Obstructive Sleep Apnea - Pulmo Lecture

Sleep Disorders

Human Sleep

ITS RECOGNITION AND MEDICAL CONSEQUENCES

Rommel D. Bayot, MD FPCP, FPCCP Division of Pulmonary and Critical Care Medicine

FUNCTIONS OF SLEEP

What is sleep? • Reversible behavioral state of perceptual disengagement from and unresponsiveness to the environment • Complex amalgam of physiological and behavioral processes

• • • • • •

Body & brain tissue restoration Energy conservation Adaptation Memory reinforcement and consolidation Synaptic and neural network integrity Thermoregulation

Caiskador and Dement

Chokroverty, 2000

SLEEP REQUIREMENT • Newborn → 16 hrs. • 3-5 years → 10 hrs • Adult → 8 hrs.

Stages of Sleep

– Sleep < 4 hrs or > 9hrs → ↑ risk for CAD, stroke and cancer Chokroverty, 2000

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Non-REM

Non-REM

• Non-rapid eye movement • 75-80% of sleep time in adult humans • Characterized by behavioral quiescence with residual muscle tone and very regular, deep breathing

• Stage I NREM – 2-5% of sleep time; lightest stage of sleep – alpha rhythm ↓ < 50% in an epoch – theta rhythm & beta waves appear – EMG activity ↓ slightly

Non-REM

Non-REM

• Stage II NREM – 45-55% of sleep time; intermediate sleep – begins after 10-12 minutes of Stage I NREM – sleep spindles, K complexes, delta waves <20% – lasts 30-60 mins

• Stage III NREM –15-20% of sleep time; deep sleep –delta waves = 20% of the epoch

REM

REM • Rapid Eye Movement –20-25% of sleep time –1st REM noted 60-90mins after onset of NREM sleep –EEG → fast rhythms and delta waves → sawtooth appearance

• Tonic Stage –desynchronized EEG, hypotonia & atonia of major muscle groups

• Phasic Stage –characterized by rapid eye movements in all directions –phasic swings in BP, HR, RR –frequently occur in early morning hours Chokroverty 2000

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CYCLES OF SLEEP • Four or five 90-minute cycles of sequential stages recur during the night • REM stage episodes increase in duration • Slow-wave sleep disappears beyond the second cycle • Infants: large REM sleep up to 2 years • Old: stage 3 diminishes or disappears, sleep fragmentation • REM : total sleep 25% • Nocturnal sleep fluctuates between 5-9 hrs

Obstructive Sleep Apnea (OSA) •

Obstructive Sleep Apnea-Hypopnea Syndrome Its Recognition and Medical Consequences

Characterized by intermittent episodes of complete or partial pharyngeal obstruction during sleep

Obstructive Sleep Apnea – Hypopnea Syndrome (OSAHS) 

When apnea and hypopnea are combined with symptoms such as daytime somnolence Bassiri & Guilleminault. Sleep Medicine 2000

Risk Factors for OSAHS

Incidence of OSAHS and OSA • Men • Women

= =

OSAHS

OSA

4% 2%

24% 9%

• Obesity – 70% of patients – BMI = 30 kg/m2 – Neck Circumference • Men > 17 inches • Women > 16 inches

Chokroverty, Sleep Disorders Medicine 2000



Adults with mean BMI of 25-28, 1 of every 5 has at least mild OSA and 1 of every 15 has at least moderate to severe OSA  OSAHS estimated to occur in 1 of 20 adults usually unrecognized and undiagnosed and results in behavioral and cardiovascular morbidity

• • • • • • •

Young, AJRCCM 2002

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Male gender Menopausal women Increasing age - = 40 years old (+) Family History - ? risk 2-4x Alcohol Smoking Increasing drug use

*Respiratory Events in OSA • Narrowing at one or more sites along the upper airway (retropalatal, retroglossal or hypopharyngeal region) snoring • Pharyngeal collapse apneas and hypopneas • Increased effort of breathing lead to arousals and fragmented sleep

Symptoms of OSAHS Nocturnal Symptoms

Daytime Symptoms

• • • • • • • • •

• • • • •

Snoring Witnessed apnea Choking Dyspnea Restlessness Diaphoresis Esophageal reflux Drooling Dry mouth

*Clinical Features Associated with OSAHS

Clinical Examination • Obesity and neck circumference – BMI – Neck circumference

• Upper Airway – Craniofacial dysmorphism – Tongue, uvula, soft palate (size, length, height) – Retroglossal area – Nose

• • •

Sleepiness Fatigue Morning headache Poor concentration Decreased libido or impotence Decreased attention Depression Personality changes

• •

Obesity Neck circumference > 40 cm Enlarged nasal turbinates Deviated nasal septum Narrow mandible Narrow maxilla Dental overjet and retrognathia

• • • • •

• • • • • •

Crossbite and dental malocclusion High and narrow hard palate Elongated and low lying uvula Prominent tonsillar pillars Enlarged tonsils and adenoids Macroglossia

Philippine Journal of Chest Diseases Vol 14 No 2 May-Aug 2008

Characteristics of Patients with Sleep-Disordered Breathing Referred to the Philippine Heart Center Sleep Clinic for Polysomnography  Middle age group, snoring, obesity, increased neck

circumference and daytime sleepiness are predictors of sleep-disordered breathing

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POLYSOMNOGRAPHY • The single MOST important laboratory

Laboratory Assessment of OSAHS

technique for assessment of sleep and its disorders

POLYSOMNOGRAPHY

What does Polysomnography measure?

• Method of identifying and evaluating sleepstate and several physiologic variable during sleep

• It monitors the multiple physiological characteristics simultaneously during sleep at night. • It allows assessment of sleep stages and wakefulness, respiration, cardio-circulatory functions and body movements. • It monitors physiological or pathological events in sleep.

ATS 1989

• A multi-parametric test that is used to study/record in detail all the biophysiological changes that occur in the human body when the person is asleep

When Is Sleep Laboratory Evaluation in Order?

What is monitored in PSG?

• Serious excessive daytime sleepiness with no known medical cause and not relieved by 2 weeks of significant increase of time in bed • Snoring with interrupted breathing or periodic limb movements • Nocturnal seizures

•

Electroencephalogram (EEG)

•

Oximetry

•

Electrooculogram (EOG)

•

Leg electromyogram (EMG)

•

Chin electromyogram (EMG)

•

Body position

•

Electrocardiogram (ECG)

•

Snoring sensors

•

Nasal and/or oral airflow

•

•

Breathing effort (chest and abdomen)

Continuous audio/video monitoring & behavior observation

Hauri et al. Sleep Disorders, 1992 AASM Practice Parameters for Indications for Polysomnography 2005

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Indications for Cardiopulmonary Sleep Studies • COPD patients with awake PaO2 > 55mmHg but with cor pulmonale • Patients with restrictive ventilatory impairment secondary to chest wall and neuromuscular disturbances and complicated by chronic hypoventilation, polycythemia, pulmonary hypertension, disturbed sleep, daytime somnolence and fatigue ATS 1989

Indications for Cardiopulmonary Sleep Studies • Patients with disturbances of respiratory control whose awake PaO2 > 45mmHg or with complications • Snoring and obesity

Indications for Polysomnography • Polysomnography is routinely indicated for the diagnosis of sleep related breathing disorders. (Standard)

• Patients with excessive daytime sleepiness • Patients with nocturnal cyclic bradytachyarrhythmia, nocturnal abnormalities of atrioventricular conduction and ventricular ectopy during sleep

• Polysomnography is indicated for positive airway pressure (PAP) titration in patients with sleep related breathing disorders. (Standard)

ATS 1989

Indications for Polysomnography • A preoperative clinical evaluation that includes polysomnography or an attended cardiorespiratory (Type 3) sleep study is routinely indicated to evaluate for the presence of obstructive sleep apnea in patients before they undergo upper airway surgery for snoring or obstructive sleep apnea. (Standard)

AASM Practice Parameters for Indications for Polysomnography 2005

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AASM Practice Parameters for Indications for Polysomnography 2005

Laboratory Assessment of OSAHS • Other Laboratory test – Thyroid function test – Pulmonary function test

SLEEP RELATED APNEA

Obstructive Apnea

(Apnea 10 sec. & ≥ 5/hr of sleep)

• Central Apnea – cessation of airflow with no respiratory effort

• Obstructive sleep Apnea – cessation of airflow through the nose or mouth with persistence of diaphragmatic & intercostal muscle activities

• Cessation of airflow, usually for more than 10 seconds • With abdominal and/or thoracic effort • Usually terminated by an arousal and/or associated with a desaturation

• Mixed Apnea – initial cessation of airflow with no respiratory effort followed by periods of upper airway OSA ATS, 1989

Central Apnea • Cessation of airflow, usually for more than 10 seconds • Without abdominal and/or thoracic effort • May be terminated by an arousal and/or associated with a desaturation • Very different type syndrome than OSA; chemo-receptor irregularities

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Mixed Apnea – Cessation of airflow >10 s (in adults) with respiratory effort – Contains both central and obstructive components, with each component lasting at least one normal respiratory cycle – Typically leads to a desaturation and an arousal – Is really just a type of obstructive event with the same consequences

Hypopnea • Reduced airflow, usually for more than 10 seconds • Many labs require at least a 50% reduction in flow; however, more and more labs do not require a specific % reduction, but look at the SaO2 and EEG to affect the decision • May be terminated by an arousal and/or associated with a desaturation

Scoring Definitions: Apnoea

Absence of or > 90% decrease in airflow compared to baseline lasting > 10s Classified as central, obstructive or mixed apnea

Hypopnoea

Any of the following respiratory events lasting >10s are scored: > 50% reduction of airflow > 30% reduction of airflow (but <50%) associated with > 4% oxygen desaturation

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Clinical Event Parameters

Clinical Event Parameters

• Apnea index (AI): number of apneas per hour of TST • Hypopnea index (HI): number of hypopneas per hour of TST • Apnea/hypopnea index (AHI): number of combined apneas and hypopneas per hour of TST • Periodic limb movement index (PLMI): number of periodic limb movements in sleep per hour of TST • Isolated limb movements index: number of nonperiodic limb movements per hour of TST

• Spontaneous arousal index: number of arousals that occur which are not associated with any other clinical event • Arousal index (AI): number of all arousals per hour of TST • Periodic limb movement arousal index (PLMAI): number of periodic limb movements associated with arousal in sleep per hour of TST • Mean Heart rate: the average heart rate during the PSG evaluation which can also be reported by sleep state, REM, non-REM, and wake.

Pathophysiological Effects of OSA on the Cardiovascular System

Cardiovascular Disease and Mechanisms of Association with Sleep-Disordered Breathing Endothelial dysfunction

OBSTRUCTIVE APNEA ↓PaO2, ↑PaCO2

Arousal

↓ Intrathoracic pressure

Reactive oxygen species Nitric oxide/superoxide

Thrombosis ↑ SNA ↑ Catecholamines

Acute

Chronic

↑ HR ↑ BP

Hypertension

Inflammation

Hypoxia

↓ Myocardial O2 delivery Sleep disorders and cardiovascular disease; Potential mechanisms CARDIAC ISCHEMIA CARDIAC ARRHYTHMIAS CARDIAC HYPERTROPHY CARDIAC FAILURE

↑ LV wall tension ↑ Cardiac O2 demand

↓ Stroke Volume

– Increased heart rate

Abnormal vascular tone

Chronic Effects • Autonomic cardiovascular derangements – – – –

• Increased myocardial oxygen demand

• Negative intrathoracic pressure • Increased blood pressure

Catecholamines Endothelin

*Proposed Pathophysiological Effects of Obstructive Apnea on the Cardiovascular System

– Intermittent hypoxia – Decreased cardiac output – Arousals from sleep – Sympathetic nervous system activation – Increase in left ventricular afterload

Alterations in lipid metabolism

Metabolic syndrome Obesity Insulin resistance

*Proposed Pathophysiological Effects of Obstructive Apnea on the Cardiovascular System Acute Effects • Reduced myocardial oxygen delivery

Leptin

Sympathetic nervous system activation Reduced heart rate variability Impaired baroreflex control of heart rate Systemic hypertension-nocturnal and diurnal

• Myocardial effects – Left ventricular hypertrophy – Left ventricular dysfunction and failure

• Increased platelet aggregability and blood coagulability – Increased susceptibility to thrombotic and embolic cardiac and cerebrovascular events

• Nocturnal myocardial ischemia • Nocturnal pulmonary edema • Cardiac arrhythmias

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Acute Cardiovascular Morbidity Associated with OSA • Myocardial infarction • Cerebrovascular disease (stroke) • Cardiac arrhythmia

Chronic Cardiovascular Morbidity Associated with OSA • Arterial hypertension • Pulmonary hypertension • Congestive heart failure

Weiss, Sleep Medicine 2000

Weiss, Sleep Medicine 2000

Incidence of CVD in OSA

Incidence of CVD in OSA • At least one CVD observed in 22 of 60 (36.7%) cases of OSA • CVD incidence in OSA – 21 of 37 (56.8%) – incompletely treated – 1 of 15 (6.7%) – efficiently treated

• Sleep Heart Health Cohort Study – Increased risk of HPN, cardiac failure, stroke and IHD in patients with even mild OSA independent of age and BMI Doherty. CHEST 2005

• OSA asso. with almost five fold increase in risk for development of CVD independent of age, BMI and smoking

• OSA severity was not associated with mortality nor a risk factor for mortality Rodriguez. CHEST 2005

Peker, AJRCCM 2002

OSA and Risk Factors for CVD

OSA and Risk Factors for CVD • Increased homocysteine level

• Increased leptin levels – Wt gain in sleep apnea asso with leptin levels – Leptin is a promoter of platelet aggregation

• Increased C-reactive protein

– Endothelial dysfunction – Increased oxidative stress – Promotes vascular smooth muscle growth

• Insulin resistance syndrome

– Asso with blunted endothelium-dependent vasodilation – Induces increase in cell adhesion molecules – Correlates with severity of sleep apnea

– IGT, HPN and/or central metabolic syndrome – Sleep apnea – higher fasting glucose – IGT → asso with severity in oxygen desaturation during sleep apnea Philipps. Curr Opin Pulm Med 2002

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Mechanisms of Myocardial Infarction in OSA

Obstructive Sleep Apnea and Myocardial Infarction • Apnea index > 5.3 episodes/hour of sleep is an independent predictor of myocardial infarction Dart. CHEST 2003

• ST-segment depression during the night occurred in 30% of patients with OSA Hanly. Am J of Cardiol. 1997

• Increased sympathetic activity may contribute to myocardial ischemia and coronary plague disruption • Chronically elevated catecholamine levels may injure the myocardium Dart. CHEST 2003 • Hypoxia triggers a generalized inflammatory response causing systemic release of inflammatory mediators Quan. Circulation 2004 • Obstructive apnea can lead to myocardial ischemia even in the absence of hypoxia Scheuf. Am Rev Resp Dis. 1992 • Main trigger of ischemia was an increase in oxygen demand rather than oxygen desaturation Pelial. J. Am Coll Cardiology

Coronary Artery Disease and OSA • Mortality:

Obstructive Sleep Apnea and Cardiac Arrhythmias • Tachyarrhythmias and bradyarrhythmias reported in >75% of patients with sleep apnea • Sinus bradycardia – during apneic phase • Atrial tachycardia, V-tach, PVC – due to catecholamine surges and hypoxemia at termination of apnea

– 38% - with OSA – 9% - without OSA

• OSA a poor prognostic indicator in CAD Peker. AJRCCM 2002

Dart. CHEST 2003

• Individuals with severe SDB have two-to-fourfold higher odds of complex arrhythmias than those without SDB even after adjustment for potential confounders

• Respiratory disturbance index, an independent predictor of mortality in CAD Yuksel. AJRCCM 2000

Mehra. AJRCCM 2006

OSA and Hypertension

Possible Mechanisms of Arrhythmias • Obstructive events →↑ myocardial wall tension and oxygen demand → myocardial ischemia • Hypoxemia and hypercarbia → lead to cortical arousals, ↑ sympathetic tone and catecholamine release

• 40% of patients with OSA have daytime HPN • 30% of middle – aged men with HPN have occult sleep apnea • Each additional episode of apnea/hypopnea per hour of sleep was asso. with a two-fold increase in systolic blood pressure Young. AJRCCM 1997 • Only systolic BP increased with OSA and CPAP significantly attenuated the increase in systolic BP and no effect on diastolic BP Tkacova. Circulation 1998

Quan. Circulation 2004

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Possible Mechanisms Linking OSA and HPN

OSA and Hypertension • OSA has a direct and disproportionate effect on systolic BP that is difficult to control with pharmacologic agents Logan , J of HPN 2001

• HPN refractory to maximal medical therapy, 87% had OSA

• Intermittent Hypoxia → stimulation of peripheral chemoreceptors → stimulate brainstem sympathetic vasoconstriction • Increased activity of adrenal glands, renal sympathetic nerves and renin angiotensin system Leung. AJRCCM 2001

• Repeated arousals during sleep is asso. with increased sympathetic activity

Leung, AJRCCM 2001

Nieto. JAMA 2000

Possible Mechanisms Linking OSA and HPN • Nocturnal hypoxemia results in significant elevation in plasma endothelin → sustained daytime BP elevation • Diminished endothelial cell production of nitric oxide → impaired vasodilatation and higher resting vascular tone • Hypoxemia and sleep deprivation induce production of pro – inflammatory cytokines → endothelial dysfunction

Possible Mechanisms Linking OSA and HPN • ↑ Platelet activation → chronic hypertension • OSA promotes atherogenesis through recurrent exposure to hypoxemia Shabarn. AJRCCM 2001

Quan. Circulation 2004

When should OSA be considered in a patient with systemic HPN? • Signs and symptoms of OSA • Unexplained or worse cardiac disease than expected based on the level of BP • Patients with resistant HPN

*Obstructive Sleep Apnea and Congestive Heart Failure • OSA was associated with a 2.38 relative odds for congestive heart failure independent of other known risk factors

Dart. CHEST 2003

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Sleep Heart Health Study, AJRCCM 2001

Obstructive Sleep Apnea and Stroke

Mechanisms of CHF in OSA • Negative intrathoracic pressure – – – –

• Patients who suffered a stroke, sleep apnea is reported to occur in 43-91% of patients

Adverse ventricular contractions Increased ventricular wall stress Reductions in cardiac output Increased PCWP

Leung. AJRCCM 2001

Sin. AJRCCM 1999

• Systemic HPN – most obvious mechanism • Ischemia and reduced contractility due to hypoxia • Cardiac myocyte injury or necrosis due to increased catecholamine stimulation

• OSA after adjustment for age and sex is related to significantly increased odds of suffering a stroke over the next 4 years Arzt AJRCCM 2005

Leung. AJRCCM. 2001

OSA & Stroke: Adverse Prognostic Implications

Mechanisms of OSA and Cerebrovascular Events • • • •

Systemic hypertension Increased platelet aggregability Blood coagulability Obstructive apnea cause a significant decline in cerebral blood flow due to ↓ in cardiac output • Abrupt alterations in vascular shear forces and acceleration of atherosclerosis • Hypoxia can lead to the elaboration of neuroinhibitory peptide such as γ-aminobutyric acid → compromise cerebral function

• Worse functional capacity • Longer period of post-stroke rehabilitation • Higher death rate Artz. AJRCCM 2005

Leung. AJRCCM 2001

Obstructive Sleep Apnea and Pulmonary Hypertension (PH) • 17% of OSAHS had PH • PH is usually mild to moderate

Obstructive Sleep Apnea and Venous Thromboembolism (VTE) •

Mechanism : Chronic hypoxemia ? pulmonary vasoconstriction and remodeling of the pulmonary vascular bed

•

Chaouat Chest 1976

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Possible association between OSAHS and VTE Due to thrombolytic coagulation abnormalities provided by recurrent episodes of hypoxemia Arnulf, JAMA 2002

*OSAHS and Impaired GlucoseInsulin Metabolism • IGT and Type 2 DM are common in patients with AHI = 10. Type 2 DM was newly diagnosed in 40% of the diabetic patients • AHI is independently related to glucose metabolism and insulin sensitivity after adjusting for confounding variables

*OSAHS and Impaired GlucoseInsulin Metabolism •

Incidence – – – –

30.1% 3.9 % 20 % 13.9 %

-

Type 2 DM in OSAHS Type 2 DM in non-apneic snorers IGT in OSAHS IGT in non-apneic snorers Meslier ERJ 2003

•

Snoring is independently associated with impaired glucose tolerance and Type 2 DM Punjab, AMJ Epidemiol 2004

Meslier. ERJ 2003

*OSAHS and Impaired GlucoseInsulin Metabolism

*OSAHS and Impaired GlucoseInsulin Metabolism • Mechanisms

•

Mechanisms

– Sympathetic hyperactivity

– Cyclical hypoxia could lead to glucose intolerance and insulin resistance by promoting release of pro-inflammatory cytokines (IL-6 and TNFα) – Sleep fragmentation increases levels of plasma cortisol ? ? glucose levels and insulin concentration and increased insulin secretion

• influences glucose homeostasis by increasing glycogen breakdown and gluconeogenesis • increases circulating free fatty acids via stimulation of lipolysis and promotes insulin resistance

– Central obesity leads to insulin resistance via ? lipolysis and fatty acid availability

Punjab, AMJ Epidemiol 2004

*OSAHS and Impaired GlucoseInsulin Metabolism •

•

•

Even mild degrees of OSA would be associated with glucose intolerance and insulin resistance Early metabolic dysfunction occurs with OSA before overt clinical manifestation of underlying disease Metabolic dysfunction associated with OSA may increase the risk of CVD morbidity and mortality

*OSAHS & Hypothyroidism • 1-3% = prevalence of hypothyroidism in OSAHS • Screening for hypothyroidism in OSAHS does not seem necessary unless patient is symptomatic of belongs to a risk group

Punjab AJRCCM 2002

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Saaresenta ERJ 2003

*OSAHS and Growth Hormone Deficiency • 70% of nocturnal GH pulses are associated with slow-wave sleep • Mechanisms – Sleep fragmentation results in decreased amount of slow wave sleep – Hypoxia inhibits growth hormone release or biosynthesis – Obesity decreases GH secretion Saareseanta ERJ 2003

Effects of Treatment • •

Effects of Treatment

10-15 % weight loss can reduce or eliminate OSA Low levels of weight reduction may curtail cardiovascular risk

• •

Punjab, AJRCCM 2002

•

Serum leptin levels decrease with CPAP without weight loss Decrease in leptin levels already observed after the first night of CPAP CPAP induced reduction in leptin level is due to improved sleep and breathing Saareseanta. ERJ 2003

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Effects of Treatment

Effects of Treatment

• Treatment of OSA by CPAP for 1 month caused dramatic improvements in LVEF (from 37% to 49%) and cardiac functional status Leung. AJRCCM 2001

• 8 - year follow-up on rate of new onset IHD – 14% = untreated group – 5% = CPAP group

• Long Term Effect of CPAP on Cardiovascular Outcome (5 - year follow up)

• The effect of nocturnal CPAP carry over into wakefulness • Effects of one month treatment – 9% absolute and 35% relative rise in LVEF – Decrease in systolic BP of 10 mmHg – Decrease in heart rates of 4 beats/ minute

– 31% = total CV events in the untreated group – 18% = CPAP group Doberty. CHEST 2005

Kaneko. NEJM 2003

Effects of Treatment

Effects of Treatment

• CPAP treatment for 3 months improved insulin responsiveness • Insulin sensitivity significantly increased after 2 days of CPAP especially in patients with BMI < 30

5-year cumulative survival rate • 96.4% = CPAP compliance >6 hrs/day • 91.3% = CPAP compliance 1-6 hrs/day • 85.5% = CPAP compliance <1hr/day Rodriquez. CHEST 2005

Harsch ASRCCM 2003

Better understanding of sleep related breathing disorders can improve health outcomes in patients suffering or at risk for its systemic consequences.

“Laugh and the world laughs with you, snore and you sleep alone.” Anthony Burgess English novelist, critic

*What-eber?! 

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