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The Future of Sleep Apnea Therapy

Atul Malhotra, MD

([email protected])

Associate Professor of Medicine

Medical Director, Sleep Program

Clinical Chief, Sleep Division


Harvard Medical School

NESS 2010

Inadequate Anatomy



Activity of

Pharyngeal Dilators


Sleep Fragmentation









Maintains Upper

Airway Patency



Sleep Onset


Loss of




Activity of

Pharyngeal Dilators

Hypoxia + Hypercapnia

Malhotra and White

Lancet 2002

Current standard therapy is cpap
Current Standard Therapy is CPAP

  • Treatment of choice meta-analysis, SLEEP 2003

  • Improves symptoms and blood pressure

  • Adherence is variable

Alternative therapies
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

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
Obstructive Sleep Apnea Underlying Mechanisms

  • Anatomy

  • Pharyngeal dilator muscle control asleep

  • Arousal Threshold

  • Loop gain

  • Lung volume

  • Vascular

Finite element modeling
Finite Element Modeling variability in AHI

  • 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 Therapy

    Laryngoscope 2007

Finite element modeling1
Finite Element Modeling variability in AHI

  • 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 variability in AHI

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

Huang, White and Malhotra Chest variability in AHI2005

Uvula Removal

Uvula removal can have a substantial effect on collapsibility:P close = -18 cmH2O with uvula removal; -13 cmH2O with intact uvula.

Comparison of different uppp treatments
Comparison of Different UPPP Treatments variability in AHI




Airway length
Airway Length variability in AHI

  • 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
Is Blinding Possible? variability in AHI

A double blind Imaging Study variability in AHI

Comparison of regions b c
Comparison of Regions b & c variability in AHI

Science fiction
Science Fiction? variability in AHI

  • 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 mechanisms1
Obstructive Sleep Apnea variability in AHIUnderlying Mechanisms

  • Anatomy

  • Pharyngeal dilator muscle control asleep

  • Arousal Threshold

  • Loop gain

  • Lung volume

  • Vascular

Richard schwab clinics in chest medicine 1998
Richard Schwab variability in AHIClinics in Chest Medicine, 1998

JCI 1991 variability in AHI

Pharyngeal motor control studies
Pharyngeal Motor Control Studies variability in AHI

  • 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 onset J. 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. variability in AHI

Malhotra et al. AJM 2006 variability in AHI

R=-0.55, p<0.001

J Physiol 2007 variability in AHI

Single motor units and sfemg
Single Motor Units and SFEMG variability in AHI

  • 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
Pharyngeal Muscle Control variability in AHI

  • 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 mechanisms2
Obstructive Sleep Apnea variability in AHIUnderlying Mechanisms

  • Anatomy

  • Pharyngeal dilator muscle control asleep

  • Arousal Threshold

  • Loop gain

  • Lung volume

Berry et al ajrccm 1997
Berry variability in AHIet al – AJRCCM, 1997

Gleeson et al 1990 am rev respir dis
Gleeson variability in AHIet al – 1990 Am Rev Respir Dis

Arousal threshold double edged sword
Arousal Threshold – Double-edged Sword variability in AHI

  • 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

Arousal threshold
Arousal Threshold variability in AHI

  • 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

ERJ 2008 stability

Pharmacology studies of sedation anesthesia in rats
Pharmacology Studies of Sedation/Anesthesia in Rats stability

  • 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 airway

Chamberlin et al.

Obstructive sleep apnea underlying mechanisms3
Obstructive Sleep Apnea stabilityUnderlying Mechanisms

  • Anatomy

  • Pharyngeal dilator muscle control asleep

  • Arousal Threshold

  • Loop gain

  • Lung Volume

  • Vascular function

Loop gain
Loop Gain stability

  • measure of the stability of negative feedback control system

    Younes AJRCCM 2001

    Wellman et al JAP 2003

    Wellman et al AJRCCM 2004

    Wellman et al J Physiol 2007

    Wellman et al. Resp Physiol 2008 Jordan et al J Physiol 2004

    Jordan et al JAP 2006

r = 0.36 stability

p = 0.076

r = 0.88 stability

p = 0.0016


Change in Ventilatory Effort Across an Obstructive Apnea stability





Effort Index = (E2 – E1) / E2

Effort Index may be a Reasonable Surrogate for Loop Gain stability


R = 0.96


P < 0.05














Loop Gain

Obstructive sleep apnea future treatment
Obstructive Sleep Apnea stabilityFuture Treatment

  • Define the apnea mechanism and treat accordingly.

Obstructive sleep apnea underlying mechanisms4
Obstructive Sleep Apnea stabilityUnderlying Mechanisms

High Loop Gain

Administer agents to reduce loop gain:

  • Oxygen

  • Acetazolamide

Effect of oxygen between groups
Effect of Oxygen Between Groups stability



p = 0.016





in AHI





Resp Physiol 2008

High Loop


Low Loop


Lung volume story
Lung Volume Story stability

  • 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

Non cpap therapies for osa
Non CPAP therapies for OSA stability

  • 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 funding
Disclosures /Funding stability

Grants 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


  • Sepracor Pfizer

  • Medtronic Philips

  • Merck NMT Medical

  • Apnex Medical Itamar Medical

  • Cephalon Ethicon/J&J