior in the this signal coupled assessed. detection of central events (38% vs 62- with visual inspection Measurement of 75%). There was also poor inter-rater of the entire study, Forehead Venous agreement for central and mixed events. patients with central Pressure (FVP) was or mixed apnoea will compared to likely be correctly oesophageal triaged. manometry, piezoelectric chest and abdominal belts. Hers et al, Case series 4 N=169 (58 male) Pilot study. The correlations between the PSG was performed 2013 [163] patients, aged 49±12 PIR sensors were highly indicative of with piezoelectric yrs, BMI 29.9 ±7.1 respiratory movement detection. bands, therefore, the kg/m2. Passive central apnoea Infrared (PIR) respiratory effort data technology for were not a validated contactless detection signal. of respiratory movements was evaluated. Curves

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were compared to those of thoracic movements recorded by classical piezoelectric belts and of pressure obtained with nasal cannula. Norman et al, Case series 4 N=62 (37 male) AHI with PSG was 25.5±3.9, AHI with 2014 [164] subjects, 54 with Sonomat was 24.1±3.6. The mean suspicion of OSA, 8 difference in AHI values was 1.4 events/h, healthy volunteers, and at a diagnostic threshold of 15 age 56±16 yrs, BMI events/h, sensitivity and specificity were 31.3±6.3 kg/m2. 88% and 91%. More than 93% of PSG defined respiratory events were identified by the Sonomat and the absence of respiratory events was correctly identified in 91% of occasions. Sonomat has the ability to differentiate central and obstructive events, and there was good correlation between these event types (obstructive

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apnoeas r =0.831, p < 0.0001; central apnoeas r = 0.888, p<0.0001; mixed apnoeas r = 0.630, p<0.0001). Only 4.3% of PSG-defined obstructive events were misclassified by the Sonomat as central events, and only 0.2% of PSG-defined central events were misclassified by the Sonomat as obstructive events. Maury et al, Case series 4 N=40 (35 male) The recognition rate of abnormal respiratory 2014 [165] subjects, 25 suffered events (OAH, CAH, MA and RERA) was from OSA, 6 from excellent: the interscorer mean agreement insomnia, anxiety, was 91%. The discrimination of OAH, CAH, depression, 6 from MA characteristics was good, with an CSAS, 2 from interscorer agreement of 81%. restless legs and 1 from enuresis, age 49±12 (25-77) yrs, BMI 29.8±5.9 (19-43) kg/m2. Mandible behaviour was assessed with

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mandibular movement recordings and oesophageal pressure, added to the classical PSG procedure. Intrascorer reproducibility and interscorer variability for mandible behaviour interpretation were assessed. Senny et al, Study on X Model tested on Compared with a manually scored PSG, the 2008 [161] tracings sleep data from 34 sensitivity and specificity of the detection recordings. Method were 86% and 87% respectively. The based on the overall classification agreement in the recording of the recognition of obstructive, central, and midsagittal jaw mixed respiratory events between the motion and on a manual and automatic scoring was 73%.

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dedicated automatic analysis of this signal. Senny et al, Study on X Model trained on Sleep recognition with a sensitivity, 2009 [160] tracings sleep data from 63 specificity and global agreement of 85%, recordings and 74%, 83% compared with PSG data. The tested on 38 sensitivity and specificity to find sleep recordings. apnoea syndrome (AHI>15) was 89% and Method based on the 84%. recording of the midsagittal jaw motion and on a dedicated automatic analysis of this signal.

e1.3.I. Measurement of flow and respiratory effort: complex algorithms

Author Design EBM Patient population Results Comments Thomas et al, Case series 4 This study made use The narrow spectral band e-LFC seemed to

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2007 [168] of 3 databases detect not only periods of central apnoea, (PhysioNet Sleep but also obstructive hypopnoeas with a Apnea Database, periodic breathing pattern. Presence of n=70; Sleep Heart narrow band e-LFC predicted an increased Health Study-I sensitivity to induction of central apnoeas dataset, n=15; sleep by positive airway pressure. laboratory database with 77 split-night studies). No other criteria reported. Khandoker et Case control 4 N= 10 OSA patients, Overall Coherence ECG-EEG in This research could al, 2008 [169] series age 54±9 yrs, BMI REM>REM sleep. Coherence ECG-EEG be useful in 30±2 kg/m2, and N=5 between OSA events with and without understanding healthy subjects, age arousals were found in NREM (0.5-25 Hz) cardiac dysfunction in 51±8 yrs, BMI and in REM sleep (3.0-12 Hz). sleep apnoea 28.5±2 kg/m2. AHI patients. not reported. Morgenstern et Case series 4 N=36 (30 male) OSA The automatic non-invasive classifier al, 2010 [171] patients, age 52±16 obtained a sensitivity of 0.71 and an (23-78) yrs, BMI accuracy of 0.69, similar to the results 28.9±4.6 (21-42) obtained with a manual non-invasive

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kg/m2, AHI 14±13 (1- classification algorithm. 91). 1069 hypopnoeas were processed. Ben-Israel et Case series 4 N= 90 (57 male) Estimation of AHI based on a whole-night Focus on obstructive al, 2012 [157] patients with snore sounds analysis algorithm. events. suspicion of OSA, Estimated AHI correlated with the AHI PSG age 53±13 yrs, BMI (r2=0.81, p<0.001). Area under ROC curve 31±5 kg/m2. 30 (21 85% and 92% for threshold 10 and 20 male) patients events/h. participated in validation study (55±14 yrs, BMI 31.1±6.0 kg/m2, AHI 23±20. Sommermeyer Case series 4 N=66 (42 males), Manually scored AHI correlated highly The combination of et al, 2012[166] age 54±14 yrs, BMI significantly with AHI analysed by photoplethysmograph 28.5±5.9 kg/m2, AHI automated algorithms. R=0.94 (AHI based ic 19±19. on nasal pressure and oximeter based signals and a nasal plethysmographic signal). flow signal provided R=0.95 (AHI based on plethysmographic an accurate

108

signal alone). Sensitivity/specificity distinction between 0.90/0.97 and 0.86/0.94 respectively. obstructive and Central apnoea index (CAI) correlated central apnoeic closely with manually scored CAI (r = 0.87 events during sleep. and 0.95, p < 0.001) with mean difference Information from a of -4.3±7.9 and 0.3±1.5 events/h, finger pulse oximeter respectively. The difference between alone is sufficient for manually and automatically scored an accurate hypopnoea indices was 4±7. diagnosis of SRBD. Morgenstern et Case series 4 N=41 (34 male) A total of 1237 hypopnoeas were visually Noninvasive single- al, 2013 [172] SRBD patients, age differentiated. The automatic analysis channel hypopnoea 53±16 yrs, BMI achieved an interscorer agreement of = differentiation is 28.7±4.37 kg/m2, 0.37 and an accuracy of 69% for scorer 1; feasible. AHI 15±12 (1-56). K= 0.40 and 70% for scorer 2 and K= 0.41 and 71% for the agreed scores of scorers 1 and 2. Thomas et al, Case series 4 This study made use The narrow spectral band e-LFC seemed to 2007 [168] of 3 databases detect not only periods of central apnoea, (PhysioNet Sleep but also obstructive hypopnoeas with a Apnea Database, periodic breathing pattern. Presence of n=70; Sleep Heart narrow band e-LFC predicted an increased

109

Health Study-I sensitivity to induction of central apnoeas dataset, n=15; sleep by positive airway pressure. laboratory database with 77 split-night studies). No other criteria reported. Khandoker et Case control 4 N= 10 OSA patients, Overall Coherence ECG-EEG in This research could al, 2008 [169] series age 54±9 yrs, BMI REM>REM sleep. Coherence ECG-EEG be useful in 30±2 kg/m2, and N=5 between OSA events with and without understanding healthy subjects, age arousals were found in NREM (0.5-25 Hz) cardiac dysfunction in 51±8 yrs, BMI and in REM sleep (3.0-12 Hz). sleep apnoea 28.5±2 kg/m2. AHI patients. not reported. Morgenstern et Case series 4 N=36 (30 male) OSA The automatic non-invasive classifier al, 2010 [171] patients, age 52±16 obtained a sensitivity of 0.71 and an (23-78) yrs, BMI accuracy of 0.69, similar to the results 28.9±4.6 (21-42) obtained with a manual non-invasive kg/m2, AHI 14±13 (1- classification algorithm. 91). 1069 hypopnoeas were processed.

110

Ben-Israel et Case series 4 N= 90 (57 male) Estimation of AHI based on a whole-night Focus on obstructive al, 2012 [157] patients with snore sounds analysis algorithm. events. suspicion of OSA, Estimated AHI correlated with the AHI PSG age 53±13 yrs, BMI (r2=0.81, p<0.001). Area under ROC curve 31±5 kg/m2. 30 (21 85% and 92% for threshold 10 and 20 male) patients events/h. participated in validation study (55±14 yrs, BMI 31.1±6.0 kg/m2, AHI 23±20. Sommermeyer Case series 4 N=66 (42 males), Manually scored AHI correlated highly The combination of et al, 2012[166] age 54±14 yrs, BMI significantly with AHI analysed by photoplethysmograph 28.5±5.9 kg/m2, AHI automated algorithms. R=0.94 (AHI based ic 19±19. on nasal pressure and oximeter based signals and a nasal plethysmographic signal). flow signal provided R=0.95 (AHI based on plethysmographic an accurate signal alone). Sensitivity/specificity distinction between 0.90/0.97 and 0.86/0.94 respectively. obstructive and Central apnoea index (CAI) correlated central apnoeic closely with manually scored CAI (r = 0.87 events during sleep.

111

and 0.95, p < 0.001) with mean difference Information from a of -4.3±7.9 and 0.3±1.5 events/h, finger pulse oximeter respectively. The difference between alone is sufficient for manually and automatically scored an accurate hypopnoea indices was 4±7. diagnosis of SRBD. Morgenstern et Case series 4 N=41 (34 male) A total of 1237 hypopnoeas were visually Noninvasive single- al, 2013 [172] SRBD patients, age differentiated. The automatic analysis channel hypopnoea 53±16 yrs, BMI achieved an interscorer agreement of = differentiation is 28.7±4.37 kg/m2, 0.37 and an accuracy of 69% for scorer 1; feasible. AHI 15±12 (1-56). K= 0.40 and 70% for scorer 2 and K= 0.41 and 71% for the agreed scores of scorers 1 and 2. Fontenla- Technical X 120 events from six The method that was finally selected was All the learning Romero et al, description different patients based on a feedforward neural network parameters are auto- 2005 [175] were used. Results trained using the Bayesian framework and adaptive and no were averaged over a cross-entropy error function. The mean external-human 100 different classification accuracy, obtained over the action is needed. simulations. test set was 84±2%. Han et al, 2008 Technical X 24 (all male) OSA A new algorithm that analyses the nasal An effective tool to [176] observation patients, age 50±11 airflow (NAF) for the detection of detect sleep apnoea, yrs, AHI 48±19 obstructive apnoeic events. It is based on looking at only a

112

(AHI>10) without mean magnitude of the second derivatives single respiratory comorbidities. (MMSD) of NAF, which can detect signal. Training set of 3 respiration strength robustly under offset or PSG recordings, baseline drift.195±94 apnoeas were while 21 PSG detected manually, while 221±106 recordings were automatically. Sensitivity was 92% and used as test set. specificity 88%. Sezgin et al, Technical X N=21 (14 male) Aim was to classify sleep apnoea syndrome 2009 [177] observation sleep apnoea by using discrete wavelet transforms (DWT) patients, age 37 (21- and an artificial neural network (ANN). The 57) yrs. Apnoeas abdominal and thoracic respiration signals were classified as were separated into spectral components 450 obstructive by using multi-resolution DWT. Then the apnoeas, 120 central energy of these spectral components were apnoeas and 220 applied to the inputs of the ANN. The neural mixed apnoeas. 120 network was configured to give three apnoeas of each outputs to classify the SAS situation of the class were selected. subject. The best global accuracy obtained was 86.84% by using both abdominal and thoracic effort signals together (86% for obstructive apnoeas, 95% for central

113

apnoeas, 80% for mixed apnoeas). Maier et al, Technical X N=140 ECG-based recognition of sleep apnoea, 2011 [167] description polysomnograms using spectral- and correlation-based and holter-ECG. features extracted from the modulation of QRS amplitude, respiratory myogram interference and RR intervals. Sensitivity 81%, specificity 86%. Babaeizadeh Technical X Database for ECG-derived respiration (EDR): sensitivity The cessation of et al, 2011 description development of 45%, specificity 76%. breathing due to [178] algorithm: N=25 (21 Heart-rate variability (HRV): sensitivity 74%, central sleep apnoea male), age 50±10 specificity 62%. Combined EDR and HRV: is remarkably visible yrs, BMI 31.6±4 sensitivity 60%, specificity 82%. in the EDR kg/m2. waveform. Database for testing: N=1907 subjects, 989 normal, 918 apnoeic subjects (AHI>15). Mooney et al, Technical X Development set: Relative prolongation (>110%) of 2012 [282] description 292 randomly inspiration time during the 2 smallest selected hypopnoeas breaths of a hypopnoea (Ti) is a good non-

114

in 20 (95% male) invasive predictor of high/low resistance in subjects, age 51±14 a dataset with both flow limited and non yrs, BMI 35.6±9.8 flow limited hypopnoeas. Combined with kg/m2. Test flow limitation, the sensitivity is 84% and set: 257 randomly specificity 77%. selected hypopnoeas in 20 (90% male) subjects, 56±17 yrs, BMI 33.9±10.6 kg/m2. Randerath et Technical X N=41 (33 male) 1170 hypopnoeas could be differentiated Algorithm includes al, 2013 [62] description patients with with both algorithm and oesophageal visual analysis of the suspected OSA, age pressure catheter. The new algorithm flattening of the 52±16 yrs, BMI allowed for correct definition of 389 of 506 inspiratory flow 28.6±4.5 kg/m2, AHI central hypopnoeas (76.9%) and for correct curve, paradoxical 15±12. 1837 definition of 402 of 664 obstructive activity of thoracic hypopnoeas were hypopnoeas (60.5%). and abdominal effort scored. bands, type of termination of the hypopnoea, position of arousal, and sleep

115

stage during which the event appears. Author Design EBM Patient population Results Comments Fontenla- Technical X 120 events from six The method that was finally selected was All the learning Romero et al, description different patients based on a feedforward neural network parameters are auto- 2005 [175] were used. Results trained using the Bayesian framework and adaptive and no were averaged over a cross-entropy error function. The mean external-human 100 different classification accuracy, obtained over the action is needed. simulations. test set was 84±2%. Han et al, 2008 Technical X 24 (all male) OSA A new algorithm that analyses the nasal An effective tool to [176] observation patients, age 50±11 airflow (NAF) for the detection of detect sleep apnoea, yrs, AHI 48±19 obstructive apnoeic events. It is based on looking at only a (AHI>10) without mean magnitude of the second derivatives single respiratory comorbidities. (MMSD) of NAF, which can detect signal. Training set of 3 respiration strength robustly under offset or PSG recordings, baseline drift.195±94 apnoeas were while 21 PSG detected manually, while 221±106 recordings were automatically. Sensitivity was 92% and used as test set. specificity 88%. Sezgin et al, Technical X N=21 (14 male) Aim was to classify sleep apnoea syndrome

116

2009 [177] observation sleep apnoea by using discrete wavelet transforms (DWT) patients, age 37 (21- and an artificial neural network (ANN). The 57) yrs. Apnoeas abdominal and thoracic respiration signals were classified as were separated into spectral components 450 obstructive by using multi-resolution DWT. Then the apnoeas, 120 central energy of these spectral components were apnoeas and 220 applied to the inputs of the ANN. The neural mixed apnoeas. 120 network was configured to give three apnoeas of each outputs to classify the SAS situation of the class were selected. subject. The best global accuracy obtained was 86.84% by using both abdominal and thoracic effort signals together (86% for obstructive apnoeas, 95% for central apnoeas, 80% for mixed apnoeas). Maier et al, Technical X N=140 ECG-based recognition of sleep apnoea, 2011 [167] description polysomnograms using spectral- and correlation-based and holter-ECG. features extracted from the modulation of QRS amplitude, respiratory myogram interference and RR intervals. Sensitivity 81%, specificity 86%. Babaeizadeh Technical X Database for ECG-derived respiration (EDR): sensitivity The cessation of

117 et al, 2011 description development of 45%, specificity 76%. breathing due to [178] algorithm: N=25 (21 Heart-rate variability (HRV): sensitivity 74%, central sleep apnoea male), age 50±10 specificity 62%. Combined EDR and HRV: is remarkably visible yrs, BMI 31.6±4 sensitivity 60%, specificity 82%. in the EDR kg/m2. waveform. Database for testing: N=1907 subjects, 989 normal, 918 apnoeic subjects (AHI>15). Mooney et al, Technical X Development set: Relative prolongation (>110%) of 2012 [282] description 292 randomly inspiration time during the 2 smallest selected hypopnoeas breaths of a hypopnoea (Ti) is a good non- in 20 (95% male) invasive predictor of high/low resistance in subjects, age 51±14 a dataset with both flow limited and non yrs, BMI 35.6±9.8 flow limited hypopnoeas. Combined with kg/m2. Test flow limitation, the sensitivity is 84% and set: 257 randomly specificity 77%. selected hypopnoeas in 20 (90% male) subjects, 56±17 yrs,

118

BMI 33.9±10.6 kg/m2. Randerath et Technical X N=41 (33 male) 1170 hypopnoeas could be differentiated Algorithm includes al, 2013 [62] description patients with with both algorithm and oesophageal visual analysis of the suspected OSA, age pressure catheter. The new algorithm flattening of the 52±16 yrs, BMI allowed for correct definition of 389 of 506 inspiratory flow 28.6±4.5 kg/m2, AHI central hypopnoeas (76.9%) and for correct curve, paradoxical 15±12. 1837 definition of 402 of 664 obstructive activity of thoracic hypopnoeas were hypopnoeas (60.5%). and abdominal effort scored. bands, type of termination of the hypopnoea, position of arousal, and sleep stage during which the event appears.

e1.3.J. Capnography as an adjunct signal for the detection of sleep apnoea

Author Design EBM Patient population Results Comments

119

Magnan et al, Case series 4 N=39 (35 males) Below 39 apnoeas per hour, the regression PetCO2 does not 1993 [205] with suspicion of curve was linear (r=0.86, p<0.001). Above allow classification of

sleep apnoea, age this threshold, PetCO2 values decreased as apnoeas as 55±12 yrs, BMI 32±7 the PSG determined AI increased. obstructive, central or kg/m2, AI>10 in mixed and does not n=23. take hypopnoeas into 10 (5 male) controls. account.

Dziewas et al, Case series 4 N=27 patients with The AHI(CO2) correlated significantly with Index events were 2005 [206] acute stroke the AHI(polygraphy)(r=0.94, p<0.001). An scored based on the

AHI(CO2)>5 turned out to be highly trend graphs of

predictive of an AHI(polygraphy)>10. PetCO2 when the

PetCO2 value dropped for >50% of the previous baseline value. Yamamori et Case series and 4 N= 19 (all male) In the clinical study, 41% of total OSA Capnograms (from a al, 2008 [207] apnoea model OSA patients, age events (in 2187 of the 5356 events) showed flow-through 48±11 yrs, BMI capnograms with prolonged and elevated capnometer) during 31.4±6.7 kg/m2, AI phase with small ripples. apnoea events

56±38 In the simulation study, reduction of CO2 diagnosed as OSA tension during no-inspiration was small and by polysomnography

120

apnoea was successfully detected. were examined.

e1.3.K. Representative studies on capnography

Author Design EBM Patient population Results Comments

Cuvelier et al, Case 4 N= 12 PtcCO2 and PtcO2 were correlated with PtcCO2 values 2005 [236] series Patients with COPD arterial values and variations

or restrictive except for PaCO2 values of >56 mm Hg accurately

respiratory failure in and PaO2 values of >115 mm Hg reflected PaCO2 the stable state. values and Age: 71,8 ± 6 yrs variations during BMI: 26,4 ± 7,2 mechanical

121

kg/m2 ventilation. Every 5 min, However, the

PtcCO2 accuracy of measurements these data (TINA TCM3) were seems to be performed and restricted to simultaneously patients compared with with PaCO2 arterial values values of <56 mm Hg. Berlowitz et al, Case 4 N= 6 Critical Care Time had a significant linear effect on Compensation

2011 [237] series Unit patients, the PtcCO2 - PaCO2 suggesting a of this drift is still age 46 ± 17 yrs. calibration drift over the monitoring unsolved

Drift of the PtcCO2 period. because a linear was analysed (8 h). interpolation has

PaCO2 was been proposed, measured each 15 but this requires min (catheter). two arterial measurements

of PaCO2 (at the beginning and

122

end of PtcCO2 recording).

Restrepo et al, AARC Detailed review of Recommendations made following the 2012 [181] Clinical 124 articles about Grading of Recommendations Practice Transcutaneous Assessment, Guideline Carbon Dioxide and Development, and Evaluation (GRADE) Oxygen Monitoring. criteria

Huttmann et al, Review Various methods for Invasive and noninvasive PaCO2 Deep analysis

2014 [182] PCO2 estimation monitoring methods differ regarding of the different have been accuracy, capacity to facilitate technologies to

developed to assess continuous assessment, availability etc. assess PaCO2 alveolar ventilation. during sleep The physiological studies. background, historical development, instrument-specific technical aspects and current

123 recommendations for its clinical application are assessed on this review

124 e1.3.L. Capnography for the detection of hypoventilation: Relationship between PaCO2, transcutaneous CO2 (PtcCO2) and end-tidal CO2 (Pet CO2 )

Author Design EBM Patient population Results Comments

Sanders et al, Case Series 4 N= 22 (gender not Difference: Neither PetCO2 nor

1994[283] reported) OSA PaCO2 - PetCO2 : -13.72 ± 10.9 mmHg PtcCO2 correlates

patients, age 47 PaCO2 - PtcCO2 : 6.8 ± 11.5 mmHg properly with PaCO2. (19-72) yrs, BMI 33 However, at present, (60-13) kg/m2 better technology is During CPAP or available.

NIV titration PaCO2 (arterial catheter) was compared with

PtcCO2 and with

PetCO2 Casati et al, Case series 4 N= 17 (9 male). Transcutaneous Difference: 2006[185] Patient receiving monitoring of CO2 general partial pressure gives PaCO2 - PetCO2 : 6 ± 5 mmHg

anaesthesia for PaCO2 - PtcCO2 : 2 ± 4 mmHg a more accurate general surgery, estimation of arterial

age 71 (60-80) yrs, CO2 partial pressure

125

weight 73 (57-90) than does PetCo2 kg, height: 170 monitoring. (158-180) cm.

PaCO2 (arterial catheter) was compared with

PtcCO2 and with

PetCO2.

Hirabayashi Case series 4 N= 15 (10 male). Difference: PtcCO2 monitor was et al, During standard PetCO2 - PaCO2: -4,4 ± 6,5 mmHg more accurate than

2009[186] anaesthesia for PtcCO2 - PaCO2 : 0,19 ± 4,8 mmHg PetCO2 in patient general surgery, receiving artificial age 60 ± 12 yrs, ventilation via an weight 55 ± 10 kg, endotracheal tube in height 160 ± 8 cm, surgically treated

PaCO2 (arterial patients. catheter) was compared with

PtcCO2 and with

PetCO2 Ozyuvaci et Case series 4 N=30 (10 male) Data after 20 minutes of insufflation: In these patients,

126 al, COPD patients PaO2: PtcCO2 and PetCO2 2012 [187] receiving standard 40,79 ± 5,74 mmHg could be used

anaesthesia for PtcCO2: instead of the elective 42,3 ± 6,93 mmHg currently preferred

laparoscopic PetCO2: method of arterial cholecystectomy 37.33 ± 5,60 mmHg blood gas sampling.

with CO2, age Although PtcCO2 is 56±10 yrs, better. BMI 26±2,5 kg/m2

PaCO2 (arterial catheter) was compared with

PtcCO2 and with

PetCO2

Liu et al, Case Series 4 N= 21 (8 male) Difference: PtcCO2 monitoring

2014 [188] patients undergoing PaCO2 - PetCO2: 10,3 ± 2,3 mmHg provides a better

laparoscopic PaCO2 - PtcCO2 : 0.9 ± 1,3 mmHg estimate of PaCO2

bariatric surgery, than PetCO2 in age 29±9 yrs, severely obese BMI 42,1±5,4 patients undergoing kg/m2, laparoscopic bariatric

127

PaCO2 (arterial surgery. catheter) was compared with

PtcCO2 and with

PetCO2

Tingay et al, Case series 4 N= 50 (gender not Difference: PtcCO2 is more

2013 [189] reported) ventilated PaCO2 - PetCO2: 4,1 ± 9 mmHg accurate to estimate

neonates without PaCO2 - PtcCO2 : the PaCO2 than

pulmonary disease, -0.8 ± 13 mmHg PetCO2. age 3 (1-10) days, weight 2873 (2225- 3410) g,

PaCO2 (arterial catheter) was compared with

PtcCO2 and with

PetCO2.

Xue et al, Case series 4 N=16 (8 male). Difference: PtcCO2 monitoring is

2010 [190] Laparoscopic PaCO2 - PetCO2 : 7,5 ± 7 mmHg more accurate than

radical PaCO2 - PtcCO2: -0.9 ± 6,4 mmHg is PetCO2 monitoring gastrectomy/ in predicting the

128

proctectomy. patients' PaCO2.

PaCO2 (arterial catheter) was compared with

PtcCO2 and with

PetCO2

Urbano et al, Case series 4 N=41 (25 male) Difference: Transcutaneous CO2

2010 [191] critically ill children, PaCO2 - PetCO2 : 5,6 ± 5.1 mmHg values correlated

age 2-192 (18, 5) PaCO2-PtcCO2 : 4,5 ± 3,7 better with PaCO2

M, than with PetCO2 weight 3, 1-72 (9) kg. Three different monitoring were

used: PtcCO2 ( Sentec, TOSCA 500, TINA TCM3)

Stein et al, Case series 4 N=30 (17 male) Difference: PetCO2 provides a

2006 [192] patients recovering PetCO2 - PaCO2 : -14,1 ± 7,4 mmHg poor assessment of

from general PtcCO2 – PaCO2: 5,6 ± 3,4 mmHg PaCO2. Tosca

anaesthesia after overestimates PaCO2

129

surgery, age 64 ± and Microcap 10 yrs. underestimates

PaCO2 (arterial PaCO2 catheter) was compared with

PtcCO2 (TOSCA)

and with PetCO2 (Microcap Plus).

De Oliveria et Case series 4 N=40 female Difference: TcCO2 demonstrate al, subjects receiving PetCO2 - PaCO2 : 1,06 ± 0,8 mmHg better agreement

2010 [193] deep sedation for PtcCO2 -PaCO2 : 0,43 ± 0,35 mmHg with PaCO2 than

hysteroscopy, PetCO2. age 42±9 yrs, BMI 25±5 kg/m2.

PaCO2 (one measurement) was compared with

PtcCO2 (Tosca 500) and with

PetCO2 (Capnomac Ultima, Datex-

130

Ohmeda) . Dion et al, Case series 4 N=25 (4 male) Difference: Both of these non-

2015 [194] obese adolescents PtcCO2 – PaCO2: 3,2 ± 3,0 mmHg invasive measures

and young adults PetCO2 – PaCO2: 3,7 ± 2,5 mmHg of PaCO2 are useful during in the young severely laparoscopic- obese population. assisted bariatric surgery, age 17±2 yrs, weight 133±31 kg, BMI 50,2 ± 11,0 kg/m2.

PaCO2 was compared with

PtcCO2 and with

PetCO2.

Tobias et al, Case series 4 N= 25 (18 boys) Difference: PtcCO2 monitoring

1997 [195] mechanically PetCO2 -PaCO2 : 6,81 ± 5,1 mmHg provided a more

ventilated infants PtcCO2 - PaCO2: 2,3 ± 1,3 mmHg accurate estimation

and toddlers with of PaCO2 than

respiratory failure, PetCO2 monitoring.

131

age 103±11 M, weight: 9±4 kg.

PaCO2 was compared with

PtcCO2 and with

PetCO2

Sivan et al, Case series N=134 (gender not Difference: PaCO2 estimation by

1992 [196] reported) children PaCO2 - PetCO2: 3,4 ± 6,6 mmHg both PetCO2 and

on mechanical PaCO2 - PtcCO2 : PtcCO2 is sufficiently ventilation, -1,3 ± 7,2 mmHg precise and reliable age 3 (2-16) yrs. for clinical use in

PaCO2 was critically ill children compared with

PtcCO2 and with

PetCO2 Reid et al, Case series 4 N=22 (5 male) Difference: Thenewtranscutaneo

1992 [197] during general PetCO2 -PaCO2 : 7,0 ± 3,1 mmHg usdevices provided

anaesthesia, PtcCO2 - PaCO2 : 2,3 ± 2,4 mmHg an effective method age 37±11 yrs, for non-invasive

weight 65±11 kg. monitoring of CO2 in

PaCO2 was situations where

132

compared with continuous, precise

PtcCO2 (Fastrac) control of CO2 level

and with PetCO2 is desired recorded from a mass spectometer (Sara). Hand et al, Case series 4 N=12 critically ill There was a linear correlation between End- tidal sidestream

1989 [198] neonates. PtcCO2 and PaCO2 (n = 51, r = .71, slope = measurements are

0.90). PetCO2 and PaCO2 did not correlate. not as clinically useful because they vary due to different ventilation/ perfusion relationships in the sick neonate.

Nosovitch et Case series 4 N=30 (16 Difference: PtcCO2 provided a al, boys)pediatric PetCO2 – PaCO2: 4,4 ± 7,1 mmHg slightly more

2002 [199] patients during PtcCO2 – PaCO2: 2,8 ± 2,9 mmHg accurate estimate of

surgical PaCO2 during procedures, intraoperative age 6±4 yrs, anaesthetic care in weight 25±18 kg children.

133

Berkenbosch Case series 4 N=25 (17 boys) Difference: PtcCO2 monitoring et al, pediatric patients PetCO2 – PaCO2: provided an accurate

2001 [200] with respiratory 6,4 ± 6,3 mmHg estimation of PaCO2

failure, PtcCO2 – PaCO2: 2,6 ± 2,0 mmHg and was superior to

age 11±4 yrs, PetCO2 monitoring in weight 42±21 kg. pediatric patients

PetCO2 and

PtcCO2 were monitored and compared with

PaCO2 values. Hinkelbein et Case series 4 N=34 (19 male) Difference: During interhospital al, critically ill and PaCO2 – PtcCO2: -0,6 ± 7,5 mmHg transport, PaCO2 and

2008 [201] mechanically PaCO2 – PetCO2: PtcCO2 provided the ventilated patients, -5,3 ± 6,1 mmHg best accuracy when age 61±19 yrs, compared with the BMI 29±8,2 kg/m2 reference measurement Griffin et al, Case series 4 N=30 (7 male) Difference: Transcutaneous

2003 [202] patients with PtcCO2 – PaCO2: 0,2 ± 0,2 mmHg carbon dioxide

morbid obesity PetCO2 – PaCO2: 0,7 ± 0,4 mmHg monitoring provides a

134

(BMI > 40 kg/m2) better estimate of

undergoing gastric PaCO2 than PetCO2

bypass surgery, (Fe’CO2) in patients age 41±8 yrs, with severe obesity weight 162±35 kg, BMI 57,3 ± 11,9 kg/m2

Tobias et al, Case series 4 N=15 (gender not Difference during OLV: During OLV, PtcCO2

2003 [203] reported). PetCO2 - PaCO2: 5,8 ± 2,3 mmHg monitoring provides a

Compared PtcCO2 PtcCO2 - PaCO2: 2,7 ± 1,4 mmHg more accurate

and PetCO2 Difference during TLV: estimate of PaCO2

monitoring during PetCO2 - PaCO2: 3,9 ± 1,6 mmHg than Et techniques

one-lung ventilation PtcCO2 - PaCO2: 2,5 ± 0,8 mmHg in pediatric patients, age 14±6 yrs, weight 53±20 kg.

Oshibuchi et Case series 4 N=26 (16 male) Difference during OLV: PtcCO2 could provide al, patients undergoing PtcCO2 - PaCO2: -0,4 ± 2,5 mmHg a more accurate

2003 [204] pneumonectomy PetCO2 - PaCO2: estimation of PaCO2

with thoracotomy, -5,8 ± 4,1 mmHg (OLV) than PetCO2 during

135

age 62±15 yrs, Difference during TLV: both TLV and OLV weight 54±9 kg. 1,4 ± 4,3 mmHg during thoracic

PetCO2 - PaCO2: anaesthesia -7,1 ± 4,6 mmHg (TLV)

Cuvelier et al, Case series 4 N=12 (10 male) PtcCO2 and PtcO2 were correlated with PtcCO2 values and 2005 [236] patients with COPD arterial values variations accurately

or restrictive except for PaCO2 values of > 56 mm Hg reflected PaCO2

respiratory failure in and PaO2 values of > 115 mm Hg values and variations stable condition, during mechanical age 72±6 yrs, ventilation. However, BMI 26,4 ± 7,2 the accuracy of these kg/m2. data seems to be Each 5 min, restricted to patients

PtcCO2 with PaCO2 values of measurements < 56 mm Hg. (TINA TCM3) were performed and simultaneously compared with arterial values Berlowitz et Case series 4 N=6 critical care Time had a significant linear effect on the Compensation of this

136

al, unit patients, PtcCO2 - PaCO2 suggesting a calibration drift is still unsolved 2011 [237] age 46±17 yrs. drift over the monitoring period. because a linear

Drift of the PtcCO2 interpolation has was analysed (8 h). been proposed, but

PaCO2 was this requires two measured every 15 arterial min (catheter). measurements of

PaCO2 (at the beginning and end of

PtcCO2 recording).

e1.3.M. Predictors of hypoventilation

Author Design EBM Patient Results Comments population

Hukins et al, Case Series 4 N= 19 Duchenne FEV1, PaCO2 and base excess were Consider to perform 2000 [74] muscular related to sleep oxygenation. blood gases if

dystrophy (DMD) FEV1<40%, and patients, PSG if

age 19 ± 4 yrs PaCO2≥40mmHg

137

BMI: 20.5 ± 5.2 and base kg/m2 excess≥4mmol/L. Comparison of parameters of daytime lung

function (FEV1,

PaCO2, base excess) with PSG outcomes. Manuel et al, Open Cross- 4 N= 17 obese Group 2 was an intermediate group. The Obese individuals

2015 [75] sectional patients, fall in SaO2 and rise in ETCO2 in with isolated base

Study age 52 ± 9 yrs ventilatory tests and TST<90% SaO2 was excess may have BMI: 47.2 ± 9.8 similar to group 3 (with established early obesity related kg/m2 hypoventilation). hypoventilation. Subjects divided into: 1) Normal daytime

PaCO2 and BE. 2) Normal daytime

PaCO2, elevated BE. 3) Elevated

138

daytime PaCO2 Ventilatory response tests and sleep study were performed.

Macavei et al, Retros-pective 4 N= 525 Significant correlations between: pCO2, High calculated

2013 [76] Analysis consecutive BMI, FEV1, FVC, AHI, nocturnal SpO2. HCO3 level

patients, HCO3 and pO2 were independent (>27mmol/L) was a age 51 ± 13 yrs. predictors of OHS. sensitive (85.7%) BMI: 34.5 ± 8.1 and specific kg/m2 (89.5%) predictor Search of OHS for OHS. predictors among obese patients with suspected OSA.

139 e1.3.N. PAP Titration

Author Design EBM Patient Results Comments population

Jaye et al, Randomised 1 N= 17 obese Small increase in mean overnight PtcCO2 Autotitrating NIV 2009 [240] crossover trial patients, (median (interquartile range) 7.2 (6.7–7.7) produced age 42 ± 18 yrs vs. 6.7 (6.1–7.0) kPa). Decrease in % comparable control

Comparison of the stage 1 sleep (mean±SD 16±9 versus of nocturnal O2 to efficacy of 19±10%) on autotitrating NIV vs. with standard NIV. automatic NIV with conventional NIV. conventional NIV in stable neuromuscular and chest wall disorder patients established on long-term ventilatory support. Berry et al, Guidelines Stable chronic Description of best clinical practices for the 2010[239] alveolar sleep centre adjustment of non-invasive NPPV Titration hypoventilation positive pressure ventilation (NPPV).

140

Task Force of syndromes the AASM Gonzalez- Consensus Systematic Description of nocturnal respiratory events Bermejo et al, analysis of which occur during NIV. 2012 [241] polygraphy or PSG SomnoNIV for identifying and Group scoring abnormal events occurring during NIV.

141 e1.3.O. Leaks

Author Design EBM Patient Results Comments population Rabec et al, Case Series 4 N= 169 patients Bench test: high correlation. Patient test: By using this 2009 [228] treated with NIV 66% abnormalities, mosty air leaks and device NIV could using VPAPTMIII, desaturation dips, solved with chin straps or be optimised and age 66 ± 16 yrs. EPAP increase. the number of Test of the sleep studies accuracy of minute may be limited to ventilation and complex cases. leak calculations of VPAPTMIII by using a device (ResLinkTM) compared to a bench and patients. Meyer et al, Case series 4 N= 6 patients All patients presented oral leaks, associated Air leaking is 1997 [230] receiving nasal with arousal (stages 1, 2 and REM). associated with NPPV for at least 6 Oxygenation was maintained despite air poor sleep M, leaking. quality. Pressure-

142

age 44 ± 7 yrs limited ventilators BMI 21.5 ± 1.8 compensate for kg/m2 leaks. Effect of air leaking on sleep quality. Nocturnal PSG and nap studies. Teschler et al, Case series 4 N= 9 patients with Unsealed vs. sealed mouth fall of: mouth Mouth leak

1999 [231] nasal bi-level leak (0.35±0.07 vs. 0.06±0.03L/s), PtcCO2 reduces effective ventilatory (7.7mmHg reduction), Arousal (35.0±3.0 vs. nasal bi-level assistance, 13.9±1.2/h). REM sleep increased (12.9±1.5 ventilatoy age 64 yrs, BMI 24 vs. 21.1±1.8%time) support. kg/m2 Increase in

Test of the acute PtcCO2. effect of sealing Sleep the mouth and architecture

PtcCO2 on sleep disruption. architecture.

143

Borel et al, Case series 4 Evaluation of 7 Intentional leak in all masks (from 30 to 45 Mask intentional 2009 [219] different masks L/min) did not influence breathing. leaks can impair connected to 4 Inspiratory and expiratory cycling was efficacy of different ventilators affected by the level of intentional leaks only ventilation adapted to a lung in obstructive lung conditions. especially when model (three >40L/min. conditions: normal, restrictive and obstructive breathing). Analysis of the impact of mask intentional leaks on efficacy of ventilation.

144 e1.3.P. Asynchronies

Author Design EBM Patient Results Comments population Fanfulla et al, Case Series 4 N= 48 COPD Blood gases improved during MV but the Asynchronies are 2007 [222] obese patients, asynchrony effort was much higher during common in age 57 ±13 yrs. the night and correlated with a high CT90. patients with Different nocturnal MV. parameters of Despite a good daytime and night tolerance and were evaluated compliance, they during mechanical have poorer

ventilation (MV). nocturnal O2 gas exchange. Crescimanno Case series 4 N= 18 chronically Asynchrony rate was low (4.32 events /h). It Most et al, 2012 ventilated increased during home PSG. Autotriggering asynchronies [223] neuromuscular was the most common, followed by IE and were associated patients, PI. with arousal and age 30 ± 7 yrs, leak. Polygraph BMI 20.57 ± 4.9 monitoring may kg/m2 help to improve Analysis of the ventilator setting.

145

impact of asynchrony on sleep disruption. Home PSG and hospital polygraphy. Blanch et al, Prospective, 4 N= 50 Intensive AI: 3.41% (it decreased when >90% of Asynchrony was 2015 [225] Non Care Unit patients. breaths were machine-triggered). Inspiratory detected in all interven- Prevalence and efforts during expiration (IEE): 2.38%. patients. It is tional time course of Asynchrony was more frequent in day-time. needed to Observa- asynchronies determine tional study during mechanical whether ventilation by asynchronies are analysing 7.027h a marker for or a recorded from the cause of ventilator. mortality. Janssens et Review Monitoring long- Description of different simple tools to al, term NIV. control NIV. 2011 [224]

146

Tables of Chapter 2.1. Pathophysiology e2.1.A Pathophysiology (human and animal data)

Author Design EBM Patient Population Results Comments Skatrud et al, Intervention 3b Passive positive No post hyperventilation in First illustration that 1983 [284] hyperventilation in wakefulness, but apnoea during chemical drives

normal subjects sleep when PETCO2 reduced 3-6 determines mmHg below Non REM sleep level breathing pattern in absence of wakefulness drive

Xie et al, Intervention 3b Passive positive Hypoxia narrows the CO2 reserve Hypoxia promotes 2001[285] pressure unstable breathing hyperventilation with and without hypoxia

Xie et al, Cross 2b N=12 patients with Lower CO2 reserve (PCO2 Illustrates role of

2011 [286] sectional mixed apnoeas and (eupnea-apnea threshold) in mixed CO2 threshold N=9 with pure OSA group

Nakayama et Intervention 2c Hyperventilation of Hyperventilation per se widened the Susceptibility for al, 2002 [287] study in dogs by increasing ∆PCO2 (needed to produce apnoea maybe

147

animals VT with pressure apnoea) dependent on support degree of ventilator stimulus Xi et al, 1993 Intervention 2c Hypoxic In Non-REM prolonged expiratory is No apnoeic [288] study in hyperventilation in related to degree of hypocapnia threshold in REM animals REM vs. Non-REM which was not the case in REM (phasic or tonic) Satoh et al, Intervention 2c Controlled Increased frequency of CMV is 2001 [289] study in mechanical critical in elimination of inspiratory animals ventilation (CMV) motor tone Xie et al, Intervention 1b N=42 patients with Responders to intervention Stabilising 2013 [290] OSA; (lowering AHI) had greater breathing pattern

isocapnic/hypercapn controller gain, smaller CO2 reserve may partially ic rebreathing; eliminate OSA measuring controller gain, plant gain Younes et al, Parallel groups 1b N=12 patients with Increasing loop gain provokes CSA Chemical control of 2001 [291] severe OSA vs 20 in the severe group (9/12) and less breathing is more patients with in the mild group (6/20) unstable in severe moderate OSA OSA

148

Tables of Chapter 2.2. Primary CSA, drug induced CSA e2.2.A. Studies in patients with chronic pain

Author Design EBM Patient Results Comments population Rose et al, Prospective 4 Chronic pain and AHI>30 in 46% of patients on opioids. High prevalence of 2014 [1] cohort study opioid medication. Central apnoea index higher (4±8) than in CSA and ventilator sleep lab reference group (0±0). Evidence failure in patients on Sleep lab N=20 of chronic ventilator failure in 45% of chronic pain therapy (reference studied patients. group),N=20(healt hy control group)

N=24, 12 male , age 52±10 yrs, BMI 35±9 kg/m2, AHI 33±26 Troitino et al, Retropective 4 Patients Response to CPAP in 25% of O-CSA and CPAP may be 2014 [15] chart study prescribed CPAP 38% of I-CSA. BiPAP and ASV both effective in a comparing at VA sleep center effective in >60% of O-CSA and >90 % of I- subgroup of patients patients with during 5 yrs. CSA with opioid treatment, opioid-related but BiPAP or ASV

149

CSA (O-CSA) N=95 (98% were superior. and idiopathic males), age 61±9 CSA (I-CSA) (O-CSA) and 62±15 (I-CSA) yrs, BMI 31±4 kg/m2, (O-CSA) and 32±5 (I-CSA) kg/m2, AHI 46+31 (O- CSA) and 37+21 (I-CSA) Ramar et Case series with 4 N=108 (71% All pts with inadequate control of sleep ASV was equally al,2012 [16] consecutive male) consecutive disordered breathing on CPAP (AHI 50 ± effective in CHF enrollment patients 32, CAI 37 ± 32). ASV successful in 28 patients and chronic undergoing ASV (60%) in the opioid group, and 43 (71%) in opioid users. Overall titration for CSA or the CHF group. Logistic regression showed success rate (AHI < complex sleep unit increases in BMI and HCO3-, as well 10/h) approached apnoea syndrome as presence of CSR were associated with 70%. due to CHF ( EF < decreased likelihood of ASV success.

45%, or > 50% with evidence for diastolic

150

dysfunction) or chronic opioid use (use of opioids > 6 M), age 65±13 yrs, BMI 32±7 kg/m2, AHI 46±27 Chowdhuri et Retrospective 4 N=162 (98% Elimination of CSA (CAI ≤ 5/h) in 84% of A titration protocol al, 2012[17] chart review (3 male) consecutive patients. CPAP was effective in 48%. A with CPAP followed

years). patients with CPAP+O2 combination was effective in an by positive airway

diagnosed CSA at additional 25%, and BPAP+O2 in 11%. The pressure with O2

a VA sleep remaining 16% were non-responders. In effectively eliminates disorders centre. forty-seven patients (29%) prescribed CSA in individuals Evaluation of a opioid therapy for chronic pain CPAP, with underlying

step-wise titration CPAP+O2, or BPAP+O2 eliminated CSA in comorbid conditions protocol using 54%, 28%, and 10% cases, respectively. and prescription

CPAP, CPAP+O2, opioid use.

and BPAP+O2, age 59±12 yrs, BMI 34±7 kg/m2, AHI 69±30 Peles et al, Case study 4 N=23 (83% male) PSG based sleep indices unchanged from No CSA in

151

2011 [11] opioid addicts 0 to 6 and 12 M. BMI increase. No central methadone program admitted to apnoea detected. patients. Weight gain methadone at 0, 6 associated with OSA. and 12 M,age 24±9 yrs, BMI 24±4 kg/m2, RDI 4±5 Guilleminault et Consecutive 4 N=44 (22 male) Persisting CSA after CPAP. Better effect BiPAP and ASV al, 2010[12] case study. consecutive with BiPAP and ASV superior to CPAP in patients on treatment of OSA chronic opioid patients on chronic therapy. N=44 opioid therapy. matched control group with OSA, , age 46±7 (cases) and 43+10 (ctrl) yrs, BMI 26±2 (cases) and 26 ± 2 (ctrl) kg/m2, AHI 44±5 (cases) and 42±5 (ctrl)

152

Sharkey et al, Prospective 4 N=71 (in nonSDB OSA (AHI > or = 5) in 35%. OSA was SDB was common in 2010 [4] cohort study group: 37% male; associated with higher BMI, longer duration MMT patients and in SDB group 47% in MMT, and non-Caucasian race. CSA OSA was more

male) patients on (CAI ≥5) in 14%. CSA was not associated common than CSA. methadone with methadone dose or concomitant drug Factors other than maintenance use. Subjective sleep disturbance sleep apnoea appear treatment (MMT) measured with the PSQI was not related to to account for for opioid OSA or CSA. complaints of dependence (>3 disturbed sleep in M) and a this population. Pittsburgh Sleep Quality Inventory (PSQI) score >5, age 37±8 (no SDB) yrs and 39±8 (SDB) yrs, BMI 27±6 (no SDB) and 30±6(SDB) kg/m2, Alattar et al, Case series 4 N=6 (66% male) BiLevel therapy effective in the control of BiLevel therapy 2009 [13] sleep lab referrals breathing effective in the

153

on opioid therapy control of breathing. for more than 6 M,

age 41-68 yrs, BMI 27-34 kg/m2, AHI 28-106 Farney et al, Retrospective 4 N=22 (41% male) Baseline AHI was 67±37, 70±33 on CPAP, ASV was 2008 [14] analysis of case consecutive sleep and 54±33 on ASV. With ASV, the mean insufficiently effective series lab referrals with OAI was significantly decreased to 2 (p < in these patients due

an AHI ≥20 tested 0.0001), and the mean HI increased to residual respiratory with ASV and a significantly to 36 (p < 0.0001). The events and history ofopioid decrease of CAI from 26 to 16 was not hypoxemia. medications (>6 significant (p = 0.127). Biot's breathing

M). Baseline PSG persisted, and oxygenation parameters compared with were unimproved with ASV. There were no CPAP and ASV, significant differences for sleep variables. age 50±13 yrs, Impact on symptoms was not assessed. BMI 33±6 kg/m2, AHI 66±37 Javaheri et al, Case series 4 N=5 (4 male) Habitual snorers with excessive daytime Opioids may cause 2008 [18] consecutive sleepiness. Opioid therapy due to chronic severe sleep apnoea patients referred pain for 2 to 5 yrs. Baseline AHI 70 which syndrome. CPAP

154

for evaluation of dropped to 55 after CPAP but CAI eliminates obstructive OSA. Baseline increased from 26 to 37. ASV resulted in a apnoeas, but PSG followed by a HI of 13, with CAI and OAI of 0. The overall increases central second CPAP arousal index decreased from 62±18 apnoeas. ASV was night and a third (baseline) to 35±20 (CPAP, NS) and to effective in the night with ASV 24±9 (ASV, p=0.02). %N1 was 7±1 at treatment of SRBD in due to baseline, 16±3 with CPAP and 8±3 with patients on chronic ineffectiveness of ASV (p<0.01 compared to CPAP). Impact opioids. CPAP, age 51±4 on symptoms was not assessed. yrs, BMI 31±4 kg/m2, AHI 70±19 Mogri et al, Retrospective 4 N=98 (58% male) Of the 98 patients, 36% had OSA, 24% had Patients on chronic 2009 [5] case series consecutive CSA and 21% had combined OSA and opioid therapy for patients on CSA. In 4%, sleep apnoea was classified chronic pain have a chronic opioid as indeterminate, and 15% had no SA. high prevalence of medications and Opioids were potentially responsible for sleep apnoea and seen in the hypoxemia during wakefulness in 10% of nocturnal hypoxemia. chronic pain clinic. patients (95% CI 5-18%) and for hypoxemia Hypoxemia can occur Sleep study with during sleep not clearly associated with during quite PSG regardless of apnoeas/hypopnoeas in 8% of patients wakefulness with and whether patients (95% CI 4-15%). Two patients (2%, 95% CI without sleep

155

had sleep 0-7%) had sleep-related hypoxemia (SaO2< apnoea. symptoms or not, , 90% for more than 5 min with a nadir of age 48 yrs, BMI ≤85%, or > 30% of total sleep time at a 2 30 kg/m . No SaO2< 90%) in the absence of sleep other criteria apnoea or hypoxemia during wakefulness. reported.

Webster et al, Retrospective, 4 N=147consecutive An AHI≥5 was found in 75% of patients SRBD was common 2008 [6] observational chronic pain (39% OSA, 4% indeterminate, 24% CSA in chronic pain study patients on and 8% had both CSA and OSA). There patients on opioids.

around-the-clock was a direct relation between AHI and the The dose-response

opioid therapy for daily dosage of methadone (p = 0.002) but relationship of sleep at least 6 M not to other around-the-clock opioids. There apnoea to (stable dose > 4 was a direct relationship between the CAI methadone and wks). No other and the daily dosage of methadone (p= benzodiazepines details reported. 0.008) and also with benzodiazepines (p= calls for increased 0.004). vigilance. Farney et al, Prospective 3b N=70 (28 males) At least mild sleep disordered breathing Buprenorphine may 2013 [2] cohort study consecutive (AHI ≥5 events/h) present in 63%. Moderate induce significant patients admitted (AHI ≥15- <30 events/h) and severe (AHI alterations of Sleep medicine for therapy with ≥30 events/h) sleep apnoea present in 16% breathing during

156

consultation and buprenorphine and 17%, respectively. Hypoxaemia, (SaO2) sleep at routine attended PSG. /naloxone <90% for ≥10% of sleep time, was present therapeutic doses. (addiction), age in 27 (39%) patients. Central apnoeas and 3212 yrs, BMI ataxic breathing were common. Breathing 25±6 kg/m2, AHI abnormalities were unrelated to smoking 20±32 history, buprenorphine dosage or associated drugs. Jungquist et al, Descriptive, 3b N=108 CSA associated with opioid use (5±13 Marginal increase of 2012 [3] cross-sectional consecutive events/h) compared with 2±6 events/h in CSA in chronic opioid study patients of sleep those without. No difference in oxygenation. users. lab referrals with no pain, pain with opioid use and pain without opioid use, AHI 46±27 Walker et al, Retrospective, 3b N=60 (33% male) AHI was greater in the opioid group (44 vs There is a dose- 2007 [7] cohort study sleep apnoea 30, p < .05) due to increased central dependent

Matched control patients taking apnoeas (13 vs 2; p <0.001). SpO2 in the relationship between

group chronic opioids opioid group was lower during both chronicopioid use matched for age, wakefulness (difference 2.1%, and the development

157

sex, and BMI with p<0.001) and NREM sleep (difference of a peculiar pattern sleep apnoea 2.2%, p < 0.001) but not during REM sleep of respiration, patients not taking (difference 1.2%) than in the nonopioid consisting of central opioids. group. Within the opioid group (controlled sleep apnoeas and Exploration of the for BMI, age, and sex), there was a dose- ataxic breathing. The effect of morphine response relationship between morphine clinical relevance of dose equivalent dose equivalent and apnoea-hypopnoea (p these observations on breathing <0.001), obstructive apnoea (p<0.001), remains to be pattern during hypopnoea (p<0.001), and central apnoea established. sleep, age 53±13 indexes (p<0.001). BMI was inversely

yrs, BMI 31±8 related to AHI in the opioid group. Ataxic or kg/m2, AHI 44±35 irregular breathing during NREM sleep was (opioid group) more prevalent in opioid group (70% vs 5.0%, p<0.001) and more frequent (92%) at a morphine dose equivalent of 200 mg or higher (odds ratio = 15.4, p =0.017). Wang et al, Prospective, 3b N=70 (35 male) Thirty percent of MMT patients had a CAI > Thirty percent of 2005 [8] case control MMT (addiction) 5, and 20% had a CAI > 10. All normal stable MMT patients study patients and age-, subjects had a CAI < 1, and the obstructive exhibited CSA. Blood

sex-, and BMI- AHI did not differ between the two groups. methadone matched normal Methadone blood concentration was the concentration only

158

subjects, (N=50 only variable (t = 2.33, p = 0.025) explained a minor MMT and 20 ctrl), associated with CAI and explained 12% of part of the variance

age 35±9 yrs the variance. Awake PaCO2, antidepressant of the respiratory (MMT) and 35±9 use, reduced ventilatory response to effect. (ctrl), BMI 27±6 hypercapnia, and widened awake alveolar-

(MMT) and 27±5 arterial oxygen pressure gradient jointly (ctrl) kg/m2 explained additionally 17% of the CAI variance. PSG and blood toxicology. Resting ventilatory responses to hypoxia and hypercapnia in the MMT group.

Teichtahl et al, Prospective, 3b N=70 (35 male) A reduced HCVR (1.27±0.61 vs 1.64±0.57 Stable long-term 2005 [9] case control MMT (addiction) l/min/mm Hg [p = 0.01]) and increased HVR MMT patients have

study patients and non- (2.14±1.58 vs 1.12±0.70 l/min/%SpO2 p = blunted central and opioid-using 0.008) was found in MMT patients elevated peripheral

subjects (n=20) compared to control subjects. Modifications chemoreceptor

159

matched for age, of respiratory rate was the major responses. sex, height, and physiologic response that contributed to the

BMI (N=50 in differences in HCVR and HVR. Variables MMT and N=20 in associated with the HCVR in MMT patients ctrl), age 35±9 yrs were the obstructive AHI (t = 5.1, p =

(MMT) and 35±9 0.00001), PaCO2 (t = - 3.6, p = 0.001), body (ctrl), BMI 27±6 height (t = 2.6, p = 0.01) and alveolar- (MMT) and 27±5 arterial oxygen pressure gradient (t = 2.5, p (controls) kg/m2 = 0.02). Variables associated with HVR in MMT patients were body height (t = 3.2, p = Determination of 0.002) and PaCO2 (t = - 2.8, p = 0.008). hypoxic (HVR) and hypercapnic (HCVR) ventilatory responses. Bernards et al, Randomised 2b N=19 (58% male) Remifentanil increased Stage 1 sleep, Despite fewer 2009 [10] placebo patients with markedly decreased rapid eye movement obstructions sleep, controlled, moderate OSA. sleep, increased arousals from sleep, and apnoea was worse

parallel trial; Placebo (N=9) or decreased sleep efficiency. The number of after remifentanil, remifentanil obstructive apnoeas was decreased while due to a marked

infusion (N=10) the number of central apnoeas was increase in central

160

(0.075 g x kg x markedly increased. Arterial hemoglobin apnoeas. Caution is h). Simultaneous oxygen saturation was significantly lower in warranted when PSG study for patients receiving remifentanil. Saline administering opioids recording of sleep infusion had no effect on sleep or to subjects with stages, apnoeas, respiratory variables. moderate OSA. hypopnoeas, and

SaO2.

age 49±11(ctrl) and 50±12 (cases) yrs, BMI 36+7 (ctrl) and 31±8 (cases) kg/m2, AHI 23±6 (ctrl) and 24±5 (cases)

Tables of Chapter 2.2. Primary CSA, drug induced CSA e2.2.B. Studies in patients treated for opioid dependency

Author Design EBM Patient Results Comments

161

population Peles et al, Case study 4 N=23 (83% male) PSG based sleep indices unchanged from No CSA in 2011 [11] opioid addicts 0 to 6 and 12 M. BMI increase. No central methadone program admitted to apnoea detected. patients. Weight gain methadone at 0, 6 associated with OSA. and 12 M,age 24±9 yrs, BMI 24±4 kg/m2, RDI 4±5 Sharkey et al, Prospective 4 N=71 (in nonSDB OSA (AHI > or = 5) in 35%. OSA was SDB was common in 2010 [4] cohort study group: 37% male; associated with higher BMI, longer duration MMT patients and in SDB group 47% in MMT, and non-Caucasian race. CSA OSA was more

162

(PSQI) score >5, age 37±8 (no SDB) yrs and 39±8 (SDB) yrs, BMI 27±6 (no SDB) and 30±6(SDB) kg/m2, Farney et al, Prospective 3b N=70 (28 males) At least mild sleep disordered breathing Buprenorphine may 2013 [2] cohort study consecutive (AHI ≥5 events/h) present in 63%. Moderate induce significant patients admitted (AHI ≥15- <30 events/h) and severe (AHI alterations of Sleep medicine for therapy with ≥30 events/h) sleep apnoea present in 16% breathing during consultation and buprenorphine and 17%, respectively. Hypoxaemia, (SaO2) sleep at routine attended PSG. /naloxone <90% for ≥10% of sleep time, was present therapeutic doses. (addiction), age in 27 (39%) patients. Central apnoeas and 3212 yrs, BMI ataxic breathing were common. Breathing 25±6 kg/m2, AHI abnormalities were unrelated to smoking 20±32 history, buprenorphine dosage or associated drugs. Wang et al, Prospective, 3b N=70 (35 male) Thirty percent of MMT patients had a CAI > Thirty percent of 2005 [8] case control MMT (addiction) 5, and 20% had a CAI > 10. All normal stable MMT patients study patients and age-, subjects had a CAI < 1, and the obstructive exhibited CSA. Blood

163

sex-, and BMI- AHI did not differ between the two groups. methadone matched normal Methadone blood concentration was the concentration only subjects, (N=50 only variable (t = 2.33, p = 0.025) explained a minor MMT and 20 ctrl), associated with CAI and explained 12% of part of the variance

age 35±9 yrs the variance. Awake PaCO2, antidepressant of the respiratory (MMT) and 35±9 use, reduced ventilatory response to effect. (ctrl), BMI 27±6 hypercapnia, and widened awake alveolar-

patients and non- (2.14±1.58 vs 1.12±0.70 l/min/%SpO2 p = blunted central and

164

study opioid-using 0.008) was found in MMT patients elevated peripheral

subjects (n=20) compared to control subjects. Modifications chemoreceptor

matched for age, of respiratory rate was the major responses.

sex, height, and physiologic response that contributed to the BMI (N=50 in differences in HCVR and HVR. Variables MMT and N=20 in associated with the HCVR in MMT patients ctrl), age 35±9 yrs were the obstructive AHI (t = 5.1, p =

Tables of Chapter 2.2. Primary CSA, drug induced CSA

165 e2.2.C. Miscellaneous studies

Author Design EBM Patient Results Comments population Bernards et al, Randomised 2b N=19 (58% male) Remifentanil increased Stage 1 sleep, Despite fewer 2009 [10] placebo patients with markedly decreased rapid eye movement obstructions sleep, controlled, moderate OSA. sleep, increased arousals from sleep, and apnoea was worse

parallel trial; Placebo (N=9) or decreased sleep efficiency. The number of after remifentanil, remifentanil obstructive apnoeas was decreased while due to a marked

infusion (N=10) the number of central apnoeas was increase in central (0.075 g x kg x markedly increased. Arterial hemoglobin apnoeas. Caution is h). Simultaneous oxygen saturation was significantly lower in warranted when PSG study for patients receiving remifentanil. Saline administering opioids recording of sleep infusion had no effect on sleep or to subjects with stages, apnoeas, respiratory variables. moderate OSA. hypopnoeas, and

SaO2.

age 49±11(ctrl) and 50±12 (cases) yrs, BMI 36+7 (ctrl) and 31±8

166

(cases) kg/m2, AHI 23±6 (ctrl) and 24±5 (cases)

Tables of Chapter 2.3. CSA in High Altitude e2.3.A. CSA at altitude (high altitude periodic breathing)

Author Design EBM Patient Results Comments population Healthy volunteers, studies at real altitude

Bloch et al, Observational 4 N=34 (27 male) At 6850 m; SpO2 64% (61-67), minute Respiratory sleep 2010[292] study: mountaineers, ventilation 11.3 L/min (9.6-13.9) and studies at various Ascent from age 45±11yrs number of AHI 132 (103-157). Within 5-8 altitudes (490; 4430; 3750 m to 7546 days at 4497m and 5533m revealed 5533; 6860 m) and at m within 19-20 increased oxygen saturation, no decrease different times during days in PB. Amount of PB Cycles correlated acclimatisation positively with days of acclimatisation. AMS allowed to assess the had no effect on PB. effect of acclimatisation Lombardi et al, Observational ; 4 N=37 (23 male) AHI at 3400 m in men 40±33, in women Women had a lower

167

2013 [293] ascent from 0 m healthy subjects , 2±3 p<0.01 vs. men; AHI at 5400 m in men AHI than men to 5400 m over age 41±11 yrs, 87±36, in women 41±44, p<0.01 vs. men. the course of 10 weight 75±11 kg, days BMI 23.7±3.0kg/m2 Johnson et al, Observational 4 N=19 (10 male) Slow wave sleep duration decreased from Effect of altitude and 2010 [294] study; ascent healthy subjects , 24±10% to 18±6% during ascend to 5000 acclimatisation was from 0 m to 5000 age 34±9 yrs, BMI m. There was no difference recorded in difficult to assess m within 11 days 23.4±2.8 kg/m2 sleep architecture and sleep separately PSG at altitudes: oxyhemoglobin saturation between subjects 0, 1400, 3500, with and without periodic breathing 3900, 4200, and 5000 m

Nussbaumer- Observational 4 N=16 (13 male) At 490 m median (quartiles), SpO2 96% Subjective sleep Ochsner et al, study; healthy (95-96) and AHI 0.1±0,0.1. In 1st night at quality was initially

168

therefore related to hypoxemia rather than to periodic breathing. Andrews et al, Observational 4 N=12 (8 male) At 5050 m, day 2-4 AHI 77±49, days 12-14 At high altitude, loop

2012 [296] study; healthy subjects, 116±20, p<0.01; decrease in PaCO2 from gain and severity of ascent to and 2 age 30±10yrs, 29±3 to 26±2 (p=0.01) CSA increased weeks stay at BMI 5050 m. 22.8±1.9kg/m2 Measurements at day 2-4 and 12-14 Burgess et al, Observational ; 4 N=12 (8 male) AHI at 5050 m, day 2-4: 77±49 Timing of measures 2013 [297] ascent from 0 m healthy subjects, 5050 m, day 12-15: 116±21 varies between to 5050 m, age 30±10yrs, subjects observations on BMI 23± 2kg/m2 days 2-4 and 12- 15 at 5050 m Lombardi et al, Observational ; 4 N=37 (23 male) AHI at 3400 m in men 40±33, in women Women had a lower 2013 [293] ascent from 0 m healthy subjects , 2±3 p<0.01 vs. men; AHI at 5400 m in men AHI than men to 5400 m over age 41±11 yrs, 87±36, in women 41±44, p<0.01 vs. men.

169

the course of 10 weight 75±11 kg, days BMI 23.7±3.0kg/m2 Clarenbach et Ascent within 4 10 (9 male) Healthy volunteers revealed mean In same study, al, 2012[298] 24h to 4559 m healthy nocturnal SpO2 of 73±3%, AHI 48±44 at subjects uffering from and stay for 3 volunteers, age 4559 m, day 1 acute mountain days. 32±4 yrs, weight sickness were also 75±9 kg, BMI studied, see below 23.6±3.0 kg/m2

Insalaco et al, Cardiorespirator 4 N=9 male elite Variables during night 1 and 10 at 5180 m Mean SpO2 during

2012 [299] y monitoring at climbers, age 24- were: SpO2 during wakefulness 77.4±3.4% PB compared with

5180 m in night 52 yrs, BMI and 82.5±2.8% (p<0.001); PB cycle time SpO2 without PB was 1 and 10 23±9kg/m2 21.7±1.9 and 26.7±2.1 (p<0.0001); night unchanged. time with PB 26.7±3.8 % to 22.2±2.9 %

(p=0.022). During PB, SpO2 varied between 68±4 to 75±4 % and 75±4 to 82± 3 %

(p<0.001), mean SpO2 during periods with and without PB was unchanged. Clarenbach et Case – control 4 N=8 (7 male) Comparison of variables in the last night Development of al, 2012[298] study. HAPE before HAPE occurred or in night 3: all 8 HAPE is preceded by Ascent within susceptibles, 10 HAPE susceptible developed HAPE; mean reduced vital capacity

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24h to 4559 m (9 male) healthy nocturnal SpO2 60±8%, AHI 97±45; and diffusing capacity

and stay for 3 ctrls , age 40±9 Healthy ctrls mean nocturnal SpO2 73±3%, during daytime and a

days. yrs (HAPE AHI 48±44 low SpO2 and high susceptibles) vs AHI during the night 32±4 yrs (healthy control group), weight 74±9 kg vs 75±9 kg, BMI 23.8±2.3 kg/m2 vs 23.6±3.0 kg/m2

Nespoulet et Case control 4 N=12 (10 male) In AMS+: Mean nocturnal SpO2 82±3 %, Subjects with AMS al, 2012[300] study subjects AMS+, 12 (10 AHI 18±18. In ctrl: mean SpO2 86±2 had lower SpO2 and with (AMS+) and male) healthy ctrl (p<0.01), AHI 33±25 (p=0.038) lower AHI without AMS (AMS-), age (ctrls). 46±13yrs (AMS+) vs 47±11yrs (AMS-), BMI 23.5±2.2kg/m2 (AMS+) vs 22.3±2.1kg/m2 (AMS-).

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Andrews et al, Observational 4 N=12 (8 male) At 5050 m, day 2-4 AHI 77±49, days 12-14 At high altitude, loop

Nussbaumer- Observational 4 N=16 (13 male) At 490 m median (quartiles), SpO2 96% Subjective sleep Ochsner et al, study; healthy (95-96) and AHI 0.1±0,0.1. In 1st night at quality was initially

2012 [295] Ascent from 490 mountaineers, 4559 m SpO2 67% (64-69), AHI 61 (21-79); impaired at altitude, rd m to 4559 m and age 45 (33-50) in 3 night SpO2 71% (69-78), AHI 87 (19- but improved with stay for 4 days. yrs, BMI 23.8 95). acclimatisation while (23.1-25.2) kg/m2 periodic breathing persisted. Sleep disturbances were therefore related to hypoxemia rather than to periodic breathing. Pagel et al, Observational 4 N=142 to 150 At 1421 m; 7/150 patients had central At higher altitude, the

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2011 [301] study; OSA patients with apnoea index (CAI)>5, there was an increase in central Split – night AHI > 15. At increase in central AHI on CPAP by 5. AHI was greater. design 1421m 95 males, At 1808 m; 34/150 patients had CAI<5, with/without age 58±10 yrs and there was an increase in central AHI on CPAP in OSA BMI 34.98±8 CPAP by 10. patients living at kg/m2. At 1808m, At 2165 m; 48/142 patients had CAI<5, different 100 males, age 55 there was an increase in central AHI on altitudes (1421 ± 10 yrs and BMI CPAP by 19.3. m, 1808 m, 2165 33.34± 6.82 m) kg/m2. At 2165m, 100 males, age 62± 10 yrs and BMI 32.74± 6.63 kg/m2.

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had no effect on PB. effect of acclimatisation Doherty et al, Retrospective 4 N=537 (537 male) CAI is 2±6 No significant 2010 [302] observational patients with correlation among study of changes severe SDB, age AHI and barometric in AHI with 47±14 yrs, weight pressure changes changes in 101 ± 32 kg and barometric BMI 34.0 ± 9.8 pressure due to kg/m2 changes in weather Johnson et al, Observational 4 N=19 (10 male) Slow wave sleep duration decreased from Effect of altitude and 2010 [294] study; ascent healthy subjects , 24±10% to 18±6% during ascend to 5000 acclimatisation was from 0 m to 5000 age 34±9 yrs, BMI m. There was no difference recorded in difficult to assess m within 11 days 23.4±2.8 kg/m2 sleep architecture and sleep separately PSG at altitudes: oxyhemoglobin saturation between subjects 0, 1400, 3500, with and without periodic breathing 3900, 4200, and 5000 m Patz et al, Observational. 4 N=11 (7 male) Descent to lower altitude was associated Altitude descent 2006 [303] Effect of altitude OSA patients with decrease in AHI 49±11 to 37±11 reduces AHI in OSA

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descent on AHI living at >2400 m, patients residing at in patients with studied at lower altitude OSA than residence altitude, age 55±7 yrs, BMI 33.9±11.3 kg/m2 Ainslie et al, Observations at 4 5 (3 male) healthy CAI increased from 0±0 to 21±23 (p<0.05) Observations on 2007 [304] 1400 m and subjects, age associated changes 3840 m 32±12 yrs, BMI in cerebral blood flow 23±2 kg/m2 Burgess et al, Observational 4 5 (all male) men Obstructive AHI at 60 m, 610 m and 2750 OSA at sea level was 2006 [305] study with with moderate m was 26±14, 17±9, 1±1. Central AHI at 60 replaced by central simulated OSA, age 54±6 m, 610 m and 2750 m was 0±0, 8±6, apnoea at 2750 m.

normobaric yrs, BMI 79±30. Nocturnal SpO2 dropped from hypoxia 29.9±6.7kg/m2 94±1% to 93±1% to 85±4% . at 60 m, 610 m, 2750 m Erba et al, Observational 4 N=21 (18 male) 11 of 21 climbers developed AMS (Lake Volunteers witth 2004 [306] study, ascent healthy climbers, Louise score>=5, AMS+). AMS+ compared acute mountain from <1200 m to age 35±12 yrs, to AMS- had a lower nocturnal in 10 sickness were also 4559 m within < BMI volunteers who remaind free of altitude studied, see below

175

2 24h 23.5±2.1kg/m related illness SpO2 of 59±13% vs. was 73±6%, a higher minute ventilation of 7.94±2.35 l/min vs. 6.06±1.34 l/min. AHI was 60±35 vs 47±43 (NS) Burgess et al, Observational 4 N=14 (8 male) 13 Subjects developed a central sleep 2004 [307] study, ascent healthy adults, apnoea with a rise of CSA-Index from 0.1/h from 0 m to 5050 age 35.8±9.8 yrs, (0.3/h) to 55.7/h (54.4/h) whilst OSA index m within 12 days BMI decreased from 5.5/h (6.9/h) to 0.1/h (0.3/h) 23.2±2.9kg/m2

Nespoulet et Case control 4 N=12 (10 male) mean SpO2 86±2, AHI 33±25 Subjects with AMS al, 2012[300] study subjects healthy were also studied, with (AMS+) and volunteers, age see below without AMS 47±11yrs, BMI (ctrls). 22.3±2.1kg/m2 Spicuzza et al, Case control 4 N=10 male In patients, the mean haematocrit was

2004 [308] study, Andean patients (EE) and 77±1% vs 54±1% in ctrl. Nocturnal SpO2 natives with and N=10 male was lower in patients 80±1% than in ctrl without controls (ctrl), all 83±1%(p<0.05) excessive Andean natives erythropoiesis living at 4380 m, (EE) at 4380 m age 39±3 yrs (EE)

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vs 39±1yrs (ctrl), BMI 23.3±0.2kg/m2vs 23.4±0.8kg/m2

Hernandez- Observational 4 N=23 (12 male) Nocturnal SpO2 of 93% (2%), 7 subjects Zenteno et al, study; healthy subjects, had an AHI > 5/h 2002 [309] residents at residents of 2240 m Mexico City, age 47±16 yrs, weight 68±11 kg, BMI 24.5±2.8kg/m2 Kinsman et al, Observational 4 N=17 cyclists (8 Total AHI at 2650 m in periodic breathers 2002 [310] study; males), age 26±5 48±34 (range 22-96), AHI 2450 m non PB simulated yrs, weight 67±8 2±1 (range 0-5) altitude of 2650 kg m normobaric hypoxic chamber Netzer et al, Observational 4 N=6 (5 male) Obstructive apnoeas and hypopnoeas [311] study; healthy travellers, increased with altitude from 36 to 68, but Ambulatory age 36-62 yrs, also central apnoea increased from 7 to 45. polygraphy at BMI 21-30 kg/m2

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500m, 4200m, 6400 m and 4 weeks after descent Zielinski et al, Observational 4 N=9 (male) No statistically significant difference in 2000 [312] study, ascent to healthy subjects, sleep quality, stage duration or total sleep 3200m, age 20±4 yrs, time. AHI at 760m 3±2, at 3200m 1st night Polysomnograph weight 66±8 kg, 16±21, 6th night 14±24. Arousals and y at 1st and 6th height 173±5 cm, awakenings were doubled at high altitude night at altitude BMI (calculated and PB occurred, mostly during NREM from paper 22.0 sleep. Its intensity remained stable kg/m2) throughout study time. Netzer et al, Observational 4 N=6 (5 male) Obstructive apnoeas and hypopnoeas 1999 [311] study; healthy travellers, increased with altitude from 36 to 68, but Ambulatory age 36-62 yrs, also central apnoea increased from 7 to 45. polygraphy at BMI 21-30 kg/m2 500m, 4200m, 6400 m and 4 weeks after descent Eichenberger Case – ctrl 4 N=21 male Percent of sleep time with periodic

178 et al, 1996 study: healthy subjects, breathing in 8 subjects developing HAPE [313] comparison of age 41±4 yrs (ctrl) 80±5%; in 5 subjects developing AMS subjects vs 36±4 yrs (AMS) 58±7%; in 8 healthy ctrl 57±9% .

developing vs 39±3 yrs The nocturnal SpO2 was 49±3%, 63±3%, HAPE or AMS in (HAPE), 63±4%, respectively 1st night after ascent to 4559 m within 24 h.

Coote et al, Observational 4 N=8 young Hematocrit was 64%, AHI 29±15, SpO2 findings 1993 [314] study; Peruvian 81±5% Residents at highlanders, age 4300 m 21±3 yrs Normand et al, Observational 4 N=6 healthy Sleep organisation was identical at sea The authors suggest

1990 [315] study; lowlanders level and altitude. Periodic breathing that the lung O2 At sea level and occurred in 3/6 subjects at altitude. During uptake during

3800 m periodic breathing, SpO2 oscillated regularly periodic breathing is between 78-90%. preserved. Latshang et al, Randomised 2a N=51 healthy The median (quartiles) AHI at 490 m was Largest randomised 2013 [316] cross-over trial, men, age 24 (20- 4.6/h (2.3-7.9), values at 1630 and 2590m, study on high altitude evaluations at 28)yrs, BMI 18- day 1 and 2, respectively, were 7.0 (4.1- periodic breathing 490, 1630 and 30kg/m2 12.6), 5.4 (3.5-10.5), 13.1 (6.7-32.1), 8.0

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2590 m (4.4-23.1); corresponding values of mean

nocturnal SpO2 were 96% (95-96), 94% (93-95), 94%(93-95), 90%(89-91), 91%(90- 92), p<0.05 vs. 490m, all instances.

Muhm et al, Randomised 2b N=20 male SpO2 at 2438 m 91% and at 305 m 96±2%.

2009 [317] double-blind healthy subjects, During sleep SpO2 at 2438 m 86±2% and at crossover trial; age 44±9 yrs, 305 m 92±2% . ODI at 2438 m was 14 (8- Simulation of weight 83±13 51) and at 305 m 2 (0-9) altitude 2438 m pounds, BMI or 305 m in a 26.1±4.2kg/m2 hypobaric chamber McElroy et al, Randomised 2b N=24 (16 male) Number of apnoea and hypopnoea 2000 [318] double-blind lowland residents overnight at room air was 82±115 and in crossover trial; , age 28 (20-48) enriched room air 32±83.

ascent to yrs The differences in evening – morning SpO2 3800m, oxygen in enriched air vs ambient air was: 2±2% vs enrichment 24% 0±2% Kinsman et al, Randomised 2b N=14 male No significant increase in respiratory 2005 [319] trial; Simulated endurance-trained disturbances altitude of 2650 athletes, age 26±5

180

m yrs. N=7 in the (1) 15 consecutive group successive (age 25±5 yrs, exposure weight 71±10 kg) nights and N=7 in the 3x 5 successive intermittent group exposure nights (age 27±6 yrs, with 2 washout- weight 67±7 kg) nights in- between Barash et al, Randomised, 2b N=12 (8 male) Deep Sleep stages (III and IV) were 17%

Nussbaumer- Randomised, 2b N=34 (32 male) At 490m; median (quartiles) SpO2 94% (93- Demonstrates Ochsner et al, placebo- patients with 95), AHI 51.2/h (31.7-74.4) emergence of central 2010 [321] controlled, diagnosed OSA central/obstructive ratio 0.1. In 1st night at apnoeas/hypopnoeas

double-blind, during CPAP 1860m; SpO2 90% (88-91), AHI 85 (54-94), in OSA patients

181

crossover trial in withdrawal at central/obstructive ratio 0.8. In 2nd night at exposed to hypobaric

OSA patients altitude, , age 62 1860m: SpO2 90% (88-91), AHI 68 (51-96), hypoxia at altitude. discontinuing (57-65) yrs, BMI central/obstructive ratio 1.0. In 1st night at Impaired

CPAP during 33.7 (27.3-38.1) 2590 m; SpO2 86% (84-89), AHI 90 (64- performance in stays at 1860 (2 kg/m2 103), central/obstructive ratio 1.9. In 2nd driving simulator

days) and night at 2590 m; SpO2 87% (84-89), AHI 89 tests at altitude; 2590m (1 day) (62-108) central/obstructive ratio 1.9 elevated blood pressure and cardiac arrhythmias at altitude Kinsman et al, Randomised 2b N=14 male No significant increase in respiratory 2005 [319] trial; Simulated endurance-trained disturbances altitude of 2650 athletes, age 26±5 m yrs. N=7 in the (2) 15 consecutive group successive (age 25±5 yrs, exposure weight 71±10 kg) nights and N=7 in the (3) 3x 5 intermittent group successive (age 27±6 yrs, exposure weight 67±7 kg)

182

nights with 2 washout- nights in- between Barash et al, Randomised, 2b N=12 (8 male) Deep Sleep stages (III and IV) were 17%

2001[320] double blind, healthy subjects , (10%) of the total sleep time with 24% O2 vs crossover study age 30±11 yrs 14% (7%) with ambient air p<0.05 in paired at 3800m 1 night analysis. There were no significant with ambient air differences in sleep quality or AMS. No data or 24% oxygen, on CSA provided. respectively McElroy et al, Randomised 2b N=24 (16 male) Number of apnoea and hypopnoea 2000 [318] double-blind lowland residents overnight at room air was 82±115 and in crossover trial; , age 28 (20-48) enriched room air 32±83.

ascent to yrs The differences in evening – morning SpO2 3800m, oxygen in enriched air vs ambient air was: 2±2% vs enrichment 24% 0±2% Healthy subjects, studies using simulated altitude or weather-related barometric changes Doherty et al, Retrospective 4 N=537 (537 male) CAI is 2±6 No significant 2010 [302] observational patients with correlation among study of changes severe SDB, age AHI and barometric

183

in AHI with 47±14 yrs, weight pressure changes changes in 101 ± 32 kg and barometric BMI 34.0 ± 9.8 pressure due to kg/m2 changes in weather Kinsman et al, Observational 4 N=17 cyclists (8 Total AHI at 2650 m in periodic breathers 2002 [310] study; males), age 26±5 48±34 (range 22-96), AHI 2450 m non PB simulated yrs, weight 67±8 2±1 (range 0-5) altitude of 2650 kg m normobaric hypoxic chamber Otherwise healthy volunteers affected by altitude related illness, studied at real altitude Erba et al, Observational 4 N=21 (18 male) 11 of 21 climbers developed AMS (Lake 2004 [306] study, ascent healthy climbers, Louise score>=5, AMS+). AMS+ compared

from <1200 m to age 35±12 yrs, to AMS- had a lower nocturnal SpO2 of 4559 m within < BMI 59±13% vs. 73±6%, a higher minute 24h 23.5±2.1kg/m2 ventilation of 7.94±2.35 l/min vs. 6.06±1.34 l/min. AHI was 60±35 vs 47±43 (NS) Clarenbach et Case – control 4 N=8 (7 male) Comparison of variables in the last night Development of al, 2012[298] study. HAPE before HAPE occurred or in night 3: all 8 HAPE was preceded

184

Ascent within susceptibles, 10 HAPE susceptible developed HAPE; mean by reduced vital

24h to 4559 m (9 male) healthy nocturnal SpO2 60±8%, AHI 97±45; capacity and diffusing

and stay for 3 ctrls , age 40±9 Healthy ctrls mean nocturnal SpO2 73±3%, capacity during days. yrs (HAPE AHI 48±44 daytime and a low

susceptibles) vs SpO2 and high AHI 32±4 yrs (healthy during the night control group), weight 74±9 kg vs 75±9 kg, BMI 23.8±2.3 kg/m2 vs 23.6±3.0 kg/m2

185

(AMS-). Eichenberger Case – ctrl 4 N=21 male Percent of sleep time with periodic et al, 1996 study: healthy subjects, breathing in 8 subjects developing HAPE [313] comparison of age 41±4 yrs (ctrl) 80±5%; in 5 subjects developing AMS subjects vs 36±4 yrs (AMS) 58±7%; in 8 healthy ctrl 57±9% .

developing vs 39±3 yrs The nocturnal SpO2 was 49±3%, 63±3%, HAPE or AMS in (HAPE), 63±4%, respectively 1st night after ascent to 4559 m within 24 h. Fujimoto et al, Case – ctrl 4 N=5 subjects Periodic breathing in controls was 1989 [322] study; developing HAPE, significantly higher compared to subjects Altitude stay at 5 healthy ctrls developing HAPE. 2760 m – 2920 (anthropometrics Patients with HAPE showed irregular m for 4 days NA) nocturnal breathing patterns. Patients with obstructive sleep apnoea syndrome Pagel et al, Observational 4 N=142 to 150 At 1421 m; 7/150 patients had central At higher altitude, the 2011 [301] study; OSA patients with apnoea index (CAI)>5, there was an increase in central Split – night AHI > 15. At increase in central AHI on CPAP by 5. AHI was greater. design 1421m 95 males, At 1808 m; 34/150 patients had CAI<5, with/without age 58±10 yrs and there was an increase in central AHI on

186

CPAP in OSA BMI 34.98±8 CPAP by 10. patients living at kg/m2. At 1808m, At 2165 m; 48/142 patients had CAI<5, different 100 males, age 55 there was an increase in central AHI on altitudes (1421 ± 10 yrs and BMI CPAP by 19.3. m, 1808 m, 2165 33.34± 6.82 m) kg/m2. At 2165m, 100 males, age 62± 10 yrs and BMI 32.74± 6.63 kg/m2. Burgess et al, Observational 4 5 (all male) men Obstructive AHI at 60 m, 610 m and 2750 OSA at sea level was 2006 [305] study with with moderate m was 26±14, 17±9, 1±1. Central AHI at 60 replaced by central simulated OSA, age 54±6 m, 610 m and 2750 m was 0±0, 8±6, apnoea at 2750 m.

normobaric yrs, BMI 79±30. Nocturnal SpO2 dropped from hypoxia 29.9±6.7kg/m2 94±1% to 93±1% to 85±4% . at 60 m, 610 m, 2750 m Patz et al, Observational. 4 N=11 (7 male) Descent to lower altitude was associated Altitude descent 2006 [303] Effect of altitude OSA patients with decrease in AHI 49±11 to 37±11 reduces AHI in OSA descent on AHI living at >2400 m, patients residing at in patients with studied at lower altitude

187

OSA than residence altitude, age 55±7 yrs, BMI 33.9±11.3 kg/m2

double-blind, during CPAP 1860m; SpO2 90% (88-91), AHI 85 (54-94), in OSA patients crossover trial in withdrawal at central/obstructive ratio 0.8. In 2nd night at exposed to hypobaric

OSA patients altitude, , age 62 1860m: SpO2 90% (88-91), AHI 68 (51-96), hypoxia at altitude. discontinuing (57-65) yrs, BMI central/obstructive ratio 1.0. In 1st night at Impaired

CPAP during 33.7 (27.3-38.1) 2590 m; SpO2 86% (84-89), AHI 90 (64- performance in stays at 1860 (2 kg/m2 103), central/obstructive ratio 1.9. In 2nd driving simulator

days) and night at 2590 m; SpO2 87% (84-89), AHI 89 tests at altitude; 2590m (1 day) (62-108) central/obstructive ratio 1.9 elevated blood pressure and cardiac arrhythmias at altitude

Muhm et al, Randomised 2b N=20 male SpO2 at 2438 m 91% and at 305 m 96±2%.

2009 [317] double-blind healthy subjects, During sleep SpO2 at 2438 m 86±2% and at crossover trial; age 44±9 yrs, 305 m 92±2% . ODI at 2438 m was 14 (8-

188

Simulation of weight 83±13 51) and at 305 m 2 (0-9) altitude 2438 m pounds, BMI or 305 m in a 26.1±4.2kg/m2 hypobaric chamber Hihgland residents

Coote et al, Observational 4 N=8 young Hematocrit was 64%, AHI 29±15, SpO2 findings 1993 [314] study; Peruvian 81±5% Residents at highlanders, age 4300 m 21±3 yrs Spicuzza et al, Case control 4 N=10 male In patients, the mean haematocrit was

189

e2.3.B. CSA at altitude, therapy

Author Design EBM Patient Results Comments population Lovis et al, Randomised 4 N=12 (11 male) Almost exclusively central apnoeas Fitted 500 ml dead 2012 [323] cross-over trial, mountaineers, age observed. For statistical analysis subjects space mask may (split night) At 39±12 yrs, BMI with AHI>30 and AHI<30 were compared. improve nocturnal 3500 m with 25.3±2.3kg/m2 Group AHI>30 (n=5), AHI decreased with breathing in additional 500ml dead space AHI 70±26 to 29±7 mountaineers with respiratory dead Group AHI<30 (n=7) no changes. severe altitude- space or without induced sleep additional dead breathing

190

space disturbances. Plywaczewski Observational 4 N=7 (? male) There were no significant differences in % et al, 1999 study ; healthy miners, of sleep stages and total sleep time. [324] PSG at 760 m, age 25±6yrs Periodic breathing appeared at altitude, at 1st night and receiving there were high differences in individual at 7th night at acetazolamide 3x variabilities in periodic breathing on both 3700m. 0.250 mg/day nights. Time spent with periodic breathing during 2 days was 4-30 minutes during 1st night and 3-17 before ascent and minutes during 2nd night. during 2 days at altitude Lovis et al, Randomised 4 N=12 (11 male) Almost exclusively central apnoeas Fitted 500 ml dead 2012 [323] cross-over trial, mountaineers, age observed. For statistical analysis subjects space mask may (split night) At 39±12 yrs, BMI with AHI>30 and AHI<30 were compared. improve nocturnal 3500 m with 25.3±2.3kg/m2 Group AHI>30 (n=5), AHI decreased with breathing in additional 500ml dead space AHI 70±26 to 29±7 mountaineers with respiratory dead Group AHI<30 (n=7) no changes. severe altitude- space or without induced sleep additional dead breathing space disturbances. Fischer et al, Randomised, 2 N=30 (all male) At 3454 m altitude AHI decreased with

191

2004 [325] placebo healthy subjects theophylline to 3 (0-11), with acetazolamide controlled to 4 (0-19) compared to placebo 16 (2-92).

double-blind Acetazolamide improved mean SpO2 more study. Ascent to than theophylline (86±2%) vs 81±3% 3454m with respectively). either theophylline (2x250mg/d) or acetazolamide (2x250mg/d) , or placebo Nickol et al, Randomised, 2b N=33 (19 male) Time with periodic breathing decreased 2006 [326] placebo- healthy subjects from 16% (0-81) to 9.4% (0-80) of total controlled, (19 first night sleep time with temazepam, no change in double-blind, temazepam), age vigilance during daytime. cross-over study 31 (23-72) yrs, with 10 mg BMI 22.1 (19.7- temazepam vs 28.4) kg/m2 placebo on two successive nights at 5000 m

192

Przybylowski et Randomised 2b N=20 workers Hyperbaric chamber treatment decreased al, 2003 [327] interventional from a gold mine ODI from 10±6 to 2±3; SpO2 84±3% vs trial; (1) at 3800 m 93±3% Simulated descent from 3800 m to 2000 m in hyperbaric chambers. (2) not pressurised

Küpper et al, Randomised 2b N=17 male In group with theophylline (n=9) compared 2008 [328] placebo healthy male to placebo group, AMS score was 1.5±0.5 controlled, subjects (N=9 vs 2.3±2.37 (p<0.001); AHI 34 vs 74 parallel trial; randomised to (p<0.05), ODI 62 vs 121 (p<0.01). 300mg theophylline and theophylline or N=8 males in the placebo during 5 placebo group), days prior age 36 yrs and 32 ascent to 4559m yrs respectively.

193

Beaumont et Randomised, 2b N=12 (all male) Zolpidem and zaleplon improved slow wave al, 2004 [329] placebo- healthy subjects , sleep at altitude controlled, age 30±3 yrs, double-blind trial weight 73±9 kg, of effect of 10mg BMI 23.4±2.6 zolpidem or kg/m2 10mg zaleplon 15 min at simulated altitude of 4000m (3 nights) Dubowitz et al, Randomised 2b N=11 Subjective improvement of sleep quality, 1998 [330] placebo- mountaineers, no but no effect on mean oxygen saturation

controlled characteristics (SpO2 75% vs SpO2 76% p=0.54) double-blind reported. crossover trial of temazepam 10mg at 5300m Beaumont et Randomised, 2 N=8 (all male) Zolpidem decreased sleep onset latency to al, 1996 [331] placebo- healthy subjects, 10±6min vs placebo (22±12min). It controlled age 38±6 yrs, BMI increased slow wave sleep duration to

194

double-blind, 26±3 kg/m2 69±28min vs 46±28min and reduced the crossover study arousal index during slow wave sleep to with zolpidem 2±1/h vs 7±4/h. 10 mg at simulated altitude of 4000m (2 nights), hypobaric chamber

Nussbaumer- Randomised, 2b N=21 HAPE In group A, n=9, nocturnal SpO2, night 1 Data suggest that Ochsner et al, placebo- susceptibles and 3 at 4559 m was median (quartiles) prophylaxis with 2012 [332] controlled, subjects: N=12 78% (77-80) vs 79% (76-82) and AHI 85 dexamethasone double-blind, males (dex-late) (53-86) vs 52 (18-70). before ascent or one parallel trial vs 9 males (dex- In group B, n=12, in night 1 and 3 at 4559 day after reaching

comparing: A) early), age 46 (40- m SpO2 was 71% (69-73) and 80% (75-82) 4559 m improved dexamethasone 53) yrs vs 49 (46- and AHI 91 (20-143) vs 10 (1-32). nocturnal 2x8 mg/d taken 56) yrs, BMI 23 oxygenation and 24 h prior to (22.1-23.6) breathing ascent and kg/m2vs 23.9 disturbances during 3 days at (22.1-27.8) kg/m2

195

4559 m vs. B) placebo 24 h prior to ascent and in the first day at 4559 m, followed by dexamethasone (2x8 mg/d) during days 2 to 3 at 4559 m.

Latshang et al, Randomised, 1b N=51 (48 male) Nocturnal SpO2 with CPAP and The results suggest 2012 [333] placebo- OSA patients acetazolamide compared to CPAP and that patients with controlled, living below 800 placebo: medians (quartiles): at 1630 m OSA, living at low double blind m, on long-term 94% (93-95) vs 91% (90-92); at 2590 m altitude (<800 m), cross-over trial. CPAP therapy, 93% (92-94) vs 89% (87-91). AHI with may benefit from 2x3 days at age 63 (59-66) CPAP and acetazolamide vs CPAP and acetazolamide in 1630 and 2590 yrs, BMI 33.0 placebo: addition to using m, once with (30.1-35.8) kg/m2 at 1630 m 6 (3-10) vs 7 (4-10); at 2590 m autoCPAP during an CPAP and 11 (5-18) vs 19 (9-29) altitude sejourn. acetazolamide (250/0/500 mg

196

per day), once with CPAP and placebo

Otherwise healthy volunteers affected by altitude related illness, studied at real altitude

197

followed by dexamethasone (2x8 mg/d) during days 2 to 3 at 4559 m. Patients with obstrucctive sleep apnoea syndrome

Nussbaumer- Randomised, 1b N=45 (42 male) Nocturnal SpO2 with acetazolamide

198

Ochsner et al, placebo- OSA patients, compared to placebo: medians (quartiles): 2012 [334] controlled, living below 800 at 1630 m 94% (93-95) vs 91% (90-92); at double blind m, discontinuing 2590 m 93% (92-94) vs 89% (87-91). AHI cross-over trial. CPAP during a with CPAP and acetazolamide vs CPAP 2x3 days at stay at altitude, and placebo: 1630 and 2590 age 64 (58-66) At 1630 m 5.8 (3-10) vs 7 (4-10); at 2590 m m, once with yrs, BMI 31.7 11 (5-18) vs 19 (9-29) acetazolamide (28.0-36.1) kg/m2 (2x250 mg per day), once with placebo [328] [326] Highland residents Richalet et a., Randomised, 2b N=30 patients with In patients with chronic mountain sickness, 2005[335] placebo- chronic mountain long-term therapy with acetazolamide (250 controlled sickness andN=10 mg/d or 500 mg/d) decreased AHI. double-blind (all male) healthy Haematocrit also decreased by 7% and 7% study with 250 subjects (CMS mg/d, 500 mg/d placebo group- acetazolamide patients: , age

199

(ACZ) or 44±9 yrs, weight placebo at 63±3 kg, height 4300m for 3 1.58±0.05 m; weeks CMS 250 mg ACZ (N=10), age 43±9 yrs, weight 65±9 kg, height 1.62±0.08 m; CMS 500 mg ACZ (N=10), age 41±6yrs, weight 67±10kg, height 1.60±0.05m [327] [329] [325] [324] [330] [331]

Tables of Chapter 2.4. CSA in cardiovascular diseases 200 e2.4.1.A. CSA in Heart Failure

Author Design EBM Patient population Results Comments Prevalence of CSA in Patients with HFrEF Javaheri et al, Single centre 4 N=100 (all male), age and 37% had CSA Minority of patients 2006 [336] prospective case BMI not reported 12% had OSA received beta- series Consecutive stable HF from a (PSG: AHI≥15/h) blocker treatment HF clinic, LVEF<45%,

10% beta-blocker use 0% spironolactone use Sin et al, 1999 Single centre 4 N=450 (382 male) stable HF 29% had CSA None of the [337] retrospective case referred to a sleep lab, 32% had OSA patients received series women: age 60±14 yrs, BMI (PSG: AHI≥15/h) beta-blocker 29.3±7.0 kg/m2, LVEF treatment 30±18% men: age 60±13 yrs, BMI 28.8±6.5 kg/m2, LVEF 27±15%

0% beta-blocker use

201

0% spironolactone use Solin et al, 1999 Single centre 4 N=75 (61 male), age 53 yrs, 32% had CSA [338] prospective case BMI 26.6 kg/m2 11% had OSA series (PSG: AHI≥15/h) Consecutive stable HF from a HF clinic, LVEF<40% Yumino et al, 2009 Single centre 4 N=218 (168 males), age 21% had CSA Between 1997 and [339] prospective case 56±13 yrs, BMI 29.2±5.3 26% had OSA 2004, the series kg/m2 (PSG: AHI≥15/h) prevalence of OSA consecutive stable HF from a and CSA did not HF clinic, LVEF<45%, change significantly 75% beta-blocker use despite significant 21% spironolactone use changes in cardiac medication Prevalence of CSA in Patients with HFpEF Chan J et al, 1997 Single centre 4 N=20 (7 males), age 64±7 20% had CSA (50% First study on this [340] prospective case yrs, BMI 28.3±4.0 kg/m2 CSR) subject series 35% had OSA Outpatients with symptomatic (PSG: AHI >10) HF(NYHA class II or III) and isolated diastolic dysfunction

202

on echocardiography 85% diagnosis of hypertension Bitter T et al, Single centre- 4 N=244 (157 males), age 64±4 29.5% had CSA Large, well defined 2009 [341] prospective case yrs, BMI 27.5±2.5 kg/m2 39.8% had OSA single centre series (PSG: AHI > 5/h) cohort. Selection Consecutive stable HF Increase in proportion of bias towards SDB patients from a HF clinic CSA with increasing HFpEF defined according to impairment of diastolic guidelines function and hemodynamic 85% diagnosis of parameters hypertension

Herrscher TE et al, Single centre 4 N=44 (31 males), age 63±10 18 % had CSA Higher prevalence 2011 [342] prospective case yrs, BMI 30.4±5.5 kg/m2 . 62 % had OSA of OSA likely series (PSG: AHI > 5/h) related to higher Stable HF outpatients from a BMI HF clinic

59% diagnosis of

203

hypertension

Sekizuka H et al, Single centre 4 N=19 (10 males), age 70±11 26% had CSA 2013 [343] prospective case yrs, BMI 23.8±4.3 kg/m2 11% had OSA series (PSG: AHI > 15/h) Consecutive patients with de novo HF

74% diagnosis of hypertension

Wachter R et al, Multicentre 4 N=352 (170 males), <4 % had CSA Well defined 2013 [344] prospective age 67±9 yrs, BMI 29±6kg/m2 21 % had OSA epidemiologic longitudinal study (PSG: AHI > 15/h) cohort with low risk (DIAST-CHF) Patients with at least one risk OSA independently of selection bias factor for diastolic dysfunction associated with diastolic dysfunction Shah et al, Single centre 4 N=403 (290 males), age 57 19% had SDB (not Likely more OSA 2014 [345] observational study (median IQR 49-64) yrs, BMI reported OSA or CSA) than CSA patients 28.7 (median IQR 25.7-31.8) LV mass and LV mass- included.

204

kg/m2 to-volume ratio higher in SA and BMI were patients with SA related to outcome Patients with either SA independently paroxysmal or persistent associated with clinical atrial fibrillation undergoing outcome ( all-cause ablation of pulmonary veins mortality/HF Mean follow-up3.3±1.5 yrs hospitalisation) in a multivariate model including diabetes, hypertension and history of HF (HR 2.14, p=0.02) Prognostic significance of CSA in patients with HFrEF Andreas et al, Single centre 4 N=36 (31 males), Follow-up 11-53 M CSR evaluated 1996 [346] observational study age 54±12 yrs, BMI 25±4 CSR (>20% of sleep also during daytime kg/m2 time) was not associated and considered to Outcome: with increased death + be present if there death+heart HF patients from a HF clinic. HTx rate were regular cycles transplantation 86% male, LVEF 20%, of increasing and (HTx) beta-blocker use not reported decreasing air flow with apnoeas during a 10 minute

205

recording of ventilation in a seated position. Daytime CSR associated with increased likelihood of death Hanly et al, 1996 Single centre 4 N=16 (all males), age 64±8 9 had CSR (not defined) [347] observational study yrs in CSR, BMI 28.1±3.5 7 had no CSR kg/m2 in CSR Follow-up 3-5 yrs Outcome: CSR: 5 deaths + 2 HTx death+HTx Male HF patients from a HF No CSR: 1 death + 0 HTx clinic. LVEF 23%, NYHA III and IV beta-blocker use not reported

Kreuz et al, 2013 Prospective 2b N=133 consecutive patients Median follow = 24±8 M. [348] observational study with HFrEF Appropriate ICD therapy 54% in SDB vs 34% in N=82 SDB defined as AHI > noSDB (p=0.03). 10 (gender not reported), age AHI>10 was the only

206

63±11yrs, BMI 29.1±1.4 independent predictor of kg/m2 appropriate ICD therapy N = 51 without SDB, age (OR 2.5, 95% CI 1.8- 61±12 yrs, BMI 24.7±2.1 4.04, p=0.01). kg/m2 Inappropriate ICD therapy also more frequent in SDB (mainly atrial fibrillation). Lanfranchi et al, Single 2c N=62 (54 males), Mean follow-up: 28±13 M 1999 [349] centreobservational age 57±9 yrs, BMI not 15 cardiovascular deaths study reported occurred. CSA with AHI≥30 was an Outcome: HF patients from a HF clinic. independent risk factor cardiovascular LVEF 23%, NYHA II and III for cardiovascular death death Beta-blocker use not reported

Sin et al, 2000 Single centre 2c N=66 (58 males), Median follow-up: 2 yrs [350] observational study age 58±10 yrs in CSA vs No CSA (AHI≥15): 60±11 yrs in no CSA, BMI not 32% events. Outcome: reported CSA (AHI≥15): death+HTx stable HF patients, 48% events, relative risk,

207

LVEF 22%, NYHA II and III 2.53; 95% CI, 1.08 to 21% beta-blocker use 5.94; p=0.032

Roebuck et al, Single centre 2c N=78 (64 males), age 53±9 Median follow-up: 52 M. Included patients 2004 [351] observational study yrs, BMI 26.8±3.7 kg/m2 Survival no CSA (AHI<5, treated for CSA. <10, <15 and <20) versus Results adjusted Outcome: death HF patients from HTx unit, CSA (AHI≥5, ≥10, ≥15, for CSA treatment. LVEF 20%, NYHA II, III and ≥20), respecively: no IV significant differencence 14% beta-blocker use (p>0.05 for all comparisons, adjusted)

Corrà et al, 2006 Single centre 2c N=133 (125 males), Median follow-up: 47 M. [352] observational study age 58±10 yrs, BMI not Outcome severe SDB reported (AHI≥30) and exertional Outcome oscillatory ventilation death+HTx Stable HF patients from a versus no SDB heart failure clinic, (AHI<30)/no exertional LVEF 23%, NYHA 2 oscillatory ventilation: HR 53% beta-blocker use 6.65, 95%CI 2.6-17.1 (p<0.01 adjusted for

208

significant confounders)

Javaheri et al, Single centre 2c N=88 (all males), age 67±9 Median follow-up: 51 M 2007 [353] observational study yrs in CSA vs 62±12 yrs in no Survival CSA (AHI≥5) CSA, BMI 26±4 kg/m2 in CSA versus no CSA (AHI<5) Outcome: death vs 28±5 kg/m2 in no CSA versus: HR 2.1, p=0.02 (adjusted) Stable HF patients, LVEF 24%, NYHA II and III 10% beta-blocker use

Jilek et al, 2011 Single centre 2c N=296 (257 males), age 65±9 Median follow-up: 49 M. Contemporary [354] observational study yrs in CSA vs 59±11 yrs in no Mortality rates severe heart failure CSA, BMI 30.3±5.6 kg/m2 in CSA (AHI≥22.5) versus treatment Outcome: death CSA vs 27.9±4.4 kg/m2 in no mild CSA (AHI<23): 38 vs CSA 16, unadjusted p=0.002, Stable HF patients adjusted for significant LVEF 33%, NYHA II and III confounders p=0.035. 89% beta-blocker use

Damy et al, 2012 Single centre 2c N=384 (315 males), age Median follow-up: 47 M. Contemporary

209

[355] observational study 59±13 yrs, BMI 28±5 kg/m2 Outcome severe CSA heart failure (AHI≥20) versus mild treatment Outcome: death + Stable HF patients, CSA (AHI<20): HR 1.61, HTx + Implantation LVEF 33%, 95%CI 1.16-2.25 of ventricular assist 46% NYHA 3-4 (p=0.018 adjusted for device 80% beta-blocker use significant confounders)

Bitter et al, 2011 Observational study 2c N=255 (195 male) HF Median follow-up: 48 In HF patients [356] patients with SDB 6 months months. higher risk for Outcome: malignant after implantation of a CRT CSA (AHI >15/h) was an appropriate ICD ventricular device with ICD, age 68 yrs in independent risk factor therapies in CSA arrhythmogenic SDB vs 66 yrs in no SDB, for appropriate ICD than OSA events BMI 27 kg/m2 in SDB vs 25 therapies: kg/m2 in no SDB CSA HR (95%CI): 3.41 (2.10-5.54), p<0.001 OSA HR (95%CI): 2.10 (1.17-3.78), p=0.01 Khayat et al, 2012 Prospective 2c N=784 consecutive Rate ratio for 6 M cardiac [357] observational cohort hospitalised patients with readmission in CSA study HFrEF compared to no SDB

210

patients = 1.53 (95% CI N=165 (137 male) CSA, age 1.1-2.2, p=0.03) Outcome: 6 M 60±15 yrs, BMI 28.4±6.2 Adjustment variables = readmission rate for kg/m2 LVEF, type of cardiac causes N=480 (347 male) OSA, age cardiomyopathy, age, 59±13 yrs, BMI 31,2±7,8 weight, sex, diabetes, kg/m2 coronary disease, length N=139 (70 male) without of stay, admission SDB, age 54±16 yrs, BMI sodium, haemoglobin, 29.8±10.4 kg/m2 blood pressure, discharge medications

Effects of HF treatment on CSA Solin et al, 1999 Single centre 4 N=7 patients with elevated Reduction in PCWP (29 [338] prospective case PCWP out of 75 (61 male) [20 to 38] to 22 [17 to 27] series patients undergoing right mm Hg) and central AHI Intervention: heart catheterisation, age 53 (39 [7 to 62] to 19 [1 to Medical HF yrs, BMI 26.6 kg/m2 31]/h treatment

Consecutive stable HF from a

211

HF clinic, LVEF<40%

Sinha et al, 2004 Single centre 4 N=14 (12 males), age 65±11 AHI before and after CRT [358] prospective case yrs, BMI 24.6±3.3 kg/m2 implantation: 19±10 to series 5±4. Intervention : CRT Consecutive HF patients with LVEF before and after CSA undergoing CRT CRT implantation: 24±6 implantation to 34±10 %.

Mansfield et al, Single centre 4 N=13 (all male) CSA, age CSA group, N=13: AHI CSA may persist 2003 [359] prospective case 54±9 yrs, BMI 26.2±3.7 kg/m2 28±15 before HTx to for >6 M after series N=9 (5 males) without SDB, 7±4.6/hour. successful HTx Intervention: HTx age 44±10 yrs, BMI 25.5±3.5 LVEF 19±9 to 54±6%. kg/m2 After HTx: N=6 no SDB, N=3 persistant mild CSA, Consecutive HF patients N=4 acquired mild OSA. undergoing HTx

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Treatment of CSA with respiratory stimulants

Szollosi et al, 2004 Observational, open 4 N=10 men, CSA (7 with Inhalation of CO2: During established [360] label chronic HF and 3 with reduced AHI (7412 to stage 2 sleep, the

idiopathic CSA), age 62±8 268) end-tidal CO2 was 2 Intervention: CO2 yrs, BMI 25.1±3.3 kg/m AI did not change raised by 2-4mm inhalation compared to room air Hg and was breathing (p=0.264) maintained for 10 minutes. Each intervention was separated by at least 10 minutes of room air breathing. Thomas et al, Open-label proof-of- 4 N=6 men, age 546 yrs, Baseline RDI: PSG titration with 2005 [361] concept severe poorly controlled 6615, Baseline nadir end-tidal and

mixed SDB (absence of renal SaO2: 8510 % transcutaneous

or HF). Intervention: CPAP+ RDI on best treatment: CO2 monitoring.

CO2 439. Immediate (<1 minute) response RDI post CPAP + CO2 intervention was in the to addition of 0.5% normal range (<5). to 1% CO2 and

213

minimal additional changes required throughout the night. Javaheri et al, Randomised, 2b N=15 (all male) patients with On theophylline 1996 [362] double blind, HFrEF, age and BMInot AHI central: from 26±20 placebo-controlled, reported to 5±5 (p <0.001) cross-over study with one week wash-out Intervention: theophylline or placebo twice daily for 5 days

Andreas et al, Single-blinded, 2b Congestive HF: Controls: Subjects studied in 2004 [363] randomised, N=22 (20 male) congestive Theophylline increased the morning, supine placebo-controlled HF patients muscle sympathetic position, 2 hours Theophylline group: age 53±4 nerve activity and after a low-calorie Intervention: yrs, BMI 25.9±0.9 kg/m2 lowered transcutaneous breakfast free of

theophylline or Placebo group: age 51±4 yrs, CO2 caffeine. Placebo

214

placebo BMI 26.1±0.9 kg/m2 or theophylline HF: infusion began after Controls: Lowered transcutaneous 10-min baseline

N=22 (20 male) CO2 only recording, loading dose of 5 mg/kg Patients were closely Controls + HF: over a period of 20 matched with healthy controls Theophylline nearly mins followed by for age, sex and BMI. doubled plasma renin continuous dose of Randomised into 2 groups: concentration (ctrl 0.5mg kg-1 h-1 over theophylline or placebo. At p<0.01; HF p<0.02) period of 10 mins baseline, HF patients had and a 15-min higher muscle sympathetic period without drug nerve activity (MSNA) infusion. compared with the healthy ctrl subjects.

Javaheri et al, RCT, double blind, 2b N=12 (all male) patients with Compared to placebo Sleep parameters 2006 [364] cross-over stable HF acetazolamide decreased not different at CSA (4928 vs. 2321) baseline vs.

Intervention: 1 week acetazolamide vs. 1 and % TST SaO2<90% placebo. Acetazolamide vs week placebo, 2 week wash- (1932 vs. 613)

215

placebo out, Acetazolamide also age 66±6 yrs, improved several BMI 26±4 kg/m2, subjective LVEF 19±6 % measures of sleep quality and fatigue

Treatment of CSA with oxygen Staniforth et al, Single centre 4 N=11 (all male)consecutive Central AHI: from 13 to 4, 1998 [365] double blind cross- HFrEF patients with CSA, 70% reduction. over study age 68±7 yrs, BMI 25±3 Urinary norepinephrine: Intervention: 2l kg/m2 from 8.3 to 4.1

O2/min for 4 weeks nmol/mmol. No improvement in symptoms and cognitive function.

Zhang et al, 2006 Single centre 4 N=14 consecutive HFrEF O2: AHI: from 35 to 28, [366] prospective cross- patients with CSA. 20 % reduction. over trial Gender, age and BMI not LVEF: from 30 to 33 % Intervention: 2l available (p>0.05).

O2/min for 12 weeks versus ASV

216

Shigemitsu et al. Single centre 4 N=18 out of 23 (19 male), AHI: from 34 to 6/h, 2007 [367] prospective trial age 65±12 yrs, BMI 25.9±3.6 82% reduction. 2 Intervention 2-3l O2 kg/m LVEF: from 45 to 46% for 16 weeks (p>0.05). Consecutive HF patients with LVEF<50% (N=11 ischemic/non-ischemic cardiomyopathy, N=7 acute myocardial infarction) and CSA (AHI≥ 20)

Toyama et al, Prospective 4 N=20 (19 male), age 65±10 AHI: from 26 to 5/h, 2009 [368] controlled trial yrs, BMInot reported 81% reduction.

Intervention: 3l Peak VO2: from 16 to 18

O2/min for 12 weeks Consecutive HFrEF patients ml/kg/min.

versus no O2 with CSA LVEF: from 27 to 37% (p<0.05).

Bordier et al, 2015 Randomised, open 4 30 consecutive patients with In NOT group [369] label, single-centre CSA and HFrEF Central AHI from 23±3 to study 8±2 at 24 h (p<0.0001)

217

N=16 (male) NOT, and to 6±1 at 6 M age 67±17yrs, BMI 28.5±2.6 (p<0.0001). Intervention: kg/m2 NOT no effect on quality nocturnal oxygen N=14 (13 male) noNOT, age of life, NYHA class, and therapy (NOT) 3.0 71±16 yrs, BMI 29.6±6.1 LVEF. l/min for 6 m kg/m2

Nakao et al, 2014 Post-hoc analysis of 4 97 (80 male) patients with In O2 treated patients vs [370] two trials CSA and HFrEF control: AHI from 20±12 to 9±11

Intervention: N=45 (36 male) O2, age vs 20±11 to 19±12,

nocturnal O2 65±11 yrs, BMI not reported p<0.01 therapy 3l/min for N=52 (44 male) ctrls, age LVEF from 34±10 to 12 weeks 66±12 yrs, BMI not reported 39±14 vs 32±8 to 34±10%, p=0.06 Specific Actvity Scale from 3.9±1.2 to 4.7±1.5 vs 4.1±1.1 to 4.1±1.2 METS, p<0.01. No effect on VA in the whole groups.

218

In severe patients (NYHA >3, AHI > 20) improvement in arrhythmia pattern in oxygen group.

Andreas et al, Single centre 2b N=22 (21 males), age 59 yrs AHI: from 26 to 10, 1996 [371] double blind RCT (range 28-71), BMI 24,9±4,2 62% reduction. 2 Intervention: 4l kg/m Peak VO2: from 835 to

O2/min for 1 week 960 ml/min. Consecutive HFrEF patients Improvement in cognitive with CSA function.

Teschler et al, Single centre RCT 2b N=14 (all male) stable After 1 night of treatment. PSG was 2001 [372] Interventions for 1 HFREF patients with CSA. Untreated AHI: 453 performed and 10

night each: age 69±6 yrs, BMI 28.9±3.3 O2 AHI : 283 of 14 had 2 1) untreated CSA kg/m CPAP AHI : 275 transcutaneous 2) O2 Bilevel AHI: 152 PCO2 measured. 3) CPAP 1 night of ASV ASV AHI: 61 4) bilevel PAP suppresses CSA in

5) Adaptive servo- HFrEF and Untreated AI: 654

219

ventilation (ASV) Oxygen AI: 303 improves sleep CPAP AI : 303 quality more than Bilevel AI : 161 CPAP or 2L/min ASV AI : 152 O2. ASV : Large increases in SWS and REM, preferred Bilevel did not to CPAP. increase PaCO2 in hypocapnic HFrEF patients Arzt et al, 2005 Prospective 2b N=26 (all male) consecutive After 12 weeks: Symptom-limited [373] controlled trial stable patients with chronic CPAP treatment: cardiopulmonary

Interventions : HF and CSA reduced VE/VCO2-slope exercise testing

Nocturnal O2 in the First 10 screened received (31.21.6 vs. 26.21.0 was performed on

first 10 patients nocturnal O2 treatment, L/min/kPa), improved a cycle ergometer. screened remaining 16 received LVEF (323 vs. 363%), Expiratory gas Nocturnal CPAP in nocturnal CPAP reduced AHI (364 vs. analysed breath by the remaining 16 124) breath Oxygen therapy: O treatment (N=10), age 2 reduced AHI (293 vs. 65±2 yrs, BMI 28.4±1.4 kg/m2 94).

Exercise capacity, LVEF

220

CPAP treatment (N=16), age and VE/VCO2-slope did 64±2 yrs, BMI 30.6±1.7 kg/m2 not change

Hu et al, 2006 Prospective, 2b N=11 (all male) stable, Compared to untreated [374] randomised, cross- optimally treated chronic HF (ctrl) night (AHI 318). over, non-blinded patients with CSR AHI decreased to:

Interventions: age 64 ± 7yrs, BMI 21.1±3.8 nasal O2 247 2 nasal oxygen kg/m CPAP 195 CPAP HFJV 204 BiPAP BiPAP 144 HFJV

In random order Sasayama et al, RCT, parallel design 2b N=56 (47 male) HF patients After 12 weeks: Improved Control group 2006 [375] with CSA/CSR. BMInot SDB, LV function and consisted of Intervention : reported QOL “normal breathing”

nocturnal O2 Improved Specific

25 (20 male) received Nocturnal O2: Activity Scale (4.0

nocturnal O2, AHI from 2111 to 1012. 1.2 to 5.0 1.5 age 6412 yrs ODI from 20±10 to 69. Mets) and QOL in

LVEF from 35±10 % to the nocturnal O2

221

31 (27 male) controls, 38±14 %. group age 64±10 yrs Ctrl: AHI from 18±11 to 17±11. ODI from 16±11 to 17±11. LVEF from 33±9 % to 34±11 %. Sasayama et al, RCT 2b N=51 consecutive HFrEF AHI: from 19 to 9/h, 2009 [376] Intervention: 3l patients with CSA 53% reduction.

O2/min for 52 weeks of whom LVEF: from 33 to 38% , p

versus no O2 25 (21 male) assigned to O2, <0.05 (no change in ctrl age 67±10 yrs, BMInot group). reported BNP: from 493 to 556 pg/m (p>0.05). QOL: from 3.9±1.2 to 4.7±1.6 specific activity scale, p<0.01. Effects of CPAP on CSA and HFrEF Takasaki et al, Open label, proof- 4 N=5 (all males), age 60±7 AHI: from 60 to 9. 1989 [377] of-concept study yrs, BMI 31±7 kg/m2 85% reduction

222

single night baseline LVEF 31 to 38%. vs. CPAP HFrEF and CSR

Davies et al, 1993 Open label, 2 week 4 N=8 (all males), age, BMInot No change in overnight 4 2 patients withdrew

[378] trial of CPAP vs. reported % SaO2 dips. as HF got worse baseline HFrEF and CSA

Naughton et al, 1 M CPAP vs. 4 N=12 (all male) consecutive AHI from 59 to 23, 1994 [379] baseline patients, age 56±3 yrs, BMI 61% reduction. 26±1 kg/m2

vs. 6 (all male) ctrl (no Overnight PCO2 CPAP), age 58±4 yrs, BMI increased by 6 mmHg. 27±2 kg/m2

HFrEF with CSA

Javaheri et al, Single night 4 N=29 male patients with HF Among CSA, 55% of 2000 [380] prospective study and CSA (N=21), age 66±9 patients studied were baseline vs. CPAP yrs, BMI 28±5 kg/m2 or responders. Decrease of OSA (N=8), AHI>15, age AHI from 36 to 4 (no

223

61±10 yrs, BMI 36±8 kg/m2 change in remaining patients). Nocturnal premature ventricular contractions and couplets decreased in the CPAP responders. Yasuma et al, Baseline vs. 1 year 4 N=5, age 75±15 yrs AHI: from 35 to 1 2005 [381] follow-up post LVEF from 24 to 32 %. CPAP CHF and CSA Schroll et al, 2014 Multicentre, open 4 N=37 (34 male) patients with No change in blood CPAP does not [382] label SDB and HFrEF, age 65±10 pressure, heart rate and cause yrs, BMI 28.9±4.3 kg/m2 cardiac output with hemodynamic Intervention: allocated to CPAP therapy as incremental CPAP. compromise in the incremental CPAP part of a RCT No differences in vast majority of

(4-10 cm H2O) maximum blood pressure patients with HFrEF application in awake Blood pressure and heart rate drop or heart rate drop condition assessed after each 1 cm between patients in sinus

H2O CPAP increase in 5 min rhythm and atrial intervals fibrillation. Cardiac output assessed in 11 patients

224

Naughton et al, RCT 2b N=24 HF and CSA/CSR, NCPAP vs control: Follow up 3M 1995 [383] receiving optimal medical Improvements in LVEF LVEF primary therapy. Randomly assigned (7.72.5 % vs -0.51.5 outcome measure to 2 groups: control (N=12 %) and AHI male), age 57±3 yrs, BMI (-28.53.9/h vs - 2 27.1±1.5 kg/m or nightly 6.17.0/h). NCPAP N=12 (male), age Fatigue and disease 2 61±3 yrs, BMI 26±2 kg/m mastery symptoms both improved (5.61.2 vs

0.80.7; 3.61.1 vs - 0.70.7, respectively). Naughton et al, RCT 2b N=35 (all male) stable HF, CSA/CSR vs. NON- Overnight sleep 1995 [384] chronic dyspnoea and CSA/CSR group: study CSA/CSR LVEF<45% (18 with LVEF was similar during stage 2 CSA/CSA and 17 without). Overnight urinary sleep. Patients with CSA/CSR, age norepinephrine (UNE) Follow up of 60±1 yrs, BMI 25.8±1.0 and awake plasma CSA/CSR patients kg/m2 were randomised into 2 norepinephrine (PNE) 1 M. groups: control (N=9) or concentrations were nightly NCPAP (N=9). greater in CSA/CSR-

225

group (30.22.5 nmol/mmol creatinine and 3.320.29 nmol/L) than Non-CSA/CSR group (15.82.1 nmol/mmol creatinine, and 2.060.56 nmol/L). After 1M : NCPAP group vs ctrl group: CSA/CSR attenuated in NCPAP but not in ctrl Greater reductions in UNE and PNE concentrations for NCPAP (-12.53.3 nmol/mmol creatinine and -0.740.40 nmol/L) vs control (-1.32.8 nmol/mmol creatinine, and 1.160.66nmol/L).

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Granton et al, RCT 2b N=17 (all male) stable HF NCPAP group: Follow up 3 M 1996 [385] patients, continued dyspnoea, MIP increased

a LVEF <45% at rest and (798 to 9110 cmH2O) CSA/CSR. LVEF increased Randomised into 2 groups: (244 to 337 %) Ctrl (N=8) age 58±2 yrs, BMI Symptoms of dyspnoea 2 25.4±1.8 kg/m and fatigue were or NCPAP (N=9), age 59±2 alleviated. 2 yrs, BMI 28.9±1.9 kg/m MEP did not change. AHI decreased (4911/h to 177/h)

Mean nadir SaO2 increased (881 to 931%) Ctrl group: no significant changes Tkacova et al, RCT 2b N=17 (all male) chronic HF After 3 M: Baseline 1997 [386] and CSA/CSR randomised to CPAP group: assessments of nocturnal CPAP + optimal LVEF increased (204 to plasma ANP medical therapy (N=9, male), 285 %) concentration and age 61±2 yrs, BMI 28.8±1.8 Mitral regurgitation Flow LVEF and MRF by

227

kg/m2 or optimal medical (MRF) decreased (338 radionuclide therapy alone (N=8, male), to 196) angiography age 59±2 yrs, BMI 25.1±1.8 Plasma atrial natriuretic 2 kg/m peptide (ANP) concentration decreased (14121 to 10417 pg/ml)

Control group : No significant changes in LVEF, MRF or plasma ANP concentration

Change in plasma ANP concentration from baseline to 3 M correlated with the change in MRF (r=0.789).

Sin et al, 2000 RCT 2b N=66 chronic HF (29 with and After 3 M: Stratified analysis [350] 37 without CSA/CSR). All patients on CPAP: was used to Patients (male) with no change in LVEF compare patients

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CSA/CSR, age 60±10 yrs, At 2.2 yrs (median) with and without BMI not reported follow-up, all patients on CSA/CSR. CPAP CPAP: not no significant Randomised into 2 groups: 60% relative risk effect on either CPAP (N=14) or control reduction (95% CI, 2% to LVEF or mortality- (N=15) 64%) in mortality-cardiac cardiac transplantation rate transplantation rate After 3M CSR-CSA for patients without patients on CPAP: CSA/CSR. Significant improvement in LVEF. After 2 yrs (median), CSA/CSR patients on CPAP: 81% relative risk reduction (95% CI, 26% to 95%) in mortality- cardiac transplantation rate. Teschler et al, Single centre RCT 2b N=14 (all male) stable HFrEF After 1 night/ treatment. PSG was 2001 [372] Interventions for 1 patients with CSA. Untreated AHI: 453 performed and 10

229

night each: age 69±6 yrs, BMI 28.9±3.3 O2 AHI : 283 of 14 had 2 1) untreated CSA kg/m CPAP AHI : 275 transcutaneous

2) O2 Bilevel AHI: 152 PCO2 measured. 3) CPAP ASV AHI: 61 1 night of ASV 4) bilevel PAP suppresses CSA in 5) Adaptive servo- HFrEF and Untreated AI: 654 ventilation (ASV) improves sleep Oxygen AI: 303 quality more than CPAP AI : 303 CPAP or 2 L/min Bilevel AI : 161 O2. ASV AI : 152

ASV : Large increases in Bilevel did not SWS and REM, preferred increase PaCO2 in to CPAP. hypocapnic HFrEF patients Krachman et al, Prospective 2b N=9 (all male) CHF, mean Nasal CPAP: All patients had 2003 [387] controlled trial LVEF of 164% and CSR. Decreased AHI (4427 to initial baseline Age 598 yrs, BMI 28±6 1524), decreased PSG, a repeat PSG 2 with nCPAP kg/m dSaO2/dt (0.420.15 to . 0.200.07), increased (90.3cmH2O) plus echocardiography postapnoeic SaO2 (875

230

to 914%). and right-heart

Preapnoeic SaO2 was not catheterisation different (p=0.8) nor was within 1 M. apnoea duration and Correlation heart rate. between baseline

postapnoeic SaO2

and dSaO2/dt (r=0.8), but no correlation between baseline

preapnoeic SaO2

and dSaO2/dt (r=0.1, p=0.7). Baseline dSaO2)/dt and the AHI correlated (r=0.1). With CPAP,

dSaO2/dt and AHI (R=0.7, p=0.04),

but dSaO2/dt and postapnoeic

231

SaO2were not correlated (R=0.1, p=0.8)

Arzt et al, 2005 Prospective 2b N=10 (all male) O2 treatment, After 12 Wks: Symptom-limited [373] Controlled Trial age 65±2 yrs, BMI 28.4±1.4 CPAP treatment: cardiopulmonary 2 kg/m Reduced VE/VCO2-slope exercise testing N=16 (all male) CPAP (31.21.6 vs. 26.21.0), was performed on treatment, age 64±2 yrs, BMI improved LVEF (31.72.6 a cycle ergometer. 2 30.6±1.7 kg/m vs. 35.72.7 %), reduced Expiratory gas AHI (364 vs. 124/h) analysed breath by Consecutive stable patients Oxygen therapy: breath with chronic HF and CSA reduced AHI (293 vs.

94/h).

Exercise capacity, LVEF

and VE/VCO2-slope did not change. Arzt et al, 2007 Post-hoc analysis of 2b N=110 (105 male) ctrl, age Responders had better [388] a multicentre RCT 64±10 yrs, BMI 29.2±5.6 LVEF and better kg/m2 transplant-free survival vs. N=100 CPAP treatment HR=0.37

232

HFrEF and CSA of whom: N=57 responders (AHI<15) (all male), age 60±9 yrs, BMI 29.9±5.4 kg/m2 N=43 (40 male) non responders, age 65±9 yrs, BMI 28.6±4.8 kg/m2

Ruttanaumpawan RCT 2b N=205 HFrEF patients with AHI from 39 to 18/h et al, 2009 [389] CSA. 54% reduction No change in arousal N=97 (94 male) CPAP group, index. age 62±9 yrs, BMI 29.4±5.2 kg/m2

N=108 (102 male) noCPAP group, age 63±10 yrs, BMI 29.2±5.6 kg/m2 Bradley et al, 2005 RCT, open label, 1 N=258 (248 male) HF After 3 M: [390] parallel design patients with CSA.

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130 (125 male) CPAP CPAP group: AHI 40±15 ∆ AHI -2116 -218/h

LVEF 25±8 ∆ mean SaO2 1.62.8 % Mean SaO2 93±4 % ∆ LVEF 2.25.4 % Age 63±9 yrs 2 BMI 28.8±5.5 kg/m No CPAP group: 130 (123 male) No CPAP ∆ AHI -218/h (ctrl) ∆ mean SaO2 0.42.5 % AHI 40±17 ∆ LVEF 0.45.3 % Mean SaO 93±3 % 2 LVEF 24±8 % Mean follow up was 2 Age 64±10 yrs yrs. BMI 29.3±6.5 kg/m2 An early divergence in

heart transplant-free survival rates favoured ctrl, but after 18 M favoured CPAP group. Overall, the event rates were not different. Effects of BPAP-S on CSA and HFrEF

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Noda et al, 2007 Randomised, 2b N=21 HFrEF patients with AHI baseline vs. 1st- [391] parallel trial CSA night BPAP-S: 2812 vs 54 N=10 BPAP-S, ∆LVEF (baseline to 3 M) age 50±3 yrs BPAP-S vs standard BMI 24.4±2.2 kg/m2 medical therapy: +208% vs +310%. N=11 standard medical therapy not reported age 51±2 yrs, BMI 23.6 ±1.1 kg/m2 Kohnlein et al, Randomised, cross- 2b N=16 (13 male), age 627 Baseline AHI: 2711 Initial PSG to 2002 [392] over study yrs, BMI 27.3±3.2 kg/m2, CPAP AHI: ↓86 exclude OSA and stable chronic HFrEF in Bilevel ventilation AHI : diagnose CSA and NYHA functional class II and ↓77 CSR. Two 14-day III, LVEF ≤35%, CSR and Arousal index Baseline : treatment cycles, CSA. 3110 separated by a 14- Age 627 yrs. Arousal index CPAP : day washout period. Randomised into: CPAP or ↓165 BPAP-S. Arousal Index BPAP-S:

235

↓167 Significant and equal improvements with CPAP and BPAP-S for sleep quality, daytime fatigue, circulation time and NYHA class.

Effects of BPAP-ST on CSA and HFrEF Willson et al, 1998 Within subjects 4 N=10 (all male) moderate to BPAP-ST: All patients initially [393] study design before severe stable chronic HFrEF reduced RDI to <5 in all had full sleep vs. after BPAP-ST and severe repetitive CSA patients studies performed (RDI>30/h) and minimal OSA Reduced AI (4814 to while breathing (<10% of respiratory events), 146/h) room air prior to age 70±11 yrs, BMI 26.7±4.6 Non-respiratory arousal BPAP-ST 2 kg/m , index increased (86 vs treatment. 7 All commenced on BPAP-ST. 135). patients underwent TST and sleep efficiency a repeat sleep were unaffected. study after nIPPV % Stage 1&2 sleep reduced (829 to 6416

236

%), SWS increased (66 to 1917 %). REM wasunchanged (p=0.08).

Wilson et al, 2001 Within subjects 4 N=9 (8 male) patients (age AHI: from 49 to 6 [394] study design before 65±11 yrs, BMI 27.3±3.8 vs. after BPAP-ST kg/m2) with CHF and CSB. AI decreased from 42 to 17. Kasai et al, 2005 Within subjects 4 N=14 (12 male) chronic HF No change in control Patients self- [395] study design before and CSA. group selected whether or vs. after 3 months of 7 (6 male) BPAP-ST, age Treatment group: not they went on therapy 68±5 yrs, BMI 27.4±3.5 AHI: from ~50 to 10/h therapy (BPAP- kg/m2, 7 (6 male) noBPAP LVEF: 36 to 46% ST). (ctrl), age 64±3yrs, BMI Mitral regurgitation (MR) 24.8±1.0 kg/m2 area: 30 to 20% BNP: 994 to 474 pg/ml NYHA functional class: III to II

Dohi et al, 2008 Within subjects 4 N=9 (male) patients with (baseline vs. BPAP-ST) [396] study design before severe CSA and HF who AHI: from 54 to 8/h

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vs. after BPAP-ST failed CPAP were studied on LVEF: 30 to 43 % BPAP-ST. BNP: 1218 to 899 pg/ml. Age 69±10 yrs, BMI 22.2±3.7 kg/m2

Fietze et al, 2008 Single centre 2b N=37 (34 males) with HFrEF BPAP-ST group: [397] parallel RCT and CSA received either RDI: 34.9±20.4 to Interventions: BPAP-ST, N=17 (15 male) 16.4±16.1 BPAP-ST or ASV (6 age 62±9yrs, BMI 26.9±2.4 LVEF 26±9 to 31±11% weeks) kg/m2 ASV group: or RDI: 32±10 to 11±9. ASV, N=20 (19 male), age LVEF 25±8 to 27±9% 56±11 yrs, BMI 28.9±4.8 kg/m2

Effects of ASV on CSA and HFrEF Oldenburg et al, Single centre, 4 N = 29 (male) stable HFrEF AHI: from 37 to 4/h 2008 prospective, (LVEF≤40%), NYHA Class ≥ Workload and maximum [398] uncontrolled, 2, oxygen uptake during observational study, AHI>15, >80% central events. cardiopulmonary exercise before and after Age 64±9 yrs, BMI 27.6±3.6 testing: 81 to 100 W

238

ASV kg/m2 (p<0.01) and 12.6 to 15.3 6 months ml/kg/min (p=0.01) LVEF: 28 to 35% (p<0.01) NT-proBNP: 2285 to 1061 pg/ml (p=0.01).

Zhang et al, 2006 Single centre 4 N=14 O2: AHI: from 35 to 28, [366] prospective cross- Consecutive HFrEF patients 20 % reduction. over trial with CSA LVEF: from 30 to 33% Intervention: 2l gender, age and BMI not (p>0.05).

O2/min for 12 weeks available versus ASV (n=14)

Arzt et al, 2008 Single centre, 4 N=14 (all male) consecutive Diagostic vs [399] prospective, non- HFrEF patients with CPAP/BPAP: randomised study, persistent CSA (AHI≥10/h) on AHI: 46 vs 22 (p<0.01). comparing before CPAP or BIPAP therapy, age CPAP/BIPAP vs ASV: and after ASV 65±1 yrs, BMI 28±1 kg/m2 AHI: 22 vs 4 (p<0.01). 6 months

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Hastings et al, Parallel, non- 4 N = 19 (all male) stable ASV vs. controls: 2010[400] randomised trial, HFrEF, LVEF<45%, NYHA LVEF +6 vs −4 (p=0.04) Follow-up 6 M Class II and III, AHI>15 BNP 0.7 vs 0.8 (p=0.59) randomised to: QoL (SF36) N=11 ASV, age 61±10 yrs, Physical score 0 vs -38 BMI 32.2±6.2 kg/m2 (p=0.09) N=8 no ASV (comparison Energy vitality score +10 group), age 64±8 yrs, BMI vs -12 (p=0.005) 29.6±5.7 kg/m2

Koyama et al, Parallel, non- 4 N=43 (36 male) consecutive LVEF: 2011 [401] randomised trial stable HFrEF, NYHA class II ASV: 44 to 48 % (p<0.01) Follow-up 12 and III, LVEF <55%, AHI>15. Ctrl: 46 to 44 % (p<0.01) months Age 75±7 yrs, BMI 23.8±3.7 kg/m2 N=27 ASV treated N=16 CPAP treated Haruki et al, 2011 Parallel, non- 4 N=30 (23 male) stable LVEF: [402] randomised HFrEF, NYHA class II and III ASV: 30 to 43 % (p<0.01) ASV (n=15) vs AHI>15, obstructive AHI≤5, Controls: 33 to 38 %

240

controls (n=15) age 69±13 yrs, not reported (p>0.5)

Bitter T et al, 2010 Single centre 4 N=60 patients with HFpEF ASV improved CSA (AHI Non-randomised [403] prospective and moderate to severe CSA from 43.5±14.7 to 3.5±1.7 study with potential (AHI > 15), of whom 21 events/h, p<0.001) and selection bias and rejected or discontinued sleep study parameters regression to the

treatment (ctrl), while 39 ASV improved VO2max mean effect. initiated and continued at CPX (but not exercise treatment (ASV group) duration) Outcome measures: PSG, ASV reduced left atrial cardiac function (Echo, diameter and cardiopulmonary exercise echocardiographic testing (CPX), BNP) measures of diastolic Mean follow-up 12±3 M ventricular performance N=39 (33 male) ASV, age No difference between 67±8 yrs, BMI 28.5±6.7 treated and ctrl in NYHA kg/m2 class and BNP values. N=21 (18 male) ctrl, age 70±8 yrs, BMI 29.8±4.2 kg/m2

Joho S et al, 2012 Open label, not 4 N=32 (28 male) patients with In ASV group:

241

[404] randomised study CSA and HFrEF who had an AHI from 27±14 to 2±3, ASV test p<0.001 Intervention: ASV N=20 (18 male) ASV LVEF from 30±9 to continued, age 62±11 yrs, 37±12%, p<0.001 Follow up: 3.5±0.8 BMI 24.0±3.5 kg/m2 BNP from 379±310 to M N=12 (10 male) non-ASV 201±202 pg/ml, p<0.01 (declined use), age 68±9 yrs, MSNA from 53±14 to BMI 22.7±2.9 kg/m2 41±15 burst/min, p<0.001 (change in AHI correlated with change in MSNA) The decrease in AHI and the average use of ASV were independent predictors of increase in LVEF. Koyama et al, Prospective, single- 4 N=19 (15 male) patients with In ASV group: 2013 [405] centre, open label, CSA and HFrEF, age 63±14 AHI from 36±14 to 9±5, not randomised yrs, BMI 25.9±5.9 kg/m2 p<0.001 LVEF from 44±10 to Intervention: ASV N=10 ASV treated 47±11%, p<0.001 for 6 M N=9 non-ASV treated Ln BNP from 5.4±1.0 to

242

At baseline and at 6 M 4.6±1.2, p=0.01 patients were submitted to No change in non-ASV [123I]Metaiodobenzylguanidine group myocardial scintigraphy to At baseline AHI analyse cardiac sympathetic correlated with cardiac activity sympathetic activity. At 6 M improvement in cardiac sympathetic activity associated with improved LVEF and reduced BNP. Yoshihisa et al, Prospective, single 4 N=50 consecutive patients AHI from 37±18 to 9±13, 2013 [406] centre, open label, with CSA and HFrEF, age p<0.001 not randomised 60±10 yrs, BMI 25.0±4.5 NTproBNP from kg/m2 1109±2173 to 913±1577 Intervention: ASV pg/mL, p=0.013 for 1 night eGFR Cyst C from 61.9±30.8 to 65.7±33.8 ml/min/1.73 cm2, p=0.009. Kourouklis et el, Prospective, single 4 N=9 patients with CSA and AHI from 43±23 to 4±1, 2013 [407] centre, open label, HFrEF compliant to ASV p<0.05 in ASV and from

243

not randomised therapy (all men), age 66±8 37±16 to 4±1, p<0.05 in yrs, BMI 28.8±4.9 kg/m2 CPAP Intervention: ASV 8 (male) OSA patients and Improvement in left and for 6 months HFrEF compliant to CPAP right ventricular function. therapy, age 66±7 yrs, BMI 27.4±5.2 kg/m2 Oldenburg et al, Prospective, single 4 N=23 patients with moderate At 3 M 2013 [408] centre, open label, to severe SDB and HF (either AHI from 43±18 to 9±6, not randomised reduced, n=8 and preserved, p<0.001 n=15 EF), age 71±9 yrs, BMI NYHA class from 2.4±0.5 Intervention: trilevel 29.2±5.4 kg/m2 showing to 1.9±0.4, p<0.001

ASV for 3 months appropriate compliance to Peak VO2 at device cardiopulmonary testing from 13.6±3.5 to 15.8±5.8 ml/kg/min, p<0.002. Takama et al, Prospective, single 4 N=76 (53 male) patients with At 6 M LVEF and BNP 2013 [409] centre, open label, CSA and HFrEF: level were significantly not randomised N=42 (32 male), LVEF <30%, improved in both groups. age 67±14 yrs, BMI 26.4±7.7 In LVEF < 30% patients: Intervention: ASV kg/m2 LVEF from 24±6 to for 6 months N=34 (21 male), LVEF ≥30%, 35±11%, p<0.0001; BNP

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age 72±9 yrs, BMI 23.2±4.8 from 591 (278-993) to kg/m2 142 (39-325) pg/ml, p=0.002 In LVEF ≥30% patients: LVEF from 42±8 to 46±13%, p<0.01; BNP from 331 (199-811) to 144 (75-278) pg/ml, p=0.002. Iwaya S et al Prospective, single 4 N=19 (all male) patients with ASV significantly 2014 [410] centre, open label, CSA and HFrEF, age 63±2 improved AHI (from 32±4 not randomised yrs, BMI 23.6±1.1 kg/m2 to 9±2, p<0.001) and decreased urinary Intervention: ASV catecholamines for 1 night (p=0.016). Ventricular premature contractions were significantly reduced both during night time (p=0.037) than during daytime (p=0.021).

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Birner et al, 2014 Subanalysis of 4 N=32 (29 male) stable HFrEF At the 12-week control [411] multicentre parallel patients with concomitant visit, diastolic function randomised diastolic dysfunction, age 66 assessed by the controlled trial yrs, BMI 30.2 kg/m2, LVEF isovolumetric relaxation 30±7%, NYHA class II 72% time (-10.3±26.1 vs. Intervention: ASV 9.3±49.1, p=0.48) and for 3 M versus ctrl deceleration time (- 43.9±88.8 vs. 12.4±68.8, p=0.40) tended to improve after ASV treatment. Aurora et al, 2012 Systematic 2a HFrEF with CSA patients CPAP: [412] metaanalysis of CPAP: Transplantfree survival: randomised Transplantfree survival: 3 9-33% eventrate for controlled trials and studies, N=71 CPAP, N=125 suppressed CPAP vs. 24- cohort studies controls 56% event rate for LVEF: 6 randomised and 1 controls non-randomised trial, N=191 LVEF: mean difference CPAP, N=186 ctrl (MD) 6.4 higher (2.4 to AHI (follow-up 1-3 M): N=139 10.5 higher) CPAP, N=143 ctrl AHI: MD 21 lower (25 to

246

17 lower) BIPAP-ST: AHI (follow-up 1 night): 3 non- BIPAP-ST:AHI: MD 21 randomised trials, N=14 lower (25 to 17 lower) BIPAP-ST, N=14 ctrl ASV: ASV: AHI MD 30.8 lower AHI (follow-up 1 night): 6 (36.4 to 25.3 lower) randomised and 3 non- LVEF MD 6.1 higher randomised trials, N=127 (3.9 to 8.4 higher) LVEF: 4 randomised and 2 non-randomised trial, N=95 Sharma et al, 2012 Systematic 2a 14 studies comparing ASV to The weighted mean [413] metaanalysis of control conditions difference in AHI (-14.64 randomised events/hour, 95% CI - controlled trials and 21.03 to -8.25) and LVEF cohort studies (0.40, 95%CI 0.08 to 0.71) both significantly favoured ASV. Teschler et al, Single centre RCT 2b N=14 (all male) stable HFrEF After 1 night/ treatment. PSG was 2001 [372] Interventions for 1 patients with CSA. Untreated AHI: performed and 10

247

night each: age 69±6 yrs, BMI 28.9±3.3 44.53.4/h of 14 had 2 1) untreated CSA kg/m O2 AHI : 283 transcutaneous 2) O2 CPAP AHI : 275 PCO2 measured. 3) CPAP Bilevel AHI: 152 1 night of ASV 4) bilevel PAP suppresses CSA in ASV AHI: 61 5) Adaptive servo- HFrEF and ASV : Large increases in ventilation (ASV) improves sleep SWS and REM, preferred quality more than to CPAP. CPAP or 2 l/min

O2.

Bilevel did not

increase PaCO2 in hypocapnic HFrEF patients

Pepperell et al, Prospective, 2b N=30 (29 male) with CSR, After 1 M: active Daytime sleepiness 2003 [414] parallel, AHI 203, stable symptomatic treatment reduced (Osler test) randomised, chronic HFrEF. excessive daytime measured before double-blind trial Randomised into 2 groups : sleepiness, the mean and after the trial. Therapeutic ASV Osler change was +8±3 Secondary

248

N=15 (all male), age 71±9 (SE) minutes, when endpoints included yrs, BMI 26.8±4.6 kg/m2 compared with control, brain natriuretic or the change was -1±2 peptide levels and Subtherapeutic ASV (SE) minutes and the catecholamine N= 15 (14 male), age 71±8 difference was 9 minutes excretion. yrs, BMI 25.5±4.1 kg/m2 (95%CI, 2-16 min). Significant reductions in plasma brain natriuretic peptide and urinary metadrenaline excretion. Philippe et al, Parallel randomised 2b N= 25 (all male) stable AHI: from 47 to 5/h 2006 [415] controlled trial HFrEF, NYHA Class II and III LVEF: 29 to 36% (N=7). 6 months AHI>15/h, >80% central events. Randomised to: N=12 ASV age 64±15 yrs, BMI 25.2±3.3 kg/m2 N=12 CPAP (ctrl) age 60±11 yrs, BMI 28.8±6.3 kg/m2

249

Morgenthaler et al, Prospective 2b Patients with persisting AHI and RAI on 2007 [20] randomised severe CSA (AHI 34.3/h and BIPAP ST (6 and 6) and crossover clinical respiratory arousal index, on ASV (1 and 2). trial comparing RAI, 32) on CPAP therapy. AHI and RAI were BIPAP ST with ASV N=6 (all male) CSA patients, significantly lower on (n=15) age 74± 6 yrs, BMI 26.8±2.5 ASV compared to BIPAP kg/m2 ST (p<0.01). N=9 (all male) complex sleep apnoea patients, age 65±13 yrs, BMI 34.4±4.1 kg/m2

Kasai et al, 2010 Parallel randomised 2b N=31 (all male) stable HFrEF ASV vs. controls: All patients had an [416] controlled trial (LVEF <50%), NYHA Class II LVEF: +9 vs +1 % obstructive and III and (p<0.05) AHI≥5/h, average Follow-up 3 M SDB AHI>15, with coexisting LVESD: -3.7 vs -0.4 proportion of OSA (obstructive AHI≥5) and (p=0.028) central apnoeas CSA. Plasma BNP: -36 vs -4 and hypopnoeas Randomised to: pg/ml (p=0.006) 53% N=16 ASV, age 57±14 yrs, Distance walked in 6 min: BMI 26.9±6.0 kg/m2 +35 versus -9 m

250

N= 15 CPAP age 57±13 yrs, (p=0.008) BMI 26.3±4.2 kg/m2 QoL (SF36): significant improvements in 4 of 8 domains. Koyama et al, Cross-over 2b N=17 (12 male) stable LVEF: 2010 [417] randomised trial HFrEF, NYHA class II and III, ASV period: 44 to 53 % LVEF <55% (p=0.002) 3 M AHI>15, >50% central Control period: 46 to 46 apnoeas and hypopnoeas. % (p=0.90) Randomised to: N=10 (8 male) ASV, age Plasma BNP: 70±6 yrs, BMI 24.6±2.7 kg/m2 ASV period: 212 to 77 N=7 (4 male) non ASV, age (p=0.04) 71±8 yrs, BMI 23.4 ±3.3 Control period: 293 to kg/m2 149 (p=0.33)

Oldenburg et al, Parallel non- 2b N=105 stable HFrEF, NYHA In ASV group: 2011 [418] randomised class II and III AHI from 39.7±17.8 to AHI>15, >80% central events. 6.1±12.1 (85% reduction) 7 months N=56 (54 male) ASV, age LVEF from 29.9±6.1 to 68±9 yrs, BMI 28.8±4.8 kg/m2 34.0±8.8% (p=0.003)

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N=59 (52 male) ctrl=rejection NYHA class from 2.6±0.6 of ASV or ASV use <50% of to 1.9±0.7 (p<0.001) nights or ASV use <4h/night, 6 minute walking distance age 62±12 yrs, BMI 27.3±4.0 from 393±96 to 423±98 kg/m2 (p=0.03). No change in control group. Campbell et al, Crossover 2b N=10 male stable HFrEF 7 patients completed Quality of life, 2011 [419] randomised AHI>15, >50% central events, treatment on ASV markers of ASV vs oxygen age 64±7 yrs, BMI 26.5 ±2.8 AHI: from 67±32 to 5±6 sympathetic (2l/min kg/m2 LVEF: from 33 to 35% activation did not 8 weeks each) (p=0.24). change over the 8- separated by a 3- week period week wash-out period Yoshihisa et al, Parallel non- 2b N=60 stable HFrEF, NYHA In ASV group Event free rate 2011 [420] randomised class II and III AHI: from 38.8±17.3 to higher in ASV than 6 months AHI>15/h, CSA. 9.0±7.9/h (p <0.01) in non-ASV group N=23 (20 male) ASV, age LVEF: from 38±18 to 61±14 yrs, BMI 26.1±4.4 46±27% (p <0.05) kg/m2 NYHA cl: from 2.5±0.6 to

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N=37 (29 male) non-ASV), 1.6±0.5 (p <0.05) age 60±17 yrs, BMI 24.1±5.0 BNP: from 499±580 to kg/m2 192±219 pg/mL (p <0.05) No change in non ASV group.

Randerath et al, Parallel 2b N=70 stable HFrEF, NYHA On ASV 2012 [421] randomised, class II-III, AHI central: from 23±13 operator- and LVEF≥20%, with coexisting to 6±8 (p <0.001 vs patient- blinded, OSA and CSA baseline, p<0.05 vs single centre (AHI>15, ≤80% central CPAP) events and 20-50% NTproBNP: from obstructive events) 538±892 to 230±297 12 months randomised to pg/mL (p <0.05 vs CPAP) N=36 (31 male) ASV, age LVEF: from 47±16 to 65±10 yrs, BMI 32.2±6.8 46±16% (NS). kg/m2 N=34 (32 male) CPAP, age 67±8 yrs, BMI 30.3±4.8 kg/m2

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Arzt et al, 2013 Multicentre parallel 2b N=72 stable HFrEF, On ASV [422] randomised NYHA Class II-III, AHI≥15/h, AHI central: from 20±16 controlled trial randomised to to 5±5 (p<0.001) N=37 (34 male) ASV, age NTproBNP: from Intervention: ASV 64±10 yrs, BMI 28.9±4.3 1039±1034 to 940±1072 for 3 M versus ctrl kg/m2 pg/mL (p=0.06) N=35 (32 male) optimal LVEF: from 29.9±7.2 to medical therapy, age 65±9 33.1±8.6% (NS) yrs, BMI 31.6±4.9 kg/m2

Hetland et al, 2013 Parallel randomised 2b N=50 (46 male) severe ASV group: [423] 3 months chronic HF (LVEF≤40%) and LVEF 32±11 to 36±13%, CSR for >25%, age 57-81 yrs p=0.013 6-min walk test 377±115 to 430±123 m, p=0.014 NYHA class 3.2 (3.0-3.0) to 2.0 (2.0-3.0), p<0.001 No changes occurred in the control group. Yoshihisa A et al, Single centre 2b N=36 (29 male) patients with At 6 M: These were not 2013 [424] randomised symptomatic HFpEF and improvement in AHI, CAI, CSA patients but

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controlled study moderate to severe SDB (AHI OAI in the ASV group rather SDB and > 15) -decrease in NYHA class, OSA patients. Stable clinical status on systolic blood pressure Non-blinded study medical therapy for at least 3 (SBP), HR and BNP in M randomly assigned to ASV the ASV group or non-ASV Event-free rate (cardiac PSG at baseline and 6 M death and heart failure Mean follow-up 543 days, hospitalisation) higher in age 64±14 yrs, BMI 25.0±3.3 the ASV group than in the kg/m2 non-ASV group (94.4% vs 61.1%, p<0.05).

Kasai et al, 2013 Prospective, single- 2b N=23 patients with HFrEF ASV more effective in [425] centre, randomised, and unsuppressed CSA suppressing the AHI single-blind under CPAP for > 3 M (from 25±7 to 2±1, p<0.001) compared to Intervention: ASV N=12 assigned to ASV mode, the CPAP mode (from device randomly age 64±9 yrs, BMI 26.3±4.2 23±8 to 23±9) assigned to ASV or kg/m2 Improvement in LVEF CPAP mode N=11 assigned to CPAP (from 32±8 to 38±9%, mode, age 66±8 yrs, BMI p<0.001) greater with the

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26.9±5.2 kg/m2 ASV mode than CPAP mode (from 33±6 to 32±6%) With the ASV mode, also decrease in urinary catecholamines and BNP and increase in 6 min walk distance, while no change in CPAP mode. Cowie et al., Multi centre parallel 1 N=1325 stable HFrEF HR for death from any 2015[426] randomised patients, NYHA class 3: 69%, cause, 1.28; 95%CI, 1.06 controlled trial age 69 yrs, BMI 28.5 kg/m², to 1.55; p=0.01; HR for LVEF 32%; CSA cardiovascular death, Intervention: ASV 1.34; 95%CI, 1.09 to versus control with 1.65; p=0.006. a median follow-up of 31 M Prognostic effects of treatment of CSA in HFrEF Jilek et al, 2011 Single centre 2c N=296 (257 male), age 65±9 Median follow-up: 49 M Contemporary [354] observational study yrs in CSA vs 59±11 yrs in no Mortality rates severe heart failure CSA, BMI 30.3±5.6 kg/m2 in CSA (AHI≥22.5) versus treatment

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Outcome: death CSA vs 27.9±4.4 kg/m2 in no mild CSA (AHI<22.5): 38 CSA vs 16, unadjusted p=0.002, adjusted for Stable HF patients, LVEF significant confounders 33%, NYHA II and III p=0.035. 89% beta-blocker use

Damy et al, 2012 Single centre 2c N=384 (315 male), age Median follow-up: 47 M Contemporary [355] observational study 59±13 yrs, BMI 28±5 kg/m2 Outcome severe CSA heart failure (AHI≥20/h) versus mild treatment Outcome: death + Stable HF patients, LVEF CSA (AHI<20/h): HR HTx + Implantation 33%, 1.61, 95%CI 1.16-2.25 of ventricular assist 46% NYHA III/IV (p=0.018 adjusted for device 80% beta-blocker use significant confounders).

Bitter et al, 2013 Observational study 2c 403 registry patients with ICD discharge in 46.5% [427] HFrEF and implanted ICD of patients with untreated Intervention: ASV 221 no CSA CSA vs 26.0% of patients 182 CSA of whom with treated CSA Outcome: malignant N=96 (83 male) treated, age Cox proportional HR for

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ventricular median 69 yrs, BMI median untreated CSA (adjusted arrhythmogenic 27 kg/m2 for age, sex, ischemic events N=86 (73 male) untreated, cause, BMI, pre-existing age median 68 yrs, BMI atrial fibrillation, LVEF, 2 Follow-up 21±15 M median 26 kg/m VO2 peak, NYHA l) = 2.65 (95%CI 1.78-3.96).

258 e2.4.2.A. CSA/CSR in Patients after Stroke or TIA

Author Design EBM Patient population Results Comments Brunner 2008[428] Observational 4 N=10 (9 male) stroke patients, Mean RDI = 47/h (OAHI Small study effect of age 68±2 yrs; BMI=26±1 kg/m2 . =14/h ; CAHI=12/h, group, Mirtazapine on PSG at 53 days post event. mixed AHI=3/hr, heterogeneous PSG in stroke HI=17/h). population, no Mirtazapine improved control group, no sleep efficiency (63 to standard protocol. 76%) but no real improvement in RDI. Disler et al, 2002[429] Observational 4 N=38 patients, 7 to 28 days 47% OSA (AHI>15, Rehab clinic after stroke, age 65±16 yrs; >60% obstructive weight 75±12 kg. events) SBD was assessed by auto- 3% CSA (1 patient) CPAP device (Auto-Set 28% of OSA received Portable II plus) CPAP

Dyken et al, 1996 Observational 4 N=24 (13 male) stroke 77% male and 64% No CSA reported [430] (hemorrhagic & ischemic,) female patients had No control group patients had PSG 2-5 wks post OSA. AHI in ischemic

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event, age 65 yrs; BMI30±2 21% 4yrs mortality: all and hemorrhagic kg/m2 had OSA stroke was equal. Dziewas et al, Prospective 4 N=102 (68 male) patients with First stroke: AHI 15/h, SAS is an 2005[431] observational first or recurrent stroke, age SAS 52%; SAS independent risk 65±14 yrs; BMI=26 kg/m2 (AHI>10/h) factor for stroke Portable respiratory polygraph Recurrent stroke: AHI recurrence (Merlin) within 72h after stroke 27, SAS 80% 58 patient (97%) with OSA, 2 patients with CSA (3%) Harbison et al, Prospective 4 N=78 (40 male) patients with AHI 31/h CSA not reported, 2003[432] observational acute stroke, age 73 yrs. SDB AHI>10: 92% sleep recording was assessed by auto-CPAP AHI>20: 67% with single device (Auto-Set Portable II Pre-stroke cerebro- thoracic plus) vascular disease and respiratory extend of white matter plethysmography, disease were no abdominal associated with worse band SDB Hermann et al, 2007 Prospective 4 N=31 (20 male) patients with 3 patients exhibited CSA occurred [433] observational first-ever stroke, age 50±13 yrs. CSA (18-24% of sleep despite normal

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PSG within 10 d after stroke, time), CSA improved at LVEF. Stroke Reassessment after 1-3 M. time of reassessment. localised in left ; cingulate cortex, left insula and right para-median thalamus Iranzo et al, 2002 Observational, 4 N=50 (30 male) patients with 62% AHI>10 (31 SA is correlated [434] prospective hemispheric ischemic stroke, patients) with early but not age 67±10 yrs, BMI26 kg/m2 OSA 48% (15 patients) late (6 M) , PSG during first night after CSA 6.5% (2 patients) neurological stroke onset, reassessment Mixed 10% (5 patients) worsening. AHI after 1 M. CSR 29% (9 patients, 6 correlated with patients with normal sleep-onset LVEF) stroke.

Jennum et al, Prospective 4 N=804 (392 male) patients, age 60 had a stroke and 180 70 year old 1994[435] observational 70 yrs; BMI25 kg/m2 observed died. A slightly higher population, 6 yrs with CV risk factors and stroke incidence was snoring is not snoring history found among snorers associated with (relative risk [RR] = 1.8; an increased risk (95% CI: 1.1–3.6). of IHD, stroke or

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When adjustments were all-cause mortality made for the above confounders, no associations could be found between snoring and ischemic heart disease, stroke or all- cause mortality. Kaneko et al, 2003 Prospective 4 N=60 (36 male) stroke 72% had SDB [AHI>10] 12% CSA [436] observational survivors, age 66 yrs, BMI=28 (60% OSA, 12% CSA) kg/m2 , had PSG. which was associated with worse functional capacity and longer time in rehabilitation Kepplinger et al, 2013 Prospective 4 N=56 (26 male) patients with 91% (51/56) had SBD After 12 months: [437] observational acute stroke or TIA, age 64±8 (AHI>5) 70% SA (19/27), yrs; BMI=27±4 kg/m2. Re- 86% OSA 25% (7/27) with evaluation after 12 M. 4% CSA NIV, Portable RP (SomnoCheck) 10% mixed 2 patients with within 3 days after stroke severe SA ( no NIV), had

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recurrent stroke McArdle et al, 2003 Prospective 4 N=86 (49 male) patients with OSA (AHI>15): No CSA reported [438] observational, TIA, age 65±11 yrs; BMI=27±5 TIA 50% OSA not matched controls kg/m2 Control 60% associated with , N=86 matched controls ODI >4%: TIA PSG at least 1 M after TIA TIA 12/h Control 6/h Martinez-Garcia et al, Prospective 4 N=95 stroke survivors 54% (n=51) had 28% (n=15) 2005 [439] observational SBD was assessed by auto- AHI>20/h tolerated CPAP device (Auto-Set AHI 37/h CPAP usage Portable II plus) within 2 M. If OAHI 31.5/h reduced new SDB, then placed on CPAP. CAHI 2/h stroke from 36 to

Follow-up 18 M for new stroke CT<90% SpO2: 10% 7% N=51 (32 male) with SDB; age 73±9 yrs; BMI=27±4 kg/m2

Martinez-Garcia et al, Prospective 4 N=166 (98 male) patients with 39 patients : AHI 10-19 AHI>20: 2009[440] observational ischemic stroke, age 73±11 yrs, 96 patients: AHI >20 28 tolerated BMI=28 kg/m2 None predominant CSA CPAP, 68 did not SDB was assessed by auto- tolerate CPAP CPAP device (Auto-Set Follow-up 5 yrs:

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Portable II plus) within 2 M. Mortality HR 1.58 for non-treated vs CPAP Martinez-Garcia et al, Prospective 4 N=166 (98 male) patients with 39 patients : AHI 10-19 AHI>20: 2012 [441] observational ischemic stroke, age 73±11 yrs, 96 patients: AHI >20 28 tolerated BMI=28 kg/m2 None predominant CSA CPAP, 68 did not SBD was assessed by auto- tolerate CPAP device (Auto-Set Follow-up 7 yrs: Portable II plus) within 2 M HR 2.87 for nonfatal cardiovascular events in non- treated patients vs CPAP Mohsenin et Prospective 4 N=10 (8 male) hemispheric 7/10 with OSA Stroke patients al,1995[442] observational, stroke patients, age 56±5 yrs, 1/10 with CSA had less SWS Matched controls BMI26±3 kg/m2 and REM sleep without stroke than controls PSG within 1 yr after stroke

Munoz et al, 2006 Prospective 4 N=394 subjects (aged 70-100 20 strokes observed No CSA

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[443] observation yrs) had baseline PSG. Follow- (incidence 11/1000 AHI>30 as up 6 yrs. person-yrs). Risk factor independent risk N=20 (17 male) strokes for stroke was AHI > 30 factor for stroke observed; age 79 yrs, BMI=27 (HR=2.52, p<0.04) kg/m2

Nachtmann et al, Observational, 4 N=32 (22 male) acute ischemic 53% had CSR (AHI>10) No OSA reported 1995 [444] control group (20 stroke, age 64 yrs, had > 1 hrs 59% and 40% with CSR 250mg age-matched limited PG with Fourier analysis in supra-tentorial and theophylline i.v. subjects) of respiratory pattern within 3 infra-tentorial stroke, over 1h in 7 days after stroke onset. respectively patients and

2l/min O2 in 5 patients suppressed CSR entirely Nopmaneejumrusler Observational, 4 N=93 (58 male) patients with 19% (n=18) had CSA 20% had CSA & et al, 2005 [445] prospective stroke (CT or MR (AHI>10). 4/18 had related to low

confirmed), age 67 yrs, BMI28 LVEF < 40%. 14 pts PaCO2& LVEF, kg/m2.All had PSG, echo, ABG with LVEF>40% had not stroke (~44 days post stroke) CVA & CSA site/type. Limitations:

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*echo not CGBPS *Rhythm not stated *OSA not stated Palomäki, 1991 [446] case control 4 N=177(all males) with recent OR of 2.13 of habitual No CSA ischemic stroke,age 49±9 yrs, or frequent snoring for BMI 38% of patients >27 kg/m2 development of stroke and 177 controls

Palombini et al, 2006 observational 4 N=21 patients with stroke, age AHI<10: 5 patients 12 of 14 agreed to [447] prospective 62±13 yrs, BMI24±4 kg/m2 AHI >10: 14 (44%) CPAP, 5 PSG CSR: 2 patients discontinued during first week, 7 (22%) continued CPAP Parra et al, 2000 [448] observational 4 N=161 (82 male) patients with AHI 11-30: 72% (116 Less CSA in TIA prospective first stroke (hemorrhagic or pat) compared to ischemic) or TIA, age 72±9 yrs, AHI>30: 38% (45 hemorrhagic BMI27±4 kg/m2 . 86 patients patients) stroke reassessed at 3 M OSA 84 (52%)

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CSB 62 (38.5%) Reduction in AHI Portable RP (Edentec) within 3 Mixed 15 (9%) after 3 M due to days after stroke 42 (26%) with CSR reduction in CAI At 3 M (86 pat): AHI>10: 62% (before 70%) AHI>30: 20% (before 33%) CAI: 3 (before 6) CSB 6 pat (before 17)

Rola et al, 2007 [449] Observational 4 N=70 (60 males), age 66±11 AHI>5: AHI correlated prospective yrs, BMI=29±4 kg/m2, 65% stroke patients with NIHSS (13% central apnoeas, (r=0.54) N=55 patients with ischemic 9% mixed) stroke and 15 with TIA 67% TIA patients Portable RP (Embletta) within 7 (11%% central days after stroke apnoeas, 9% mixed)

Sahlin et al, 2008[450] case control 4 N=132 stroke patients had RP 40% (53 pat) had 33 patients tried

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(Resp-EZ, EPM Systems) AHI>15 (21% CSA; CPAP, 10 within 23 days 17% OSA, 2% mixed). continued (4 CSA, N(CSA)=28 (15 males), age 79 controls (AHI<15) 6 OSA) 79±7 yrs, BMI=25±4 kg/m2 OSA, not CSA, associated with OSA = CSA increased mortality (OR 1.8); 10 year follow-up: 116 deaths (88%) Scala et al, 2009[451] observational 4 N=12 (4 male) stroke patients, AHI>5: 90% No CSA reported. age 75±6 yrs, BMI27±5 AHI>10: 60% CPAP accepted kg/m2.SBD was assessed by AHI>15: 50% by 84% during auto-CPAP device (Auto-Set one night, 42% Portable II plus) within 48h after used stroke CPAP>6h/night

PetCO2 lower with CPAP Selic et al, 2005 [452] Observational 4 N=41 (33 male) stroke patients, 68% had AHI>10 High AHI related age 63±13 yrs, BMI27±4 kg/m2 to CSA. Portable RP (Auto-Set Embletta 27% had AHI >30 Effect of SDB on PDS) during first night after (OAI=5/h;CAI=24/h, ambulatory BP. admission AHI=50/h) Severity of SA

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correlated with BP. Siccoli et al, 2008 observational 4 N=74 (49 male) patients within AHI>10/h: 55% CSR patients [453] 96h after stroke onset, age AHI 33/h were older, had 63±13 yrs, BMI28±4 kg/m2 OAI 5/h lower LVEF, more Portable RP (Auto-Set Embletta CAI 12/h ECG PDS) during first night after CSR: > 3 cycles/h: abnormalities and admission. CSR in 72%, more severe (>10% recording time) stroke. in 41%, (>50% CSR more recording time) in 9% frequent (54%) in total anterior circulation strokes, particularly left sided. Szücs et al, 2002 observational 4 N=106 (70 male) patients, age 51/106 with ODI>10 No CSA reported [454] 66±14 yrs, 46 pat with BMI>30 (48%) After 3 M, ODI kg/m2: 73 ischemic and 33 decreased in hemorrhagic stroke hemorrhagic but Portable RP (MESAM IV during not in ischemic

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4h at night) within 6 days after strokes admission 51 reevaluated after 3 M

Turkington et al, observational 4 N=120 (50 male) acute stroke 61% with RDI>10 OSA was 2002[455] patients, age 79±10 yrs, 9% more CSA than position- BMI24±4 kg/m2 OSA dependent, BMI PSG within 24h of stroke onset 38% with intermittent and neck- CSR, circumference 12% with CSR during correlated with >10% recording time OAI Wessendorf et al, Observational 4 N=147 (95 male) patients with RDI>10: 44% Neck 2000 [456] first stroke, age 61±10 yrs, BMI, RDI>15: 32% circumference 28±5 kg/m2 Predominant CSA: 6% and coronary PSG within 46 days (9 pts), 6 pts (4%) heart disease mixed, were associated 3 pts (2%) with CSR, with RDI but RDI<10 Wessendorf et al, Observational 4 N=105 (80 male) stroke 75% pts tolerated CPAP No CSA

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2001 [457] patients with OSA, age 61(59- CPAP associated with 63) yrs, BMI 29 (28-30) kg/m2 improved well being Response to CPAP 1 M

Wierzbicka et al, 2006 observational 4 N=43 (35 male) patients with 63% with AHI>5 [458] stroke or TIA, age 69±11 yrs, 37% with AHI 5-10 BMI29±5 kg/m2.Portable RP 30% with AHI 10-20 (Embletta) within one week 33% with AHI>20 after stroke OSA 81.5% CSA 11% Mixed 7.4%

Yan-fang et al, Prospective, 4 N=60 (41 male) stroke 65%: AHI>5 At 3 M: 2009[459] observational patients,age 58±9 yrs, BMI25±3 Of these: 15 pts with SDB kg/m2 50% AHI>15 At 6 M: PSG within 7d after stroke 30% AHI>30 11 pts with SDB onset 97% OSA SDB associated 3% (1 pt) CSA with functional outcome at 3, but not at 6 M Arzt et al, 2005 [460] Cross-sectional and 3 N=1475 and 1189 subjects If AHI>20/h, OR for No mention of

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longitudinal (cross-sectional and stroke 4.33 (cross- CSA, subjects longitudinal, respectively) from sectional) and OR 3 n.s. were examined the Wisconsin Sleep Cohort (longitudinal); OSA before stroke PSG at 4, 8 and 12 yrs precedes and may occurred N=1475 (809 men); age 47±8 cause stroke . yrs; BMI=30±7 kg/m2 Bassetti et al, 1999 Comparison of 3 N=80 of 128 (71 male) patients 51% of 128 were No mention of [461] acute with acute cerebrovascular regular snorers. 62.5% CSA. cerebrovascular disease (75 stroke, 53 TIA) had of 80 and 12.5% of TIA = Stroke event (stroke and PSG 1-71days post event. 25 controls had AHI>10, all Stroke location TIA) with healthy matched controls, OSA. not significant matched control age 59±15 yrs; BMI=29±8 group kg/m2 Bassetti et al, 2006 Prospective, 3 N=152 (103 male) patients with Initial AHI 18±16/h, No mention of [462] observational acute ischemic stroke, age AHI>10 in 58%, AHI>30 CSA 56±13 yrs; BMI=26±4 kg/m2 in 17% of patients. AHI More SBD in . SBD was assessed by auto- decreased 6 M after macro- CPAP device (Auto-Set stroke from 32 to 16/h. angiopathic than Portable II plus) 36 patients were in cardio-embolic discharged with CPAP, strokes 8 patients continued

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CPAP after 6 M. SBD is associated with post- stroke mortality Bonnin-Villaplana et Prospective, 3 N=68 (31 male) consecutive CSR in 20.6% (>10% CSR associated al, 2012[463] observational patients with first-ever lacunar sleep-time with CSR) with higher stroke Patients with CSR: functional stroke within 48h after stroke; CAHI 13/h severity, longer age 73 yrs; BMI=26 kg/m2 OAHI 22/h hospital stay and worse prognosis (association n.s.) Broadley et al, Prospective, 3 N=55 (32 male) consecutive 53% with OSA 57% of patient 2007[464] observational patients with new-onset stroke, 38% additional CSA with OSA were age 71 yrs; BMI=27±4 kg/m2 5.5% pure CSA treated with Portable respiratory polygraph After 6 w: CPAP, 35% (Embletta) CAHI decreased from 7 tolerated CPAP to 4/h well. Sleepiness prior to stroke predicted OSA Cadilhac et al, 2005 Observational 3 N=78 (53 male) patients 3 yrs AHI>5: 81% Predictors of AHI: [465] after stroke, age 64±15 yrs; OSA (AHI>5 and Hemorrhagic BMI=28±6 kg/m2 ESS>10): 20% stroke and stroke

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Portable respiratory polygraph If AHI>10 (45%): severity at 1 (Embletta) 67% OSA month 10% mixed 23% central

Hui et al, 2002 [466] Observational, 3 N=51 (28 male) stroke Stroke:49% AHI > 20/h CPAP titration matched control survivors, age 64±13 yrs; 67% AHI>10/h tolerated by 16 of BMI=24±4 kg/m2 CAI 3.7±6.3/h 34, only 4 & 25 non stroke controls Controls: proceeded to matched for age and BMI 24% AHI > 20/h home treatment PSG within 4 days of stroke All OSA onset, reassessment after 1 M Subgroup of 20 patients: CAI 5±8 at baseline and 2.5±6 after 1 M OAHI 27/h at baseline and 21/h after 1 M. Sandberg et al, 2001 Case control 3 N=133 stroke patients had RP AHI>10: 59% (78 pat) CSA-patients had [467] (Resp-EZ, EPM Systems) 22% OSA more often within 23 days 26% CSA ischemic heart N=132 (55 males), age 77 yrs, 6% mixed disease,

274

BMI24 kg/m2 congestive heart 55 controls (AHI<10) failure, delirium and depression than patients with AHI<10 Yaggi et al, 2005 [468] Observational 3 N=1022 subjects from OSA in 68% “CA was rare”, no Cohort community. Follow-up 3.4 yrs OSA correlated with RR numbers reported with PSG [OSA = AHI>5] of stroke or death N=697 subjects had OSA (537 (HR 1.97) men), age 61 yrs, BMI34 kg/m2

Hsu et al, 2006 [469] RCT of CPAP 2 N=66 (45 male) stroke patients, Median AHI 31/h 30 patients with therapy after stroke age 72 yrs; BMI=26 kg/m2 Median CAHI 0.4/h AHI>30 Portable respiratory polygraph 9 patients with randomized to (Embletta) 14-19 d after stroke intermittent CSR CPAP or 46 patients with AHI>15 conservative therapy CPAP use 1.4h/night No benefit from CPAP

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Sandberg et al, 2001 RCT of CPAP in 2 N=63 stroke patientswith SDB Reduction in depression No CSA [470] stroke with SDB were randomised, 4 dropouts. if treated with CPAP, no (AHI ≥ 15) N=59 (27 male) patients with change in ADLs. SDB,CPAP group: n=31 (14 overall CPAP use males), age 78±6 yrs, BMI 4.1h/night 24.5±4.1 kg/m2, AHI 32±11. 16/31 used CPAP>4 Ctrl group: n=28 (13 male), age h/night 77±8 yrs, BMI 24.8±4.8 kg/m2, AHI 29±13. Johnson et al, 2010 Meta-analysis Analysed 29 papers on 17 papers reported on Decrease of SA [471] frequency of SA in stroke and CSA/CSR during recovery TIA patients Frequency of CSA/CSR for both OSA and 7% (CI 4.5-12%) CSA Nachtmann et al, Retrospective, N=235 (165 male) patients with 25% with severe OSA Severe OSA was 2003 [472] observational stroke, age 64±11 yrs. (RDI>20), 18% with light associated with Portable RP (Nellcor OSA (RDI 5-20) extra-cranial EdenTrace) as screening within 1 patient with CSA artery disease 27 d after stroke, if positive: (excluded form (OR 2) PSG analysis)

Noradina et al, observational N28 (20 male) patients with OSA (AHI>10): 78.5% No CSA reported,

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2006[473] prospective ischemic stroke, age 60±9 yrs, AHI>15: 45% thoracic BMI23±4 kg/m2 movements not SDB was assessed by auto- recorded CPAP device (Auto-Set All lacunar strokes Portable II plus) within 1-4 had AHI>5 weeks after stroke Diabetes and smoking history were predictors of SBD

277

Tables of Chapter 2.5. CSA in other internal diseases or neurological diseases, other than cardiovascular diseases e2.5.A. Acromegaly (AM)

Author Design EBM Patient population Results Comments (M/F) Akkoyunlu et 4 N=42 (18 male) AM 20/42 had OSA, 3 of them showed a CAI AASM evaluation Case series, al, 2013 [474] patients, median age above 10. Sleep apnoea was severe criteria from 2007. n=42, 41 (IQR 35-41) yrs), (AHI≥30) in 11 cases. RDI was evaluated uncontrolled 22 with active After 6 M hormonal treatment of AM, CAI with included follow up of disease, 20 had decreased from 3 to 1 (n=14 patients, apnoeas, medical AM controlled AM. p=0.038). Three patients with CSA hypopnoeas, and treatment (n=14) Median BMI 31 (IQR reduced CAI substantially (according to RERA events. No 31-33) kg/m2. In the figure in the article). detailed sensor AM active disease description. group, PSG was reassessed 6 M after medical treatment of AM. Roemmler et Case series 4 52 (25 male) AM 30 patients had sleep apnoea (58%), 25 No group means in al, 2012 [475] patients, age 51 obstructive, 2 mixed and 3 with dominant AHI, desaturation (19-82) yrs, BMI 27 central type. and oxygenation

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(21.8-40.0) kg/m2 levels reported. Sensors include pressure transducer for flow, respiratory plethysmography and microphone. No criteria for respiration stated. Vannucci et al, Case series 4 25 (9 male) AM The prevailing form was OSA (12/14 Severe cases seem [476] patients, age 47-79 patients). 2 patients with CSA. AHI to be correlated with yrs, AM disease between 11 and 119. smoking and lung duration 0.5-31 yrs, disease. BMI 22.0-34.1 kg/m2. Hernandez- Case series 4 N=35 (15 male) AM 34 out of 35 patients had AHI≥5, mean AHI Sensors include Gordillo et al, patients, age 51 34, mean central AI 0.1, one subject with pressure transducer 2012 [477] (IQR 39-63) yrs, BMI central AI 14, but CAII <50% of total AHI in and thermistor for 29 (26-33) kg/m2, all patients. No assiociation between IGF-1 flow assessment, OSA treatment was levels and CAI. AASM 2007 criteria. offered to n=30 City of investigation patients. 8 were re- is at an altitude of assessed with PSG 2240 m which may

279

using CPAP. have affected type and amount of SDB and hypoxia. Sze et al, 2007 Uncontrolled 4 N=13 (6 male) 6 of 13 patients had sleep apnoea (AHI Use of calibrated [478] prospective untreated AM 41±21, CAI 13). 12 weeks after surgery plethysmography, no study pre/post patients, mean age AHI decreased in all subjects (AHI 11±13, direct assessment of surgical AM 48±16 yrs, mean CAI 3±2). One patient had predominantly flow. No scoring treatment BMI 27.9±3.4 kg/m2 ; CSA. reference stated. trans-sphenoidal adenomectomy performed in all patients, one re- operation Herrman et al., Uncontrolled 4 N=14 (6 male) Al patients had an obstructive respiratory Flow assessment 2004 [479] prospective untreated AM disturbance index (RDI)≥5, RDI≥20 in 50% with thermistors, use study pre/post patients, mean age of patients. No central apnoea observed. of respiratory medical AM 57±4 yrs, BMI RDI decreased by treatment in 9/14 plethysmography. treatment 30.8±1.5kg/m2, pre patients. No criteria for scoring and post 6 M of respiration stated. octreotide acetate No mean values for treatment. RDI or hypoxia levels

280

stated. Pelttari et al, Case control 4 N=11 (6 male) AM 10/11 AM patients had SDB (91 vs 29.4% Nocturnal breathing 2005 [480] study patients, mean age in ctrl, p<0.001). One patient had Cheyne is recorded by means 58±12 yrs, mean Stokes Respiration explained by of the static charge BMI 29.3±3.4 kg/m2 concomitant heart failure. 13.9% of sensitive bed and 197 (97 male) nocturnal breathing was characterised by (validated method). population based symmetric irregular breathing, which may Thereby, traditional controls, age 44±6 correspond at least in part to central classification of yrs, BMI apnoeas/hypopnoeas. obstructive, central 26.0±4.1kg/m2 and mixed apnoeas not performed. no AHI, AI or ODI levels reported. Grunstein et al, Consecutive 4 N=53 (39 male) AM 43/53 patients had sleep apnoea. OSA 1991 [481] case series patients, 33 referred was the pre-dominant type of SDB (67%), for suspected sleep while CSA was present in 33%. Patients

apnoea. with CSA had lower waking PaCO2 levels N= 43 (34 male) than did those with OSA (39±1 mmHg vs sleep apnoea 42±1 mmHg). Only central apnoea was patients, age 54±2 associated with insulin-like growth factor 1 yrs, BMI 29±1 kg/m2, (IGF-1) and random growth hormone (GH).

281

random growth factor 12,7±4,4 µg/L, IGF-1 90,0±7,5 nmol/L. N=10 (5 male) sleep apnoea patients, age 40±4 yrs, BMI 30± kg/m2, random growth hormone 14.2±4.9 µg/L, IGF-1 90.0±10.0 nmol/L. Grunstein et al, Consecutive 4 N=54 AM patients, 11 patients classified as central, 33 as Assessment of SDB 1994 [482] case series (17), age in CSA OSA (RDI>5) and 10 free of SDB. In CSA, by nasal pressure 51±5 yrs, in OSA ventilatory responses to hypoxia and transducer, 55±2 yrs, and no hypercapnia were associated with respiratory apnoea 40±3 yrs, circulating GH and in part with IGF -1 plethysmography and BMI in CSA 29±2 levels. diaphragmatic EMG, kg/m2, ,in OSA 29±1 scoring criteria kg/m2 and no include EMG signal. apnoea 29±2 kg/m2 36 out of 54 patients already reported in

282

the study Grunstein et al. 1991. Grunstein et al, Uncontrolled, 4 N=19 (14 male) AM RDI was reduced by 50% (19 vs 39, GH was also 1994 [483] open-label, patients, age 50±2 p<0.001) after 6 M of treatment. Mean significantly reduced, prospective (26-68) yrs, change in RDI was -20 (-14 tp -26). but no association study assessment of the Growth hormone was reduced by >75% (9 between both effects of octreotide, vs 40, p<0.001) after 6 M of treatment. phenomena was a somatostatin Mean change in GH was -31 (-18 to -43). observed. analog, on sleep apnoea. Perks et al, Consecutive 4 N=11 (5 male) AM 3 patients had an AI>5, two of them had Assessment of 1981 [484] case series patients, age 51±12 dominant central apnoeas (AI 12 and 32) respiration with yrs, weight 82±18kg accompanied with cardiomegaly. thermistor, strain gauge and thoracic impedance.

283 e2.5.B. Diabetes mellitus (DM)

Author Design EBM Patient population Results Comments Kashine et al, Observational 4 N=40 (27 male) 31/40 DM patient had sleep apnoea (AHI Polygraphy, no sleep 2010 [485] case series patients with Type 2 ≥5) with a even distribution of apnoea assessment, sensors DM, age 59±2 yrs, severity classes, 10 patients had a CAI≥5 not described in BMI 29.6±1.4 kg/m2, which was associated with thickened detail. OSA was in the apnoea group, arterial wall, increased haemoglobin, and predominant. 23.9±1.6 in the non elevated BNP levels. apnoea group Bottini et al, Case control 4 N=26 (23 male) non- 9 out of 16 DM with AN had mild OSA Apnoea assessment 2003 [486] study obese DM patients, (AHI≥5) mainly during REM sleep, no sleep by thermistors, age 45 yrs (CI 41- apnoea in controls and DM without AN. respiratory 50), BMI 25 (23-26) Very few central apnoeas (< AHI 5) and no plethysmography and kg/m2 , 18 with and 8 periodic breathing in DM patients with AN. microphone. without autonomic neuropathy (AN), and 10 non diabetic controls, age 42 (36- 48) yrs, BMI 24 (23- 25) kg/m2

284

Mondini et al, Observational 4 N=19 (13 male) DM 5 out of 7 patients with Type 1 DM had Assessments of SDB 1985 [487] case series patients (12 with central and obstructive sleep disordered with strain gauges Type 1 and 7 with breathing, 1 out 7 patients with Type 2 DM and thermistors in 12 type 2 DM), age 52 showed OSA. pts and with RIP in 7 (41-59) yrs, all>5% pts. over ideal weight, 5 with >15% over ideal weight Resnick et al, Population 3 N=470 (46% male) Sleep apnoea was elevated in diabetic Sensors or SDB 2003 [488] based study, participants with DM, subjects (RDI 6 vs 3, p<0.001). CSA was detection were oro- cross sectional age 64±10 yrs, BMI rare (<5% for all cut offs) and tended to be nasal thermistor and analysis 31.3±6 kg/m2 , and higher in DM patients. Time in periodic respiratory inductive N=4402 non diabetic breathing was elevated in DM patients (3.8 plethysmography. participants of the vs 1.8, p=0.002) compared with non DM DM classified SHHS without subjects. according to self- previous CV disease report and use of history (55.7% medication females), age 62±11 (insulin/oral yrs, BMI hypoglycemics). 28.1±5kg/m2

285 e2.5.C. End Stage Renal Disease

Author Design EBM Patient population Results Comments Nicholl et al, Observational 4 N=254 (164 male) Prevalence of sleep apnoea increased with Limited sleep test 2012 [489] case series patients), age 60±16 kidney disease severity: maintained gFR using flow (pressure yrs, BMI 29.6±8 (27%), chronic kidney disease (41%), and transducer), kg/m2, recruited from ESRD (78.1%). The proportion of patients microphone and nephrology with Cheyne Stokes Respiration increased oximeter. Central vs outpatient and with decline of kidney function (2, 4, and obstructive SDB haemodialysis clinic 12%, respectively). classified manually by shape of the flow signal.

Kumagai et al, Uncontrolled 4 N=40 (31 male) 23/40 patients fulfilled criteria for O2- PSG based 2008 [490] treatment study patients (age 64±13 therapy, data from 11 patients available: assessment of yrs, no BMI given) AHI decreased from 31±9 to 13±9, p<0.01; treatment effects, no on peritoneal dialysis central apnoea: from 4 ±4 to 1±1, p<0.05), sleep data or scoring were screened by obstructive apnoeas unchanged. criteria stated; oximetry. 11 (10 treatment duration 1 male) patients (age month. 64±4 yrs, BMI 25.1±4kg/m2) with

286

ODI>5 or average nocturnal oxygen saturation < 95% received 2 l

nocturnal O2 therapy. Tada et al, Observational 4 N=119 (68 male) 41/119 had sleep apnoea defined as PSG with flow and 2007 [491] case series haemodialysis ODI>5, 27/41 had related clinical effort sensors, not patients, age 61±11 symptoms. further specified. yrs, BMI 20.7±4 8/30 showed CAI >5, central AI correlated 2 kg/m ) screened with negatively with PaCO2 . oximetry, 30 patients (age 60±10 yrs, BMI 25.1±4 kg/m2) with ODI≥5 underwent PSG. Hanly et al, Uncontrolled, 4 N=14 (10 male) Nocturnal dialysis was associated with an One patient with 2001 [492] non-randomised, patients, age 45±9 AHI reduction (25±25 to 8±8, p=0.03). Flow assessed with

cross over yrs) on Nocturnal oxygen saturation, carbon end tidal CO2 study haemodialysis dioxide, and bicarbonate increased in measurement, changed (3 d/week) parallel. Effect was seen for all types of respiratory inductive to nocturnal dialysis breathing disorder. plethysmography.

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(6-7d/week). Cheyne-Stokes Assessment of sleep respiration converted apnoea after 6-15 M. to obstructive BMI not stated. breathing disturbances. Jean et al, Uncontrolled 4 N=10 (8 male) CSA was elevated during the night PSG based 1995 [493]* treatment study ESRD patients, age following acetate dialysis: 33 (0-180) assessment of 35-71 yrs on versus 3 (0-15) with bicarbonate, p<0.05. treatment effects ; hemodialysis were Obstructive apnoeas were unchanged. treatment duration 6 randomly assigned dialysis sessions to dialysis session with acetate or bicarbonate buffer Pressman et Uncontrolled 4 N=8 (6 male) All eight patients had severe sleep apnoea No detailed a., 1993 [494] treatment study patients with ESRD, with AHI 64±42 (dominant central or mixed description of sensor age 52±16 yrs, BMI type) at baseline. CPAP reduced AHI to technology. Un- 24-37 kg/m2, 6±4, p< 0.02) in 6 out of eight patients. blinded scoring of referred for sleep studies. evaluation of sleepiness or insomnia with pre-

288

identified sleep apnoea.

Kimmel et al, Observational 4 N=26 (19 male) 16/26 had sleep apnoea, 7 had primarily No detailed 1989 [495] case series ESRD patients on central sleep apnoeic events. description of sensor hemodialysis, age technology. 57±3 yrs, symptomatic group, BMI not stated.

* No article reviewed. Information obtained from abstract.

289 e2.5.D. CSA and Pulmonary Hypertension

Author Design EBM Patientpopulation Results Comments Dumitrascu R Cohort study 2b N=169 (64 male) Prevalence of CSA 10.6%, of OSA16.0% Polygraphy: et al, 2013[496] patients , age 61±14 Cut-off point for sleep yrs, BMI 27.2±5.9 apnoea: ≥10. kg/m2. Patients with CSA were older and more hypocapnic compared to OSA Minic M et al, Cohort study 2b N=52 (22 male) Prevalence of CSA 15.4%, of OSA 55.8%. Retrospective; 2014[497] patients, age PSG: 53±15 yrs, BMI Cut-off point for sleep 29.6±9.2 kg/m2. apnoea: ≥5

Prisco D et al, Cohort study 2b N=28 (6 male) Central apnoeas were not observed; 50% of PSG: 2011[498] patients, age 55±12 patients with an AHI≥5; mean AHI 11±20; cut off point for sleep yrs, BMI 31.1±9.3 25±27% of disordered breathing events were apnoea: ≥5; kg/m2. classified as obstructive apnoeas; the amount of central remainder were hypopnoeas. hypopnoeas not clear

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Schulz R et a., Cohort study 2b N=20 (3 male) Periodic breathing in 30%; mean AHI 37±5. PSG: 2002 [499] patients, age 45±3 Cut-off point for sleep yrs, BMI 23.5±1.1 apnoea: ≥10 kg/m2. Ulrich S et al, Cohort study 2b N=38 (11 male) Prevalence of CSA 45%, no obstructive Polygraphy in 38 2008 [500] patients, age 61 yrs, events. outpatients and PSG BMI 25 kg/m2. in 22 of these 38; Cut-off point for sleep apnoea: ≥10

Ulrich S et al, Randomised, 1b N=23 (8 male), age Medians (quartiles) of nocturnal mean SpO2 This trial in patients 2015 [501] double blind 66 (quartiles 56;71) with oxygen, acetazolamide and placebo with precapillary placebo- yrs, BMI 26.6 (25.2; were: 92% (91;94), 90% (88;92), 86% pulmonary controlled trial. 29.3) kg/m2. (84;89), respectively (p<0.001 both oxygen hypertension stable Participants were and acetazolamide vs. placebo). The AHI with on treatment with randomized to oxygen, acetazolamide and placebo were: 9/h specific drugs shows nocturnal oxygen (6;24), 7/h (3;27), 18/h (6;40), respectively that both nocturnal 3L/min per nasal (P<0.001 both oxygen and acetazolamide vs. oxygen and cannula, placebo). In addition, the 6 min walk distance acetazolamide acetazolamide with oxygen, acetazolamide and placebo was: improve nocturnal 2x250 mg/d or 480 m (390;528), 440 m (368; 468), 454 m oxygenation and sleep placebo for one (367;510), respectively, p=0.027 oxygen vs. apnoea. In addition,

291

week each with a placebo. nocturnal oxygen 1 week washout increases the exercise period. performance. e2.5.E. Central sleep apnoea in neurodegenerative diseases like Parkinson´s Disease (PD) Author Design EBM Patient population Results Comments level Apps et al, 1985 [502] Case- 4 N=12 (9 male) PD In this case control study, Thermistor recording for controlled patients, 58± 9 yrs, occasionally central apnoeas nasal/oral flow, no weight and BMI not (AHI<5) occurred in 5 patients and specific criteria stated. stated; normal controls, each. One PD case had controls: N=12 (9 30 central apnoeas. One PD males), age 57±8 yrs. patient with autonomic dysfunction 2 PD pts with patients suffered from OSA (no autonomic AHI given) with paralysis of dysfunction. abduction of the vocal cord. Ferini-Strambi Case- 4 N=26 (11 males) PD RDI > 10 events/h in 8/26 of No subdivision into et al, 1992 [503] controlled patients, 65 yrs; patients. obstructive vs central normal ctrl: N=15 (8 Similar mean RDI between apnoeas.

males), 63yrs groups; no difference in SaO2. Maria et al, 2003 Case- 4 N= 15 (12 male) PD 1 patient with central sleep Classification of

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[504] controlled patients,, 63±4yrs, apnoea but central AHI not breathing by nasal BMI 27±1.3 kg/m2; : elevated in PD patients. 10/15 canula pressure N= 15 (12 males) ctrl, patients with AHI > 5 events/h. In transducer, 60±4yrs), BMI 9 patients AHI between 15 and 30 thoracic and abdominal 27±1.2kg/m2 events/h. Greater median AHI in bands, microphone. PD (11 vs 6, p = 0.048); median Scoring according to

SaO2 93%. AASM guidelines from 1999. Diederich et al, 2005 Case- 4 N= 49 (38 male) AHI > 5 events/h reported in 21/49 Methodology: Triple oro- [505] controlled Parkinson patients, patients. Total AHI 9±13 nasal thermistor, 65±9 yrs, BMI (PD)/11±17 (ctrl), central AI respiratory 25.8±4.3kg/m2 ,N= 49 1.3±3.7 (PD)/1.5±5.9 (ctrl) (not plethysmography, (38 male) normal significant). microphone. Detailed controls:, age 61±15 description of scoring yrs, BMI criteria without reference. 28.5±6.7kg/m2 BMI was significantly lower in PD patients (25.8 kg/m2 vs 28.5 kg/m2 in controls), which may have affected SDB prevalence.

293

Shpirer et al, Case- 4 N= 46 (23 male) Mean AHI was greater for PD No specific description of 2006 [506] controlled Parkinson patients , patients (7.9 vs 2.7 events/h, p = sensors used for apnoea age 67±9 yrs), weight 0.01). Two statements in the classification, AASM not stated, AHI 8±13 paper: OSAS was found in 17 out 1999 criteria applied for N= 30 (18 male) of 46 PD patients and 4 out of 30 apnoea scoring. No normal ctrl, age 65±5 controls. OSAS with AHI>10 was subdivision into yrs, AHI 3±3 found in 10/46 PD patients. obstructive vs. central apnoeas. Cochen De Cock et Case- 4 N= 50 (70% male) PD patients had less SDB than Control group recruited al, controlled unselected PD controls (27% vs 40%, p=0.002), from subjects with 2010 [507] patients, 62.1±10 yrs, AHI was lower and oxygen suspected venous BMI 24.5±3kg/m2, N= desaturation nadir was higher in thrombosis, which may 50 (70% males) the PD group. The proportion of have increased the sleepy PD patients, central and mixed apnoeas was probably for SDB. Nasal 63±9 yrs, BMI similar in PD and controls: pressure transducer for 24.8±5kg/m2, 23±33% vs 18±31% vs 9±17% in flow measurement, N= 50 (70% males) controls and unselected/sleepy AASM criteria from 1999 ctrl: 62±14 yrs, BMI PD, respectively, n.s. differences. applied.

24.7±5kg/m2,

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Trotti et al, Case- 4 N= 55 (37 male) AHI > 5 events/h in 43.6% of No subdivision into 2010 [508] controlled Parkinson patients, patients obstructive vs central age 64±9yrs, BMI (14.5% with AHI >= 15 events/h). apnoeas 26.8±8.8 kg/m2, PD patients did not have more compared with the SDB than controls. population based sample of the Sleep Heart Health Study,n=6132, age 63±11 yrs. Yong et al, 2011 Case- 4 N= 56 (34male) No difference in AHI in PD and Scoring according to [509] controlled Parkinson patients, controls (total AHI 12.5±15.6 vs Rechtschaffen and Kales age 65±9yrs), BMI 12.2±13.1, central AI 0.7±4.7 vs 1968. Standard deviation 23.9±3.8 kg/m2 0.2±0.6, respectively); prevalence in central AI suggests a N= 68 (48 male) ctrl, of OSA (AHI≥5) was 49.1% (PD) few PD patients with 59±9 yrs, BMI and 65.7% (ctrl). central sleep apnoea. 23.9±3.8 kg/m2

295 e2.5.F. Central sleep apnoea in neurodegenerative diseases like Alzheimer´s Disease (AD)

Author Design EBM Patient population Results Comments (M/F) Cooke et al, Uncontrolled follow-up 4 N=10 (7 male) CPAP The group treated with Small number of patients 2009 [510] study on sustained users, 5/5 non-/ CPAP showed less cognitive included, explorative CPAP use (13.1±5.2 compliant, age 76±6 yrs, decline, stabilised study. Follow up of the months) in 5 AD patients BMI 25.9±3 kg/m2 depressive symptoms and study from Anconi-Israel who continued CPAP had less increase in daytime 2008 (2) (CPAP+) vs. 5 patients somnolence. who discontinued CPAP (CPAP-) Ancoli-Israel et Randomised double- 2 N=52 patients with AD After one treatment night, tCPAP resulted in al, 2008 [511] blind placebo-controlled and OSA, divided in the tCPAP group had improved sleep even trial. Participants were therapeutic CPAP group significantly less % Stage 1 after 3 weeks. randomised to (n=27 (19 males), age (p=0.04) and more % Stage Patients had OSA, no therapeutic CPAP 79±7 yrs, BMI 26.1±4 2 sleep (p=0.02) when information on central AI. (tCPAP) for 6 weeks or kg/m2)and in the placebo compared to the pCPAP SDB assessment with placebo CPAP (pCPAP) CPAP group (n=25 (20 group. piezo-electrical bands for 3 weeks followed by males), age 78±8 yrs, A comparison of pre- and and nasal flow sensor. therapeutic CPAP for 3 BMI 25.0±4 kg/m2) post-treatment Planned randomisation

296

weeks neuropsychological test of 50 patients per arm scores after 3 weeks of according to power therapeutic CPAP in both calculation. groups showed a significant improvement in cognition in the tCPAP group. Chong et al, Randomised, double- 2 N=39 (29 male) Within the therapeutic CPAP No subdivision into 2006 [512] blind, placebo-controlled community-dwelling group, ESS scores were obstructive or central trial elderly patients with reduced from 8.9 during breathing events. No mild-moderate probable baseline to 6.6 after 3 weeks detailed description on AD with SDB, age 78±7 of treatment (P=.04) and to used sensors for SDB yrs, BMI 24.8±4 kg/m2). 5.5 after 6 weeks of assessment. treatment (p=0.004). In the sham CPAP group, there was no significant difference after 3 weeks of sham CPAP, but a significant decrease from 7.7 to 6.5 (p=0.01) after 3 weeks of therapeutic CPAP. Ayalon et al Randomised (CPAP or 2 N=30 (23 male) patients Patients used CPAP for 4.8 AD patients with SDB

297

[513] sham CPAP) with AD,age 78±7 yrs, hours per night. More are willing to use CPAP. BMI 24.7±4 kg/m2. depressive symptoms were No efficacy data nor data associated with worse on central sleep apnoea adherence (r=-0.37; N=30, reported. p<0.04). Patients who continued using CPAP had fewer depressive symptoms and better adherence during the trial. Moraes et al, Placebo controlled RCT 2 N=23 AD (8 male) Obstructive AHI was SDB assessment with 2008 [514] patients subdivided in significantly reduced from nasal pressure cannula, three M treatment with 19.4 to 9.2/h and time <90% thermistor and 2 effort donepezil 5 mg o.d. oxygen saturation was belts. Neurocognitive (N=12, age 77±6 yrs, reduced from 13.4 to 3.7% function improved with BMI 26.3±5 kg/m2) or only in the D-group, central donepezil and the drug placebo (n=11, age AI was low (0.1 /h) in both was well tolerated. Small 73±11 yrs, BMI 26.6±4 groups and did not change sample size. kg/m2) by treatment

298

Tables of Chapter 2.6. Treatment-Emergent CSA e2.6.A. Treatment-Emergent CSA

Author Design EBM Patient population Results Comments Allam et al, Retrospective chart 4 N=100, CompSAS CPAP AHI 31 (17-47)(p= 0.02 vs. Retrospective, Chest 2007 review, PSG (63%), CSA (22%), baseline), mainly CSA. heterogenous [26] CSA/CSR (15%), BPAP-S AHI 75 (46-111)(p = 0.055). population. AHI 48 (24-62), age BPAP-ST AHI 15 (11-31) (p = 0.002). 72 (60–79) yrs, BMI ASV AHI 5 (1-11) (p < 0.0001 vs. 31 (28-33) kg/m2 , baseline and CPAP). ESS 11 (7–14) ASV increased REM vs. baseline and CPAP. Kuzniar et al, Retrospective 4 N=150 CompSAS 97 patients, (64.7 %) had ≥ 1 risk factor Sleep Breath analysis of patient pts. for CSA. 2013 [515] data base. Low prevalence of low LVEF and hypocapnia. PAP treatment adherence 73.3 %. Lehman et al, Retrospective study, 4 N=99 consecutive CSA-CPAP: 13 patients. (13.1%), 46% JCSM 2007 PSG, clinical OSAS, CSA at baseline (vs 8% p <0.01). At [28] records. N=13 (12 male) baseline higher AHI (72 vs 53, p = 0.02), CSA-CPAP higher ArI (43 vs. 29, p <0.01), higher

299

patients, age 55±16 mixed AI (7 vs 1, p = 0.03), higher CPAP yrs, BMI 33.4±7.9 to eliminate OSA (11 vs 9, p = 0.08), kg/m2: CAI ≥5/h at more frequent history of CAD or HF.

±1 cmH2O No difference in age or BMI. prescribed CPAP.

N=86 (68 male) NoCSA-CPAP patients, age 57±11 yrs, BMI 33.1±5.8 kg/m2 Javaheri et al, Retrospective study, 4 N=1286 OSA N=84 (70 male) patients developed CSA JCSM 2009 PSG, CPAP patients with PAP ≥ 5, age 53±13 yrs, BMI 33±4 kg/m2. [29] titration. titration. Overall incidence 6.5%. 4 weeks follow-up. Second PSG in 42 patients: Adherence to CPAP. Elimination of CSA in 33/42. CSA remaining in 9/42: most severe OSA at baseline; 5 had CAI ≥ 5 at baseline; 2/9 on opioids. Pusalavidyasa Retrospective 4 N=133 (64% male) CPAP prescribed in 94 and 88% of OSAS gar et al, review. OSAS, age 58±12 and CompSAS, respectively (P=0.284),

300

Sleep Med yrs and N=34 (82% no significant difference in CPAP 2006 [30] male) CompSAS, pressures (P=0.112) and in prescription age 54±16 yrs. frequency of alternative therapies. First follow-up shorter in CompSAS (46±47 vs 54±37 days; p=0.022). No difference in CPAP compliance and ESS. Interface problems more common in CompSAS air hunger/dyspnoea (0.8 vs 8.8%) and inadvertent mask removal (2.6 vs 17.7%) (all p<0.050). Yaegashi H et Retrospective chart 4 N=297 OSAS 17 patients (5.7%) had CompSAS. al, Int Med review. patients referred for Multiple, stepwise, and logistic regression 2009 [31] CPAP titration, analyses: CAI in the supine position AHI≥20. during NREM (p=0.026) significantly N=280 (84% male) distinguished CompSAS from OSAS OSAS patients, age (2.5±3.1 vs. 0.9±2.3), variables were 59±15 yrs, BMI within normal range. 25.7±3.9 kg/m2, AHI 48±20. N=17 CompSAS patients, age 55±16

301

yrs, BMI 28.8±6.1 kg/m2, AHI 56±24. Brown SE et Retrospective cohort 4 N=25 consecutive No significant change of AHI under PAP al, JCSM 2011 Study, ASV patients with PAP- as compared to baseline. CAI increased [32] refractory CSA, age 35±24, p <0.001). ASV: AHI fell to 4±4 60±17 yrs, BMI 30.4 (p<0.001). AHI<10 in 92% patients, CAI ± 6.1 kg/m2, AHI 1±2, (p<0.001). Respiratory arousals 49±30, CAI 11±16). showed parallel improvements on ASV. 18 established CompSAS. Kuzniar TJ et Non-randomised 4 N=76 (61 male) 35 VPAP-AdaptSV®, 41 BIPAP- Inhomogenous al, Sleep Med parallel cohorts, consecutive AutoSV®. Adherence 73.7%, nightly use population, no 2011 [33] retrospective, 4-6 patients, , age 65 5 (3-6) for VPAP-AdaptSV® vs 6 (4-7) for substantial weeks (54-78) yrs, ESS 11 BIPAP-AutoSV® (p=0.081); Higher differences between (8-14) with baseline AHI and higher ESS the devices CompSAS, PSG, improvement in the BIPAP-AutoSV® 4 CPAP followed by (1-9) vs 3 (0-5), p=0.02. VPAP-AdaptSV® or BIPAP-AutoSV®. N=35 (28 male) VPAP-AdaptSV®

302

patients, age 66 (59-78), ESS 11 (8- 13). N=41 (33 male) BIPAP-AutoSV®, age 64 (53-78), ESS 12 (9-16). Ramar et al, Retrospective study. 4 N=106 (89 male) ASV: AHI 11±13, AHI<10: 81.1 %. Sleep Breath ASV titration with consecutive Elevated narrow band low frequency 2013 [34] PSG signals CompSAS patients, coupling in 45.3 %. amenable to age 63 yrs. No correlation of eNB-LFC with ASV cardiopulmonary Baseline AHI 38 success. coupling (CPC) (21-56), AHI under analysis. CPAP 37 (23-58), CAI 23 (13-39).

Dernaika et al, Cross-sectional 3 N=42 OSA patients No difference in demographics, left Chest 2007 analysis, split-night with (21) and ventricular systolic dysfunction. CSA: [23] PSG without (21) CPAP- decreased sleep efficiency, increased S1, related CSA. sleep stages shift, WASO, total arousals. With CSA: age 92% of CSA patients.: complete or near-

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59±12 yrs, BMI complete resolution of CSA on follow-up 35.9±6.1 kg/m2. PSG, improvement in sleep parameters. Without CSA: age 59±12 yrs, BMI 36.8±5.9 kg/m2. Echocardiography, lung function testing, ABG analysis. PSG after 2-3 M CPAP in CSA group patients.

Cassel et al, Prospective study, 3 N=675 (86% male) 12.2% CompSA at baseline. 28 lost to ERJ 2011 [24] PSG baseline, first OSA patients, age follow-up. CompSA at follow-up in 14/54 night and after 3 M 56±12 yrs, BMI of remaining pts. CompSA at follow-up in CPAP. 32.2±5.7 kg/m2. 16/ 382 patients, not initially diagnosed ESS 11±5. with CompSA. CompSA at follow-up N=82 (86.6% 6.9%. Individuals with CompSA were 5 males) with yrs older, 40% CAD. CompSA, age 60±10 yrs, BMI

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31.8±5.3 kg/m2, AHI 36 (22-55). N=593 (86% males) without CompSA, age 55±12 yrs, BMI 32.3±5.8 kg/m2, AHI 26 (15-44). Nakazaki et al, PSG, LVEF, nasal 3 N=52 patients with CompSAS: Nasal resistance higher Sleep Breath resistance. suspected OSA, in CompSAS vs OSAS (0.30 ± 0.10 vs. 2012 [25] age 51±13 yrs: 0.19 ± 0.07 Pa/cm3/s, p=0.004), normal OSA: N=38 (90% LVEF.

male), age 50±14 OSAS: ArI, S1, SaO2 significantly yrs, BMI 30.3±5.3 decreased, REM significantly increased kg/m2, under CPAP. CompSAS: N=5 (100% male), age 45±10 yrs, BMI 28.7±7.1 kg/m2 CSA: N= 9 (characteristics not reported).

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Morgenthaler Prospective 1b N=21 (20 male) 15 patients got initially CPAP with et al, Sleep randomised patients, age 65±12 persistent respiratory events(AHI 34±26, 2007 [20] crossover, NIV vs. yrs, BMI 31±5 RAI 32±30). ASV, in CSA/CSR, kg/m2, AHI 52±23 (6 NIV (n=21): AHI 6±8 and RAI 6±8. predominantly mixed CSA/CSR, 6 ASV : AHI 1±2 and RAI 2±5. AHI and RAI apnoeas, and predominantly were both significantly lower using ASV CompSAS in an mixed apnoeas, 9 (p<0.01). acute setting. CompSAS), baseline AHI 52±23, RAI 46±27. Morgenthaler RCT, CPAP vs. 1b N=66 patients, 33 in Initial AHI on ASV 5±8 (CAI 1±4), on et al, Sleep ASV, 90 dyas each arm, age CPAP 14± 21 (CAI 9±16) (p≤0.0003). At Med 2014 [21] 59±13 yrs, BMI 35.0 90 days, ASV AHI 4±10, CPAP 10±11 ±8.0, ESS 10±5, (p=0.0024). AHI<10: ASV 89.7%, CPAP AHI 38±28, CAI 64.5% (p=0.0214). No difference in 3±6. compliance, ESS, SAQLI. Dellweg et al, RCT, ASV vs. BPAP- 1b N=30 (21 male) NIV vs ASV titration night: AHI (9±4 vs Sleep 2013 ST (NIV), PSG after CompSAS,baseline 9±6), CAI (2±3 vs 3±4). After 6 weeks: [22] 6 weeks. data under CPAP AHI 17±8 vs 7±4, p=0.027, CAI 10±5 vs prior to 2±2, p<0.0001. Other sleep parameters randomisation were unaffected by any form of treatment.

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(NIV group vs ASV group) : age 64±11 vs 61±11, male gender 10 vs 11, BMI 29.7±4.2 kg/m2 vs 30.3±4.3, AHI 29±6 vs 28±10, AI 19±6 vs 21±9, CAI, 17±5 vs 18±7.

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Tables of chapter 2.7. Idiopathic Central Sleep Apnoea e2.7.A. Idiopathic Central Sleep Apnoea

Author Design EBM Patient population Results Comments Xie, A. et al. Case series 4 N = 8, patients with Minute ventilation (VI) was greater (6.3 +/- 0.7 1994 [243] ICSA (mean +/- versus 5.4 +/- 0.8 L/min, p < 0.05) and mean SEM, 45.4 +/- 4.7 transcutaneous PCO2 (PtcCO2) was lower central apneas and (37.8 +/- 1.3 versus 38.9 +/- 1.6 mm Hg, p < hypopneas/h TST). 0.05) during periodic breathing than during stable breathing. VI during the ventilatory phase of the periodic breathing cycle increased progressively with increasing grades of associated arousals from Grade 0 (no arousal) (10.3 +/- 1.4 L/min) to Grade 1 (EEG arousal) (12.6 +/- 1.6 L/min) to Grade 2 (movement arousal) (14.1 +/- 1.6 L/min, p < 0.01). There was a corresponding progressive increase in central apnea length following the ventilatory period from no arousal (14.1 +/- 2.0) to EEG arousal (16.4 +/- 1.8) to movement arousal (18.1 +/- 2.0 s, p < 0.01).

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We conclude that arousals and hyperventilation interact to trigger hypocapnia and central apneas in ICSA. Xie, A. et al. Case series 4 Patients with ICSAS; Apneas and hypopneas decreased from 43.7 1997 [244] fraction of end-tidal +/- 7.3 on N1 to 5.8 +/- 0.9, during N3 (P < CO2 and 0.005) from 43.8 +/- 6.9, during room air transcutaneous breathing to 5.9 +/- 2.5; during CO2 inhalation PCO2 were during N2 (P < 0.01), and to 11.6% of the room measured: during air level on N4 (P < 0.005). room air breathing (N1), alternating room air and CO2 breathing (N2), CO2 breathing all night (N3), and addition of dead space via a face mask all night (N4). Quadri, S. Case series 4 N=20, patients with 9 week follow-up polysomnography showed 2009 [245] ICSA received 10mg AHI and CAHI decreased, 30.0 +/- 18.1 (SD) Zolpidem at bedtime to 13.5 +/- 13.3 (p = 0.001), and 26.0 +/- 17.2

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to 7.1 +/- 11.8 (p < 0.001). Total number of arousals per hour decreased under zolpidem, 24.0 +/- 11.6 to 15.1 +/- 7.7 (p < 0.001), leading to significant improvement in sleep efficiency. DeBacker, W. Case series 4 N= 327 patients CAI (25.5 +/- 6.8 at N1) already decreased et al. 1995 screened, 14 (4,3%) during N2 (13.8 +/- 5.2) and further during N3 [246] patients with (6.6 +/- 2.9) and N4 (6.8 +/- 2.8) p < 0.01). OAI suspicion of SRBD remained unchanged. Total sleep time (TST) with CAI > 5 or AHI > and sleep efficiency index (SEI) did not change 10 and OAI < 5 significantly. The number of arousals included decreased from 62 +/- 11 at N1 to 40 +/- 5 at N3 (p = 0.019 Banno et al. Case series 4 N = 3, patients with Mean abnormal breathing events index 2006 [247] ICSB examined the decreased from 35.2 to 3.5/h sleep on ASV. feasibility of using Significant reduction in mean number of ASV to treat them. arousals caused by abnormal breathing from The patients had a 18.5 to 1.1/h sleep. After 6-12 M ASV use, periodic breathing significant improvement in subjective daytime pattern resembling alertness and mood. Cheyne-Stokes

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Breathing.

Tables of chapter 3.2. Treatment of congenital central hypoventilation syndrome: e3.2.A. Mechanical ventilation

Author Design EBM Patient population Results Comments Weese-Mayer et al, Case series 4 N=32 (19 male) CCHS In 22 living patients, 12 1992 [261] patients, all with severe required continuous sleep hypoventilation ventilator support and

(alveolar PCO2 62±3 N=10 breathed

mmHg, SaO2 65%). spontaneously while awake Awake hypoventilation on and require ventilator initial assessment in support while asleep. N=12. 13% were black, 81% non-Hispanic white and 6% Hispanic. The diagnosis was made in the neonatal period in all but one case. Hartmann et al, Case series 4 N=9 CCHS patients, age VNEP was successfully VNEP is an effective 1994 [266] 20 days-57 months, initiated in n=7. Additional non-invasive

311 treated with Negative inspired O2 was initially treatment in infants Extrathoracic Pressure required in all but 2 with CCHS if Ventilation (VNEP). patients during sleep and initiated before wakefulness until ages 2- tracheostomy. If 12 M (median 4 M), and upper airway during sleep thereafter in obstruction is a three patients until ages of problem in the first 12-18 M. 1 patient was on year of life, it may be continuous additional combined with nasal inspired oxygen. All mask CPAP. patients required additional inspired oxygen during subsequent respiratory tract infections and this was given in sufficient amounts to produce normal

SaO2 levels. N=6 patients are receiving VNEP at home. In N=3 patients, hypoventilation improved with time. In N=2, VNEP

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failed. These patients underwent long term IPPV via tracheostomy. Jardine et al, 1999 Case series 4 N=141 children in UK N=18 (13%) had CCHS. [516] requiring long-term N=13 were living at home, ventilation. N=5 were living in the hospital. Kamm et al, 2001 Case series 4 N=13 patients with N=6 patients received The number of [517] CCHS. positive pressure ventilator-supported ventilation with children with tracheostomy, n=5 patients neuromuscular got positive pressure disorders did not ventilation with non- outnumber the ones invasive mask. N=2 were with CCHS. treated with diaphragmatic pacing. Children with CCHS who required ventilation from birth (n=10) remained in the hospital 6 to 14 months before home care became possible.

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Faroux et al, 2003 Case series 4 N=9 patients with CCHS Volume-targeted ventilation [518] in a series of 102 children was preferred in 56% of the with noninvasive cases. Patients with CCHS mechanical ventilation. were ventilated for the Gender was equally longest time (22% more distributed. Only 1 than 5 years). Sleep patient was <3 yrs. studies were performed on a routine base (no data provided). Symptoms of nocturnal hypoventilation were present in nearly all patients with CCHS. Tibballs et al, 2003 Case series 4 N=4 CCHS patients, age Illustration of the choice of [519] range 6-16 yrs. assisted ventilation. NIPPV generally outweigh the disadvantages and complications such as aerophagia and facial pressure. Vanderlaan et al, Case series 4 N=196 (98 male) patients Hirschsprung’s disease Focus on medical 2004 [267] with CCHS, age 10±7 present in 16%. 62% of and social

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(0.4-38) yrs. N=13 were the children had characteristics of over 20 yrs and N=59 tracheostomy, 14% were children with CCHS. were ≤5 yrs. 21% of the never tracheotomized. Respiratory support children were born 39% did not have a approaches varied, prematurely, with a mean tracheostomy at time of but clearly reflected gestation age of 32±8 survey. 10% were 24-hr the trend towards weeks. ventilator-dependent, 82% earlier and more were requiring mechanical widespread ventilatory support only transition to while asleep, 4% received noninvasive mechanical ventilation ventilatory during sleep plus another modalities.The hour sometime during the majority of home

day, another 4% received CO2 monitor users

mechanical ventilation se the high CO2 during sleep plus during alarm at 46-55 several hours during mmHg, while over daytime. In USA : 24% is half of the remaining ventilated without a users set the alarm tracheostomy, in Europe limit at >55 mmHg. this 53% (France : 35%, Backup ventilators

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UK and Germany 67%, were present in 60% Italy 47%). For the 24-hr of patients at home. ventilator-dependent children (n=20), 65% were discharged by age of 7 months. 49% used a pressure or volume home ventilator, 2% used a bilevel positive pressure device, 28% used nasal or facemask ventilation without tracheotomy. 3% used negative-pressure ventilators without tracheotomy. The transition to NIV occurred between the ages 6-11 yrs. 34% aged ≤5 yrs were using NIV. Two-third of these children were able to

316

adequately maintain ventilatory homeostatsis during waking hours by age 12 months, while another quarter of the children were ≥1 year before they achieved such an ability. Trang et al, 2005 Case series 4 N=70 (29 male) patients All patients required [264] with CCHS. ventilatory support during the neonatal period. In N=50 who lived beyond 1 year of age, all but 1 received nighttime ventilatory support. Ottonello et al, 2007 Case series 4 N=9 children with CCHS All patients with CCHS [520] in a larger series of started mechanical children treated with ventilation acutely (in home mechanical emergency conditions). 1 ventilation. CCHS patient needed 24 h support.

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e3.2.B. Diaphragmatic pacing

Author Design EBM Patient population Results Comments Hunt et al, 1978 Case series 4 N=3 CHHS infants. Case 1 died of problems [271] primarily related to severe cor pulmonale. Case 2 died due to extensive phrenic nerve damage incurred by 19 days of continuous pacing. Case 3 has been able to maintain normal quiet sleep ventilation. Weese-Mayer et al, Case series 4 N=23 CCHS patients, The mean time to need for Diaphragm pacing is 1989 [272] N=2 with late onset replacement of any effective but not CCHS, N=3 Arnold-Chiari implanted component was without risk of malformation and 56 M. 26 failures occurred biomedical myelomeningocoele, and requiring component component failure. N=5 with quadriplegia. replacement: N=15 receiver failure,

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N=6 electrode wire or wire insulation breakage, N=3 infection requiring diaphragm pacer system removal, N=2 mechanical nerve injury. Flageole et al, 1995 Case series 4 N= 3 CCHS patients, age In N=2, a bilateral axillary [273] 1, 2, and 5 yrs. thoracotomy was used. In N=1, an anterior thoracotomy was used. No infectious complications in any patient. Implant failure on 2 separate occasions in 1 patient within 10 yrs. Weese-Mayer et al, Case series 4 N=14 CCHS patients in a The incidence of 1996 [274] series of N=64 patients mechanical trauma was treated with diaphragm 3.8%. The incidence of pacing. The mean electrode and receiver pacing duration among failure were 3% and 6%. pediatric CCHS patients Receiver failure was was 1.7±0.8 yrs. None of significantly greater among

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the CCHS children was pediatric CCHS patients. paced continuously, Internal component failure rather they were typically greater among pediatric paced 12-15 h/d. CCHS compared to pediatric tetraplegic patients. Complications free successful pacing occurred in 60% of pediatric and 52% of adult patients. Infections occurred only among 4 CCHS patients and significantly greater than among pediatric tetraplegic patients. Entrapment of a phrenic nerve in an electrode occurred in 1 pediatric CCHS patient. Shaul et al, 2002 Case series 4 N=9 CCHS children, age Phrenic nerve electrodes [275] 5-15 yrs. were implanted thoracoscopically. Average

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procedure time 3.3 2.5- 4.6 hours. Average hospital stay 4.2 days. Abdullah et al, 2008 Case series 4 N=6 (2 male) CCHS Surgery on an average age [276] patients, age 4-23 yrs. of 48 M, with bilateral axillary thoracotomy. All patients are ventilator-free during the day. In N=2, the receiver was replaced once at 3 and 5 yrs from insertion. N=1 had the receiver replaced once on each side at 9 and 12 yrs from the time of insertion. The average time to failure of a receiver was 97 M (compared to 63 M for the duration of the implanted components. Nicholson et al, Case series 4 N=18 (10 male) CCHS Thoracoscopic procedure, The majority of 2015 [277] patients, age 5.7 (4.5- with no conversions to patients was able to

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12.1) yrs open procedures. Mean achieve pacing surgical time was 3.3±0.7 goals. h. N=11 (61%) patients achieved their daily goal pacing times within the follow-up period. Diep et al, 2015 Case series 4 N=18 (8 male) CCHS N=11 could be Obesity prevented [278] patients, age 20±10 yrs. decannulated and were successful Had been using home successfully ventilated by diaphragmatic portable positive diaphragm pacing without pacing in one pressure ventilation via tracheostomy. patient. Upper tracheostomy (N=14), via airway obstruction endotracheal tube (N=1) prevented success or noninvasively (N=3). in another patient.

Table e3.2.C. Respiratory stimulants

Author Design EBM Patient population Results Comments Oren et al, 1986 Case series 4 N=12 CCHS children. There was no significant Almitrine is not a [279] N=7 received 4.5 mg/kg improvement in ventilator useful ventilatory

322 almitrine. N=6 received and gas exchange stimulant in children 6mg/kg almitrine. parameters at either dose with CCHS. of almitrine, despite appropriate peak serum concentration of the drug at the time of the studies.

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3. Hypoventilation or Hypoxemic Syndromes

Tables of chapter 3.3. Hypoventilation/hypoxic diseases secondary to internal or neurological disorders e3.3.A. Amyotrophic Lateral Sclerosis

Author Design EBM Patient population Results Comments Aboussouan et Prospective 4 N=39 ALS patients, Patients tolerant to NIV show NIV tolerance was al, 1997[521] cohort study 18 tolerant to NIV, FVC 45 ± better survival (RR, 3.1 [95% CI, defined as > 4 h 13 %Pred, MIP 35 ± 20 1.8 to 9.6] consecutive use of NIV

%Pred, PaCO2 52 ± 8 mmHg. 21 intolerant to NIV, FVC 38 ± Moderate to severe bulbar Bulbar function was 13%Pred, MIP 29 ± 13 %Pred, symptoms have a higher assessed by the

PaCO2 50 ± 7 mmHg. prevalence in intolerant patients speech and swallow (67 vs 33%) components of the amyotrophic lateral sclerosis severity scale Carratu et al, Retrospective 4 N = 72 ALS patients, Patients tolerating NIV showed 2009 [522] cohort study 44 (27 male) patients with FVC better survival (χ²: 5.32, p = 0.02) > 75 %Pred, age 51 ± 7 yrs, No difference in survival was

FVC 83 ± 12 %Pred, PaCO2 found between patients tolerating 36 ± 7 mmHg. NIV and patients with FVC > 75 %

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16 (9 male) patients with FVC Pred (χ² : 0.408, p = 0.5) < 75 %Pred and NIV, age 56 ± The slope of decline of FVC was 5 yrs, FVC 65 ± 13 %Pred, significantly lower in patients using

PaCO2 42 ± 9 mmHg. NIV (1.52 ± 0.3 vs 2.81 ± 0.8; p < 12 (7 male) patients with FVC 0.0001) < 75 %Pred refusing or not tolerating NIV, age 58 ± 7 yrs,

FVC 62 ± 13 %Pred, PaCO2 40 ± 9 mmHg Siirala et al, 2013 Retrospective 4 N = 84 ALS patients, In patients ≤ 65 yrs, no difference [523] cohort study 42 patients ≤ 65 yrs of whom in survival was found between NIV 23 (10 male) patients, age 61 and conventional treatment (14

(range 49-65) yrs, PaCO2 6.3 ± (range 1-60) vs 15 (range 5-38) M; 1.5 kPa) were treated with NIV HR = 0.88, 95% CI 0.44-1.77, p = and 19 (10 male) patients, age 0.7). 58 (range 49-65) yrs conventionally treated In patients > 65 yrs, NIV users 42 patients > 65 yrs of whom survived longer than 18 (9 male) patients, age 76 conventionally treated patients (22

(range 66-85) yrs, PaCO2 6.5 ± (range 3-65) vs 8 (range 1-26) M; 1.3 kPa, were treated with NIV HR = 0.25, 95% CI 0.11-0.55, p <

325

and 24 (8 male) patients, age 0.001). 77 (range 66-84) yrs conventionally treated Escarrabill et al, Retrospective 4 N = 10 (8 male) ALS patients, Patients on NIV showed In the NIV group, 3

1998 [524] cohort study age 59 ± 8 yrs, FVC 50.7 ± improvement in nocturnal SpO2 patients used volume-

19.9 %Pred, PaCO2 52.5 ± 8.1 (SpO2< 90%, 8% (range 0.6-32%) controlled and 3 mmHg. vs 62% (range 7-97%), p < 0.005). patients used pressure-

4 patients got TIV PaO2 increased from 78 ± 3 to 87 controlled ventilation

6 patients got NIV ± 9 mmHg. PaCO2 decreased from 53 ± 8 to 43 ± 9 mmHg). Overall survival was 60% at 6 M and 30% at 12 M. Shoesmith et al, Retrospective 4 N = 21 (16 male) ALS patients Mean survival time in respiratory 2007[525] cohort study with respiratory onset, age 66 onset did not differ from survival in ± 7 yrs. bulbar onset (p = 0.43). Kaplan- Meier survival curves were not significantly different (log-rank statistic, p = 0.39)

NIV was tolerated in 9 patients. Survival with NIV differed from

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survival without NIV (36 ± 16 vs 22 ± 16 M, p = 0.02) Lo Coco et al, Prospective 4 N = 33 (25 male), age 62 ± 12 The ALSFRS score was a Patients who could be

2007 [526] cohort study yrs, PaCO2 83 ± 7 mmHg. significant predictor of length of extubated or weaned All patients on TIV because of hospital stay (HR : 2.86, 95% CI: from tracheostomy and hospitalisation for ARF 1.1-5.1) and survival (HR : 0.52, placed on NIV were ALSFRS =11 (IQR 7-15.5) at 95% CI :1.4-9.7) after TIV excluded hospitalisation Laub et al, 2007 Prospective 4 N = 1526 After NIV, the probability for 4% of ALS patients [527] cohort study 165 (112 male) ALS patients, survival in ALS was 20% after 2 used TIV,

age 64 ± 11 yrs, PaCO2 6.6 ± yrs and 5% after 5 yrs. 19% among other NMD 1.4 kPa. used TIV 224 (130 male) NMD patients,

age 49 ± 16 yrs, PaCO2 7.3 ± Significant factors for 1.7 kPa. survival were found for the entire group, of which only 389/1526 patients had NMD. Farrero et al, Retrospective 4 N = 64 (46 male) ALS patients, Higher incidence of TIV and ICU 2005 [528] cohort study age 60 ± 11 yrs. initiation observed in group A N=15 non-protocolised NIV in group A showed a younger

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patients (Group A), age and more severe baseline N=49 protocolised (prospective ABG alterations respiratory evaluation) patients Non-bulbar patients showed better (Group B) survival (27 ± 4 vs 15 ± 2 M, p = 0.03) N=57 patients used NIV (27 Bulbar involvement was an bulbar) independent predictor for survival (RR 1.6, 95% CI1.01 to 2.64, p = 0.04) Lyall et al, 2001 Prospective 4 N=16 (15 male) patients in the The SF-36 « vitality » subscale [529] cohort study NIV group, age 61 ± 7 yrs, VC improved after initiation of NIV and

53 ± 22 %Pred, PtcCO2 51 ± 9 was maintained, despite disease mmHg. progression. 11 (9 male) patients in the age- Other subscales did not show any matched control (normal improvement. diaphragmatic function) group, age 61 ± 8 yrs, VC 95 ± 15

%Pred, PtcCO2 35 ± 3 mmHg. Butz et al, 2003 Prospective 4 N = 30 (22 male) ALS patients, NIV improved sleep quality, NIV provides long- [530] cohort study age 30-74 yrs daytime sleepiness, physical lasting benefit on fatigue and depression. NIV symptoms and quality

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improved PaCO2, PaO2 and SaO2 of life for ALS patients. for up to 7 M. Boentert et al, Retrospective 4 N = 65 (36 male) ALS patients, At baseline, 60% showed 2015 [531] cohort study age 63 ± 12 yrs, BMI 25.0 ± nocturnal hypercapnia. 26% 4.3 kg/m², FVC 51 ± 23 showed daytime hypercapnia. %Pred. %REM was negatively correlated

with mean and maximum PtcCO2 (r = -0.45 and r = -0.44 respectively, p < 0.001)

First night on NIV showed improvements in sleep stage changes (22 ± 20 vs 17 ± 10 /h TST, p< 0.05), %N3 (19 ± 10 vs 23 ± 11 %, p < 0.01), %REM (10 ± 6 vs 14 ± 7 %, p < 0.001), AHI (13 ± 20 vs 5 ± 7 /h TST, p = 0.001), ODI (10 ± 12 vs 5 ± 7 /h TST, p <

0.0001), mean SpO2 (91 ± 3 vs 92 ± 3 %, p < 0.0001), time with

SpO2< 90% (97 ± 135 vs 66 ± 111

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min, p < 0.01), RR (18 ± 4 vs 16 ± 2 bpm, p < 0.0001) and maximal

PtcCO2 (52 ± 8 vs 49 ± 7 mmHg, p < 0.01).

Bulbar patients also improved in

SEI, but not in time with SpO2<

90% and maximal PtcCO2

Non-bulbar patients also improved did not improve in sleep stage changes.

No systematic deterioration of sleep quality was detectable over time. Vrijsen et al, Prospective 4 N = 24 (21 male) ALS patients, Non-bulbar patients showed 2015 [532] cohort study age 60 ± 10 yrs, VC 56 ± 14 improvement in sleep structure

%Pred, MIP 35 ± 12 cmH2O, after 1 M NIV (TST: 311 (IQR 107-

PaCO2 46 ± 6 mmHg. 128) vs 364 (273-457) min, p < 0.05; SE: 62 (19-81) vs 72 (52-85)

330

%, p < 0.05; N1: 23 (8-56) vs 5 (4- 11) %, p < 0.01; N3: 0 (0-6) vs 16 (13-19)%, p < 0.01; REM: 6 (0-12) vs 22 (10-23)%, p < 0.01; AI: 42 (36-82) vs 17 (12-26), p < 0.01)

Bulbar patients showed no improvement in sleep structure.

Patient-reported sleep quality and quality of life improved in non- bulbar patients, while bulbar patients only improved sleep quality, but not quality of life.

Non-bulbar patients showed

improvement in SpO2 and PtcCO2 over the total night and different sleep stages, while bulbar patients

only improved in SPO2 during REM.

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Patients with worse nocturnal

PtcCO2 at initiation showed better therapeutic compliance. Sanchoet al, Prospective 4 N = 32 (13 male) stable non- 15 patients needed NIV during 2015 [533] cohort study ventilated ALS patients, age 61 respiratory tract infections. ± 11 yrs, FVC 56 ± 23 %Pred. FVC %Pred (OR 1.06, 95% CI 1.01-1.11, p = 0.02) and PCF (OR 2.57, 95% CI 1.18-5.59, p = 0.02) were predictors of need for NIV Lyall et al, 2001 Prospective, 4 N = 81 (65 male) ALS patients, Without significant bulbar The non-invasive SNIP [534] observational age 61 ± 9 yrs, VC 71 ± 28 involvement, sniff Pdi had the is more sensitive than study %Pred, MIP 45 ± 31%Pred, greatest predictive power (OR 57) VC and MIP SNIP 51 ± 32 %Pred. for ventilator failure, with 16 (10 male) patients in the specificity 87% and sensitivity bulbar group, age 61 ± 8 yrs, 90%. SNIP % Pred (OR 25) VC 65 ± 26 %Pred, MIP 34 ± showed specificity 85% and 29%Pred, SNIP 42 ± 25 sensitivity 81%, while for VC %Pred. %pred (OR6), specificity was 65 (55 male) patients in the 83% and sensitivity 55%. No test limb group, age 61 ± 9 yrs, VC had significant predictive power

332

72 ± 28 %Pred, MIP 48 ± for the presence of hypercapnia in 32%Pred, SNIP 55 ± 32 the subgroup of bulbar patients. %Pred) In 35 patients who underwent PSG, SNIP was significantly correlated with AHI (p = 0.026). Gruis et al, 2005 Retrospective 4 N = 139 (72 male) ALS 72 patients were prescribed NIV Tolerance to NIV was [535] cohort study patients, age 63 ± 12 yrs, BMI and information of tolerance was defined as ≥ 4 hours 25.8 ± 7.1 kg/m², FVC 47 ± 12 available in 50 patients nocturnal use. kg/m². Mutivariable analyses showed limb onset being the only independent predictor of NIV tolerance (OR = 6.25, 95% CI 1.09-33.33). Lo Coco et al, Prospective 4 N = 38 (15 male) ALS patients, Average time without chronic Patients were followed- 2006 [536] observational age 60 ± 12 yrs, FVC 87 (IQR hypoventilation was12 M (95% CI up for 26 M and study 72-104) %Pred. 9-20) occurrence of alveolar hypoventilation was N=14 patients were identified 20 patients started NIV with recorded as study end- as slowly, N=10 patients as survival of 17 M (IQR 7-22) point. intermediate and N=14

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patients as rapidly progressive The category of disease progression was the only variable showing a significant risk ratio (RR12.71, 95% CI 3.51-46.07, p < 0.0001) for development of chronic hypoventilation

Yamauchi et al, Prospective 4 N = 43 ALS patients, G2 had worse PaCO2 at NIV All respiratory function 2014 [537] cohort study Group 1:N=17 (6 male) initiation. parameters at NIV patients, age 60 ± 12 yrs, FVC initiation were

72 ± 24 %Pred, PaCO2 43 ± 8 PaCO2 was the only parameter significantly worse in mmHg, started NIV while identified by multivariate analysis group 2. DCMAP was normal as independently associated with Group 2: N=26 (15 male) low DCMAP at NIV initiation (OR patients, age 65 ± 13 yrs, FVC 233.3, 95% CI 3.2-89,002.4, p =

53 ± 24 %Pred, PaCO2 51 ± 9 0.01) mmHg, started NIV when DCMAP < 220 μV. Tollefsen et al, Retrospective 4 N = 308 (215 male) ALS M/F ratio of 2.3/1 in ventilated ALS Statistically significantly 2010 [538] cohort study patients on NIV or invasive patients. more men than women ventilation, age 62 (27-89) yrs. with ALS are using mechanical ventilation.

334

Lechtzin et al, Retrospective 4 N = 92 ALS Median time from ALS diagnosis Clinicians should 2007[539] cohort study N=25 (64% male) started NIV to death was longer in early group encourage earlier use when FVC >65% Pred, age 59 (2.7 yrs vs. 1.8 yrs, p=0.045) of NIV in ALS ± 3 yrs ; N=65 (57% male) patients. started NIV when FVC < 65% Pred, age 63 ± 1 yrs Gordon et al, Retrospective 4 N=2037 (1111 male) ALS Compared to patients first seen Better survival results 2012[540] cohort study patients before 2004, the HR of from improved death was 0.97 (95% CI = 0.85– respiratory care in ALS 1.11, p = 0.6721) for patients. patients first seen in 2004–2005, 0.96 (95% CI = 0.83–1.10, p = 0.5125) for 2006–2007, and 0.56 (95% CI = 0.46–0.69, p<0.0001) after 2007, while adjusting for other survival predictors. Sivori et al, Prospective 4 N = 97 (62 male) ALS patients, Median survival: 2007[541] cohort study age 54 ± 13 yrs. N=29 No riluzole, no NIV: 10.7 ± 7.9 M patients received NIV and Riluzole, no NIV: 11. 2 ± 7.8 M N=68 did not. NIV, no riluzole: 13.5 ± 13.4 M Riluzole, NIV: 16.6 ± 11.00 M (p =

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0.021 vs no riluzole, no NIV)

NIV vs no-NIV survival: 15.4 ± 7.8 vs 10.9 ± 7.8 M (p = 0.028) Gonzalez- Retrospective 4 N=82 ventilated ALS patients. Survival was better in Group 1 NIV effectiveness to Bermejo et al, cohort study N=40 (68% male) « correctly (75% survival at 12 M) than in correct nocturnal O2 2013 [542] ventilated », age 63 ± 12 yrs Group 2 (43% survival at 12 M, desaturations is an and N=42 (83% male) « not p = 0.002). independent prognostic correctly ventilated », age 64 ± factor. 10 yrs. Sancho et al, Retrospective 4 ALS patients ; N=82 (62 male) Effective NIV was achieved in Vol-NIV and Pres-NIV 2014 [543] cohort study with pressure-cycled 72% Vol-NIV patients and in 49% present similar survival ventilation, age 64 ± 12 yrs Pres-NIV patients ( p < 0.001). No in ALS. and N=62 (28 male) with differences were found in survival volume-cycled ventilation, age from NIV initiation. 62 ± 9 yrs Wei et al, 2015 Prospective 4 N = 1049 (627 male) ALS NIV treatment showed a positive [544] cohort study patients, age 53 ± 12 yrs effect on survival rate (HR = 0.491, 95% CI 0.310-0.777) Pinto et al, 1995 Prospective 4 N=20 (11 male) bulbar ALS, Improved total survival (100% vs Palliative management [545] cohort study age 57 (range 51-69) yrs. 89% after 1 yr ; 88 vs 22 after 3 was described as

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N=10 patients on NIV (VC 48 ± yrs ; p = 0.004) and survival since treatment with O2, 13 %Pred, PCO2 41 ± 4 onset of diurnal disorder of gas bronchodilators and mmHg); exchange ( 89 vs 22% after 6 M ; other palliative N=10 patients with palliative 74 vs 0% after 1 yr ; p = 0.0006) measures management (VC 64 ± 11 was found in the NIV treated %Pred, PCO2 40 ± 2 mmHg) group VC at baseline differed significantly Kleopa et al, Retrospective 4 N = 122. Patients using NIV > 4h showed No dissociation was 1999 [546] cohort study N=38 (19 male) patients used better survival (since diagnosis made between bulbar NIV > 4h, age 60 ± 13 yrs, and NIV) compared to those using and non-bulbar patients FVC 40 ± 14 %Pred. NIV < 4h or those refusing NIV N=32 (9 male) patients used Patients using NIV < 4h showed NIV < 4h, age 63 ± 10 yrs, better survival (since NIV) FVC 36 ± 11 %Pred. compared to those refusing NIV N=52 (24 male) patients refused NIV, age 64 ± 11 yrs, The slope of decline of FVC was FVC 37 ± 9 %Pred. significantly lower in patients using NIV > 4h Bourke et al, Prospective 4 N = 22 (15 male) ALS patients. QoL domains assessing sleep- Orthopnoea was the 2003 [547] cohort study N=17 subjects were offered a related problems and mental best predictor of benefit trial of NIV; 15 accepted, and health improved (effect sizes 0.88 from and compliance

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10 continued treatment to 1.77, p < 0.05) and were with NIV. Daytime subsequently, age 32-74 yrs. maintained for 252 to 458 days. hypercapnia and Median survival following nocturnal O2 successful NIV initiation was 512 desaturation also (191-793) days. predicted benefit, but Survival and duration of QoL were less sensitive. benefit were strongly related to Moderate or severe compliance. bulbar weakness was VC decreased less strong associated with lower following NIV initiation compliance and less improvement in QoL. Dreyer et al, 2014 Prospective 4 N=409 (245 male) ALS The average treatment time in the NIV followed by [548] cohort study patients, age 62 (23-97) yrs, groups was: 1) 23 M (range 1 – invasive ventilation has divided into four groups : no 164); 2) 26 M (range 1 – 145); 3) a significant effect on treatment, NIV, NIV followed 57 M (range 14 – 207); and 4) 34 survival in ALS by TIV, TIV M (range 6 – 88). patients. Aboussouan et Prospective, 4 N = 47 ALS patients, age 62 NIV has no impact on the rate of al, 2001 [549] observational (32-79) yrs, FVC 41 (16-70) decline of lung function and may

study %Pred, FEV1 44 (17-78) have deleterious effects on %Pred. spirometric measures. 23 patients were tolerant to Median survival in the intolerant

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NIV group was 5 M compared to 20 M 24 patients were intolerant to in the tolerant group (p = 0.002) NIV Peysson et al, Retrospective 4 N = 33 (24 male) ALS patients, Median survival from ALS onset Advanced age at 2008 [550] cohort study age 60 (55-65) yrs. was 34 M and worsened diagnosis and with increasing age and bulbar airway mucus onset of the disease. The median accumulation represent survival from initiation of NIV was poorer prognostic 8.4 M and was significantly poorer factors of ALS patients in patients with advanced age treated with NIV. or with airway mucus accumulation. Lo Coco et al, Prospective 4 N = 71 (46 male) ALS patients, Slower decline of FVC in tolerant 2006 [551] cohort study age 62 ± 11 yrs, BMI 25.2 vs intolerant patients (p = 0.002). (22.7-28.4 kg/m²). Slope of FVC decline and NIV tolerance were independent 44 patiens NIV tolerant predictors of survival after NIV in 27 patients NIV intolerant tolerant patients (RR: 0.77, 95% CI: 0.61 to 0.96, p = 0.022). Jackson et al, Retrospective 4 N = 146 ALS patients using NIV compliance is strongly The factors which are 2006 [552] cohort study NIV correlated with dyspnoea and most closely associated

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orthopnoea symptoms as well as with NIV use are with use of other therapies: PEG symptomatic tubes, augmentative speech orthopnoea and devices and riluzole. dyspnoea. Chio et al, 2012 Retrospective 4 N=1260 (687 male) ALS 259 (21%) underwent NIV. Young Efforts should be made [553] cohort study patients, age65 ± 11 yrs male patients and subjects to remove obstacles, in attending the tertiary ALS centres order to spread the use were more likely to undergo NIV. of NIV in all ALS patients with respiratory failure. Spataro et al, Prospective 4 N=87 (55 male) ALS patients Tracheostomy increases median Survival after 2012[554] cohort study with tracheostomy mechanical survival (TMV, 47 M vs NT, 31 M, tracheostomy is ventilation, age 61 (47-66) yrs. p=0.008), with the greatest effect generally increased, in patients younger than 60 at with the stronger effect onset (TMV ≤ 60 yrs, 58 M vs NT in patients younger ≤ 60 yrs, 39 M, p=0.002). than 60.

Mahajan et al, Retrospective 4 N= 354 ALS patients with NIV 55 ALS patients used part-time DP provided no benefit 2012 [555] cohort study and N=8 ALS patients with NIV NIV for 20 M until on VC or mechanical and diaphragm pacing (DP), tracheostomy/death, whereas 113 ventilation-free survival. age 47-70 yrs. others used it for 11 M until CNIV

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dependence for another 13 M. After placement, 7 DP users were CNIV dependent in 8 M, whereas 6 underwent tracheostomy/died in 18 M.

Bach et al, 1998 Retrospective 4 N = 672 (NIV and TIV) Higher incidence of pneumonia Exclusion of patients [556] cohort study 18 ventilator users with and respiratory hospitalisations in who had died relatively gastrostomy tubes patients with gastrostomy tubes soon after starting Ventilatory assistance decreases ventilation the risk of pneumonia and hospitalisation Supplemental oxygen alone was related to higher risk of pneumonia and hospitalisations NIV can replace TIV, even in 24h- support Full-time NIV had the lowest incidence of pneumonia and hospitalisations NIV users had less pneumonias

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and hospitalisations than TIV users

Katzberg et al, Prospective 4 N=12 (42% male) ALS Time spent below 90% SaO2 was NIV improved 2013 [557] cohort study patients, age 66 ± 17 yrs, also significantly better with NIV oxygenation, but evaluated with PSG before and (30% vs 19%, p < 0.01). Apnoea showed no significant while using NIV index (3.7 to 0.7), hypopnoea effects on sleep index (6.2 to 5.7), and apnoea efficiency, sleep hypopnoea index (9.8 to 6.3) did arousals, restful sleep, not significantly improve after or sleep architecture. introducing NIV. de Carvalho et al, Prospective 4 N = 261 (141 male) ALS 45 (17%) patients showed Periodical pattern of O2

2009 [558] cohort study patients, age 62 (range 29-89) periodical pattern of O2 desaturation: yrs, were followed over 5 yrs desaturation. - a decrement of more than 10% of the mean

837 nocturnal oximetries were 13 patients in Group 1 (7 males, O2 saturation of the performed 69 ± 8 yrs, FVC 96 ± 15 % Pred) previous baseline if 28 patients in Group 2 (17 males, stable; and lasting for Those with normal phrenic 65 ± 9 yrs, FVC 63 ± 19 % Pred) more than 10 min. nerve responses and normal - two or more episodes EMG of the Nocturnal oximetry showed similar as defined above diaphragm were classified in results in both groups. MOP/FVC overnight;

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group 1 (G1), while patients differed between G1 and G2 ( - the episodes should with abnormal 0.87 ± 0.20 vs 1.65 ± 1.02, p = be separated from each neurophysiological results 0.009) other for more than 60 constituted group 2 (G2). min. This interval was decided considering that it was hypothesised that those

periods of O2 desaturation would occur during REM sleep. In addition, the aim was to exclude

cluster episodes of O2 desaturation. Ferguson et al, Prospective 4 N = 18 (8 male) ALS, age 64±7 ALS patients had more arousals, a SDB occurs in ALS 1996 [559] cohort study (48-75) yrs, BMI 22.8±3.5 shorter sleep time and a higher patients. kg/m2; N = 10 (all male) ctrl , AHI. age 56±12 (42-71) yrs. Atkeson et al, Prospective 4 N=23 (68 % male) ALS Mean asynchrony index was 69 Patient-ventilator 2011 [232] cohort study patients, age 59 ± 10 (range 15–146/hour). Mean asynchronies are yrs,consistently using NIV asynchrony time as a percent of frequently present in

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evaluated with home PSG recording time was 17. ALS patients consistently using NIV.

Mendoza et al, Retrospective 4 N = 161 (98 male) ALS The MIP criterion (< 60 cmH2O) For patients with clinical 2007 [560] cohort study patients, age 61 (range 22-86) was reached 4 to 6.5 M earlier signs and symptoms yrs than the FVC criterion (FVC < 50 needing treatment %Pred) with NIV, a MIP <60 cm

H2O allows US clinicians to obtain noninvasive ventilatory support for patients earlier than based on the FVC criterion alone. Jackson et al, Randomised 2b N = 20 ALS patients FVC% correlates poorly with 2001[561] controlled study Patients were randomised to respiratory symptoms, while MIP receive NPPV based upon and nocturnal oximetry may be nocturnal oximetry studies more sensitive measures of early suggesting oxygen respiratory insufficiency desaturation <90% for one cumulative minute ("early intervention") or a FVC <50% Pred ("standard of care")

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Bourke et al, Randomised 1b N =41ALS The total group showed significant 2006 [562] controlled trial 22 (14 male) randomised to better survival (219 (75-1382) vs NIV, age 64 ± 10 yrs, VC 56 ± 171days (1-878)) and QoL when 19 %Pred, MIP 31 ± 11 using NIV. %Pred, SNIP 23 ± 11 %Pred,

PaCO2 46 ± 8 mmHg. Normal and moderately severe 19 (10 male) randomised to bulbar patients showed significant standard care, age 63 ± 8 yrs, better survival (216 (94-681) vs VC 49 ± 21 %Pred, MIP 31 ± 11 (1-283) days) and QoL when 11 %Pred, SNIP 24 ± 11 using NIV.

%Pred, PcCO2 48 ± 9 mmHg. Severe bulbar patients show some benefit in QoL, but no improvement in survival. Bensimon et al, Double-blind 1b N = 155 ALS, N=77 (45 male) Riluzole improves survival and Riluzole is the only 1994[563] RCT assigned to riluzole, N=78 (46 slows deterioration of muscle FDA-approved drug for male) assigned to placebo. strength ALS

e3.3.B. Duchenne Muscular Dystrophy

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Author Design EBM Patient population Results Comments

Hukins et al, Prospective 4 N = 19 DMD patients (19 ± 4 An FEV1< 40 % Pred was

2000 [74] cohort study yrs, FEV1 29 ± 17 %Pred, FVC sensitive (91%) but not specific

28 ± 16 %Pred, PaCO2 48 ± 7 (50%) to indicate sleep

mmHg, BE 3.2 ± 2.2 mmol/L) hypoventilation. PaCO2 ≥ 45 mmHg was equally sensitive (91%), but more specific (75%). BE ≥ 4 mmol/L was highly specific (100%), but less sensitive (55%) Suresh et al, Retrospective 4 N= 34 DMD patients, age 10 During a 5-year period, 32 Symptoms and lung 2005[564] cohort study (1-15) yrs. 64 % symptomatic. patients progressed to a PSG: function did not - 15 patients had a normal accurately predict the study, median age 10 yrs, AHI severity of SRBD. PSG 5 (2-13) significantly helped in - 10 patients showed OSA, the diagnosis of SRBD. median age 8 yrs, AHI 13 (3- 29) - 11 patients showed hypoventilation, median age 15 yrs, AHI 13 (3-29) and NIV was offered

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AHI improved after NIV initiation (mean difference= 11.31, 95% CI 5.91-16.70, p = 0.001) Toussaint et al, Prospective 4 N = 114 DMD patients. Group D and group N could be 2007 [565] cohort study N=38 patients with nocturnal discriminated by cut-off values of

hypercapnia (N), age 18 ± 3 VC ≤ 680 ml, MIP ≤ 22 cmH2O yrs, BMI 20.3 ± 6.7 kg/m², VC and Vt/VC < 0.33. 28 ± 12 %Pred, MIP 34 ± 14 VC ≤ 680 ml was very sensitive

cmH2O. (90%) in predicting daytime N=39 patients with diurnal hypercapnia. hypercapnia, despite nocturnal Nocturnal hypercapnia is likely to NIV (D), age 23 ± 5 yrs, BMI develop when VC < 1,820 ml 16.1 ± 5.4 kg/m², VC 12 ± 4

%Pred, MIP 16 ± 7 cmH2O) N=37 patients with normocapnia and spontaneous breathing (S), age 17 ± 3yrs, BMI 19.4 ± 5.2 kg/m², VC 37 ± 13 %Pred, MIP 42 ± 17

cmH2O) Smith et al, 1989 Prospective 4 N=6 DMD patients, age 16-22 Minute ventilation was 6.9 l/min Although awake minute

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[566] cohort study yrs, analysed with PSG with but fell, owing to decreases in ventilation is normal,

and without O2 supplemention both tidal volume and frequency, hypoventilation can to 4.9 l/min (p<0.05) in slow wave occur in all sleep sleep stages, especially when and to 4.5 l/min (p<0.05) in REM diaphragmatic sleep. Similar dysfunction is present. falls were seen during oxygen supplementation. Leger et al, 1994 Retrospective 4 N = 276 patients (16 DMD, age Hospitalisation rate decreased in DMD patients were [567] cohort study 21 ± 3 yrs, FVC 14 ± 5 %Pred, year 1 (7 ± 8 days/yr) and 2 (2 ± 1 found to be the highest

PaCO2 55 ± 10 mmHg) days/yr) compared to the year percentage (44%) of before NIV (18 ± 6 days/yr, p < discontinuation of NIV. 0.003). Simondset al, Prospective 4 N = 23 DMD patients, age 20 ± One yr and five yr survival

1998 [568] cohort study 3 yrs, VC 306 ± 146 ml, PaCO2 rates were 85% (95% CI 69 to 10.3 ± 4.5 kPa. 100) and 73% (95% CI 53 to 94), respectively

PO2 increased from 7.6 ± 2.1 kPa

to 10.8 ± 1.3 kPa, PCO2 decreased from 10.3 ± 4.5 kPa to 6.1 ± 1.0 kPa. Improvements in

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gas exchange were maintained over 5 yrs Toussaint et al, Prospective 4 N = 42 DMD patients at time of 1-, 3-, 5- and 7 yr MIPPV survival 2006 [569] cohort study MIPPV, 4 ± 3 yrs after rates were 88%, 77%,,58% and nocturnal NIV, age 24 ± 4 yrs, 51% respectively. BMI 17.6 ± 5.2 kg/m², VC 11 ± MIPPV stabilised lung function for

4 %Pred, MIP 16 ± 5 cmH2O. 5 yrs. Soudon et al, Prospective 4 N=42 full-time ventilated DMD Ages and respiratory The authors support the 2008 [570] cohort study patients ; N=16 with TIV, age characteristics at death and use of noninvasive 33 ± 5 yrs and N=26 with NIV, causes of death were comparable interfaces as default age 27 ± 6 yrs. between groups. Morbidity was choice when assisted worse in TIV compared with NIV ventilation patients is required for daytime use. Bach et al, 2011 Prospective 4 N=134 DMD patients, age 30 ± Hypoventilation symptoms NIV in DMD patients [571] cohort study 6 yrs. appeared at age 16, when can be used up to nocturnal NIV was started. continuously and long- Continuous NIV dependence term, maintaining it for started at 22 yrs of age. over 25 yrs in some patients. Nardi et al, 2012 Prospective 4 N=26 tracheostomised DMD, Sleep and respiratory parameters Tracheostomy ensures

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[572] cohort study median age 29 (26-36) yrs, improved in the four patients who better nocturnal gas BMI 15.5 (13.9-19.3) kg/m2, agreed to use cuffed tubes. exchanges than NIV in

PaCO2 35 (30-39) mmHg; 11 Tracheostomised patients had DMD patients, but does

were matched with 11 NIV lower maximal PtcCO2 (P=0.02) not guarantee that MV DMD and base excess values (p=0.045) is effective during compared to NIV controls. sleep. McKim et al, Prospective 4 N = 12 DMD NIV started at 18 ± 4 yrs, VC 0.90 Many missing data and 2013 [573] cohort study L (21 % Pred), MPV started at quality of data could not 20±3 yrs, VC 0.57 L (13 % Pred) always be confirmed in presence of symptoms of diurnal respiratory failure or

increasing daytime CO2 Mean survival on MPV is 5.7 yrs (range 0.17 to 12 yrs) Smith et al, 1989 Prospective 4 N=6 DMD patients, age 16-22 Minute ventilation was 6.9 l/min Although awake minute [566] cohort study yrs, analysed with PSG with but fell, owing to decreases in ventilation is normal,

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falls were seen during oxygen supplementation. Eagle et al, 2007 Retrospective 4 N = 100 DMD patients, Median survival in spinal surgery [574] cohort study N=20 patients with spinal and NIV was 30 yrs compared to surgery, 22 yrs in NIV alone. Patients N=27 patients with spinal without spinal surgery or NIV had surgery and NIV, a median survival of 17 yrs (all p = N=14 patients with NIV alone, 0.0001) N=39 patients without spinal surgery and NIV. Biggar et al, 2006 Retrospective 4 N = 74 DMD patients. By the age of 18 yrs, none of the [575] cohort study N=40 patients used patients using deflazacort were deflazacort, age 15 ± 3 yrs, nocturnally ventilated, compared N=34 patients did not use to 46% ventilated patients in the deflazacort, age 15 ± 3 yrs non-deflazacort group.

Eagle et al, 2007 Retrospective 4 N = 100 DMD patients, Median survival in spinal surgery [574] cohort study N=20 patients with spinal and NIV was 30 yrs compared to surgery, 22 yrs in NIV alone. Patients N=27 patients with spinal without spinal surgery or NIV had surgery and NIV, a median survival of 17 yrs (all p =

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N=14 patients with NIV alone, 0.0001) N=39 patients without spinal surgery and NIV. Raphaëlet al, Randomised 2b N = 70 DMD patients. Relative risk of death was Requirement for 1994 [576] controlled trial N=35 randomised to estimated at tenfold higher in the mechanical ventilation conventional treatment, age 15 NIV group. (FVC < 20 %Pred),

± 4 yrs, FVC 1135 ± 352 ml, PaO2< 60 mmHg,

PaCO2 38 ± 4 mmHg. PaCO2> 45 mmHg N=35 randomised to were part of the conventional treatment plus exclusion criteria. This NIV, age 16 ± 3 yrs, VC 1334 ± results in preventive

398 ml, PaCO2 39 ± 3 mmHg. treatment with NIV

Conventional treatment (combination of antibiotics, physiotherapy) included therapy deemed appropriate by treating clinicians, except for corticosteroids.

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Buyse et al, 2015 Double-blind 1b N = 31 DMD in the idebenone Idebenone attenuated fall in PEF Idebenone reduced [577] RCT group, age 14 ± 3 yrs, and and had effect on FVC and FEV1 loss of repiratory N=33 DMD in placebo group, function in patients with age 15 ± 3 yrs Duchenne muscular dystrophy

e3.3.C. Myotonic Dystrophy (MD)

Author Design EBM Patient population Results Comments Rimmer et al, Prospective 4 N = 11 (4 male) MD patients, As myotonia occurred only rarely 1993 [578] cohort study age 35 (range 27-40) yrs, FVC with tidal breathing, no definite 90 (range 72-119) %Pred, evidence to support myotonia as a

PaCO2 41 (range 32-48) cause of ventilatory failure was mmHg. found in MD. Bégin et al, 1997 Prospective 4 N = 134 MD patients. Hypercapnic subjects are shown [579] cohort study Patients were divided in 5 to be older, and more often males, categories (0-4) from no and to have a higher degree of clinical impairment (0) to muscular disability and a higher

severe proximal weakness (4) FEV1/FVC ratio, but lower inspiratory and expiratory muscle

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strength. The prevalence of hypercapnia wasincreased in higher MDRS levels..

Kumar et al, 2007 Prospective 4 N = 25 (15 male) MD1 The whole group showed a SRBD was present [580] cohort study patients, age 40 ± 11 yrs, correlation between FVC and when there was upper

9 SRBD patients, age 43 ± 10 PaCO2 ( r = -0.7, p < 0.05). airway collapsibility, yrs, FVC 72 ± 30 %Pred, BMI REM sleep 28.4 ± 6.2 kg/m²., FVC < 60 %Pred predicted hypoventilation,

16 non-SRBD patients, age 39 underlying SRBD.. significant nocturnal O2 ± 11 yrs, FVC 79 ± 18 %Pred, desaturation and/or

BMI 24.6 ± 9.3 kg/m². Daytime PaCO2 was higher in evidence of daytime SRBD patients (6.3 ± 0.9 vs 5.8 ± hypercapnia. 0.3 kPa). Pincherleet al, Retrospective 4 N = 40 (24 male) MD1 Sleep hypoventilation was Ventilatory support was 2012 [581] cohort study patients, age 39 ± 9 yrs, BMI observed in 4/22 patients which used in 9/40 patients (5 23.0 ± 3.2 kg/m². showed OSA. with CPAP and 4 with Blood gas analysis showed BiPAP) hypercapnia in 17/40 patients.

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The need for ventilatory support was correlated with AHI, ODI, decrease in MEP and VC. Pousselet al, Prospective 4 N = 69 (26 male) MD 1 No difference was found between The reduced ventilatory 2015 [582] cohort study patients, age 44 ± 13 yrs. hypercapnic and non-hypercapnic response to patients for measurements of MIP hypercapnic Patients were categorized into and MEP. stimulation, 3 levels: MIRS 1-2, MIRS 3 independently of lung

and MIRS 4-5. Ventilatory response to CO2 was function impairment not correlated to respiratory greatly suggests a

muscle weakness. central cause of CO2 insensitivity.

Nugent et al, Retrospective 4 N = 13 (6 male) myotonic At discharge PaCO2 decreased No significant changes

2002 [583] cohort study dystrophy patients, age 48 (36- from 64 to 54 mmHg on and PaO2 in spirometry or 69) yrs. increased from 53 to 65 mmHg. maximum mouth At reassessment, improvements in pressures were arterial blood gas levels were observed

maintained. Mean overnight SaO2 increased significantly.and was maintained at 90% at

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reassessment.

e3.3.D. Acid Maltase Deficiency

Author Design EBM Patient population Results Comments Kansagra et al, Retrospective 4 N = 17 (10 male) patients with Overall AHI of 2.6 (range 0–8.4). OSA and 2013 [584] cohort study infantile-onset Pompe disease, Obstructive AHI was 1.4 (range 0– hypoventilation were age 8 (0.5-17.5) M 8.4). Six patients had mild OSA common among this with an AHI between 1 and 5, and cohort, even in those 1 patient had moderate OSA with that did not have an AHI of 8.4. Six patients of the symptoms of SDB. All

16 that had PCO2 recorded met patients with infantile- the cutoff for hypoventilation. onset Pompe disease should undergo PSG as a routine part of their care. Mellies et al, Prospective 4 N = 8 patients with late-onset Despite further decrease of VC NIV reversed 2005 [585] cohort study Pompe disease, age 36 ± 11 and inspiratory muscle strength, respiratory failure.

yrs, VC 31±11 % Pred, PaCO2 NIV normalised SaO2 during sleep

67±18 mmHg, PaO2 56±11 (96 ± 1%), daytime CO2 tensions

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mmHg, treated with NIV (44 ± 4 mmHg), and symptoms. Smith et al, 2013 Prospective 4 N = 5(4 male) ventilator- Evaluation of 180-day safety and Alglucosidase alfa [586] cohort study dependent patients with Pompe ventilatory outcomes in a phase stabilised disease I/II clinical trial of AAV-mediated neuromuscular deficits GAA gene therapy (rAAV1-hGAA) over 1 year with mild following functional improvement. intradiaphragmatic delivery. Unassisted tidal volume was significantly larger (median [interquartile range] 29% increase [15–35], p < 0.05). Further, most patients tolerated appreciably longer periods of unassisted breathing (425% increase [103– 851], p = 0.08). Boentert et al, Prospective 4 N = 65 (33 male) patients with Reduced sleep quality was highly In adult Pompe 2015 [587] cohort study Pompe disease, age 47 (18- prevalent (PSQI > 5; 43%) and disease, sleep 75) yrs, BMI 23.6 ± 5.5 kg/m² correlated with both excessive disturbances are a daytime sleepiness (ESS > 10; common cause 24.6%) and fatigue (FSS > 4; of excessive daytime 72%). The SF-36 health-related sleepiness and fatigue.

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quality of life questionnaire was Sleep-related reduced in the physical domains, symptoms may be and was inversely correlated with indicative of respiratory sleep quality, FVC and motor muscle weakness and performance. In 11 out of 17 non- should give rise to ventilated patients with further work-up of SDB. polysomnography records, SDB was present, and duration of nocturnal oxygen desaturation (SaO2< 90%) was signiﬁcantly correlated to the PSQI global score. Mellies et al, Prospective 4 N = 27 patients with Pompe SDB depends on diaphragm SDB is predictable from 2001 [588] cohort study disease, age 39 ± 19 yrs dysfunction and degree of daytime lung function. ventilatory restriction. Kishnani et al, Prospective 4 N = 18 (11 male) patients with Treatment reduced the risk of Recombinant human 2007 [589] cohort study rapidly progressive infantile- death by 99%, reduced the risk of GAA is safe and onset Pompe treated with death or invasive ventilation by effective for treatment recombinant human GAA, age 92%, and reduced the of infantile-onset 5 ± 2 yrs risk of death or any type of Pompe disease. ventilation by 88%, as compared

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to an untreated historical control group. Nicolino et al, Prospective 4 N = 21 (10 male) children with Alglucosidase alfa reduced Biweekly infusions with 2009 [590] cohort study Pompe disease, age 16 ± 11 the risk of death by 79% (P < alglucosidase alfa yrs; N = 86 (36 male) untreated 0.001) and the risk of invasive prolonged survival and reference cohort ventilation invasive by 58% (P < 0.02). Left ventricular ventilation-free survival. mass index improved or remained normal in all patients evaluated beyond 12 weeks; 62% (13/21) achieved new motor milestones. Kansagra et al, Retrospective 4 N = 10 (6 male) patients with They had an overall AHI, Patients demonstrated 2015 [591] cohort study infantile-onset Pompe disease, obstructive AHI and central AHI of relative stability in SDB, receiving enzyme-replacement 2.5, 1.2, and 1.4 at baseline, and with a trend towards therapy 1.0, 0.5, and 0.5 at follow-up, improvement in both respectively. OSA and CSA. e3.3.E. Mixed NMD studies

Author Design EBM Patient population Results Comments Lyager et al, Prospective 4 N = 25 After 18 M, data were analysed None of the SMA 2

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1995 [592] cohort study 11 patients with SMA 2, age 26 retrospectively for their predictive patients needed NIV (9-53) yrs, FVC 32 (11-83) value for NIV initiation. Seven although FVC < 1.2l %Pred). patients needed NIV. EK sum > and some with worse 14 patients with DMD,age 19 20 and smallest values for FVC < disability (15-31) yrs, FVC 26 (16-50) 1.2l were predictive for NIV need. %Pred. Correlation (r² = 0.821, p = 0.023) between first FVC% and time until NIV. Ragette et al, Prospective 4 N = 42 (25 males), age 29 ± 16 IVC correlated with P0.1/MIP (R= - No patient was using 2002 [593] cohort study yrs, BMI 18.7 ± 5.4 kg/m². 0.68, p < 0.0001) and daytime ventilatory support

10 DMD, 10 congenital PaO2 (R= 0.53, p < 0.001) and

muscular dystrophy, 7 LGMD, PaCO2 (R= -0.50, p= 0.001). 12 acid maltase deficiency (AMD), 1 nemaline myopathy, 1 SDB evolved in 3 distinct patterns, MD and 1 non-classified from REM sleep hypopnoeas in myopathy mild ventilatory restriction to REM sleep hypopnoeas with REM hypoventilation in moderate ventilatory restriction, to sleep stage independent (continuous) hypoventilation, with or without

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REM sleep hypopnoeas in severe restriction.

SDB was highly correlated with IVC (R= 0.88, p < 0.0001), MIP (R= 0.65, p < 0.0005), P0.1/MIP (R= 0.7, p < 0.0005) and mean

PtcCO2 (R= -0.83, p < 0.0005)

Hypoventilation (as % of total sleep time) occurred in 2±3 % of those with REM hypopnoeas

(mean PtcCO2 6.0 ± 0.3 kPa,

maximal PtcCO2 6.4 ± 0.4 kPa), in 20 ±21 % of those with REM hypopnoeas with REM

hypoventilation (mean PtcCO2 6.2

± 0.4 kPa, maximal PtcCO2 7.3 ± 0.8 kPa), and in 66.2 ± 36.1% of those with continuous

hypoventilation (mean PtcCO2 7.0

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± 0.4 kPa, maximal PtcCO2 7.9 ± 0.9 kPa). IVC and MIP also

correlated with mean SpO2 and

mean PtcCO2.

Multiple regression analysis identified IVC (p<0.0001) and PImax (p<0.001), but not age or BMI, as the strongest determinants of SDB. Dreher et al, Retrospective 4 N = 66 NMD patients. Differences were found in age and Well-defined selection 2007 [594] cohort study N=19 (18 male) ALS patients, awake blood gases at NIV criteria should be age 62 ± 9 yrs, BMI 24.4 ± 3.3 initiation. elaborated for each

kg/m², PaCO2 62 ± 20 mmHg, Compared with ALS, DMD specific neuromuscular FVC 40 ± 12 %Pred, MIP 2.3 ± patients were more underweight, disorder to address the 1.1 kPa. but less hypercapnic. uncertainty about the N=12 (12 male) DMD patients, In slowly progressive diseases, appropriate time to age 20 ± 4 yrs, BMI 20.2 ± 6.4 FVC improved after 2 M. ALS and establish HMV.

kg/m², PaCO2 44 ± 6 mmHg, DMD did not show any FVC 34 ± 22 %Pred, MIP 3.3 ± improvement of FVC.

2.1 kPa. PaCO2 improved in all patients.

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N=35 (18 male) slowly progressive NMD, age 47 ± 18 The 2 and 5-yr survival for all yrs, BMI 24.7 ± 7.0 kg/m², patients were 64.2 and 39.3%

PaCO2 53 ± 11 mmHg, FVC 42 respectively. ± 19 %Pred, MIP 3.2 ± 1.6 kPa. Median survival in DMD, slowly progressive disorders and ALS were respectively 132, 82 and 16 M. Restrick et al, Randomised 4 N = 12 (8 male) S and S/T mode showed 1993 [595] cross-over study NMD/CWD/COPD patients (age comparable results in

57 yrs, FVC 1.5 l, PaCO2 7.3 improvement of daytime and

kPa): nocturnal SpO2 and PtcCO2 N=7 (3 male) NMD/CWD measurements.

patients, 22-68 yrs, PaCO2 S and S/T modes were also

7.9±1.3 kPa, PaO2 8.2±1.4 kPa, comparable in patient comfort and VC 1.3±0.3 L. perceived sleep quality N=5 (all male) COPD patients,

51-71 yrs, PaCO2 6.9±0.6 kPa,

PaO2 7.0±1.2 kPa. Elliott et al, 1995 Prospective 4 N = 14 In the NMD group, the overnight In the patients with

[596] cohort study 7 (6 male) patients with peak PtcCO2 decreased (7.3± 0.9 COPD, EPAP conferred

363

neuromuscular/skeletal kPa vs 8.1 ± 1.4 kPa) and the no advantage

disorders, age 46-58 yrs minimum SpO2 increased (84 ± 7 (5 male) patients with COPD, 4% vs 77 ± 7%) when using EPAP age 54-71 yrs Barbé et al, 1996 Prospective 4 N = 8 (2 male) NMD, age 51±5 Patients were receiving NIV for 18 All patients were [597] cohort study (22-70) yrs, BMI 23±3 kg/m2, ± 2 M volume-cycled VC 50 ± 6 %pred, MIP 34 ± 7 Sleep structure and improved ventilated

cmH2O, PaCO2 46 ± 3 mmHg. (RDI 22 ± 6 vs 1 ±1, N1 + N2 81 ± Among them: 4 myasthenia 5 vs 64 ± 5 %, SWS 8 ± 3 vs 16 ± gravis, 3 LGMD, 1 Scotland 3%, SEI 59 ± 8 vs 83 ± 5%, all p < myopathy. 0.05) nNocturnal oximetry improved

(time with SaO2 < 90% 160 ± 53

vs 8 ± 4 min, p < 0.05; mean SaO2 88 ± 3 vs 95 ± 1 %, p < 0.05;

Minimal SaO2 67 ± 5 vs 89 ± 1 %, p < 0.005 Lung mechanics were unchanged at follow-up

PaCO2 decreased from 46 ± 3 to 41 ± 1 mmHg

364

Piper et al, 1996 Retrospective 4 N = 14 (11 male) patients : Long-term nocturnal ventilation Highlights the presence

[598] cohort study 8 NMD; N = 6 scoliosis, PaCO2 improves nocturnal of a significant

8.2±1.6 kPa, PaO2 7.5±1.2 kPa, hypoventilation, respiratory reversible element in

VC 35±14 % Pred, FEV1 muscle function and respiratory sleep-induced 1.08±0.6 L. drive. hypoventilation.

Annane et al, Prospective, 4 N = 14 (10 male) NMD and After NIV PaO2 increased (+2.3

1999 [599] observational Chest Wall Disease patients, kPa, p < 0.001) and PaCO2 study age 51 yrs, VC 1457 ± 719 ml, decreased (-1.8 kPa, p < 0.001).

PaCO2 7.3 ± 0.9 kPa, PaO2 8.1 The AHI (-24) and nighttime

± 1.1 kPa. RDI 27±19, VC SpO2< 90% (-101 min, p = 0.002) 38±17 % Pred. decreased. Sleep efficiency (+16%, p < 0.01) and mean

nighttime SpO2 (+5%, p = 0.002) increased.

Reduction in PaCO2 correlated with the increase in the slope of

ventilator response to the CO2 curve. (r= -0.68, p = 0.008) Brooks et al, Retrospective 4 N = 34 (21 male) NMD patients, Daytime (maximum change 12.9 Measurements were

2002 [600] cohort study age 44 ± 3 yrs; VC 41 ± 5 mmHg) and nighttime PaCO2 performed at baseline, %Pred. (maximum change 11.7 mmHg) 1 to 2 yrs, 5 and 10 yrs

365

N=40 (18 male) KS patients, improved over time (p = 0.004) age 58 ± 2 yrs, VC 27 ± 2 % 6MWD increased with Pred. No improvement in sleep structure 51m in a subgroup of was found. ambulatory patients

Hart et al, 2002 Prospective 4 N = 15 patients with NMD and Similar improvements in SpO2,

[601] cross-over study Chest Wall Disease, age 46 ± PtcCO2, minute ventilation, tidal 15 yrs, VC 1.0 ± 0.3l. volume and respiratory rate were 3 patients could not trigger both found. modes (PSV and PAV) Mean percentage fall in EMGdi was greater during PSV (-81 ± 11%) than during PAV (-41 ± 35%; p = 0.01). Effort of breathing (1.6 ± 1.2 vs 3.7 ± 2.3 cm, p =0.004) and synchrony with the ventilator (7.5 ± 1.8 cm vs 4.5 ± 2.8 cm, p=0.004) were enhanced more with PSV than with PAV.

Mellies et al, Prospective 4 N = 30 (14 male) NMD patients, Nocturnal PtcCO2 decreased Withdrawal (n=10) 2003 [602] cohort study age 12 ± 4 (6-19) yrs. (baseline versus latest control) resulted in prompt After at least 6 M of successful from 54 ± 10 to 42 ± 5 mmHg and deterioration of

366

NIV, all patients were nocturnal SpO2 increased from nocturnal and diurnal asked to take a 3 night break 91% ± 8% to 96 ± 2% (p < 0.001). hypoventilation nearly

from NIV prior to the following Diurnal PaCO2 decreased from 48 back to baseline. control visit. Ten of the 30 ± 12 to 41 ± 4 mmHg. Diurnal Resumption of NIV

patients that completed the trial PaO2 improved from 65 ± 13 to 85 during the following were re-evaluated after 3 nights ± 9 mmHg (p < 0.01) (n=14). NIV nights immediately without NIV and after 2 nights improved RDI (11 ±13 vs 3 ± 4, p< normalised nocturnal resumption of NIV 0.001) , AI (21 ±14 vs 10 ± 4, p < respiration and diurnal 0.001) and sleep architecture (N1 blood gases within 2 + N2: 55 ± 12 vs 44 ± 13%, p < nights/days 0.05; N3: 24 ± 9 vs 34 ± 9%, p < VC decreased in 5 0.05) (n=17) adolescents with DMD - 183 ± 111 ml/yr but remained stable in 25 children with other conditions Katz et al, 2004 Retrospective 4 N = 15 (6 boys), age 12 (4-18) Compared to one yr pre-NIV, an [603] cohort study yrs. annual decrease post-NIV was observed in hospitalisations/yr, hospital days/yr, ICU days/yr,

minimal nocturnal SpO2 and

367

PtcCO2 Fanfulla et al, Randomized 4 N = 9 (7 male) NMD patients, NIV is effective in improving Patients were 2005 [604] cross-over study already on NIV, age 35 ± 12 daytime ABG and in unloading randomized to usual yrs, VC 39 ± 21 %Pred, MIP 41 inspiratory muscles independently (US) clinically

± 21 cmH2O, PaCO2 53 ± 5 of settings according to patient’s determined setting or mmHg. comfort (US) or the patient’s physiological (PHYS) respiratory mechanics (PHYS). setting based on the PHYS was associated with better recordings of sleep architecture (SEI 67 ± 22 vs inspiratory muscle 81 ± 10%, p= 0.01; REM 9 ± 7 vs effort. This setting 17 ± 5%, p < 0.05; AI 30 ± 17 vs provides an inspiratory 16 ± 13, p = 0.01), nocturnal gas aid sufficient to reduce exchange (ODI 28 ± 25 vs 8 ± 9, p the Pdi tidal swing by

< 0.05; minimal SpO2 68 ± 14 vs more than 40% and

86± 5, p = 0.0009; SpO2< 90 31 ± less than 80% and/or 30min vs 7 ± 9 min, p < 0.05) and to avoid any positive ineffective efforts (63 ± 75 vs 15 ± deflection in Pes during 20/h, p < 0.05) expiration. PEEPe was set at approximately 80% of the PEEPidyn recorded

368

during spontaneous breathing Crescimanno et Prospective 4 N = 28 (26 male) NMD, age 28 PSV-VTG showed similar results al, 2011 [605] cross-over study ± 8 yrs, FVC 765 ± 621 ml, MIP in morning ABG and subjective

20 ± 14 cmH2O, PaCO2 44 ± 7 comfort compared to PSV and mmHg. APCV

PVA and nocturnal SaO2< 90% were worse in PSV-VTG compared to APCV Crescimanno et Prospective 4 N = 50 NMD patients. Age, plasma BE, higher IPAP, and al, 2014 [606] cohort study N=17 (13 male) patients, age indices of poor objective 22 ± 7 yrs, BMI 22.1 ± 5.1 sleep quality were individually kg/m², with good sleep quality associated with high global (PSQI < 5 PSQI score. N=33 (26 male) patients, age BE and amount N3 were 30 ± 10 yrs, BMI 21.0 ± 6.1 significant and independent kg/m², with poor sleep quality predictors of the global PSQI (PSQI ≥ 5) Meyer et al, 1997 Prospective 4 N = 6 (2 male) NMD and Chest Sleep structure was abnormal in Patients used pressure- [230] cohort study Wall Disease patients, age 44 ± all patients. controlled ventilation, 7 yrs, BMI 21.5 ± 1.8 kg/m², Leakage was present for 62 ± for at least 6 M.

369

PaCO2 61 ± 3 mmHg. 11% in N1, 88 ± 5% in N2, 100 ± 0% in N3 and 80 %± 12 in REM sleep.

Mean SpO2 is 94 ± 3 % and

minimal SpO2 is 90 ± 4 %. Arousals were markedly present in N1, N2 and REM and were associated with leakages. Young et al, 2007 Retrospective 4 N = 14 NMD patients, age 8 ± 5 NIV improved symptoms (morning [607] cohort study (2-16) yrs headaches and daytime somnolence). Sleep quality improved and hospitalisation and health care costs decreased. QoL remained stable Crescimanno et Prospective 4 N = 18 (16 male) chronically PVA have a low rate of Polygraphic monitoring al, 2012 [223] cohort study ventilated NMD, age 30 ± 7 yrs, occurrence, but are related with may help to improve

BMI 20.57±4.9 kg/m2, PaCO2 awakenings. ventilator setting.

42±4 mmHg, PaO2 86±11 mmHg, FVC 564 (360-607) mL.

Ward et al, 2005 Randomised 2b N = 26 patients with NMD and Percent time PtcCO2> 48.8 mmHg In the control group, 7 [608] controlled trial chest wall disorders, was lower in NIV group (mean patients met the preset

370

24 M follow-up difference p = 0.049, 95% CI: - criteria for starting NIV N=14 randomised to NIV, age 91.5 to -0.35). Mean overnight within the first 12 M

26 ± 14 yrs, VC 1.01 ± 0.34 l, SaO2 was better in the NIV group and, by 24 M, only one

MIP 55 ± 28 cmH2O, SNIP 53 ± (mean difference p = 0.024, 95% patients continued

22 cmH2O, diurnal PaCO2 43 ± CI: 0.69 to 7.5) without NIV.

5 mmHg; Daytime PaCO2 did not differ. N=12 randomised to control group, age 21 ± 11 yrs, VC 0.81

± 0.61 L, MIP 35 ± 12 cmH2O,

SNIP 29 ± 25 cmH2O, diurnal

PaCO2 45 ± 3 mmHg (70% of the control group started NIV before 12 M) Chatwin et al, Randomised 2b N=28 NMD and Chest Wall No difference was found between Patients with severe

2008 [609] controlled trial Disease. groups for peak overnight PtcCO2, bulbar dysfunction were

N=14 patients randomised to time spent with PtcCO2> 49 excluded, as these

outpatient NIV initiation (PaCO2 mmHg, time spent with SaO2< individuals may need

44 ± 8 mmHg) 90% and lowest overnight SaO2 more intensive support N=14 patients randomised to and daytime ABG changes

inpatient NIV initiation (PaCO2 Inpatient patients spent more time 44 ± 5 mmHg) in hospital (4 vs 0.5 days, p <

371

0.001), while healthcare professional contact time did not differ

Tables of chapter 3.4. Kyphoscoliosis e3.4. A. Articles on sleep(breathing)

Author Design EBM Patient Population Results Comments Mezon et al, Case series 4 N=5 (60% male) sleep architecture * no hypopnoea's scored 1980 [610] age 54±17 yrs, wake: 14±8% **Cheyne Stokes breathing in 2 patients VC 0.84±0.26 L, A-index*(**): AI>5 in 1 patient Summary:

PaO2 60±12 mmHg, O2 saturation*** Increased amount awake and Stage 1,

PaCO2 45±8 mmHg. in all patients lowest value in REM: REM tended to be less than normal, in (65±18%) 2 patients there was no SWS sleep. No overt apnoea problem and if present events were central with longest events

in REM followed by severe O2 desaturation.Even patients without

apnoea demonstrated lowest O2 saturation in REM.

372

Guilleminault Case series 4 N=5* (? male), AH-index: 48±23 * 3 patients selected because of et al, age 51±7 yrs, O2 saturation symptoms ~ OSA 1981 [611] VC NA, Minimal value awake (supine)/NREM/REM: summary:

PaO2 NA, 87±2/72±9/57±16% Highest AHI and highest obstructive

PaCO2 NA. amount in the 3 patients recruited ~ OSA suspicion. Presence of hypopnoeic events of long duration up to 6 min. most probably ~ hypoventilation, associated with severe

O2 desaturation, especially in REM.

Bach et al, Case series 4 N=7* (43% male), O2 saturation *1 with post-tbc pleuroparietal sequelae

1995 [612-613] age 56±15 yrs, % time night SaO2<95% and <90%: 98±4 **5/7 using O2 VC 38±8 % Pred, and 80±30

PaO2**: 63±7 mmHg,

PaCO2**: 53±8 mmHg. Cirignotta et al, Case series 4 N=6 (33% male), AH-index: AHI < 5/h. *N=5

1993 [613] age 43±11yrs, O2 saturation summary: VC* 42±20 % Pred, during REM, 3/6 showed hypoventilation no overt apnoea problem but REM

PaO2 69±16 mmHg, periods, lasting from 90 sec. to several min., sleep hypoventilation with long O2

PaCO2 42±9 mmHg. associated with O2 desaturation, reaching desaturation periods values 80-40%.

373

Ellis et al, Case series 4 N=7 (71% male), O2 saturation *N=5

1988 [614] age: 43±18 yrs, min SaO2 NREM/REM: 79±7%/44±12% summary:

[615] VC 0.97±0.5 L, CO2 gas exchange disturbances most

PaO2 51±13 mmHg, max PtcO2 NREM/REM: 69±4/85+/-10 pronounced in REM

PaCO2 62±6 mmHg. mmHg

Piper et al, Case series 4 N=6 (67% male), O2 saturation

1996 [598, 614] age 44±19 yrs, baseline SaO2: 88±3 %

VC 32±12% Pred, min SaO2 NREM/REM: 78±9%/53±14%

PaO2 55±7 mmHg, min SaO2 REM: 53±14%

PaCO2 59±9 mmHg. CO2

baseline PtcCO2: 62±4mmHg

max PtcO2 NREM/REM: 69±4/81±6 mmHg

max PtcO2 REM: 81±6mmHg Ferris et al, Case series 4 N=16 (? male, sleep architecture *>4%, lasting 8 sec. 2000 [616] age 57±9 yrs, TST: 264±112min; sleep efficiency: 60±23% [612] FVC 36±11 % Pred, stage 1: 78±19%, stage 2: 5±11%,

PaO2 62±10 mmHg, stage 3: 1±1%, stage 4: 0±-0%, stage REM

PaCO2 55±6 mmHg. 17±18%, number of awakenings/arousals: 60±34/16±17 AH-index:14±8

O2 saturation

374

O2 desaturation* index: 41±49, time

SaO2<90%: 16±19%, minimum SaO2: 79±9%

Brooks et al, Case series 4 N=40 (45% male), sleep architecture 2002 [600] age 58±2 yrs, sleep efficiency 75±18% (N=34), arousal [598] VC 27±2 % pred, index 13±13 (N=17)

PaO2 52±1*** mmHg, AH-index (mean±SEM): 10±11 (N=33)

PaCO2 60±2*** mmHg. O2 saturation (mean±SEM)****: 89±1% (N=31)

CO2 (mean±SEM)****: 68±3mmHg (N=31)

Nauffal et al, Case series 4 N=35 (60% male), O2 saturation

2002 [616-617] age 53±16 yrs (men), SaO2< 90%: 42±37% age 61±19 yrs (women), FVC 42±19 % Pred,

PaO2 58±8 mmHg,

PaCO2 57±13 mmHg. Sawicka et al, Case series 3b N=11(27% male), AH-index * median value 1987 [615] age* 48 yrs Apnoea was uncommon. Number of summary: FVC* 28 % Pred hypopnoea’s in NREM and REM higher in in REM presence of hypopnoea’s with

375

PaO2* 74 mmHg patients vs. matched controls (p<0.02, significantly higher PetCO2 in REM

PaCO2* 39 mmHg. p<0.02). Hypopnoea duration in REM higher sleep, compatible with hypoventilation in patients vs. matched controls (p<0.01).

O2 saturation

Mean SaO2 in NREM and REM lower in patients vs. matched controls (p<0.05, p<0.02)

CO2

Mean PetCO2 in REM sleep higher in patients vs. matched controls (p<0.02)

e3.4.B. Articles on impact of NIV on sleep(breathing)

Author Design EBM Patient Population Results Comments

376

Ellis et al, Case series 4 N=7 (71% male), after 3 M treatment* *CPAP in 2/NIV in 5 1988 [614] age 43±18 yrs, sleep architecture **n=5 VC 0.97±0.5 L, increase in length and quality of REM sleep summary: after 3 M

PaO2: 51±13 mmHg, O2 saturation sleep: ↑ O2 saturation and ↓ PCO2,

PaCO2: 62±6 mmHg. min SaO2NREM: 79±7-->94±3 % (p<0.005) especially in REM sleep with increase

min SaO2REM: 44±1-->93±3 % (p<0.0001) in length and quality of REM sleep

CO2 accompanied by amelioration of

max PtcO2NREM**: 69±4-->58±9 mmHg (NS) subjective sleep quality

max PtcO2REM**: 85±10-->57±13 mmHg (p<0.05) subjective awakened refreshed and started to dream again Bach et al, Case series 4 N=7* (43% male), sleep architecture *1 with post-tbc pleuroparietal 1995 [612] age 56±15 yrs, sleep disruption and sleep changes associated sequelae

VC: 38±8 % Pred, with frequent transient O2 desaturations **5/7 using O2

PaO2**: 63±7 mmHg, and massive insufflation leakage summary:

PaCO2**: 53±8 mmHg. O2 saturation sleep: ↑ O2 saturation, but

% time night SaO2<95% and <90%: 98±4 and accompanied by PSG sleep 80±30 (baseline) --> 47±28 and 4±5 (NIV) disruption ~ insufflation leakage

377

Ferris et al, Case series 4 N=16 (? male), after 6 M on NIV summary:

2000 [616] age 57±9 yrs, sleep architecture sleep: ↑ O2 saturation without FVC 36±11 % Pred, no change in sleep architecture parameters change in sleep parameters, but

PaO2 62±10 mmHg, AH-index accompanied by amelioration of

PaCO2 55±6 mmHg. no change in AHI daytime hypoventilation symptoms

O2 saturation and subjective sleep quality

O2 desaturations (≥4%): 41±49-->12±11

(p<0.05), time SaO2<90%: 16+/19-->1+/-1

(p<0.01), minimum SaO2: 79+/-9-->87+/-4 (p<0.01) subjective on VAS scale (0-100): ↓ hypoventilation symptoms with ↑ sleep quality (p<0.001)

378

Brooks et al, Case series 4 N=40* (45% male), when ventilation was established (t1), after 1-2 *35 started NIV/5 TIV 2002 [600] age 58±2 yrs, yrs (t2), after 5 yrs (t3), after 8-10 yrs (t4) ** number re-evaluated dropped with VC 27±2 % Pred, sleep architecture (mean±SEM) time

PaO2 52±1** mmHg, sleep efficiency: unchanged at t1 and t2 summary:

PaCO2 60±2** mmHg. arousal index: unchanged at t1, t2, t3 and t4 sleep: ↑ O2 saturation and ↓PCO2, AH-index (mean±SEM) without change in sleep parameters, AHI: unchanged at t1, t2, t3 and t4 already reached over short term

O2 saturation (mean±SEM) sustained for years 89% (n=31**) -->92 (t1) -->93 (t2) -->92(t3) -->93 (t4) (trend (p=0.065))

CO2 (mean±SEM) 68mmHg (n=31**)-->51 (t1)-->50 (t2) -->53 (t3) -->52 (t4) decrease (p<0.001) Nauffal et al, Case series 4 N=35 (60% male), during 18 M (on a 3 M re-evaluation base) summary:

2002 [617] age 53±16 yrs (men), O2 saturation sleep: ↑ O2 saturation

age 61±19 yrs (women), significant increase in SaO2< 90% FVC 42±19 % Pred, after 3 M and sustained over 18 M

PaO2 58±8 mmHg,

PaCO2 57±13 mmHg.

379

Gonzalez et Case series 4 N=16 (? male), after 3 yrs summary: al, age 57±9 yrs, subjective amelioration of daytime 2003 [618] FVC 38±7 % Pred, on VAS scale (0-100): ↓ hypoventilation hypoventilation symptoms and

PaO2 63±7 mmHg, symptoms with ↑ sleep quality (p<0.05) subjective sleep quality

PaCO2 52±3 mmHg. already reached over short term (see Ferris (8)) sustained for yrs

e3.4.C. Articles on impact of NIV on daytime blood gases, respiratory muscle force, vital capacity, respiratory drive and dyspnoea

Author Design EBM Patient Population Results Comments Ellis et al, Case series 4 N=7* (71% male), after 3 M treatment* *CPAP in 2/NIV in 5 1988 [614] age 43±18 yrs, Daytime arterial blood gases summary: after 3 M

VC 0.97±0.5 L, PaO2: 51±13-->64±4 mmHg (p<0.05) amelioration of daytime PaO2 and

PaO2 51±13 mmHg, PaCO2: 62±6-->49±5 mmHg (p=0.01) PaCO2 and increase in inspiratory

PaCO2 62±6 mmHg. Respiratory muscle force muscle force without change in VC

Pimax -42±25-->-77±23 cmH2O (p<0.05) VC: 0.97±0.5-->1.1±0.5 l (p=NS)

380

Zaccaria et Case series 4 N=3 baseline, after 6 M and after 1 year summary: al, gender: NA, Daytime arterial blood gases (mean±SEM) trend for amelioration of daytime

1993 [619] age: NA, PaO2: 55±6-->69±3-->72±3 mmHg (p=NS) PaO2 and PaCO2

VC: NA. PaCO2: 65±10-->48±3-->44±3 mmHg (p=NS) Leger et al, Case series 4 N=105 (45% male), baseline, after 1 year and after 2 yrs *excluded patients who did not use 1994 [567] age 57±13 yrs, Daytime arterial blood gases (mmHg)* NIV for 2 yrs

FVC 33±14 % Pred. PaO2:54±10-->64±11(p<0.0001)--> summary:

64±11(p<0.0001) mmHg amelioration of daytime PaO2 and

PaCO2:53±8-->43±7(p<0.0001)-->43±8 PaCO2 sustained over 2 yrs without (p<0.0001) mmHg change in FVC FVC*(p=NS) Zaccaria et Case series 4 N= 13 (54 % male), after 1 M, 6 M, 1 year summary: al, age 53±13 yrs, Daytime arterial blood gases amelioration of daytime PaO2 and

1995 [620] FVC 33±8 % Pred. PaO2: 55±6-->68±10(p<0.0001)-->67±11--> PaCO2 sustained over 1 yr 66±9 mmHg

PaCO2: 61±11-->47±4(p<0.0001)-->46±4 -->45±5 mmHg

381

Bach et al, Case series 4 N=7* (43% male) after 31±15 M *1 with post-tbc pleuroparietal 1995 [612] patients, Daytime arterial blood gases sequelae

age 56±15 yrs, PaO2: 63±7**-->67±8 mmHg (p=NS) **5/7 using O2

VC 38±8 % Pred. PaCO2: 53±8**-->40±6 mmHg (p<0.005) summary:

FVC amelioration of daytime PaCO2 38±8-->39±12 %pred (p=NS) without change in FVC Piper et al, Case series 4 N=6 (67% male), after NIV for at least 6 M summary:

1996 [598] age 44±19 yrs, Daytime arterial blood gases amelioration of daytime PaO2 and

VC 32±12 % Pred. PaO2: 55±7-->73±10 mmHg (p<0.005) PaCO2 without change in inspiratory

PaCO2: 59±9-->48±5 mmHg (p<0.05) muscle force or VC Respiratory muscle force Pimax 54±21-->74±26 %pred (p=NS) VC 32±12 --> 38±10 %pred (p=NS) Ferris et al, Case series 4 N=16 (? male), after 6 M summary:

2000 [616] age 57±9 yrs, Daytime arterial blood gases amelioration of daytime PO2, in- and

FVC 36±11 % Pred. PaO2: 63±7-->68±9 mmHg (p<0.05) expiratory muscle force and FVC

PaCO2: 52±3-->50±5 mmHg (p=NS) with ↓ in P0.1 and evidence for Respiratory muscle force improvement in lung/chest wall Pimax 52±20-->65±24 %pred (p<0.001) compliance plus amelioration of Pemax 64±21-->74±24 %pred (p<0.05) dyspnoea and reduction of limb

382

Vt 419±92-->511±86 ml (p<0.01) oedema FVC 36±11-->44±11 %pred (p<0.05) Respiratory drive

P0.1: 4.98±1-->3.04±1 cmH2O (p<0.001),

P0.1/Vt: 9.95±4.02-->6.38±2.27 cmH2O/l (p<0.001), P0.1/(VT/Ti): 11.35±3.85 -->7.69±2.05 (p<0.01), P0.1/Pimax: 0.09±0.05 -->0.05±0.02 (p<0.001) plus less dyspnoea based on VAS (1-100) (p<0.001) and Sadoul scale (range 1-5): 3.7+/- 0.8-->1.5+/-0.5 (p<0.01), disappearance of limb oedema, present in 44% pretreatment, in all except 1

383

Brooks et al, Case series 4 N=40* (45% male), when ventilation was established (t1), *35 started NIV/5 TIV 2002 [600] age 58±2 yrs, after 1-2yrs (t2), after 5 yrs (t3), after 8-10 yrs **number re-evaluated dropped with VC 27±2 % Pred. (t4) time Daytime arterial blood gases (mmHg)** summary:

PaO2: 52-->63(t1)-->65(t2)-->62(t3)-->62(t4) amelioration of daytime PaO2 and

(p=0.001) PaCO2 plus increase in 6 min

PaCO2: 60-->50(t1)-->50(t2)-->53(t3)-->53(t4) walking test, sustained over a longer (p<0.001) time up to 10 yrs FVC drop over time: at t4 drop of 5.8% (p<0.05) plus increase in 6 min walk test (meters)**: 334-->426(t1)-->400(t2)-->400(t3)-->380(t3) (p<0001)

384

Nauffal et al, Case series 4 N=35 (60% male), during 18 M (on a 3 M re-evaluation base) summary:

2002 [617] age 53±16 yrs (men), Daytime arterial blood gases amelioration of PaCO2 sustained

age 61±19 yrs (women), no change in PaO2 after 3 M: 58±17-->60±17 over a longer time up to 18 M FVC 42±19 % Pred. mmHg (p=NS) without change in inspiratory muscle

significant decrease in PaCO2 after 3 M: force, VC or Borg dyspnoea scale 57±13-->49±6 mmHg (p<0.05) and sustained over 18 M Respiratory muscle force no change in Pimax after 3 M: 58±17-->60±17 %pred (p=NS) FVC no change in FVC%pred after 3 M: 42±19 -->44±17 %pred (p=NS) plus no change in Borg scale after 3 M: 2.7±1.9 -->2.34±1.8 (p=NS)

385

Gonzalez et Case series 4 N=16 (? male), after 3 yrs summary: al, age 57±9 yrs, Arterial blood gases over a long-term of 3 yrs (still*)

2003 [618] FVC 38±7 % Pred. PaO2: 63±7-->68±9 mmHg (p<0.05) amelioration of PaO2, respiratory

PaCO2: 52±3-->50±5 (p=NS) muscle force and FVC and Respiratory muscle force dyspnoea

Pimax 56±17-->79±18 cmH2O (p<0.001)

Pemax 54±18-->72±11 cmH2O (p<0.05) * short term values published by FVC Ferris (8) 38±7-->48±12 (p<0.05) plus based on a VAS scale (0-100): ↓ dyspnoea (p<0.05)

386

Buyse et al, Case control 4 N= 18 on NIV(±LTOT) after 10±3 M (NIV±LTOT) vs. 10±4 M (LTOT) * N=11 (4 died) 2003 [621] series vs N=15 on LTOT, Arterial blood gases **N=9

(comparison gender: 78 vs 67 %male, PaO2: 44±8-->66±10 (p<0.0001) (NIV±LTOT) ***N=12 with LTOT) age: 61±7 vs 62±7 yrs, vs summary:

FVC: 32±12 vs 50±7-->56±9* (p=NS) (LTOT) mmHg amelioration of PaO2, PaCO2 values

40±16 % Pred (p=NS). PaCO2: 60±8-->47±8 (p<0.0001) (NIV±LTOT) and FVC only in NIV±LTOT group vs (absent in the LTOT group) with ↑ in 55±7-->52±5* (p=NS) (LTOT) mmHg inspiratory muscle force FVC FVC: 32±12 --> 44±12 (p<0.005)(NIV±LTOT) vs. 40±16-->48±12** (p=NS) (LTOT) %pred Respiratory muscle force Pimax***: 44±13-->57±17 (p<0.05) (NIV±LTOT) %pred

387

Duiverman Case series 4 N= 95* (? male) patients, after 9 M --> 5 yrs *65 idiopathic (IK), 30 post-polio(PP) et al, age 56±13 (IK), Arterial blood gases ** N=22

2006 [622] 50±16 (PP) yrs, PaO2**: 59±15-->72±11 (p<0.01)-->70±10 *** N=29 VC 1.11±0.44 l (IK), (p<0.01) mmHg summary:

1.16±0.61 l (PP). PaCO2***: 56±10-->45±6 (p<0.001)-->47±6 amelioration of daytime PaO2,

(p<0.001) mmHg PaCO2 values on the short-term and VC longlasting for 5 yrs with an VC***: 1.29±0.58-->1.42±0.63 (p<0.05) amelioration in VC on the short- -->1.39±0.64 l term.

e3.4.D. Articles on impact of NIV on hospitalisations for acute problems (unless stated otherwise)

Author Design EBM Patient Population Results Comments Leger et al, Case series 4 N=105 (45% male), Hospitalisation days*: *patients who did not survive or 1994 [567] age 57±13 yrs, yr before: 34±31 continue NIV for a minimum of 1 FVC 33±14 % Pred, 1st yr on NIV: 6±6 (p<0.0001) year were excluded; N=56

PaO2 52±10 mmHg, 2nd yr on NIV: 5±9 (p<0.0001)

PaCO2 52±8 mmHg.

388

Zaccaria et al, Case series 4 N= 13 (54 % male), Hospitalisation days*: *most admissions were 1995 [620] age 53±13 yrs, 41±27 (1 yr before)-->13±3* (1 yr after) for elective follow-up of NIV FVC 33±8 % Pred, (p<0.005)

PaO2 55±6 mmHg,

PaCO2 61±11 mmHg. Ferris et al, Case series 4 N=16 (? male), Hospitalisation days: 2000 [616] age 57±9 yrs, 11±13 days (6 M before) -->0 days (6 M after) FVC 36±11 % Pred,

PaO2 62±10 mmHg,

PaCO2 55±6 mmHg. Nauffal et al, Case series 4 N=35 (60% male), Hospitalisation rate*: * in the paper the period studied 2002 [617] age 53±16 yrs (men), 1.2±1.8-->0.8±1.2 (p=0.01)* was not defined 61±19 yrs women), FVC 42±19 % Pred,

PaO2 58±8 mmHg,

PaCO2 57±13 mmHg.

e3.4.E. Articles on impact of NIV on survival

Author Design EBM Patient Population Results Comments

389

Leger et al, Case series 4 N=105 (45% male), Likelihood of continuing NIV* *more favorable outcome in 1994 [567] age 57±13 yrs, at 1 yr: 89% kyphoscoliosis (and post-tuberculosis FVC 33±14 % Pred, at 2 yr: 81% sequelae) compared to

PaO2 52±10 mmHg, at 3 yr: 77% bronchiectasis, COPD and

PaCO2 52±8 mmHg. Duchenne. Simonds et Case series 4 N=47 (? male), Likelihood of continuing NIV*: *more favorable outcome in al, age 49±12 yrs, at 1 yr: 90% kyphoscoliosis than in COPD or 1995 [623] FVC 0.83±0.4 L, at 2 yrs: 90% bronchiectasis

PaO2 50±12 mmHg, at 3 yrs: 79%

PaCO2 61±11 mmHg. at 5 yrs: 79% Janssens et Case series 4 N=19 (? male), survival rate on NIV**(***) * at 7±4 M after start NIV al, age* 60±15 yrs, at 3 yrs: 79% **analysis based on compliant 2003 [624] VC: NA, at 5 yrs: 79% patients not lost during follow up

PaO2: NA, *** similar to OHS and significantly

PaCO2: NA. higher than post-polio, posttuberculosis sequelae and COPD

390

Duiverman Case series 4 N= 95 (? male), 5-yrs survival rate on HMV*: *patients with miscellaneous disease et al, age 56±13 yrs, 84%** (thoracoplasty, (partial) lung 2006 [622] VC 1.11±0.44 L, resection, posttuberculosis sequelae,

PaO2 56±15 mmHg, bronchiectasis, post radiotherapy

PaCO2 58±13 mmHg. atelectasis) demonstrated a significantly lower survival (p<0.01); and patients with post-polio a significantly higher survival (p<0.05) **72% on NIV / 9% on NPV / 9% on TIV Marti et al, Case series 4 N=49 (? male), 5-yrs survival: 75% 2010 [625] age: NA, FVC: NA,

PaO2: NA,

PaCO2: NA. Chailleux et Case control 3b N=912* (35% male), Relative risk (RR) of death according to initial *30% NIV/ 13% TIV / 57% LTOT al, series age 60±17 yrs, support vs LTOT alone **more favorable outcome in 1996 [626] (comparison VC 47±18 %pred (men), RR: 0.4(CI: 0.26-0.8) for NIV (p<0.001)** kyphoscoliosis using NIV or TIV than with LTOT) 50±19 %pred (women), RR: 0.45(CI: 0.25-0.8) for TIV (p<0.01)** LTOT alone

PaO2 54±9 mmHg (men),54±10 mmHg

391

(women),

PaCO2 50±9 mmHg (men),51±9 mmHg (women).

Buyse et al, Case control 3b N= 18 on NIV(±LTOT) Likelihood of continuing NIV±LTOT *more favorable outcome in 2003 [621] series vs N=15 on LTOT, vs LTOT alone*, respectively, kyphoscoliosis using NIV±LTOT than (comparison gender 78 vs 67 %male, at 1 yr: 100% vs 66% LTOT alone with LTOT) age 61±7 vs 62±7 yrs, at 2 yrs: 100% vs 59% FVC 32±12 vs at 3 yrs: 100% vs 54% 40±16 % Pred (p=NS)

PaO244±8 vs 50±7 mmHg (p<0.05)

PaCO2 60±8 vs 55±7 mmHg (p=NS)

392

Gustafson et Case control 3b N=100 on HMV* survival rate NIV±LTOT vs. LTOT alone, *27 HMV+LTOT; NIV/TIV=93/7 al, series vs N=140 on LTOT, respectively: ** adjusted for gender, age, 2006 [627] (comparison gender 32 vs 31% male, at 1 yr: 92% vs 70% concomitant respiratory diseases: with LTOT) age 63±13 vs at 2 yrs: 85% vs 50% More favorable outcome in 74±9 yrs (p<0.001), at 3 yrs: 82% vs 37% kyphoscoliosis using NIV or TIV than FVC: NA, at 5 yrs: 73% vs 18% LTOT alone

PaO2 56±13 vs adj HR** for death in HMV vs. LTOT alone: 48±7 mmHg (p<0.001), 0.3 (95%CI 0.18-0.51)

PaCO2 57±9 vs 52±10 mmHg (p<0.005).

Tables of chapter 3.5. Obesity Hypoventilation Syndrome e3.5.A. Obesity Hypoventilation Syndrome

393

Author Design EBM Patient population Results Comments NIV Borel et al, Retrospective 4 N=107 (44% male) In multivariate analysis, combination In OHS co-morbidities 2013[628] cohort OHS, initiated in of cardiovascular agents was the only should be addressed by acute (36%) or factor independently associated with multimodalities treatment chronic conditions. higher risk of death (HR = 5.3; 95% CI Follow-up: 43±14 M. 1.18; 23.9). The 1, 2, 3 years survival rates were 99%, 94%, and 89%, respectively Pasquina et al, Retrospective 4 N=150 (83 male) Compliance 436 min/24h, leakes 2012[43] analysis of data patients including 8.4l/min, rr – backup rr 2/min. downloaded 38 patients with from home OHS, age 66±14 ventilators yrs, BMI 45.4 ± 2 Case series 7.5kg/m ,Data of Efficacy of NIV OHS patients

FEV1% 75 (62-94)% Pred., IPAP 20 (18-

23) cmH20, EPAP 8

394

(7-10) cm H2O, RR 14/min. Gursel et al, Retrospective 4 N=73 patients, Differences in admission reasons, 2011[44] NIV in obese divided in 2 groups: pulmonary oedema and pulmonary and non-obese infection, no difference in blood gas patients. BMI > 35 kg/m2, improvement. Obese patients had N=29 (8 males), age higher end expiratory pressure: 63±14 yrs, BMI Diagnoses in patients with BMI > 35 43±7 kg/m2, AHI kg/m2: obstructive lung disease 62%, 41±36, Apache II OSAS+OHS 90%, neuromuscular

18±4, FEV1 56±18 disease 3%. % Pred., Diagnoses in patients with BMI ≤ 35 kg/m2 : obstructive lung disease 69%, BMI < 35 kg/m2, OSAS+ OHS 21%, neuromuscular N=44 (26 males), disease 8%. age 68±13 yrs, BMI 26±5 kg/m2, AHI Admission reasons: pulmonaryo 29±21, Apache II edema 86% vs 48%, pulmonary

17±3, FEV1 41% infection 46% vs 62%, COPD/asthma Pred.). attack 54% vs 60%, postextubation respiratory failure 11% vs 11%.

395

Priou et al, Retrospective 4 N=130 (74 male) Mean follow up 4.1 ± 2.9 years, 2010[46] analysis. OHS patients, age 18.5% died, 18,5 discontinued NIV. 60 ± 14 yrs, BMI 44 Mortality lower than in historical ± 8,5 kg/m2, AHI groups of untreated OHS. Significant 83±36. Treatment improvement of blood gases and ESS initiation under after 6 M NIV, female sex predictive of stable conditions (in lower long term adherence. No n= 92), and during differences between acute and stable hypercapnic groups. Significant differences in

exacerbation (in baseline PaO2, PaCO2, pH, n=38). bicarbonate, comorbid hypertension Chang et al, Retrospective 4 N=45 (24 male) of Subjective compliance 96% adherent, 2010[629] audit tool on 73 patients mean daily use 7.2 h, 75% treatment compliance and completed the ≥ 2 yrs, 98% positive responses, 62% subjective study, age 55 yrs, without hospital stay during the last 12 efficacy of NIV OHS 37%, overlap M. syndrome 22%

Windisch et al, Case series 4 N=85 of 135 Significant improvement of PaCO2,

2008[630] QoL after 1 M patients completed PaO2, bicarbonate, several and 1 year NIV, the study, 9 of 85 subdomains of SF 36 and SRI questionnaires patients with OHS questionnaire.

396

SF 36 and (77% male, age 59 severe ± 6 yrs, BMI 40 ± 7 2 respiratory kg/m , FEV1 57 ± insufficiency 19% Pred, TLC 79 ± (SRI) 23% Pred, IPAP 23

questionnaire ± 3 cm H2O, EPAP

1 ± 2 cm H2O, RR 19 ± 2/min. Janssens et al, Case series 4 N=211 (? male) Compliance 6.2 ± 2.5 h 2003[624] 7 year follow-up patients under NIV, including OHS 71 patients. OHS patients: age 64 ± 11 yrs, BMI 42 ± 10 2 kg/m , FEV1 61 ± 19

% Pred, PaO2 60 ±

12 mmHg, PaCO2 49 ± 10 mmHg, NIV

patients: PaO2 71 ±

11 mmHg, PaCO2 42 ± 7 mmHg,

397

Pankow et al, Cross sectional 4 18 obese subjects Endtidal CO2 decreased in OHS 1997[51] study on the (5 healthy under NIV. Reduction of inspiratory effect of NIV on controlled, 7 OSA, 6 muscle activity in all groups. respiratory OHS), muscles in obesity, BMI > Simple obesity: 40 kg/m2. N=5 (1 male), age Inspiratory 42 ± 20 yrs, BMI muscle activity 43.5 ± 4.5 kg/m2. measured as diaphragmatic OSA: pressure time N=7 (3 male), age product (PTPdi) 55 ± 16 yrs, BMI during 43.5 ± 4.7 kg/m2. wakefulness. OHS: N=6 (3 male), age 52 ± 10 yrs, BMI 46 ± 6.2 kg/m2. Windisch et al, Cross-sectional 3b N=226 patients, Physical and mental component 2003[631] study, including 12 OHS. summary significantly lower in general multicentric, population.

398

QoL under NIV Masa et al, Study on 2 3b N=22 (6 male) OHS Significant improvement of symptoms 2001[41] cohorts of patients, age 61 ± and blood gas parameters with no patients with 14 yrs, BMI 40.8 ± difference between the groups: 2 hypercapnic 8 kg/m . OHS: PaO2 53 ± 10 mmHg to 64 ± 11

respiratory mmHg, PaCO2 58 ± 10 mmHg to 45 ± failure under 4 N=14 (7 male) KS , 5 mmHg.

months NIV, age 43 ± 20 yrs, KS: PaO2 53 ± 6 to 65 ± 5, PaCO2 59 OHS vs. BMI 24.8 ± 8 kg/m2. ± 11 mmHg to 45 ± 4 mmHg. kyphoscoliosis Lemyze et al, Prospective 2c N=76 (23 male) NIV failure in 13 patients, success in 2014[632] cohort study. consecutive OHS 63, including 33 with delayed patients with response (hypercapnic acidosis > 6 NIV for ARF. BMI>40 kg/m2, age h). NIV failure associated with 63 (58-77) yrs, BMI pneumonia (n = 12/13, 92% vs n = 49.6 (45-57) kg/m2, 9/63, 14%; p,0.0001), high SOFA (10 83% OSAS vs 5; p,0.0001) and SAPS2 score (63 vs 39; p,0.0001) at admission. In- hospital mortality in failure 92.3% vs 17.5%; p,0.001. Contal et al, RCT aiming to 2b N=10 (? male) OHS, Spontaneous mode was associated

399

2013[220] investigate the age 56± 9 yrs; BMI with the occurrence of a highly impact of 48.5 ± 5.1 kg/m2 significant increase in respiratory backup (3 PSG nights in events, of mainly central and mixed respiratory rate spontaneous, low origin (BURR) settings and high back up on the efficacy rate). of ventilation in obesity hypoventilation syndrome (OHS). Borel et al, RCT, 1 M 2b N=18 (44% male) Significant improvement in NIV vs

2012[35] treatment NIV vs NIV vs N=17 (41% non-NIV in PaCO2 (-3.5 mmHg), AHI lifestyle male) non-NIV: age (-40.3/h). counseling, 58±11 vs 54±6 yrs, Improvements in sleep structure and measurements: BMI 39.6±6.3 vs sleep fragmentation. No significant blood gases, 39.6±4.5 kg/m2, difference in metabolic parameters

daytime PaCO2 48 ± 4 and endothelial function. sleepiness, mmHg vs. 45 ± 3 metabolic and mmHg. inflammatory

400

parameters, endothelial function Murphy et al, RCT, 2 centres, 2b N=50 (25 male) Significant improvements in

2012[36] AVAPS vs. fixed OHS patients, BMI PaCO2and SRI in both groups. No 2 PS 50 ± 7kg/m , age 55 difference between groups.

3 months ± 11 yrs, AVAPS PaCO2 from 7.0±0.7 to

6.4±0.8 kPa. Fixed PS PaCO2 from 6.8±0.8 to 6.2±0.8 kPa. Ambrogio et al, Single blind 2b N=28 (all male) Minute ventilation lower during NIV- 2009[38] cross over RCT, patients, OHS in 20 PS than AVAPS NIV-PS vs patients, age 63±9 AVAPS yrs, BMI 39.0±8.5 kg/m2 [35, 220, 628, 632][36, 38, 41, 43-44, 46, 51, 624, 629-631]NIV/CPAP Pérez de Llano Case series 4 N=24 OHS No intergroup differences regarding et al, 2008[47] CPAP vs. NIV, patients:N=11 (91% age, BMI, ESS, PaO2/PaCO2 at post hoc male) CPAP, age baseline. Lower FVC in the NIV

analysis to 63±11 yrs, BMI group, AHI and baseline SaO2< 90% compare the 2 44±8 kg/m2, ESS in the CPAP group. cohorts. No 17±3, AHI 56±23,

401

randomisation. FVC 73±14 % Pred. Patients were treated with NIV N=13 (62% male) if CPAP was NIV, age 62±4 yrs, insufficient. BMI 43±7 kg/m2, ESS 15±3, AHI 37±23, VC 57±14. Resta et al, Cross sectional 4 N=130/286 patients CPAP effective in 77%, PSV required 1998[50] study, included, 105 (88 in 23%, mean IPAP 13.9 ± 2.9 cm

prescription of males) completed H2O. PSV required in 11/17 OHS CPAP or PSV in the study, age patients and 9/16 COPD with OSAS OSAS, CPAP 53±12 yrs, BMI patients. trial, if ineffective 34.5±6.7 kg/m2, PSV FEV1 82±23

%Pred, PaCO2

42±5 mmHg, PaO2 79±12 mmHg. Castro-Añón et 2 retrospective 2c N=110 (56% male) 5 year-mortality in OHS 15.5%, in al, 2015[633] cohorts of OHS patients with OHS OSAS and OSAS. and 220 (56% male) 4.5% (p< 0.05). Matching 1:2 patients with OSAS. OHS: risk of mortality OR 2; 95%

402

according to Mean follow-up was CI: 1.11–3.60; cardiovascular risk OR sex, age and 7±4 yrs. 1.86; 95% CI: 1.14–3.04. time since Agein OHS 64±11 Independent predictors of mortality:

initiation of yrs; Age in OSAS diabetes, baseline diurnal SaO2<

CPAP/NIV 64±11. 83%, EPAP <7 cmH2O, adherence to therapy. BMI (kg/m2) in OHS NIV <4 h/d. 42.4 ± 8.0 kg/m2; Mortality and BMI in OSAS 34.9 ± cardiovascular 7.4 kg/m2 morbidity in NIV- treated patients with severe OHS vs. CPAP- treated OSAS. Identification of predictors of mortality in OHS. Piper et al, RCT 2b N=18 CPAP treated Significant improvement of daytime

2008[39] Bilevel vs. patients, 18 bilevel PaCO2 in both groups, no difference CPAP, exclusion treated patients, no between the groups. No difference in of patients with difference in compliance. Better subjective sleep

403

persisting anthropometric and quality and vigilance test performance

SpO2< 80% for baseline under bilevel ventilatory support > 10 min. or bloodgases and carbondioxide lungfunction retention > 10 parameters: mmHg despite CPAP CPAP: N= 18 (14 male) patients, age 52±17 yrs, BMI 52±7 kg/m2, PaCO2 52 (49-55) mmHg.

BILEVEL: N=18 (9 male) patients, age 47±13 yrs, BMI 54±9 kg/m2, PaCO2 49 (47-57). [39, 47, 50]CPAP Banerjee et al, Prospective one 3b N=23 (10 male) No difference in lung function, BMI, 2007[42] night study of moderate to severe AHI. Lower oxygen saturation in OSA CPAP in OSAS OSA vs 23 (15 + OHS. Significant improvement in

404

vs. OSAS + male) moderate to parameters of sleep and respiration

OHS severe OSA + OHS: during sleep. SpO2< 90% in 43% age 40 vs 43 yrs, patients OSA + OHS, 9% OSA BMI 59.9 vs 58.7 2 kg/m , FEV1 2.34 vs 1.3 %, FVC 74.1 vs

69.2% Pred, PaO2 83.2 vs 60.9 mmHg

(p < 0.001), PaCO2 42.9 vs 44.3 mmHg (< 0.001) [42]Lin et al, Cohort study on 4 N=6 (5 male) Improvement of AHI in hypercapnic 1994[52] hypercapnic and hypercapnic OSAS: OSAS from 87 ± 14 to 8 ± 4, in eucapnic OSAS. age 48 ± 7 yrs, BMI eucapnic OSAS from 63 ± 17 to 6 ± 3. Hypercapnic 39.1 ± 2.4 kg/m2, Hypercapnic and hypoxic ventilatory

and hypoxic FEV1 70 ± 4 % drive impaired in hypercapnic OSAS

ventilatory Pred, PaO2 10.0 ± at baseline as compared to eucapnic

response prior 0.7 kpa, PaCO2 6.3 OSAS, improvement of ventilatory

and after CPAP ± 0.2 kpa. response and PaCO2 under CPAP in therapy, 1 M N=24 (21 male) hypercapnic OSAS. follow-up eucapnic OSAS:

405

age 47 ± 10 yrs, BMI 34.1 ± 2.1 2 kg/m , FEV1 84 ± 7

% Pred,PaO2 11.9 ±

0.7 kpa, PaCO2 5.3 ± 0.5 kpa Oxygen

Hollier et al, RCT, double- 2b N=14 (4 male) OHS: SaO2 stable under 2013[634] blind, effect of stable untreated FiO2 0.28 and 0.50.

moderate 0.28 OHS, age 49±12 ΔPavCO2 0.3±0.2 kPa (p=0.013),

and 0.5 FiO2 (20 yrs, BMI 52.0±7.0 minimal change in VE and VD/VT. 2 min) on blood kg/m , PaCO2 FiO2 0.50: increase of PavCO2

gases, VE, 6.7±0.5 kPa; PaO2 0.5±0.4 kPa (p=0.012), acidaemia VD/VT 8.9±1.4 kPa., and VD/VT by 3±3% (p=0.012). 14 (5 male) healthy Decrease of VE by 1.2±2.1 L/min.

controls, age 45±12 No change in controls. yrs, BMI 24.6±3.3 kg/m2,

PaCO25.4±0.5 kPa,

PaO2 14.1±1.1 kPa Wijesinghe et al, RCT, double 2b N=76 screened, 24 PtCO2 increase 5 mmHg (95% CI 3.1 Data valid only in acute

406

2011[37] blind, cross over (14 male) included, – 6.8) under oxygen, decrease of VE setting study, inhalation age 47±12, BMI 1,4 l/min (0.11 – 2.6), dead space/TV of 100% oxygen 52.4 ± 11.3 kg/m2, 0.067 (0.035 – 0.1), all < 0.05

vs room air for PtcCO2 49±6 20 minutes on 2 mmHg, FEV1 separate days 74±16% Pred. Bariatric Surgery Lumachi et al, Case series 4 N=11 (4 male) Reduction of BMI to 32.5 ± 2.7 kg/m2 2010[45] patients, age 41±10 12 M post surgery, improvement of

yrs, BMI 52.7 ± 2.4 PaCO2 to 38±5 mmHg, increase of 2 kg/m , PaO2 71± 5 PaO2 to 86±7 mmHg.

mmHg, PaCO2 43±6 mmHg. Helling et al, Retrospective 4 N=34 (12 males), Mean percent EWL 61 ± 17 and mean 2005[48] cohort analysis, age 42 ± 8 yrs, BMI percent reduction in BMI was - 44 ± Roux-en-Y 78.3 ± 8.5 kg/m2, 11. Mortality early 1 (3 M, renal gastric bypass in OSA 55%, OHS failure), late (7-36 M) 4 (12%), major extreme obesity 32%. complications 3, minor complications BMI ≥ 70kg/m2. 4. ICU 47%, extended mechanical ventilation 35%. Dávila-Cervantes Prospective 4 N=30 (3 males), age Reduction of BMI after 1 year surgery

407 et al, 2004[49] cohort study in 35 ± 8 yrs, BMI 44 ± to 32 ± 4 kg/m2. Improvement of FVC, 2 vertical banded 4 kg/m at baseline. tidal volume, SaO2, PaCO2. gastroplasty, 1 year follow-up. Lung function, blood gases, hemoglobin.

Sugerman et al, Cohort study 4 N=46 morbidly No difference in body weight, blood Definition OHS, PaO2 < 1988[635] preoperative, obese patients (26 pressure, cardiac index. Significantly 55 mmHg and/or

bariatric surgery, with and 20 without higher PAPmean and PC in OHS. 18/26 PaCO2> 47 mmHg. pulmonary OHS). OHS patients reevaluated 3 – 9 M

artery N=26 (54% male) post surgery: PaO2 50 ± 10 mmHg to

catheterization. OHS, age 44 ± 11 69 ± 14 mmHg, PaCO2 52 ± 7 to 42 ± yrs, 81% pulmonary 4 mmHg. Weight loss 42 ± 19% comorbidity (PC), excess weight. Significant decrease of

%IBW 225 ± PAPmean (36 ± 14 to 23 ± 7) and PC 46.N=20 (15% (17 ± 7 to 12 ± 6). male) controls: age 36 ± 9 yrs, 10% pulmonary

408

comorbidities, %IBW 229 ± 47. Sugerman HJ Cohort study 4 N=38 of 263 Mortality 1 of post operative 1986[53] under efficacy of morbidly obese complications, 1 after 5 weeks post

gastric surgery patients underwent surgery. Increase of PaO2 from 53 ± 9 in OSAS and gastric surgery: to 68 ± 11 mmHg and reduction of

OHS. 10 (0 male)patients PaCO2 from 51 ± 7 mmHg to 41 ± 4 with OHS, mmHg in OHS patients. Improvement

9 (1 male) with of lungfunction tests (FVC, FEV1, SAS, 19 (15 male) ERV, FRC, TLC). OSA+OHS. [632] [634] [220] [628] [35] non-NIV [36] [43] [37] [44] [45]

409

[46] [629] [38] [47] [630] [39] [624] [42] [48] [49] [631] [41] [50]

[51] [52] [635] [53]

410

Tables of chapter 3.6. Chronic NIV in COPD e3.6.A. Chronic NIV after acute respiratory failure

Author Design EBM Patient Results Comments population Funk et al, RCT of 2b N=26 (15 male) The NIV group had a lower probability of 2011 [636] continuation or COPD patients, clinical worsening compared to the withdrawal of age 63 ± 6 yrs, withdrawal group. In addition the time to NIV. Primary BMI 25 ± 5 kg/m2, clinical worsening in the NIV group was 391

outcome: FEV1 31% Pred, days, while this was 162 days in the

Time to clinical PaCO2 93 mmHg withdrawal group worsening: on admission (1) ICU admission (2) . NIV with severe dyspnoea (2a)

or ↑PaCO2 ≥ 10%

Cheung et al, RCT of BiPAP 2b N=47 (43 male) A significantly higher proportion of patients High drop-out 2010 [637] versusCPAP. COPD patients, in the CPAP group developed AHRF NIV: 8

411

Primary age 71± 8 yrs, compared to the NIV at 1 year , 60% versus CPAP: 4 outcome: BMI 19 ± 4 kg/m2, 38 %, respectively

Recurrent FEV1 35% Pred,

exacerbation PaCO2 7.5 kPa with AHRF (pH <7.35 and

PaCO2>6 kPa) resulting in repetitive NIV, intubation or death)

Struik et al, RCT 1b N=201 (118 male) 1 year after discharge, 65% versus 64% of Daytime PaCO2 2010 [638] NIV versus COPD patients, patients (NIV vs standard treatment) were improved equally in standard care. age 64± 8 yrs, readmitted to hospital for respiratory causes both groups. Primary BMI 25 ± 6 kg/m2, or died; time to event was not different

outcome: FEV1 0.7 L, (p=0.85). Daytime PaCO2 was significantly

Time to event PaCO2 7.9 kPa improved in NIV versus standard treatment. (readmission for HRQL showed a trend (p=0.05, Severe respiratory Respiratory Insufficiency questionnaire) in cause or death) favour of NIV

412

413 e3.6.B. Chronic NIV in COPD patients with stable hypercapnic respiratory failure

Author Design EBM Patient Results Comments population Bhatt et al, Prospective 2b N=27 (20 male) 15 patients in the NPPV group and 12 in the Mainly patients with 2013 [639] randomised COPD patients, control group completed the study. NPPV normocapnia were controlled trial. age 69± 7 yrs, use was associated with a small included Patients BMI 25 ± 4 kg/m2, improvement in the CRQ-Mastery domain

received FEV1 30% Pred, (0.6 versus -0.1, P=0.04).

domiciliary PaCO2 43 mmHg NPPV (BiPAP) or usual therapy for 6 M. Primary outcome was HRQOL (CRQ)

De Backer et Prospective, 2b N=15 (10 male) PaCO2 dropped significantly Posthoc analysis al, 2011 [640] parallel, COPD patients, only in the NIV group and not in the control showed that the NIV- randomised, age 66± 7 yrs, arm. treated patients

controlled study. FEV1 29% Pred, improved their blood

Patients were PaCO2 55 mmHg gases more if their, randomised for mass flow was also

414

maximal redistributed towards pharmacological areas with higher treatment (n = 5) vessel density and versus maximal less emphysema. pharmacological This indicates that treatment + NIV flow was redistributed during 6 M (n = towards areas with 10). a better perfusion. Primary outcome variables were arterial blood gas values and functional imaging of the lungs.

McEvoy et al, Randomised, 2a N=144 (94 male) NIV improved sleep quality and sleep- FEV1 and PaCO2 2009 [641] parallel, COPD patients, related hypercapnia acutely, while measured at 6 and controlled study age 68± 9 yrs, compliance was reasonable (4.5±3.2 h). 12 M were not 72 patients BMI 25 ± 5 kg/m2, NIV+LTOT compared with LTOT alone different between

received FEV1 0.59 L, showed an improvement in survival . study groups.

415

standard care + PaCO2 54 mmHg. Patients assigned to NIV + LTOT had nocturnal BiPAP reduced general and mental health and (13/5) for 24 M vigour. and 72 continued optimal standard care. Primary outcome was survival

Clini et al, 2002 Randomised, 2a N=90 (69 male) PaCO2 while using oxygen, resting [642] parallel, COPD patients, dyspnoea and HRQL, as assessed by the controlled study age 65± 10 yrs, Maugeri Foundation Respiratory Failure 43 patients BMI 26 ± 5 kg/m2, Questionnaire, changed differently over

received FEV1 29 % Pred, time in the two groups in favour of the NIV

standard care + PaCO2 55 mmHg. group . Overall hospital admissions showed nocturnal BiPAP a significant positive trend for the NIV (14/2) and 47 group. Survival, lung function, inspiratory continued muscle function, exercise tolerance and optimal standard sleep quality score did not change over time care. Primary in either group. outcome

416

measures were arterial blood gases, hospital and intensive care unit (ICU) admissions, length of stay and HRQL. Casanova et Randomised, 2a N=52 (43 male) One-year survival was similar in both al, 2000 [643] parallel, COPD patients, groups (78%). The number of hospital controlled study age 66 ± 5 yrs, admissions was decreased at 3 M in the 26 patients BMI 25 ± 4 kg/m2, NPPV group (5% vs 15% of patients, p

received FEV1 0.85 L, <0.05), but this difference was not present

standard care + PaCO2 51 mmHg. anymore at 6 M. NIV only lead to an nocturnal improved Borg dyspnoea rating, and in one BiPAP, while the of the neuropsychological tests other 26 (psychomotor coordination). continued optimal standard care. Primary outcome was

417

survival Strumpf et al, Randomised, 2b N=23 (19 male) No improvements were found in pulmonary 4 out of 23 patients 1991 [644] controlled, COPD patients, function, respiratory muscle strength, gas were excluded crossover study age 66± 1 yrs, exchange, exercise endurance, sleep because of OSAS.

Nocturnal BiPAP FEV1 0.54 L, efficiency, quality or oxygenation, or From the remaining

(15/2) for 3 M, PaCO2 49 mmHg. dyspnoea ratings. 19 patients, 7 while the control withdrew because of group continued intolerance of the optimal medical mask, 5 because of care intercurrent illness, Only 7 completed the entire study. Gay et al, 1996 Randomised, 2b N=13 COPD 4 out of 7 patients in the BiPAP group were Only 1 patient had a

[645] parallel, patients, FEV1 still using the ventilator at the end of the substantial reduction

controlled study 0.67 L, PaCO2 52 trial, compared to all 6 in the sham group. in PaCO2 ( from 50 7 patients mmHg. Lung function, nocturnal oxygen saturation, mm Hg to 43 mm received and sleep efficiency did not change in both Hg). nocturnal BiPAP groups. (10/2) for 3 M, while 6 received sham BiPAP

418

(with maximal medical care)

Meecham Randomised 2b N=14, PaO245±6 Significant improvement in PaO2/PaCO2, Correlation between

Jones et al, controlled trial: mmHg, improvement in TST, SEI, overnight PaCO2, daytime PaCO2&

1995 [646] Comparison PaCO256±4 Quality of lifein group I compared to Group Nocturnal PtcCO2:

between FEV10.86±0.32 L. II. r=0.69 ; p=0.01 NIPPV+LTOT NIPPV+LTOT (Group I):

(Group I) vs. PaCO2 from 56±4 to 53±5 and PaO2 from LTOT (Group II) 45±6 mmHg to 50±7 in stable LTOT (Group II):

hypercapnic PaCO2 from 56±4 to 57±6 and PaO2 from COPD. 4wk 45±6 mmHg to 44±7 run-in, 3 M follow-up. Kohnlein et al, Prospective, 1b N=195 (121 male) 1-year mortality was significantly lower in NPPV was targeted 2014 [647] multicentre, COPD patients, the intervention group than in the control to reduce baseline

randomised, age 63± 8 yrs, group, 12 versus 33% respectively. HRQOL PaCO2 by at least controlled BMI 25 ± 6 kg/m2, significantly improved in the NIV as 20% or to achieve

clinical trial FEV1 27% Pred, compared to the control group PaCO2 values lower

Patients were PaCO2 7.7 kPa. than 6.5 kPa. randomly

419

assigned to continue optimised standard treatment (control group) or to receive additional NPPV for at least 12 M (intervention group). The primary outcome was 1-year all- cause mortality Sin et al, 2007 Prospective, 1b N=195 (121 male) 1-year mortality was significantly lower in NPPV was targeted [648] multicentre, COPD patients, the intervention group than in the control to reduce baseline

randomised, age 63± 8 yrs, group, 12 versus 33% respectively. HRQOL PaCO2 by at least controlled BMI 25 ± 6 kg/m2, significantly improved in the NIV as 20% or to achieve

clinical trial FEV1 27% Pred., compared to the control group PaCO2 values lower

Patients were PaCO2 7.7 kPa. than 6.5 kPa. randomly

420

assigned to continue optimised standard treatment (control group) or to receive additional NPPV for at least 12 M (intervention group). The primary outcome was 1-year all- cause mortality

e.3.6.C. Chronic NIV in COPD patients in combination with rehabilitation

Author Design EBM Patient Results Comments population Duiverman et Randomised, 2a N=72 COPD NIPPV did not significantly improve the

421 al, 2008, 2011 parallel, patients were Chronic Respiratory Questionnaire

[649-650] controlled study randomised; FEV1 compared to rehabilitation alone. However to compare the 0.9 ±0.38 L, the addition of NIPPV did improve HRQoL

outcome of 2- PaCO2 6.8 ±0.68 assessed with the Maugeri Respiratory

year home- kPa, PaO2 Failure questionnaire, dyspnoea (Medical based nocturnal 7.8±1.03 kPa. Research Council, gas exchange, 6-minute NIPPV in 6 dropouts. walk distance, Groningen Activity and

addition to Restriction scale and FEV1. Exacerbation rehabilitation PR Group: frequency was not changed. (NIPPV + PR) N=35 (17 male), versus age 61±7 yrs, BMI rehabilitation 27.5±6.3 kg/m2. alone (PR)

The primary NIPPV+PR outcome was Group: health-related N=31 (18 male), quality of life age 63±10 yrs, (HRQoL). BMI 27.1±6.4 kg/m2. Garrod et al, Randomised 2a 45 patients with There were significant improvements in 2000 [651] controlled trial. severe stable mean shuttle walk test and Chronic

422

Patients were COPD were Respiratory Disease Questionnaire (CRDQ) randomised to randomised, in the NPPV + ET group compared to the domiciliary FEV1 0.92±0.28 L, ET group.

NPPV and PaCO2 46±8 exercise training mmHg, PaO2 (ET) or exercise 65±9 mmHg. training alone. Primary ET group: outcome N=22, age 67 (55- parameters were 79) yrs, FEV1 exercise 0.89±0.28 L, capacity and PaCO2 46±9 health status . mmHg, PaO2 67±9 mmHg.

NIPPV+ET: N=23, age 63 (38-

84) yrs, FEV1 0.96±0.31 L,

PaCO2 44±7

mmHg, PaO2

423

64±9 mmHg.

424

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