Recognition and Management of High Loop Gain Sleep Apnea Robert Joseph Thomas, M.D. Beth Israel Deaconess Medical Center, Boston, MA 02215 Associate Professor of Medicine, Harvard Medical School NEPS 2016
Conflicts and support MyCardio LLC: ECG-spectrogram patent, license Patent: CO 2 device for central / complex apnea DeVilbiss-Drive: Grant, intellectual property, past consulting NHLBI Periodic breathing foundation & Robert Daly
Why do we not do better? Sleep apnea phenotypes Pathophysiological phenotypes Obstruction Airway collapsibility, genioglossus responsiveness Arousal threshold Loop gain Central (hypocapnic usually, but not always) Hypoventilation Sleep fragmentation Sleep regulatory phenotypes Long and short sleep Downstream phenotypes Recovery phenotypes
Downstream phenotypes Subjective sleepiness Fatigue Pain sensitization Cognitive impairment Dysexecutive syndrome Affective disorder Inflammation Metabolic Endothelial-vascular Cardiac Chemoreflex sensitization Hypertension
Recovery phenotypes (time Immediate scales) Sleep quality, rebound stages and states, subjective sleepiness Intermediate (weeks to few months) Hypertension, metabolic, cognition, brain functional and structural networks, chemoreflex sensitization, upper airway neuropathy, migraine Delayed (months to years) Cardiac-vascular remodeling, brain networks, endothelial function Permanent (never return to normal?) Brain structural network, atherosclerosis, cognition
A minimum approach to SDB Adaptive Ventilation Control Oxygen Carbon dioxide Drugs: T, Ac, others Obstruction Hypoventilation Minimize iatrogenic Mechanics The target is to understand and then change system behavior Minimize SW transitions Induce stable NREM sleep Sleep
The phenotype problem
Strong chemoreflex influences are underestimated Scoring is biased to obstruction Periodic breathing not usually scored ICSD-2 explicitly considers mixed apnea as obstructive Central hypopnea is not usually scored Desaturation linked criteria underestimates Flow limitation is considered a marker of primary obstruction (ICSD-2) CAI threshold of 5 is too high, and requiring 50% of events being central is even worse These are convenience / insurance coverage rather than biologically based
ICSD-3 Improvements and new problems Various CSA categories Treatment-emergent CSA is one of them Accepts co-existences High bar (> ) 50 % of events should be central In principle, central hypopneas need to be scored but is optional and no one does it, so. CAHI becomes CAI Using a CAI threshold of 5 and 50% of events misses most of chemoreflex activation Central hypopnea rules in manual are wrong
The phenotype of sleep state Wake-NREM-REM NREM is bimodal
Detection of Chemoreflex (high loop gain) Phenotype Assessment during stable NREM sleep NREM CO 2 reserve (Dempsey method) Proportional assist ventilation (Younes method) Dial down (Wellman method) Assessment during unstable NREM sleep Conventional central apnea / periodic breathing scoring (arbitrary, biased) NREM vs. REM dominance (too blurred) Visual inspection and description (subjective) Oscillatory mapping Single signal: oximetry, HRV, flow Coupled
CO 2 reserve Dempsey method
Chemoreflex strength - Wellman
Proportional Assist Ventilation - Younes
Wellman s group-from standard PSG MATLAB program, needs arousal scoring and flow measures. NREM dominance and short cycles also consistent with high loop gain. European Respiratory Journal 2015; 45: 408 418
Phenotyping risk
Baseline Study Baseline AHI 5.16, RDI 40.07, Oxygen saturation nadir 88%.
Attempt at CPAP
Attempt at CPAP: 5 minute view
Home sleep study
Home sleep study
Home sleep study
Opiate dysintegrative pattern
The phenotype of therapeutic failure CPAP Adaptive ventilators
Adaptive Ventilation Different machines (available and in development) ResMed Adapt SV, Respironics BiPAP SV Auto Advanced Very different machines, complex internal algorithms Pressure profiles are different Tries to keep ventilation a target % of averaged shortterm means Both can improve AND destabilize breathing Respiratory pro-arrhythmia Power machines that need to be used with skill and care
Pressure cycling can come..
Pressure cycling can go.
Persistent pressure cycling can persist
AirCurve 10 ASV pressure cycling
ASV pressure cycling
ASV-uncompressed
#1 CPAP, NV, acetazolamide, zolpidem
#1 ASV, acetazolamide, NV, zolpidem
#1 Adapt SV, acetazolamide, NV, zolpidem
#2 ASV
#2Transition to CPAP
#2 Transition to stable breathing
BiPAP AutoSV Advanced, O2, NV, acetazolamide, temazepam
Auto SV - decompressing
Auto SV - decompressed
AutoSV Advanced note pressure cycling
Bench Testing of ASV s Unable to create stable breathing Devices respond but do not enable system stability Zhu K, Kharboutly H, Ma J, Bouzit M, Escourrou P. Bench test evaluation of adaptive servoventilation devices for sleep apnea treatment. J Clin Sleep Med 2013;9:861-71.
What can we do about failure Recognize Target pathophysiology Track Repeat
We Have Four More Options For Use With PAP 1. Give oxygen prevent hypoxia 2. Give sedating drugs stabilize sleep 3. Give small doses of inhaled CO 2 4. Acetazolamide decrease loop gain, increase delta CO 2 Using all or some of these will permit PAP to work
NREM sleep, pre-papgam BiPAP 12/8 + 4L / minute O2
NREM sleep, PAPGAM BiPAP 12/8 + 0.5% CO2, no O2
Low concentration CO 2 effects
Enhanced Expiratory Rebreathing Space (Dead space) Published reports: central sleep apnea, congestive heart failure Problem: 400-600 cc, lack of PAP benefits in CHF, no upper airway support, partial effectiveness Dead space adjunct to PAP -1000 + patients with complex disease (100+ CHF) -non-vented oronasal mask -50-150 ml additional EERS
Unstable breathing in CHF
50 EERs added
Oxygen Long history of use for central sleep apnea, with or without congestive heart failure Clinically used off-label Intermittent reports Improves but leave behind residual disease Can be combined with PAP More likely effective in high loop gain patients Can help even if saturations already in 90 s Insurance coverage may not be possible if patients do not desaturate to lung levels As a group, hypocapnic central sleep apnea patients hyperventilate so, hypoxia in the conventional sense is less common
CPAP refractory
CPAP refractory, now with EERS
CPAP refractory, now with EERS + 4 L O2
Provent for central sleep apnea / periodic breathing
Provent for central sleep apnea / periodic breathing
Acetazolamide Carbonic anhydrase inhibitor (original idea) Direct reduction of CB activity, effects on aquaporin channels, redox (new thinking) Reports in mixed and central sleep apnea / CSR (including congestive heart failure) Residual disease is universal Greatest effect in those with high loop gain High altitude effectiveness and CPAP users exposed to altitude Temazepam vs. acetazolamide, subjective sleep effects better with benzodiazepine
Acetazolamide + CPAP in complex apnea
Use of sedatives Normally considered verboten! Sedatives can kill!! Lack of proper phenotyping is the core cause of this misconception Sedatives are appropriate for NREM-dominant sleep apnea (aka altitude-like) Data from several reports - sedatives benefit breathing at altitude (classic and non classic benzodiazepines) Those with low arousal threshold likely benefit most (Eckert DJ, et al Clin Sci 2011;120:505-14.
How do I use sedatives NREM-dominant apnea / periodic breathing Recognize the sleep fragmentation phenotype some combination of N1 > 30%, efficiency < 70% (70-80 borderline) Prolonged sleep-wake transitions Slow return to sleep (full micro-wake after arousal or slow waves only > 5 seconds after arousal) No / minimal non-cap (N3 per se too scarce to use) Poor clinical tolerance despite reasonable lab efficacy in complex apnea patients Approaches to use Bedtime: zolpidem 5 /10 (women/men) mg or clonazepam 0.5 mg Pharmacological challenge: during study, zolpidem or zaleplon
What about hypoventilation No CO 2 monitoring = too bad, tough, you will never know
Hypercapnic periodic breathing Periodic breathing is supposed to be hypocapnic Hypoventilation is by definition hypercapnic There cannot be hypocapnic hypoventilation Can there be hypercapnic periodic breathing? Subset of patients Obesity, usually morbid, or COPD + CHF CO 2 is in 50 s or 60 s Breathing pattern is SHORT cycle periodic Acetazolamide helps
Summary Recognize NREM dominance Self-similar events Pressure cycling Manage Reduce loop gain Stabilize sleep Ignore AASM rules
Thank you for the ear rthomas1@bidmc.harvard.edu Welcome to MD nights at BIDMC-Needham, Fridays, about 15 times a year ( the worst of the worst )