Advances in the Evaluation and Management of Adult OSA

Michelle Cao, DO Clinical Associate Professor

Pulmonary, Critical Care, and Sleep Medicine Stanford University

Conflict of Interest Disclosure

I declare that the content for this activity, including any presentation of therapeutic options, is well balanced, unbiased, and to the extent possible, evidence-based.

Learning Objectives

Review the latest discoveries in obstructive sleep apnea pathogenesis

Detail the clinical work-up for a patient suspected of having OSA

Understand the benefits of CPAP in cardiovascular disease prevention

Become familiar with novel alternative treatments for obstructive sleep apnea beyond PAP therapy

Case

64 y/o executive requesting a second opinion on sleep apnea treatment. He was diagnosed with ”severe sleep apnea” in Singapore 3 years ago, tried CPAP but did not notice any improvements with use, so he stopped.

He denies night time or daytime symptoms of sleep apnea. He sleeps 6 hours per night and states, “I go to bed

thinking I’m wasting my time away for every hour that I’m sleeping.”

His cardiologist is considering adding a third anti-hypertensive for difficult to control hypertension.

Other Pertinent Info

PMH: hypertension, seasonal allergies Social Hx: nonsmoker, social alcohol use PE:

BMI 26 kg/m2, BP 145/85, HR 75, SpO2 97% ENT: septum midline, Mallampati class 3 airway, tonsils 1+ GEN: pleasant, thin man Cardiovascular: RRR Lungs: CTA Extremities: No peripheral edema

Diagnostic in-lab PSG: • Total sleep time: 7 hours 10 minutes • Apnea Hypopnea Index (AHI): 70 events per hour • Oxygen Desaturation Index (ODI): 61 events per

hour • Minimum SpO2 76% (REM sleep) • T<90: 44 minutes

What would you recommend next?

A. Initiate empiric auto bilevel PAP therapy B. Proceed with in-laboratory CPAP / bilevel titration

study C. Referral for mandibular advancement device D. Referral to sleep surgery E. Reassure patient that treatment is not required as he is

not symptomatic

What would you recommend next?

A. Initiate empiric auto bilevel PAP therapy B. Proceed with in-laboratory CPAP / bilevel titration

study C. Referral for mandibular advancement device D. Referral to sleep surgery E. Reassure patient that treatment is not required as he is

not symptomatic

Questions to think about:

Who should be tested? Who should be treated? What are the benefits of treatment?

SLEEP –RELATED

BREATHING DISORDERS

OSA

CSA Syndromes

Sleep Hypoventilation

Syndromes

“...and there sat a fat and red-faced boy, in the state of somnolency.” C. Dickens

OSA: what it is?

Recurrent narrowing or closure of the upper airway during sleep superimposed on an existing narrow upper airway

Repetitive obstruction leads to repetitive oxygen desaturations, cortical arousals, consequent sympathetic activation

Termination of the obstruction requires arousal from sleep to re-establish upper airway tone and allows ventilation to resume

Anatomy of the Upper Airway

PPSM 6th edition, Chapter 143: Oropharyngeal Growth & Malformations. Quo, Bliska, Hyunh

Eckert et al. Proc Am Thorac Soc 2008

Eckert et al. Proc Am Thorac Soc 2008

Prevalence: 20 years later

Wisconsin Sleep Cohort (4% women; 9% men) 2007-2010 Prevalence estimates of moderate to severe OSA

30–49 year old men: 10% 30–49-year old women: 3% 50–70-year old men: 17% 50–70 year old women: 9%

Peppard P et al. Am J Epidemiol. 2013.

Proposed Pathophysiology

A. Narrow upper airway anatomy (collapsed upper airway with poor neuromuscular reflexes - starting at early age)

B. Instability of respiratory control system (high loop gain with resultant unstable ventilatory system)

C. Low arousal threshold (propensity to be aroused from sleep)

D. Factors that impair upper airway dilator muscle function (neuronal injury, myopathy of genioglossus, pharyngeal sensory impairment, etc)

Obstructive Apnea

Ventilatory Drive

CO2, O2

Arousal

Hyperventilation Return to Sleep

Hypoventilation

Upper Airway Narrowing,

Collapse

Increase Arousal Threshold

Increase UA Dilator Muscle Activity

CPAP Oral Appliance

Decrease Loop Gain

Low arousal threshold

Increased ventilatory response

Decreased UA caliber

Reduced UA muscle activity

A “Systemic” Disorder

OSA Cardiovascular

Neurodegeneration

Insulin Resistance

Increased Cancer

Incidence

Interplay Between Heart Disease and OSA

Translational approaches to understanding metabolic dysfunction and cardiovascular consequences of obstructive sleep apnea. Am J Physiol Heart Circ Physiol. 2015

OSA

intermittent hypoxia cortical arousals

increased oxidative stress

sleep fragmentation

Repetitive Obstructive

Apneas Hypopneas

• Daytime sleepiness Nonrestorative sleep

• Neurocognitive impairment OSA-arousal

• Cardiovascular consequences

• Metabolic derangements

OSA-desaturation

Two Major Pathophysiological Consequences

RISK FACTORS PHYSIOLOGICAL

• Pcrit (collapsibility of passive upper airway)

• Loop gain (measure of instability of ventilatory control system)

• Arousal threshold to hypoxia, hypercapnia

• Reflex response of upper airway dilator muscles to negative intraluminal pressure

STRUCTURAL

•Craniofacial dimensions

• Increased upper airway soft tissue

•Retrognathia •Obesity •Fat deposition

in tongue & lateral pharyngeal wall

SUSPECTED

•Smoking •Menopause •Alcohol use at

bedtime •Nighttime

nasal congestion

•Pregnancy

Sleep. 2014; 37(10):1639–1648

Obese, - OSA Obese, + OSA

OBESITY and OSA

TERMINOLOGY…

AHI: apnea hypopnea index # of abnormal respiratory events per hour of sleep

ODI: oxygen desaturation index # of oxygen desaturation events per hour of sleep

RDI: respiratory disturbance index AHI + respiratory effort related arousal (RERA)

REI: respiratory event index Used in home sleep testing when there is no EEG

AHI < 5 AHI > 30

Defining OSA severity

AHI 5-15 AHI 16-30

OSA should be regarded as a disease spectrum rather than a diagnosis based on AHI cut-off values.

Limitations of ”AHI”

Other findings NOT included in AHI could impact overall severity of clinical syndrome: Duration of hypoxemia Duration of hypoventilation Duration of airflow limitation Degree of sympathetic activation

CLINICAL FEATURES

Habitual snoring Choking or gasping from sleep Witnessed apneas Disturbed sleep, poor quality sleep Unintentionally falling asleep during the day (high Epworth

Sleepiness Scale score) Unrefreshing sleep even after a full night’s sleep Chronic daytime fatigue/tiredness Insomnia Morning headaches Neurocognitive impairment

Icelandic Sleep Apnea Cohort: identify distinct clinical subgroups

Subgroup 1 Primary complaint-insomnia, not sleepy

Subgroup 2 Least symptomatic Normal ESS Highest prevalence of heart disease

Subgroup 3 Excessive sleepiness 35% reported drowsy driving

Ann Am Thorac Soc 2016: 13(9):1456–1467.

There are different clinical subtypes of OSA: I. Disturbed sleep—insomnia II. Minimally symptomatic – high prevalence of heart

disease III. Excessively sleepy – daytime consequences

Physical Examination

CRANIOFACIAL EXAM

Small mandible or lower jaw (micrognathia) Short mandible or lower jaw (retrognathia) Recessive maxilla bone Excessive soft tissue in throat Enlarged tonsils Narrow nasal passages Deviated nasal septum Hypertrophied nasal turbinates Nasal valve collapse Large neck size

Men = 17 in Women = 16 in

Mallampati Scale

Mallampati I

Mallampati II

Mallampati III

Mallampati IV

Diagnostic Testing

The Sleep Study

Overnight in-lab polysomnogram (Gold Standard)

Home sleep testing (portable or home studies)

Sleep Testing Category

Type I: Traditional in-lab attended PSG EEG, Eye, chin EMG, EKG, heart rate, nasal and oral airflow,

respiratory effort, SpO2, legs, arms, and respiratory muscles, respiratory effort, CO2, video

Type II: Minimum of 7 leads (EEG, EOG, chin, ECG/heart rate,

airflow, respiratory effort, SpO2) Type III: Minimum 4 leads (airflow, respiratory effort, ECG/heart

rate, SpO2) Type IV: Minimum 1– 2 leads (oximetry/airflow) **Medicare requires 3+ channels

Una

ttend

ed

Atte

nded

AASM Indications for Portable Monitoring

False negative rates of ~ 17% False positive rates vary; up to 31%

Appropriate conditions: High pretest probability of mod-severe OSA NOT for general population screening In lab PSG not possible due to critical illness, immobility, or

safety No other cardiopulmonary, neurologic, or sleep disorders Requires comprehensive sleep medicine evaluation by board

certified sleep medicine specialist Must follow up to discuss results

J Clin Sleep Med. 2007 Dec 15;3(7):737-47.

Contraindications for Portable Monitoring

NO comprehensive sleep evaluation prior to study Significant known co-morbid conditions

Moderate to severe pulmonary or heart disease Neuromuscular disease Congestive heart failure Neurologic disease To evaluate other sleep disorders

o hypoventilation, central sleep apnea, periodic limb movements, parasomnias, seizures, narcolepsy, etc

Advantages & Disadvantages of HST

Advantages Increased access for patients and referring providers Lower cost Does not require attendant, easy to set up Disadvantages Less data (fewer channels) Recording time ≠ sleep time Leads can fall off before test is completed Can “over call” or “under call” abnormalities because of limited

detection strategies

Treatment

Goals of Treatment

Treatment goals for OSA include: Improvement in daytime symptoms and quality of

life Improved sleep quality and reduction in

cardiometabolic risks Normalization of AHI and nocturnal oxygen

desaturations Individuals may have different treatment goals

FDA Approved

I. Positive airway pressure devices (e.g. CPAP, bilevel) II. Mandibular advancement devices III. Sleep surgery (nasal vs. soft tissue vs. ”bone surgery”) IV. Alternatives

Hypoglossal nerve stimulation (Inspire)

CPAP Therapy – 38 years later

Initial introduction by Dr. Colin Sullivan in 1981 The unit requires a mask interface through which

airflow is delivered by an air blower Designed to overcome the obstruction by “stenting”

the upper airway open Established improvements on quality of life, neuro-

cognition, cardiovascular health CPAP continues to be an established gold standard

treatment

Sullivan C: Nasal Positive Airway Pressure and Sleep Apnea: Reflections on an experimental method that became a therapy. AJRCCM. 2018

Features of CPAP

CPAP is very effective in treating OSA, but it is NOT a “one size fits all”

Understanding how each device works allows the clinician to better select the best device and settings for a given patient – personalized treatment

The modern CPAP unit

CPAP has undergone many changes since 1980 Size and portability (from 15 down to 2 lbs, travel CPAP ~ 1 lb) Noise (26 dB ~ equal to whispering) Recognize and differentiate types of breathing events Adjust output to specific events Communicate remotely with treatment team and patient Includes features designed to improve effectiveness and patient

comfort Data collection systems can track compliance, pressure, leak, and

efficacy

Drawbacks to CPAP

Poor adherence (40-85% depending on studies) Nasal discomfort, congestion, mask leak, claustrophobia,

aerophagia Adherence defined by CMS as > 4 hours/night, more than 70%

of nights in a 30-day period Tied to insurance reimbursement Not a clear threshold for reversal of OSA adverse effects

Linear dose response relationship: the greater the usage, the greater improvements in sleepiness, QoL, blood pressure outcomes

Benefits of CPAP Are Dependent on Hours of Use:

Normal scores for Epworth Sleepiness Scale (squares)

Functional Outcomes of Sleep Questionnaire (diamonds)

Multiple Sleep Latency Test (triangles)

• Terri E. Weaver; Ronald R. Grunstein; Proc Am Thorac Soc 2008, 5, 173-178

CPAP Reduces Cardiovascular Death and Non-fatal Events in Patients With OSA

Meta-analysis of 11 studies, 4620 patients with OSA End point:

• Incidents of cardiovascular deaths, non-fatal cardiovascular events

• Myocardial infarction, stroke, bypass surgery, PTCA

Results: risk reduction • Cardiovascular death: 68%, OR 0.32 (0.24-0.41) • Nonfatal events: 43%, OR 0.57 (0.43-0.75)

Wang J et al. International J Cardiology 2015; 191:128-131.

CPAP on Cardiovascular Death Reduction

Wang J et al. International J Cardiology 2015; 191:128-131.

Moderate-Severe OSA

Wang J et al. International J Cardiology 2015; 191:128-131.

Association of PAP Therapy With Cardiovascular Events and Death in Adults with OSA

Meta-analysis of 10 RCTs (PAP versus Control) N=7266, 80.5% men, mean age 60.9 years, mean BMI

30 kg/m2

Moderate to severe OSA (AHI>15) Results: no difference

Major cardiovascular events, RR 0.7 (0.53-1.13) Cardiac death, RR 1.15 (0.88-1.5) All cause death, RR 1.13 (0.99-1.29)

Yu J et al. JAMA 2017; 38(2):156-166.

Meta-analysis of 10 RCTs (PAP versus control) N=7266 5683 OSA 1583 central sleep apnea

7 RCTs met criteria for OSA and PAP intervention Heterogeneous group of primary vs. secondary prevention Mean follow up of 6 months – 6 years Mean PAP adherence of 1.4 - 6.6 hours per night N= 4562, with 356 outcomes events 73% derived from a single study (SAVE trial)

Sleep Apnea Cardiovascular Endpoints (SAVE) Study Secondary Prevention Trial

Largest RCT evaluating effectiveness of CPAP in reducing rate of cardiovascular events in OSA patients

2717 patients (81% men) with mod-severe OSA + coronary or cerebrovascular disease, age 45-75 years, minimal daytime sleepiness

Randomized to CPAP + Usual Care or Usual Care alone 3.7 years follow up Primary endpoint: death or hospitalization from cardiovascular

causes, MI, stroke Secondary endpoint: QoL, sleepiness, snoring, mood

McEvoy D, et al. N Engl J Med 2016;375:919-31.

Results: Average CPAP use: 3.3 hours/night AHI improved from mean 29 to 3.7 events/hour CPAP did not prevent cardiovascular events

compared to usual care 229 primary endpoint events occurred in CPAP group

(17%) vs. 207 in UC group (15.4%), P=0.34

CPAP did reduced snoring, daytime sleepiness, improved quality of life and mood

CPAP Had No Effect on Secondary Prevention of Cardiovascular Events

N Engl J Med 2016;375:919-31.

Sub-group Analysis in CPAP-Adherent Patients

CPAP Adherent + UC (n=561)

Usual Care (n=561)

HR (95% CI) P value

Stroke 19 (3.4) 31 (5.5) 0.56 (0.32-1.0) 0.05

Major cerebral events

20 (3.6) 35 (6.2) 0.52 (0.30-0.90) 0.02

42% used ≧4 hours per night

Mandibular Advancement Devices

Predictors of success Lower baseline AHI Lower BMI Younger age

Appropriate for Mild to moderate OSA Patients who prefer oral appliance to PAP Unsuitable candidates for PAP Treatment attempts with PAP failed

2-Year Follow Up of Oral Appliance vs CPAP for OSA

Oral appliance trended towards decreased compliance Oral appliance dropped out 47% vs. 33% CPAP

dropped out)

Deterioration in success based on lowering of AHI. Why? Loosening and adaptation of soft tissue structures and

musculature Genioglossus muscle tone negatively correlates with age

Sleep 2013; 36(9):1289-1296.

Sleep Apnea Surgery

Maxillo-mandibular advancement (MMA) most effective long-term Success dependent on severity of sleep apnea, age, BMI,

surgeon’s experience and expertise

Nasal surgery (septoplasty, turbinectomy, nasal valve reconstruction): corrects nasal valve collapse, improves CPAP comfort, nasal breathing, sleep quality

UPPP or “palatal” surgery less and variable effectiveness, not long-term solution

Comparison on Surgical Efficacy

Holty and Guilleminault. Med Clin N Am 2010

Bariatric surgery Long term elimination of OSA varies by studies Studies show OSA re-emerges or persists after surgery

Weight loss 10 kg reduction in body weight can yield a reduction in

AHI roughly about 5 events/hour (Foster, the Sleep AHEAD Study, Arch Intern Med, 2009)

OSA resolved in 63% of patients with mild OSA 13% of severe OSA had remission

Novel Therapies

Hypoglossal Nerve Stimulation – STAR Trial

Multicenter, single group cross-over design sponsored by Inspire Medical Systems (STAR Trial)

Surgical implantation of upper airway stimulation device

Exclusion: BMI>32, AHI<20>50, complete concentric collapse of upper airway

N=126, 83% men, mean age 54.5 years, BMI 28.4 Primary outcomes: AHI, ODI

Strollo PJ et al. Upper Airway Stimulation for OSA. NEJM 2014;370:139-149.

Eligibility

FDA approved 2015, insurance coverage is determined on a “case by case” basis

Currently recommended specifically for PAP intolerance

> 22 years of age or older BMI < 32 kg/m2

AHI range 15-65 (< 25% central apneas) Requires drug induced sleep endoscopy to rule out

retropalatal complete concentric collapse

Results: Outcome Baseline 12 months P value

AHI 32.0±11.8 15.3±16.1 <0.001

Median AHI 29.3 9.0

ODI 28.9±12.0 13.9±15.7 <0.001

Median ODI 25.4 8.6

FOSQ 14.3±3.2 17.3±2.9 <0.001

Epworth 11.6±5.0 7.0±4.2 <0.001

T<90 (%) 8.7±10.2 5.9±12.4 0.01

Strollo PJ et al. NEJM 2014;370:139-149.

Response in 64% of participants at 18 months

OSA Screening in the Primary Care Setting US Preventive Task Force Recommendations

110 studies (N = 46,188) Asymptomatic adults including those with unrecognized

symptoms Screening Tools: ESS, STOP Questionnaire, STOP-BANG,

Berlin, Wisconsin Sleep, MVAP No RCTs compared screening with no screening 2 studies (n = 702), the screening accuracy of the multivariable

apnea prediction score (MVAP) followed by HST for detecting severe OSA syndrome (AHI ≥30 and ESS score >10) showed AUC 0.80 (0.78-0.82) and 0.83 (0.77-0.90) These studies oversampled high-risk participants

JAMA. 2017;317(4):415-433.

Recommendations

I • Evidence on use of validated screening questionnaires in

asymptomatic or patients with unrecognized symptoms to identify who will benefit from diagnostic testing is insufficient.

II

• Treatment with CPAP or MAD improves intermediate outcomes (AHI, daytime sleepiness, BP).

• However the applicability of this evidence to screen populations is limited.

III • Current evidence is insufficient to assess the

balance of benefits and harms of screening for OSA in asymptomatic adults.

IN SUMMARY

CPAP is recommended for symptomatic benefit in any OSA severity

CPAP is recommended for OSA and resistant hypertension CPAP should be considered for those with established or

with risk factors for vascular/heart disease CMS mandated adherence criteria of “4 hours of nightly use

for 70% of the nights in a 30-day period” should be reconsidered

The cardiovascular benefits of CPAP may not be achieved with a typical use of 3–4 hours at the beginning of the night

My Algorithm

Suspect OSA

Mild (AHI 5-14) Asymptomatic

Consider holding treatment, monitor

Mild (AHI 5-14) Symptomatic

Recommend treatment

Moderate to Severe (AHI>15)

Highly recommend treatment

HST vs In Lab PSG