The Future of Sleep Apnea Therapy Atul Malhotra, MD 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 A pressure and state-dependent muscle contraction model and its application in the computational simulation of human upper airway collapse JAP Mandibular advancement and UPPP effects on pharyngeal mechanics based on FEA IEEE The impact of anatomical manipulation on pharyngeal mechanics: results from a computational model, Chest Invididualizing Therapy Laryngoscope 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 cmH 2 O with; -13 cmH 2 O without mandibular advancement Huang, White and Malhotra, Chest 2005

Uvula Removal Uvula removal can have a substantial effect on collapsibility: P close = -18 cmH 2 O with uvula removal; -13 cmH 2 O with intact uvula. Huang, White and Malhotra Chest 2005

Comparison of Different UPPP Treatments   

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 Schwab Clinics 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 Within-breath control of genioglossal muscle activation in humans: effect of sleep-wake state J. Physiol Control of upper airway muscle activity in younger vs older men during sleep onset J. Physiol The impact of wakefulness stimulus on pharyngeal motor control Lo et al Thorax Mechanisms of Compensation Jordan et al Thorax 2007, Sleep 2009

Stanchina et al.

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 Saboisky et al. J Neurophysiol 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

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 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 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 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

Thermostat Analogy

Cheyne Stokes Respirations

r = 0.36 p = 0.076

r = 0.88 p = AJRCCM 2004

Effort Index = (E2 – E1) / E2 Change in Ventilatory Effort Across an Obstructive Apnea PNPN ABD E2 E1

R = 0.96 P < Loop Gain Effort Index Effort Index may be a Reasonable Surrogate for Loop Gain

Obstructive Sleep Apnea Future Treatment Define the apnea mechanism and treat accordingly.

Obstructive Sleep Apnea Underlying Mechanisms High Loop Gain Administer agents to reduce loop gain: Oxygen Acetazolamide

Effect of Oxygen Between Groups High Loop Gain Low Loop Gain % Reduction in AHI p = Resp Physiol 2008

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

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 /Funding Grants PI: Malhotra NHLBI RO1 HL cardiovascular NHLBI RO1 HL electrophysiology NHLBI RO1 HL aging airway mechanics NHLBI K24 HL mentoring award NHLBI PPG Project 2 (Overall PI Saper) AHA Established Investigator Award N Industry SepracorPfizer MedtronicPhilips MerckNMT Medical Apnex Medical Itamar Medical CephalonEthicon/J&J SHCSGS