Obstructive Sleep Apnea - Pulmo Lecture

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Sleep Disorders

Rommel D. Bayot, MD FPCP, FPCCP

Division of Pulmonary and Critical Care Medicine

ITS RECOGNITION AND MEDICAL CONSEQUENCES Human Sleep

What is sleep?

• Reversible behavioral state of perceptual disengagement from and unresponsiveness to the environment

• Complex amalgam of physiological and behavioral processes

Caiskador and Dement

FUNCTIONS OF SLEEP

• Body & brain tissue restoration

• Energy conservation

• Adaptation

• Memory reinforcement and consolidation

• Synaptic and neural network integrity

• Thermoregulation

Chokroverty, 2000

SLEEP REQUIREMENT

• Newborn → 16 hrs.

• 3-5 years → 10 hrs

• Adult → 8 hrs.– Sleep < 4 hrs or > 9hrs →↑ risk for CAD, stroke

and cancer

Chokroverty, 2000

Stages of Sleep

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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

Non-REM

• 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

• 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

Non-REM

• Stage III NREM–15-20% of sleep time; deep sleep

–delta waves = 20% of the epoch

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

REM

• 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 hoursChokroverty 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-Hypopnea Syndrome

Its Recognition and Medical Consequences

Obstructive Sleep Apnea (OSA)• 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

Incidence of OSAHS and OSA

• Men = 4% 24%• Women = 2% 9%

OSAHS OSA

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

Chokroverty, Sleep Disorders Medicine 2000

Young, AJRCCM 2002

Risk Factors for OSAHS• Obesity – 70% of patients

– BMI = 30 kg/m2

– Neck Circumference• Men > 17 inches• Women > 16 inches

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

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*Respiratory Events in OSA

• Narrowing at one or more sites along the upper airway (retropalatal, retroglossal or hypopharyngealregion) snoring

• Pharyngeal collapse apneas and hypopneas

• Increased effort of breathing lead to arousals and fragmented sleep

Symptoms of OSAHS

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

Daytime Symptoms• Sleepiness• Fatigue• Morning headache• Poor concentration• Decreased libido or

impotence• Decreased attention• Depression• Personality changes

Clinical Examination

• Obesity and neck circumference– BMI– Neck circumference

• Upper Airway– Craniofacial dysmorphism– Tongue, uvula, soft palate (size, length,

height)– Retroglossal area– Nose

*Clinical Features Associated with OSAHS

• 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 tonsillarpillars

• Enlarged tonsils and adenoids

• Macroglossia

Philippine Journal of Chest DiseasesVol 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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Laboratory Assessment of OSAHS

• The single MOST important laboratory

technique for assessment of sleep and its

disorders

POLYSOMNOGRAPHY

POLYSOMNOGRAPHY

• Method of identifying and evaluating sleep-state and several physiologic variable during sleep

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

ATS 1989

What does Polysomnography measure?

• 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.

When Is Sleep Laboratory Evaluation in Order?

• 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

Hauri et al. Sleep Disorders, 1992

What is monitored in PSG?

• Electroencephalogram (EEG)

• Electrooculogram (EOG)

• Chin electromyogram (EMG)

• Electrocardiogram (ECG)

• Nasal and/or oral airflow

• Breathing effort (chest and

abdomen)

• Oximetry

• Leg electromyogram (EMG)

• Body position

• Snoring sensors

• Continuous audio/video

monitoring & behavior

observation

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

• Patients with excessive daytime sleepiness

• Patients with nocturnal cyclic bradytachyarrhythmia, nocturnal abnormalities of atrioventricularconduction and ventricular ectopy during sleep

ATS 1989

Indications for Polysomnography

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

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


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)


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Laboratory Assessment of OSAHS

• Other Laboratory test– Thyroid function test– Pulmonary function test

SLEEP RELATED APNEA

• Central Apnea– cessation of airflow with no respiratory effort

• Obstructive sleep Apnea– cessation of airflow through the nose or mouth

with persistence of diaphragmatic & intercostalmuscle activities

• Mixed Apnea– initial cessation of airflow with no respiratory

effort followed by periods of upper airway OSAATS, 1989

(Apnea 10 sec. & ≥ 5/hr of sleep)Obstructive Apnea

• 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

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 > 10sClassified 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

• 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 non-periodic limb movements per hour of TST

Clinical Event Parameters

• 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.

OBSTRUCTIVE APNEA

Arousal ↓PaO2, ↑PaCO2 ↓ Intrathoracic pressure

↑ SNA ↑ Catecholamines ↓ Myocardial O2 delivery

Acute Chronic

↑ HR ↑ BP Hypertension

CARDIAC ISCHEMIA CARDIAC ARRHYTHMIAS CARDIAC HYPERTROPHY

CARDIAC FAILURE

↓ Stroke Volume

↑ LV wall tension ↑ Cardiac O2 demand

Pathophysiological Effects of OSA on the Cardiovascular System

Sleep disorders and cardiovascular disease; Potential mechanisms

Leptin Alterations in lipid metabolism

CatecholaminesEndothelin

Abnormal vascular tone

Metabolic syndrome Obesity

Insulin resistance

Hypoxia

Inflammation

Thrombosis

Endothelial dysfunction

Reactive oxygen species Nitric oxide/superoxide

Cardiovascular Disease and Mechanisms of Association with Sleep-Disordered Breathing

*Proposed Pathophysiological Effects of Obstructive Apnea on the Cardiovascular System

Acute Effects

• Reduced myocardial oxygen delivery– Intermittent hypoxia– Decreased cardiac output

• Increased myocardial oxygen demand– Arousals from sleep– Sympathetic nervous system activation

– Increase in left ventricular afterload• Negative intrathoracic pressure

• Increased blood pressure

– Increased heart rate

• Nocturnal myocardial ischemia

• Nocturnal pulmonary edema

• Cardiac arrhythmias

*Proposed Pathophysiological Effects of Obstructive Apnea on the Cardiovascular System

Chronic Effects

• Autonomic cardiovascular derangements– 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

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Acute Cardiovascular Morbidity Associated with OSA

• Myocardial infarction• Cerebrovascular disease (stroke)• Cardiac arrhythmia

Weiss, Sleep Medicine 2000

Chronic Cardiovascular Morbidity Associated with OSA

• Arterial hypertension• Pulmonary hypertension• Congestive heart failure

Weiss, Sleep Medicine 2000

Peker, AJRCCM 2002

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

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

Incidence of CVD in OSA

• 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

• OSA severity was not associated with mortality nor a risk factor for mortality

Doherty. CHEST 2005

Rodriguez. CHEST 2005

OSA and Risk Factors for CVD

• Increased leptin levels– Wt gain in sleep apnea asso with leptin

levels– Leptin is a promoter of platelet aggregation

• Increased C-reactive protein– Asso with blunted endothelium-dependent

vasodilation– Induces increase in cell adhesion

molecules– Correlates with severity of sleep apnea

Philipps. Curr Opin Pulm Med 2002

OSA and Risk Factors for CVD

• Increased homocysteine level– Endothelial dysfunction– Increased oxidative stress– Promotes vascular smooth muscle growth

• Insulin resistance syndrome – IGT, HPN and/or central metabolic

syndrome– Sleep apnea – higher fasting glucose– IGT → asso with severity in oxygen

desaturation during sleep apnea

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Obstructive Sleep Apnea and Myocardial Infarction

• Apnea index > 5.3 episodes/hour of sleep is an independent predictor of myocardial infarction

• ST-segment depression during the night occurred in 30% of patients with OSA

Dart. CHEST 2003

Hanly. Am J of Cardiol. 1997

Dart. CHEST 2003

Quan. Circulation 2004

Scheuf. Am Rev Resp Dis. 1992

Pelial. J. Am Coll Cardiology

Mechanisms of Myocardial Infarction in OSA

• Increased sympathetic activity may contribute to myocardial ischemia and coronary plague disruption

• Chronically elevated catecholamine levels may injure the myocardium

• Hypoxia triggers a generalized inflammatory response causing systemic release of inflammatory mediators

• Obstructive apnea can lead to myocardial ischemia even in the absence of hypoxia

• Main trigger of ischemia was an increase in oxygen demand rather than oxygen desaturation

Coronary Artery Disease and OSA

• Mortality:– 38% - with OSA– 9% - without OSA

• OSA a poor prognostic indicator in CAD

• Respiratory disturbance index, an independent predictor of mortality in CAD

Peker. AJRCCM 2002

Yuksel. AJRCCM 2000 Mehra. AJRCCM 2006

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

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

Dart. CHEST 2003


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

OSA and Hypertension

• 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

• Only systolic BP increased with OSA and CPAP significantly attenuated the increase in systolic BP and no effect on diastolic BP

Young. AJRCCM 1997

Tkacova. Circulation 1998

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OSA and Hypertension

• OSA has a direct and disproportionate effect on systolic BP that is difficult to control with pharmacologic agents

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

Logan , J of HPN 2001

Leung, AJRCCM 2001

Possible Mechanisms Linking OSA and HPN

• Intermittent Hypoxia → stimulation of peripheral chemoreceptors → stimulate brainstem sympathetic vasoconstriction

• Increased activity of adrenal glands, renal sympathetic nerves and renin angiotensinsystem

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

Leung. AJRCCM 2001

Nieto. JAMA 2000



• 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

Shabarn. AJRCCM 2001


• ↑ Platelet activation → chronic hypertension• OSA promotes atherogenesis through

recurrent exposure to hypoxemia

Dart. CHEST 2003

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

Sleep Heart Health Study, AJRCCM 2001

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Mechanisms of CHF in OSA

• Negative intrathoracic pressure– Adverse ventricular contractions– Increased ventricular wall stress– Reductions in cardiac output– Increased PCWP

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

catecholamine stimulation

Sin. AJRCCM 1999

Leung. AJRCCM. 2001

Obstructive Sleep Apnea and Stroke

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

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

Leung. AJRCCM 2001

Arzt AJRCCM 2005

Leung. AJRCCM 2001

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

Artz. AJRCCM 2005

OSA & Stroke: Adverse Prognostic Implications

• Worse functional capacity• Longer period of post-stroke

rehabilitation• Higher death rate

Obstructive Sleep Apnea and Pulmonary Hypertension (PH)

• 17% of OSAHS had PH• PH is usually mild to moderate

Mechanism :Chronic hypoxemia ? pulmonary

vasoconstriction and remodeling of the pulmonary vascular bed

Chaouat Chest 1976

Obstructive Sleep Apnea and Venous Thromboembolism (VTE)

• Possible association between OSAHS and VTE

• Due to thrombolytic coagulation abnormalities provided by recurrent episodes of hypoxemia

Arnulf, JAMA 2002

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*OSAHS and Impaired Glucose-Insulin 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

Meslier. ERJ 2003


• Incidence– 30.1% - Type 2 DM in OSAHS– 3.9 % - Type 2 DM in non-apneic snorers– 20 % - IGT in OSAHS– 13.9 % - IGT in non-apneic snorers

Meslier ERJ 2003

• Snoring is independently associated with impaired glucose tolerance and Type 2 DM

Punjab, AMJ Epidemiol 2004


• Mechanisms– 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


• Mechanisms – Sympathetic hyperactivity

• 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


• 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

Punjab AJRCCM 2002

*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

Saaresenta ERJ 2003

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*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• 10-15 % weight loss can reduce or

eliminate OSA • Low levels of weight reduction may

curtail cardiovascular riskPunjab, AJRCCM 2002

Effects of Treatment

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

• 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)– 31% = total CV events in the untreated group– 18% = CPAP group

Leung. AJRCCM 2001

Doberty. CHEST 2005

Kaneko. NEJM 2003


• 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


• CPAP treatment for 3 months improved insulin responsiveness

• Insulin sensitivity significantly increased after 2 days of CPAP especially in patients with BMI < 30

Harsch ASRCCM 2003Rodriquez. CHEST 2005


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

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

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Obstructive Sleep Apnea - Pulmo Lecture