The Future of Sleep Apnea Therapy

Atul Malhotra, MD

(amalhotra1@partners.org)

Associate Professor of Medicine

Medical Director, Sleep Program

Clinical Chief, Sleep Division

BWH and SHC

Harvard Medical School

NESS 2010

Inadequate Anatomy

Compensatory

Reflex

Activity of

Pharyngeal Dilators

(GG)

Sleep Fragmentation

Neurocognitive

Sequelae

Airway

Collapse

Maintains Upper

Airway Patency

Sleep Onset

Loss of

Reflex

Activity of

Pharyngeal Dilators

Endothelin

Vagus

Cardiovascular

Sequelae

Sympathetic

Activation

Arousal

Respiratory

Effort

Hypoxia + Hypercapnia

Malhotra and White

Lancet 2002

Current Standard Therapy is CPAP

• Treatment of choice meta-analysis, SLEEP 2003

• Improves symptoms and blood pressure

• Adherence is variable

Alternative Therapies

• Bi-level – no convincing data• APAP – Patel et al. SLEEP 2004• Cflex – Aloia et al. Chest 2005• CRT in CHF – Stanchina et al. Chest 2007• Oral appliances – variable response, limited data• Surgery – poor efficacy, minimal ability to predict

who will respond

OSA Pathogenesis

•Patients do not all get OSA for the same reason.•There are likely to be multiple mechanistic pathways and we need to recognize and target them.

Owens et al. SLEEP 2009; Saboisky Thorax 2010

Obstructive Sleep Apnea Underlying Mechanisms

• Anatomy• Pharyngeal dilator muscle control asleep• Arousal Threshold• Loop gain• Lung volume• Vascular

Pharyngeal anatomy explains only a minimal portion of the variability in AHI

Finite Element Modeling• 1. Upper airway mechanics: influence of gender

IEEE 2002• 2. A pressure and state-dependent muscle contraction model

and its application in the computational simulation of human upper airway collapse JAP 2005

• 3. Mandibular advancement and UPPP effects on pharyngeal mechanics based on FEA IEEE 2003

• 4. The impact of anatomical manipulation on pharyngeal mechanics: results from a computational model, Chest 2005

• 5. Invididualizing TherapyLaryngoscope 2007

Finite Element Modeling

• Signal average MRI• Muscle contracts per experimental data• Tissue elastic modulus derived from back

calculations from the literature• Allows tissue displacement and air-solid

interactions• Measure Pcrit as primary outcome variable

Mandibular Advancement

A 1-cm mandibular advancement has a substantial impact on collapsibility:

P close = -21 cmH2O with; -13 cmH2O without mandibular advancement

Huang, White and Malhotra, Chest 2005

Uvula Removal

Uvula removal can have a substantial effect on collapsibility:

P close = -18 cmH2O with uvula removal; -13 cmH2O with intact uvula.

Huang, White and Malhotra Chest 2005

Comparison of Different UPPP Treatments

0

1

2

3

4

5

6

Negative closing

pressure

without UPP

position 1

position 2

position 3

Airway Length

• Normal men have longer airway than women (Malhotra et al. AJRCCM 2002)

• Boys develop longer airway at puberty as compared with girls (Ronen et al., Pediatrics 2007)

• Women experience airway lengthening at menopause (Malhotra et al. AJM 2006)

• OSA patients also have gender differences in some data sets (Pillar et al., S & B 2008)

• Modeling shows that length affects mechanics• Airway length may explain considerable variance in airway

mechanics and components of various epidemiological risk factors

Is Blinding Possible?

A double blind Imaging Study

Construction of 3D Structure Using Multiple MR Images

Comparison of Regions b & c

Science Fiction?• Can we individualize therapy based on imaging?• Our imaging collaborators do intraoperative MRI

during craniotomy to simulate brain deformation following tumor resection

• Neurosurgeons are now using this in real time to determine the extent of tumor resection

• Requirement that individual anatomy can be down-loaded into the FEA model

Obstructive Sleep Apnea Underlying Mechanisms

• Anatomy• Pharyngeal dilator muscle control asleep• Arousal Threshold• Loop gain• Lung volume• Vascular

Richard SchwabClinics in Chest Medicine, 1998

JCI 1991

Pharyngeal Motor Control Studies

• 1. Genioglossal But Not Palatal Muscle Activity Relates Closely to Pharyngeal Pressure Malhotra et al. AJRCCM 2000a,2000b AJRCCM 2002

• 2. Within-breath control of genioglossal muscle activation in humans: effect of sleep-wake state

J. Physiol. 2003• 3. Control of upper airway muscle activity in younger vs

older men during sleep onsetJ. Physiol. 2004

• 4. The impact of wakefulness stimulus on pharyngeal motor control

Lo et al Thorax 2007• 5. Mechanisms of Compensation

Jordan et al Thorax 2007, Sleep 2009

Stanchina et al.

0

100

200

300

400

500

-12 -10 -8 -6 -4 -2 0

Pepi (cmH2O)

Gen

iogl

ossa

l EM

G

(% s

tabl

e sl

eep

leve

l)

OSA patient, AHI = 52 events/hr,

Pcrit = -0.27 cmH2O

Healthy subject,

Pcrit = -0.11 cmH2O

0

5

10

15

20

25

30

35

-45 -35 -25 -15 -5

PEPI (cmH2O)

GG

-EM

G (%

Max

imu

m)

Malhotra et al. AJM 2006

R=-0.55, p<0.001

J Physiol 2007

Single Motor Units and SFEMG

• Wilkinson et al. SLEEP 2008• Saboisky et al. J Physiol. 2007 • Saboisky et al. J Neurophysiol. 2006 • Wilkinson et al. SLEEP 2010

• High frequency sampling of EMGs• Can “see” activity of single cells in humans• Has opened possibility of pharmacological targets

Pharyngeal Muscle Control

• There are likely to be subgroups of patients who respond to efforts to augment muscle activation

• Perhaps targeting this subgroup would make sense in pharmacological studies (JAP 2008)

• Increasing upper airway muscle responsiveness may be deleterious in patients with unstable ventilatory control

Obstructive Sleep Apnea Underlying Mechanisms

• Anatomy• Pharyngeal dilator muscle control asleep• Arousal Threshold• Loop gain• Lung volume

Berry et al – AJRCCM, 1997

Gleeson et al – 1990 Am Rev Respir Dis

Arousal Threshold – Double-edged Sword

• A low arousal threshold could lead to premature arousal with inadequate time to accumulate respiratory stimuli (CO2 and neg pressure)

• A high arousal threshold could lead to substantial hypoxemia and hypercapnia with end-organ impact

• Therapies to manipulate arousal threshold are likely to benefit some patients and theoretically hurt others

Saboisky et al. Thorax 2010

0

5

10

15

20

25

30

35

-45 -35 -25 -15 -5

PEPI (cmH2O)

GG

-EM

G (%

Max

imu

m)

Arousal Threshold• Agents that increase arousal threshold e.g. sedatives can

prevent state instability Younes et al SLEEP 2007

Park et al SLEEP 2008

• Certain patients who arouse easily may be more amenable to these than others

• Ideally the agent does not suppress UA muscle activity

• Delaying arousal may allow time for UA muscles to ↑

• Most OSA patients have some periods of stable breathing

• UA muscles are necessary and sufficient to stabilize breathing (SLEEP 2009)

Sleep 2009

•Most OSA patients have spontaneous periods of breathing stability

•Studied GGEMG, TPEMG, EELV etc

ERJ 2008

Pharmacology Studies of Sedation/Anesthesia in Rats

• Unwarranted Administration of Acetylcholinesterase Inhibitors Can Impair Genioglossus and Diaphragm Muscle Function. Anesthesiology 2007

• Differential effects of isoflurane and propofol on genioglossus muscle function and breathing. Anesthesiology 2008

• Sugammadex Brit J. Anesth. 2008• Pentobarbital Anesthesiology 2009• Rocuronium vs. Cisatracurium AJCC 2009• Pentobarbital in humans ERJ in press

• Agents have differential effects on the upper airwayChamberlin et al.

Obstructive Sleep Apnea Underlying Mechanisms

• Anatomy• Pharyngeal dilator muscle control asleep• Arousal Threshold• Loop gain• Lung Volume • Vascular function

Loop Gain

• measure of the stability of negative feedback control system

Younes AJRCCM 2001

Wellman et al JAP 2003Wellman et al AJRCCM 2004Wellman et al J Physiol 2007Wellman et al. Resp Physiol 2008

Jordan et al J Physiol 2004Jordan et al JAP 2006

Thermostat Analogy

Cheyne Stokes Respirations

Loop gain vs. AHI

0

20

40

60

80

100

0.1 0.3 0.5 0.7

Loop gain

AH

I (e

pis

od

es/

ho

ur)

r = 0.36p = 0.076

Atmospheric Pcrit Group

0

20

40

60

80

100

0.1 0.3 0.5 0.7

Loop gain

AH

I (e

pis

od

es/

ho

ur)

r = 0.88p = 0.0016

AJRCCM 2004

Effort Index = (E2 – E1) / E2

Change in Ventilatory Effort Across an Obstructive Apnea

PN

ABD

E2E1

R = 0.96

P < 0.05

0

0.2

0.4

0.6

0.8

1

0 0.2 0.4 0.6 0.8 1 1.2

Loop Gain

EffortIndex

Effort Index may be a Reasonable Surrogate for Loop Gain

Obstructive Sleep Apnea

Future Treatment

• Define the apnea mechanism and treat accordingly.

Obstructive Sleep ApneaUnderlying Mechanisms

High Loop Gain

Administer agents to reduce loop gain:• Oxygen• Acetazolamide

Effect of Oxygen Between Groups

-280

-20

0

20

40

60

80

100

High LoopGain

Low LoopGain

% Reduction

in AHI

p = 0.016

Resp Physiol 2008

Cardiovascular andRespiratory Reflexes

Genioglossus

Localupperairwayreceptors

VentrolateralMedulla

Nucleus of thesolitary tract

+

Cortex

+

+

Tensor palatini

+

+

Orexin

PPT/LDT

LCRaphe

V

XII

Malhotra and White Lancet 2002

Lung Volume Story

• EELV can alter pharyngeal mechanics• Van De Graaf JAP • Mechanisms debated• Prior studies during wakefulness are seriously

confounded

• Stanchina et al. SLEEP 2003• Heinzer et al. AJRCCM 2005• Heinzer et al. Thorax 2006• Heinzer et al. Sleep 2008• Owens et al. JAP in press

+990 cc Baseline EELV -770 cc

CP

AP

Req

uir

ed t

o E

lim

inat

e IF

L

0

2

4

6

8

10

12

14

16

18

20

Mean

* †

Non CPAP therapies for OSA

• 1. Oxygen• 2. Lung volume augmentation • 3. sedatives• 4. Pressure relief strategies• 5. Tailored therapy e.g. UPPP• 6. Neuropharmacology• 7. Block vascular complications

Disclosures /FundingGrants PI: Malhotra• NHLBI RO1 HL 073146 cardiovascular• NHLBI RO1 HL 085188 electrophysiology• NHLBI RO1 HL 090897 aging airway mechanics• NHLBI K24 HL 093218 mentoring award• NHLBI PPG Project 2 (Overall PI Saper)• AHA Established Investigator Award 0840159N

Industry• Sepracor Pfizer• Medtronic Philips• Merck NMT Medical • Apnex Medical Itamar Medical• Cephalon Ethicon/J&J• SHC SGS