Obstructive Sleep Apnea: A Physiological Approach Robert L. Owens, - - PDF document

2/13/2018 1

Obstructive Sleep Apnea:

A Physiological Approach

Robert L. Owens, MD February 2018

Outline

• Cause(s) of OSA
• Can we measure the causes in an individual?
• Is that useful?

2/13/2018 2

Thoracic pressure swings (↑LV aerload)

What happens when you fall asleep: normal

Ventilation Ventilatory Demand Time

Wake Sleep

2/13/2018 3

What happens when you fall asleep: normal or OSA

Ventilation Ventilatory Demand Time

Wake Sleep Ventilation ≠ Demand Because of poor anatomy

Ventilation Ventilatory Demand Time

Wake Sleep Hypoventilation leads to increased ventilatory demand, which will activate upper airway muscles to improve ventilation. But, muscle recruitment and improvement in ventilation is variable. Good muscle response achieves acceptable ventilation

What happens when you fall asleep: normal or OSA

2/13/2018 4

What happens when you fall asleep: OSA

Ventilation Ventilatory Demand Time

Wake Sleep Hypoventilation leads to increased ventilatory demand, which will activate upper airway muscles to improve ventilation. But, muscle recruitment and improvement in ventilation is variable. Poor muscle response does not achieve acceptable ventilation

Ventilation Ventilatory Demand Time

Wake Sleep Arousal Threshold Arousal Poor muscle response does not achieve acceptable ventilation and the respiratory arousal threshold is crossed

What happens when you fall asleep: OSA

2/13/2018 5

Ventilation Ventilatory Demand Time

Wake Sleep How quickly the ventilatory demand increases for a change in ventilation is the loop gain of the system Loop gain Arousal Threshold Arousal

What happens when you fall asleep: OSA

Ventilation Ventilatory Demand Time

Wake Sleep Arousal Threshold This patient has OSA – when they go to sleep they hypoventilate, and wake themselves up due to: Anatomy, upper airway muscles, arousal threshold, and loop gain Arousal

What happens when you fall asleep: OSA

2/13/2018 6

Better muscles can prevent OSA

Ventilation Ventilatory Demand Time

Wake Sleep Arousal Threshold For same anatomy, better muscles can lead to stable flow limited breathing, no arousal

↑ arousal threshold may prevent OSA

Ventilation Ventilatory Demand Time

Wake Sleep Arousal Threshold Similarly, with same anatomy and muscle response, a higher arousal threshold may allow respiratory drive to increase enough to recruit muscles sufficiently to sustain ventilation.

2/13/2018 7

Decreased loop gain can help, too

Ventilation Ventilatory Demand Time

Wake Sleep Arousal Threshold Similarly, a lower loop gain may prevent ventilatory demand from rising above the arousal threshold. Obstructive Sleep Apnea Small, collapsible upper airway High loop gain Poor upper airway muscle response Low arousal threshold

Pathogenesis of sleep apnea

2/13/2018 8

Outline

• Cause(s) of OSA
• It might be more than just a fat neck
• Can we measure the causes in an individual?
• Is that useful?

Can we measure the response to hypoventilation during sleep?

Ventilation Ventilatory Demand Time

Wake Sleep

2/13/2018 9

5 10 15

CPAP level (cmH2O)

Therapeutic pressure

Yes, by letting the airway collapse

• 10
• 5

5

CPAP level (cmH2O)

50 100 150 200 250 2 4 6 8

Time (seconds) Ventilation (L/min)

5 10 15

CPAP level (cmH2O)

Therapeutic pressure Anatomy Eupnea

Measuring anatomy

With repeated drops, we can measure how much the upper airway is open at different pressures, or at atmospheric pressure (0cmH2O)

2/13/2018 10

50 100 150 200 250 2 4 6 8

Time (seconds) Ventilation (L/min)

5 10 15

CPAP level (cmH2O)

Therapeutic pressure Passive UA UA muscle response Eupnea

Measuring muscle response

With hypoventilation, ventilatory demand will increase an unknown amount, and some muscle recruitment will occur ?

50 100 150 200 250 2 4 6 8

Time (seconds) Ventilation (L/min)

5 10 15

CPAP level (cmH2O)

Therapeutic pressure Passive UA UA muscle response Eupnea

Measuring loop gain

Return to holding pressure opens upper airway and reveals ventilatory demand Obstruction removed, ventilation again matches ventilatory drive

2/13/2018 11

50 100 150 200 250 2 4 6 8

Time (seconds) Ventilation (L/min)

5 10 15

CPAP level (cmH2O)

Therapeutic pressure Passive UA UA gain = muscle response/ventilation deficit Eupnea Ventilatory Drive

Measuring loop gain

With knowledge of the ventilatory drive, can calculate loop gain

• f the system, and upper airway gain

50 100 150 200 250 2 4 6 8

Time (seconds) Ventilation (L/min)

5 10 15

CPAP level (cmH2O)

Therapeutic pressure Passive UA UA gain = muscle response/ventilation deficit Eupnea

• vershoot ventilation

Loop gain = ventilation deficit Ventilatory Drive

Measuring loop gain

With knowledge of the ventilatory drive, can calculate loop gain

• f the system, and upper airway gain

2/13/2018 12

50 100 150 200 250 2 4 6 8

Time (seconds) Ventilation (L/min)

5 10 15

CPAP level (cmH2O)

Therapeutic pressure Passive UA Eupnea Ventilatory Drive?

Measuring arousal threshold

Some CPAP drops, the ventilation will be so low, that the ventilatory drive gets so high that you have an arousal. X ?

50 100 150 200 250 2 4 6 8

Time (seconds) Ventilation (L/min)

5 10 15

CPAP level (cmH2O)

Therapeutic pressure Passive UA Eupnea Ventilatory Drive at arousal

Measuring arousal threshold

Use loop gain to predict ventilatory drive at this point = AT X

ventilatory drive Loop gain = ventilation deficit

√ √ = arousal threshold

2/13/2018 13

50 100 150 200 250 2 4 6 8

Time (seconds) Ventilation (L/min)

5 10 15

CPAP level (cmH2O)

Therapeutic pressure Passive UA UA muscle response Eupnea

• vershoot ventilation

Loop gain = ventilation deficit Ventilatory Drive

Measuring the traits

Wellman JAP 2011

Automated methods to measure the traits!

2/13/2018 14

Outline

• Cause(s) of OSA
• It might be more than just a fat neck
• Can we measure the causes in an individual?
• Yes
• Is that useful?

2013 N = 75 subjects

2/13/2018 15

As expected, anatomy worse in those with OSA

AHI (OSA Severity)

Worse Anatomy Better Anatomy

But no difference in muscle responsiveness…

Controls OSA

2/13/2018 16

Or Loop Gain between controls and those with OSA And Arousal Threshold goes the wrong way?!

Controls OSA Harder to wake up (Protective??)

2/13/2018 17

Obstructive Sleep Apnea Small, collapsible upper airway High loop gain Poor pharyngeal muscle response Low arousal threshold

Pathogenesis of sleep apnea So is this true? Is it just having a fat neck?

Upper airway passive anatomy Exposure Open Closed No OSA (High LG – CSA?) (Low AT – insomnia?) OSA Outcome Effect modifiers

A new model that includes Effect Modification

2/13/2018 18

Upper airway passive anatomy Exposure Open Closed No OSA OSA Outcome Loop gain Arousal threshold Upper airway gain Vulnerable Anatomy Effect modifiers

Non anatomical traits are important in some people Anatomy is important in everyone

AHI (Apnea Severity)

Worse Anatomy Better Anatomy

Always have OSA Never have OSA Vulnerable anatomy – could go either way

2/13/2018 19

Loop gain is important if you have vulnerable anatomy

In this anatomically vulnerable group

• f patients, whether you have OSA is

dependent on LG

HIGH LG LOW LG

Muscle responsiveness is important if you have vulnerable anatomy

No difference in slope, until you get to vulnerable anatomy Good muscles (no sleep apnea) Bad muscles (OSA)

2/13/2018 20

Upper airway passive anatomy Exposure Open Closed No OSA OSA Outcome Loop gain Arousal threshold Upper airway gain Vulnerable Anatomy Effect modifiers

Non anatomical traits are important in some people

Will always have OSA Probably should not have OSA Probably should have OSA, but many could be treated without CPAP?

2/13/2018 21

Outline

• Cause(s) of OSA
• It might be more than just a fat neck
• Can we measure the causes in an individual?
• Yes
• Is that useful?
• Potentially

Physiology may help:

• Understand the cause of OSA in an individual (or group of people)
• Predict the improvement with non PAP anatomical therapy (e.g.

surgery, oral appliance)

• Choose a primary treatment for OSA?
• Predict adherence to therapy?
• Predict symptoms related to OSA?

2/13/2018 22

Why do different people have OSA? Why do different groups of people have OSA?

2/13/2018 23

Can physiology predict those who respond to

• ral appliances and surgery?

Can physiology predict those who respond to

• ral appliances and surgery?

2/13/2018 24

Can physiology predict those who respond to

• ral appliances and surgery?
• Arousal Threshold
• Sedative hypnotics (eszopiclone, trazodone)
• ?Behavioral therapy
• Loop Gain
• Oxygen
• Acetazolamide
• Upper airway muscles
• HGNS
• Drugs?

Treatments to improve the non‐anatomical traits

+ non CPAP Anatomy Improvements Position Therapy Oral Appliance

2/13/2018 25

Targeting the problem

Eckert Clin Sci 2011

Does low ArTH predict adherence?

2/13/2018 26

Does low ArTH predict adherence?

Ye ERJ 2014

2/13/2018 27

• Endotype – a subtype of a condition that has a

distinct functional or pathobiological mechanism

• Phenotype – observable consequences of a disease

Genotype Endotype Phenotype Treatment Two copies of Delta 508 mutation CFTR dysfunction Cystic Fibrosis Supportive + Ivacaftor Many other mutations Supportive Associated with certain HLA genotypes Decreased insulin production Diabetes Mellitus Exogenous insulin Various genes implicated Insulin resistance Insulin-sensitizing drugs ? (unknown, area of active investigation) Low arousal threshold OSA “disturbed sleep” CPAP, but sedative- hypnotics might be alternative High Loop Gain OSA with cardiovascular disease CPAP, but Oxygen, acetazolamide might be alternatives Moderate AT, moderate LG OSA “minimally symptomatic” None needed

Questions?

rowens@ucsd.edu