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Speech Outline 1 Aging & Sleep 2 The Upper Airway in Sleep 3 Sleep-Disordered Breathing 4 Consequence of OSA E-mail : 47822@cch.org.

and 2 sleep Decreased stage 3 and 4 sleep or slow wave sleep (SWS) Fewer sleep cycles through per night Decreased rapid-eye movement (REM) sleep Sleep onset or latency becomes delayed Increased

1 Speech Outline 1 Aging & Sleep 2 The Upper Airway in Sleep 3 Sleep-Disordered Breathing 4 Consequence of OSA @cch.org.tw Speech Outline Typical Changes in Sleep Patterns with Age 1 Aging & Sleep 2 The Upper Airway in Sleep 3 Sleep-Disordered Breathing 4 Consequence of OSA Total sleep time decreases Increased stage 1 and 2 sleep Decreased stage 3 and 4 sleep or slow wave sleep (SWS) Fewer sleep cycles through per night Decreased rapid-eye movement (REM) sleep Sleep onset or latency becomes delayed Increased daytime napping Increase in awakenings and arousals Decreased sleep efficiency Circadian phase advanced (early to bed and early to rise) Awake Non Rapid Eye Movement (NREM) N1 N2 N3 Rapid Eye Movement (REM) Hypnogram From Young & Elderly 24 EOG L EOG R EEG Sleep Stages EMG Percentage of total sleep (Young/elderly) Characteristic wave forms 2-5%/8-15% 40-50%/60-80% 20%/0-5% 20-25%/20% Theta wave (4-7Hz) Theta wave (4-7Hz) Interspersed with Sleep spindles (short brusts of activity between Hz) and K- complexes Delta wave (<4 Hz) Low voltage high frequency EEG (similar to that in wakefulness), muscle atonia and presence of rapid eye movement 72 Clinical Significance Increased duration suggests sleep fragmentation Formally divided into stage N3 and N4 based on the % amount of delta wave present. Also referred to as slow wave sleep. Restorative phase of sleep Recurring every minutes Speech Outline Anatomy of Upper Airway 1 Aging & Sleep 2 The Upper Airway in Sleep 3 Sleep-Disordered Breathing 4 Cosequence of OSA

Pressure-area curve of Velopharynx Nasal

Traumatic Injury Nasal Congestion Polyps

sinusitis Nasopharynx Oropharynx Choanal

scarring Tonsil hypertrophy Elongated uvula

2 Pressure-area curve of Velopharynx Nasal Pathology Developmental Obstruction Traumatic Injury Nasal Congestion Polyps Neoplasm Deviated septum Allergic rhinitis sinusitis Nasopharynx Oropharynx Choanal Stenosis Adenoid Enlargement Bulky Upper Portion of Soft palate Chronic nasopharyngitis Tumor Post-surgical scarring Tonsil hypertrophy Elongated uvula Palatal hypertrophy Lowered palatal arches Enlarged tongue Webbing of palate Hypopharynx Larynx Lingular Tonsil Hypertrophy Macroglossia Micrognathia Posterior mandibular displacement Laryngeal obstruction Abnormal epiglottis Glottis Edema Vocal cord Paralysis

Speech Outline 1 Aging & Sleep 2 The Upper Airway in Sleep 3 Sleep-Disordered Breathing 4 Consequence of OSA 1.

00 Gender Male Female Sleep Breath (2012) 16:453 460 40.00 Patient Weight Normal Weight Obese Male Gender Sleep Breath (2012) 16:453 460 Female 30.00 Mean AHI 20.00 15.

00 21-25 26-30 31-35 36-40 41-45 46-50 51-55 56-60 61-65 66-70 71-75 76-80 Age Groups 21-25 26-30 31-35 36-40 41-45 46-50 51-55 56-60 61-65 66-70 71-75 76-80 Age Groups

3 Speech Outline 1 Aging & Sleep 2 The Upper Airway in Sleep 3 Sleep-Disordered Breathing 4 Consequence of OSA 1. Epidemiology Age- and gender-related characteristics of OSA Age- and gender-related characteristics of OSA Gender Male Female Sleep Breath (2012) 16: Patient Weight Normal Weight Obese Male Gender Sleep Breath (2012) 16: Female Mean AHI Mean AHI Age Groups Age Groups Age Groups The Male Predisposition to Pharyngeal Collapse The Male Predisposition to Pharyngeal Collapse 80 top of the hard palate base of the epiglottis Airway Length (mm) women Gender men 0.5 Am J Respir Crit Care Med Vol 166. pp , 2002 Normalized Airway Length (mm/cm) women Gender men

A Community Study of Sleep-Disordered Breathing in Middle-aged Chinese Men in Hong Kong Increased Prevalence of Sleep-Disordered Breathing in Adults sleep apnea among middle-aged men in Hong Kong

1% 14-55 % A Community Study of Sleep-Disordered Breathing in Middle-aged Chinese Men in Hong Kong Chest 2001 119: 62-69 American Journal of Epidemiology, 2013 Sleep-Disordered Breathing in

4 A Community Study of Sleep-Disordered Breathing in Middle-aged Chinese Men in Hong Kong Increased Prevalence of Sleep-Disordered Breathing in Adults sleep apnea among middle-aged men in Hong Kong using full PSG demonstrated an estimated prevalence of (AHI 5 and EDS) at 4.1% % A Community Study of Sleep-Disordered Breathing in Middle-aged Chinese Men in Hong Kong Chest : American Journal of Epidemiology, 2013 Sleep-Disordered Breathing in Community-Dwelling Elderly Predictors of Sleep-Disordered Breathing in Community-Dwelling Adults Percent of Subjects N=427 >65Y 62%, RDI>10 No reliable predictors of RDI Prevalence of an AHI 15,% Respiratory Disturbance Index Sleep December ; 14(6): Age, y Arch Int med, 2002 The reciprocal interaction between obesity and OSA ALTERATION IN AIRWAY ANATOMY CHANGES TO Pcrit / AIRWAY COLLAPSIBILITY DESTABILIZATION OF RESPIRATORY CONTROL CENTRE (LOOP GAIN) REDUCTION IN LUNG VOLUMES EFFECT OF NEUROHORMONAL MEDIATORS (LEPTIN) ON VENTILATION OBESITY OSA CHANGE IN ENERGY EXPENDITURE WORK OF BREATHING ACTIVATION OF SYMPATHETIC NERVOUS SYSTEM MODIFICATION OF PHYSICAL ACTIVITY EFFECT OF ADAPTIVE THERMOGENSIS MODIFICATION OF DIETARY CHOICES LEPTIN RESISTANCE GHRELIN MODIFICATION OF DIETARY CONSUMPTION SECONDARY TO SLEEP DEPRIVATION Sleep Medicine Reviews 17 (2013) 123e131 Key Points Box Mean apnea-hypopnea index at baseline and the increase 8 years later in 282 participants in the Wisconsin Sleep Cohort Ф Obesity is very strong risk for OSA Ф All measures of obesity neck and waist girths, weight, skin folds predict OSA Ф An increase of 1 kg/m 2 in BMI (e.g., a 71b. gain in a 5 10 person) yields an estimated 30 increase in the odds of developing OSA Ф An increase (decrease) of 1 kg/m 2 in BMI yields an estimated 9 increase (decrease) in the AHI Caples, S. M. et. al. Ann Intern Med 2005;142:

5 All Cause Mortality Study in OSA (Mod-Severe) HR 1.46 (1.14~1.86) AHI>20 EDS : HR 2.28 (1.46~3.57) AHI>20 EDS : HR 0.74 (0.39~1.38) Key Points Box Ф Obstructive sleep apnea is prevalent in the general adult population Ф The severity spectrum of undiagnosed OSA ranges from mild to very severe Ф of is undiagnosed 233 F: M: FAHI>50 : OR 0.18 (P0.001) FAHI 30~50 : OR 0.74 (P 0.001) M: NS AHI 20~40 : OR 0.42 (0.26~0.67) AHI>40:NS Ф An estimated 9 of women and 24 of men have sleep-disordered breathing of at least mild severity Ф 1 4 of middle-aged adults have OSA that meets the criteria for Ф OSA is very common in older adults; symptoms and outcomes may differ from those in middle-age Pathogensis of 2. Pathogenesis A. Pharyngeal Anatomy airway lumen size is compromised in most OSA patient oval shape of pharyngeal airway B. Control of upper airway patency a. pharyngeal dilator muscles: central & local reflex, PO 2 & PCO 2 muscle of tongue muscle influencing hyoid position muscle of the palate b. neuromuscular compensation C. Other factors tissue pressure influenced by position blood flow or vascular volume lung volume D. Central neuromuscular mechanisms serotonin adrenaline Pathogenesis of Maximum GGEMG during wakefulness Upper airway receptor mechanisms pressure/collapse Sleep () Compensation for their Inadequate airway anatomy () Upper airway patency CNS % of Maximum GG EMG Activity * 1. Abnormal anatomy 2.Increased collapsibility of the pharyngeal airway () 10 Activity of pharyngeal dilators Genioglossus () Sleep 0 CONTROLS (n=8) OSA PTS (n=10) Aging Influences on Pharyngeal Anatomy and Physiology: The Predisposition to Pharyngeal Collapse Fat Pat Thickness (mm) Am J Med January ; 119(1): 72.e Age (years)

6 Aging Influences on Pharyngeal Anatomy and Physiology: The Predisposition to Pharyngeal Collapse OSA Am J Med January ; 119(1): 72.e Potential contributors Lung volume Loop gain (LG) Arousal Threshold Upper airway (UA) anatomy Pharyngeal dilator muscles Reflex Activity (%) Age (years) Potential aging effects Intermediate effects Long-term consequences TLC tethering effect on UA Metabolic dysfunction LG? threshold Obstructive Sleep Anpea Autonomic dysregulation (i.e. altered SNA activity and vagal tone) Endothelial dysfunction fat deposition muscle bulk UA mechanoreceptor sensitivity Airway length Metabolic disorders Mortality and morbidity Cardiovascular consequences muscle recruitment Inflammation and oxidative stress Neurocognitive dysfunction Symptom of Nighttime Daytime 3. Clinical Features Snoring Witnessed Apnea Choking Dyspnea Restlesness Nocturia Diaphoresis Reflux Drooling Sleepiness Fatigue Morning headache Poor concentration Decreased libido or impotence Decreased attention Depression Decreased Dexterity Personality change Clinical Feature Associated with Obesity(BMI>28) Cross-bite and dental malocclusion Neck circumference>40 cm High and narrow hard palate Enlarged nasal turbinate Elongated and low-lying uvula Deviated nasal septum Prominent tonsillar Pillars Narrow mandible Enlarged tonsils and adenoids Narrow maxilla Macroglossia Dental overjet and retrognathia Diagnosis of Sleep Apnea Likelihood Rations for Symptoms and Physical Characteristics Symptom / Physical Characteristics Daytime EDS Weight gain over previous 2 years Impotence Clinical Prediction Rule Sleep Apnea Clinical Score (SACS) Level Yes, against one s will Yes, but willingly None 10 pounds 10 pounds Likelihood Ratio Yes No Diagnosis of Sleep Apnea Likelihood Rations for Symptoms and Physical Characteristics Diagnosis of Sleep Apnea Likelihood Rations for Symptoms and Physical Characteristics Symptom / Physical Characteristics Nocturnal Snoring frequency Loud, disruptive Snoring frequency Snoring intensity Partner s report of choking/gasping Partner s report of apneas Nocturia Level 3 nights per wk 3 nights per wk 3 nights per wk 3 nights per wk Extremely loud Louder than talking As loud as talking Slightly louder than heavy breathing 1 night per month 1-8 nights per month 3 nights per wk Likelihood Ratio Yes 1.4,1.5 No 0.2,0.5 Yes No Symptom / Physical Characteristics Physical Examination Pharyngeal exam Hypertension Level Abnormal Normal Yes NO BMI 25 kg / m kg / m 2 30 kg / m 2 Waist Circumference 90 cm cm 110 cm Waist Hip Ratio Neck Circumference 38 cm cm 44 cm Likelihood Ratio , 2.2, , 0.6, ,

Clinical Feature Associated with Clinical Feature Associated with

mild to moderate OSA progresses in severity over time Ф Some OSA

ratio for OSA prevalence is 2 : 1 Ф Snoring and sleepiness are the

underreport their snoring Ф Menopause is a risk factor for OSA,

Two or more of the following that are not better explained by other

sleep, un-refreshing sleep, daytime fatigue, impaired

Overnight monitoring demonstrates 5 or more obstructed breathing

7 Clinical Feature Associated with Clinical Feature Associated with Clinical Feature Associated with Key Points Box Ф Most untreated mild to moderate OSA progresses in severity over time Ф Some OSA regresses in severitybut rarely disappears Ф The male : female ratio for OSA prevalence is 2 : 1 Ф Snoring and sleepiness are the strongest predictors of OSA for both men and women Ф Women probably underreport their snoring Ф Menopause is a risk factor for OSA, independent of age and weight for height 4. Diagnosis Diagnostic criteria for A. EDS that is not better explained by other factors, or B. Two or more of the following that are not better explained by other factors choking or gasping during sleep, recurrent awakenings from sleep, un-refreshing sleep, daytime fatigue, impaired concentration; and / or A or B + C D C. Overnight monitoring demonstrates 5 or more obstructed breathing events per hour during sleep D. 15 or more obstructed breathing events per hour regardless of associated symptom SLEEP, Vol. 22, No. 5, 1999 Overnight computerized PSG (20 signals in one epoch)

Obstructive apnea / Hypopnea event 1. A clear decrease (> 50 %) from baseline in the amplitude of a valid measure of breathing during sleep.

an arousal 3. The event lasts 10 seconds or longer Respiratory Effort- Related Arousal Respiratory Effort- Related Arousal RERA 1.

8 Obstructive apnea / Hypopnea event 1. A clear decrease (> 50 %) from baseline in the amplitude of a valid measure of breathing during sleep. Baseline is defined as the mean amplitude of stable breathing and oxygenation in the 2 minutes preceding onset of the event or the mean amplitude of the 3 largest breaths in the 2 minutes preceding onset of the event 2. A clear amplitude reduction of a validated measure of breathing during sleep that does not reach the above criterion but is associated with either an oxygen de-saturation of > 3 % or an arousal 3. The event lasts 10 seconds or longer Respiratory Effort- Related Arousal Respiratory Effort- Related Arousal RERA 1. Increase respiratory effort last 10 seconds or longer leading to arousal from sleep, but which does not fulfill the criteria for apnea or hypopnea 2. Detect with nocturnal esophageal catheter pressure measurement which demonstrate a pattern of progressive negative esophageal pressure Eso Pressure Nasal Cannula Respiratory Disturbance Index/ Apnea-Hypopnea Index RDI = Apnea, Hypopneas, RERA events / Hour AHI =Apnea, Hypopneas / Hour

Severity AHI > 5 and Daytime sleepiness Dimension Mild Moderate Severe Sleepiness AHI 5-14 15-29 >30 OSA Severity Assessment Respiratory disturbance index (RDI) Amount of supine sleep and

Cartwright and Lloyd defined positional patients (PP): 9-60% OSA patients in whom the RDI was at least twice as high in the supine position as in the lateral position.

9 Severity AHI > 5 and Daytime sleepiness Dimension Mild Moderate Severe Sleepiness AHI >30 OSA Severity Assessment Respiratory disturbance index (RDI) Amount of supine sleep and REM sleep Respiratory arousal index Severity of daytime sleepiness Severity of arterial oxygen desaturation Comorbid illness Sleep associated arrythmia Positional & Nonpositional OSA 1984 Cartwright and Lloyd defined positional patients (PP): 9-60% OSA patients in whom the RDI was at least twice as high in the supine position as in the lateral position. nonpositional patients (NPP). Those patients in whom the RDI in the supine position was less than twice that in the lateral position. Heart rate (HR) and SaO2 tracing in a typical positional OSA patient OSA 6. Treatment

Diagnosis of OSA syndrome Behavioral treatment -Weight loss -Increased physical activity -Avoidance of

Oral appliance Alternative therapy Surgery -Uvulopharingopalatoplasty -Maxillo-mandibular -advancement

-Oxygen supplementation Symptoms resolved? CPAP tolerated?

10 Diagnosis of OSA syndrome Behavioral treatment -Weight loss -Increased physical activity -Avoidance of alcohol and sedatives before bedtime Accepted CPAP not accepted Evaluation of adherence and outcome Oral appliance Alternative therapy Surgery -Uvulopharingopalatoplasty -Maxillo-mandibular -advancement osteotomy -Laser assisted uvuloplasty -Radiofrequency ablation Adjunctived therapies -Pharmacotherapy -Oxygen supplementation Symptoms resolved? CPAP tolerated? yes no Evaluation of outcome Symptoms resolved? no Long-term follow-up yes Mechanism Pneumatic splint mechanism Increase in lung volume (Rebound Effect)

11 CPAP Titration End Point v Apnea prevention v Desaturation prevention v Respiratory arousal prevention v No airflow limitation Side effect of nasal CPAP Problem Nasal Side effect Rhinorrhea Nasal congestion,dryness Epistaxis Mask Skin abrasion/rash conjunctivitis Flow-related Chest discomfort Aerophagy Claustrophobia Difficult exhaling Pnemothorax Pneumoencephaly Sinus discomfort Positional Therapy

A Novel Nasal Expiratory Positive Airway Pressure (EPAP) Device for the Treatment of OSA : A RCT Patients who have rejected or are non-compliant with prescribed CPAP

Sleep-Disordered Breathing and Mortality: A Prospective Cohort Study 1 Aging & Sleep 2 The Upper Airway in Sleep 3 Sleep-Disordered Breathing 4 Consequence of OSA

PLoS Medicine, 2009 Cardiovascular sequelae Systemic hypertension Coronary heart disease Heart failure Cardiac arrhythmias -Atrial fibrillation -Supraventricular

12 A Novel Nasal Expiratory Positive Airway Pressure (EPAP) Device for the Treatment of OSA : A RCT Patients who have rejected or are non-compliant with prescribed CPAP Newly diagnosed mild/moderate OSA patients without significant co-morbidities CPAP compliant patients looking for alternatives for travel Speech Outline Sleep-Disordered Breathing and Mortality: A Prospective Cohort Study 1 Aging & Sleep 2 The Upper Airway in Sleep 3 Sleep-Disordered Breathing 4 Consequence of OSA Sleep-Disordered Breathing and Mortality: A Prospective Cohort Study Baseline mortality rate? Survivor Effect? PLoS Medicine, 2009 Cardiovascular sequelae Systemic hypertension Coronary heart disease Heart failure Cardiac arrhythmias -Atrial fibrillation -Supraventricular tachycardia -Ventricular tachycardia/fibrillation -Sinus bradycardia -Heart block Pulmonary hypertension Stroke Neurocognitive sequelae Impaired vigilance Deficit in executive functioning Impaired fine-motor coordination Depression Cardiovascular Sequelae

European Heart Journal (2013) 34, 809 815 The Association between Sleep

factor for hypertension and consequent cardiovascular morbidity in the

Prospective study of the association between sleep-disordered breathing

The Association between Sleep Apnea and Hypertension Compared with

ambulatory diastolic blood pressure during both day and night, and

Mullins R L, Barbour C, Davies R J, Stradling J R.

13 European Heart Journal (2013) 34, The Association between Sleep Apnea and Hypertension sleep-disordered breathing is likely to be a risk factor for hypertension and consequent cardiovascular morbidity in the general population Peppard P E, Young T, Palta M, Skatrud J. Prospective study of the association between sleep-disordered breathing and hypertension. N Engl J Med 2000; 342: The Association between Sleep Apnea and Hypertension Compared with closely matched control subjects, patients with OSA have increased ambulatory diastolic blood pressure during both day and night, and increased systolic blood pressure at night Davies C W, Crosby J H, Mullins R L, Barbour C, Davies R J, Stradling J R. Case-control study of 24 hour ambulatory blood pressure in patients with obstructive sleep apnoea and normal matched control subjects. Thorax 2000; 55:

Cheyne-Stokes Respiration Heart Failure Cardiac Output Obstructive sleep apnea and hypertrophic cardiomyopathy: A common and

system Myocardial hypertrophy Hyperventilation Chemosensitivity Delayed Transmission in ABG Alterations Acute in Ventilation PCO2 OSA

CSA Atrial Fibrilation Increased risk of sudden death Sleep Medicine Reviews 17 (2013) 201e206 The Association between Sleep Apnea

340(11):847-51, 1999 Sleep-Disordered Breathing, Hypoxia, and Risk of Mild Cognitive Impairment and Dementia in Older Women

14 Cheyne-Stokes Respiration Heart Failure Cardiac Output Obstructive sleep apnea and hypertrophic cardiomyopathy: A common and potential harmful combination LVEDP Pulmonary Congestion Vagal Stimulation Circulation Time Overstimulation of sympath etic nervous system Myocardial hypertrophy Hyperventilation Chemosensitivity Delayed Transmission in ABG Alterations Acute in Ventilation PCO2 OSA Left atrium dilation HCM Triggering CSA Ventilatory Overshoot/Undershoot Arousal Apneic CO2 Threshold Sleep Cheyne-Stokes respiration CSA Atrial Fibrilation Increased risk of sudden death Sleep Medicine Reviews 17 (2013) 201e206 The Association between Sleep Apnea and the Risk of Traffic Accidents Neurocognitive Sequelae. New England Journal of Medicine. 340(11):847-51, 1999 Sleep-Disordered Breathing, Hypoxia, and Risk of Mild Cognitive Impairment and Dementia in Older Women Obstructive Sleep Apnea: Brain Structural Changes and Neurocognitive Function before and after Treatment 82.3 Y/O JAMA. 2011;306(6): Am J Respir Crit Care Med Vol 183. pp , 2011

15 Obstructive Sleep Apnea and Delirium Vascular Injury Cognitive Dysfunction Tissue Hypoxia OSA Low Grade Systemic Inflammation and Oxidative Stress Nauronal Injury and Apoptosis + Decrease in IGF-1 Delirium Sleep Breath, 2013 Cognition

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untitled (Cardiac Insufficiency) (introduction) (Concept of heart failure) (Cardiac insufficiency & heart failure) (Concept of congestive heart failure) (Underlying and predisposing causes of heart failure) (Underlying