Sleep Apnea Pathogenesis and Clinical Presentation Disclosure: - PowerPoint PPT Presentation

Sleep Apnea Pathogenesis and Clinical Presentation Disclosure: Atul Malhotra, MD Nothing to disclose UCSD Pulmonary and Critical Care Director of Sleep Medicine San Francisco 2014

Increased prevalence of sleep apnea in US adults over the last 20 years* 47% increase • 13% were normal • 33% had mild OSA • 30% had moderate OSA • 23% had severe OSA * “Sleep apnea” = apnea-hypopnea index ≥ 15 events per hour. Data from the National Health and Nutrition Examination Surveys and the Wisconsin Sleep Cohort Study. Diabetes Care 2009 American Journal of Epidemiology 2013; DOI: 10.1093/aje/kws342 Clinical Presentation Inadequate Anatomy ↑ Endothelin Roughly 60-70% of OSA patients are obese Compensatory ↓ Vagus Reflex OSA is very common in CHF, DM, bariatric surgery ↑ Activity of Cardiovascular Pharyngeal Dilators (Macdonald JCSM 2007) Sequelae (GG) Maintains Upper Airway Patency Sleepiness is common clinically but the minority of Sympathetic Sleep Fragmentation Activation afflicted patients Sleep Onset Arousal Neurocognitive Sequelae Sleepiness is uncommon in patients with cardiovascular Loss of Reflex disease (Arzt Archives 2006) ↑ Respiratory Effort ↓ Activity of Airway Jordan et Pharyngeal Dilators Collapse al. Lancet 2013 Hypoxia + Hypercapnia

Obstructive Sleep Apnea Underlying Mechanisms OSA Pathogenesis • Anatomy •Mechanisms underlying OSA are highly variable. • Pharyngeal dilator muscle control asleep •There are likely to be multiple mechanistic • Arousal Threshold pathways which when targeted in individuals are • Loop gain likely to improve OSA. • Lung volume • Vascular SLEEP 2009; Thorax 2010; AJRCCM 2014 Schwab Clinics in Chest Medicine, 1998 Pharyngeal anatomy explains only a minimal portion of the variability in AHI

Obstructive Sleep Apnea Schwab Clinics in Chest Medicine, 1998 Underlying Mechanisms • Anatomy • Pharyngeal dilator muscle control asleep • Arousal Threshold • Loop gain • Lung volume • Vascular Most OSA patients have some periods of stable breathing •Studied GGEMG, TPEMG, EELV etc •Genioglossus activity was invariably high during stable breathing •Genioglossus is necessary and sufficient to stabilize breathing spontaneously in OSA JCI 1991 Sleep 2009

Correlation Between Negative Epiglottic Pressure and GG Peak Phasic Activation Pharyngeal Motor Control Studies ( one man awake and asleep) • 1. Genioglossal But Not Palatal Muscle Activity Relates 60 Closely to Pharyngeal Pressure awake R = -0.976 p = <0.0001 Malhotra et al. AJRCCM 2000a,2000b AJRCCM 2002 asleep R = -0.611 50 • 2. Within-breath control of genioglossal muscle activation in p = 0.0265 humans: effect of sleep-wake state GG peak (% of max) J. Physiol. 2003 40 • 3. Control of upper airway muscle activity in younger vs older men during sleep onset 30 J. Physiol. 2004 • 4. The impact of wakefulness stimulus on pharyngeal motor 20 control Lo et al. Thorax 2007 • 5. Mechanisms of Compensation 10 Jordan et al. Thorax 2007, Sleep 2009, JAP 2010a, 2010b -16 -14 -12 -10 -8 -6 -4 -2 Malhotra et al. Epiglottic Pressure (cm H 2 O) AJRCCM 2000 Pharyngeal dilator muscles can respond during stable sleep if stimuli are given in sufficient magnitude and for adequate duration

500 35 Healthy subject, 30 GG-EMG (% Maximum) 400 Pcrit = -0.11 cmH 2 O (% stable sleep level) 25 Genioglossal EMG 300 20 15 200 10 OSA patient, 100 5 AHI = 52 events/hr, Pcrit = -0.27 cmH 2 O 0 0 -45 -35 -25 -15 -5 -12 -10 -8 -6 -4 -2 0 P EPI (cmH 2 O) Pepi (cmH 2 O) Malhotra et al. AJM 2006 R=-0.55, p<0.001 J Physiol 2007

Single Motor Units and SFEMG • Wilkinson SLEEP 2008 • Saboisky J Physiol. 2007 , JAP 2012 • Saboisky J Neurophysiol. 2006 , AJRCCM 2012 • Wilkinson SLEEP 2010a, 2010b • McSharry SLEEP 2012, in review • High frequency sampling of EMGs • Can “see” activity of single cells in humans • Has opened possibility of pharmacological targets Obstructive Sleep Apnea Pharyngeal Muscle Control Underlying Mechanisms There are likely to be subgroups of patients who respond to efforts to augment muscle activation • Anatomy Perhaps targeting this subgroup would make sense • Pharyngeal dilator muscle control asleep in pharmacological studies (JAP 2008) • Arousal Threshold Increasing UA muscle response may be deleterious • Loop gain in patients with unstable ventilatory control . • Lung volume

Berry et al. – AJRCCM, 1997 Gleeson et al. – 1990 Am Rev Respir Dis Arousal Threshold – 35 Double-edged Sword 30 GG-EMG (% Maximum) • A low arousal threshold could lead to premature arousal with 25 inadequate time to accumulate respiratory stimuli • A high arousal threshold could lead to substantial hypoxemia 20 and hypercapnia with end-organ impact 15 • Therapies to manipulate arousal threshold are likely to benefit 10 some patients and theoretically hurt others 5 • PPG funded (PI: Saper) 0 -45 -35 -25 -15 -5 P EPI (cmH 2 O) Saboisky et al. Thorax 2010

60 60 AHI (Number of events/h of sleep) AHI (Number of events/h of sleep) 50 50 40 40 30 30 * * 20 20 10 10 0 0 Placebo Eszopiclone Placebo Eszopiclone European Respiratory Journal 2008 Pharmacology Studies of Sedation/Anesthesia Arousal Threshold Summary • Unwarranted Administration of Acetylcholinesterase Inhibitors Can Impair Genioglossus and Diaphragm Muscle Function. Anesthesiology 2007 • Arousal threshold is highly variable in OSA • Differential effects of isoflurane and propofol on • Agents can raise the arousal threshold without genioglossus muscle function and breathing. Anesthesiology 2008 suppressing UAM activity • Sugammadex Brit J. Anesth. 2008 • Can buy time to activate respiratory muscles • Pentobarbital Anesthesiology 2009 using endogenous respiratory stimuli • Rocuronium vs. Cisatracurium AJCC 2009 • Pentobarbital in humans ERJ 2010 • Agents have differential effects on the upper airway Chamberlin et al.

Obstructive Sleep Apnea Thermostat Analogy Underlying Mechanisms • Anatomy • Pharyngeal dilator muscle control asleep • Arousal Threshold • Loop gain • Lung Volume • Vascular function Cheyne Stokes Respirations Loop gain vs. AHI AHI (episodes/hour) 100 r = 0.36 p = 0.076 80 60 40 20 0 0.1 0.3 0.5 0.7 Loop gain

Atmospheric Pcrit Group Obstructive Sleep Apnea Underlying Mechanisms AHI (episodes/hour) 100 High Loop Gain r = 0.88 Administer agents to reduce loop gain: 80 p = 0.0016 • Oxygen (Resp Phys 2008) 60 • Acetazolamide (Sleep 2013, J. Physiol. 2012) 40 20 0 0.1 0.3 0.5 0.7 Loop gain AJRCCM 2004 Cortex Obstructive Sleep Apnea Underlying Mechanisms Orexin + • Anatomy PPT/LDT • Pharyngeal dilator muscle control asleep + LC + • Arousal Threshold Raphe + • Loop gain V Tensor palatini XII • Lung volume + Nucleus of the Genioglossus solitary tract • Vascular Local V entrolateral upper Medulla airway receptors Malhotra et al. Lancet 2013 Cardiovascular and Respiratory Reflexes

Lung Volume Story 20 * † 18 • EELV can alter pharyngeal mechanics CPAP Required to Eliminate IFL 16 • Van De Graaf JAP ; Begle ARRD 14 • Mechanisms debated • Prior studies during wakefulness are confounded 12 10 • Stanchina et al. SLEEP 2003 8 • Heinzer et al. AJRCCM 2005, Thorax 2006, Sleep 2008 6 • Owens et al. JAP 2010, JCSM 2011, JAP 2013 4 • Jordan et al. JAP 2010 2 0 +990 cc Baseline EELV -770 cc Mean Disclosures /Funding Grants PI: Malhotra • NIH and AHA Industry (none since May 2012) • Pfizer Philips Lancet • Apnex SHC 2013 • SGS Apnicure

Effort Index may be a Reasonable Change in Ventilatory Effort Surrogate for Loop Gain Across an Obstructive Apnea P N 1 R = 0.96 0.8 P < 0.05 0.6 Effort Index 0.4 E2 E1 0.2 ABD 0 0 0.2 0.4 0.6 0.8 1 1.2 Loop Gain Effort Index = (E2 – E1) / E2