"Sleep Apnea Endotypes: Implications for Precision Sleep Medicine" Danny Eckert, PhD (01/18/2023)
February 10, 2023ID9473
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- 00:00I have the pleasure of introducing Dr.
- 00:02Danny Ecker today.
- 00:03Doctor Eckert received his Bachelor
- 00:05of Science degrees with honors,
- 00:07followed by his PhD in Sleep respiratory
- 00:10Physiology from Adelaide University.
- 00:12He's currently a Matthew Flinders professor
- 00:14and the director of Adelaide Institute
- 00:16for Sleep Health at Flinders University.
- 00:18He's also the principal research scientist
- 00:20and director of the Sleep Program
- 00:22at Neuroscience Research Australia.
- 00:24After his education,
- 00:25he worked briefly in the division of
- 00:27Sleep Medicine at Brigham and Women's
- 00:29Hospital in Harvard Med School.
- 00:30Before moving back to Australia,
- 00:32his research aims to improve understanding
- 00:35of obstructive sleep apnea and
- 00:37respiratory disease pathophysiology,
- 00:39identify novel therapeutic agents
- 00:41and develop new targeted therapies.
- 00:43His most well known for his work on
- 00:45respiratory endophenotype being leading
- 00:47to a new precision medicine therapeutics.
- 00:49Along with his research on the role
- 00:52of arousal mechanisms and hypnotics
- 00:54and sleep apnea pathogenesis treatment
- 00:56as well as OSA pharmacotherapy,
- 00:59he has received many awards.
- 01:00Is a recipient of several grants,
- 01:02including from the National Health and
- 01:05Medical Research Council of Australia
- 01:07and has authored over 100 and 8080
- 01:09publications including in JAMA Blue Journal,
- 01:12European Respiratory Journal.
- 01:13Doctor Eckert has also held leadership
- 01:15position in many national and
- 01:17international societies and has
- 01:19served in many editorial boards
- 01:21including Sleep Medicine Reviews.
- 01:23Thank you so much for being with us
- 01:25Doctor Eckert at 5:30 AM your Australian
- 01:28time and without further delay I
- 01:29would like to hand it over to you.
- 01:31To share your expertise on sleep apnea
- 01:33endives implications for precision
- 01:35Sleep Medicine, thank you again.
- 01:38Many, Many thanks for the kind
- 01:40words and introductions and and
- 01:42and good afternoon everyone.
- 01:43It's it's great to be here from afar.
- 01:46So to begin, as highlighted there are
- 01:49majority of my work funded by the NIH,
- 01:52NIH equivalent now NHMRC,
- 01:54but I do have various industry partnerships
- 01:57given the interest in developing new
- 02:01therapies for sleep apnea as listed here.
- 02:05I want to begin by acknowledging
- 02:07the land on which I I meet today.
- 02:09It's the land of the traditional owners
- 02:11or the custodians and the land of the
- 02:13Ghana people of the Adelaide planes,
- 02:15where learning and teaching has been
- 02:16taking place for 10s of thousands
- 02:18of years down here in Adelaide,
- 02:20Australia.
- 02:20But you can see with all these orange dots,
- 02:23we have a rather unique landscape and
- 02:26these are all the areas in which our
- 02:29university has campuses throughout
- 02:30these rather unique landscape.
- 02:35OK. So I guess the begin, you know,
- 02:37why do we need these new therapeutic
- 02:39approaches for sleep apnea?
- 02:40You know, perhaps I don't
- 02:42have to spend much time.
- 02:44But yeah, I think it's fair to
- 02:46say that the current ones are.
- 02:49In which the CPAP is,
- 02:51is typically delivered as as,
- 02:55as monotherapies is quite time consuming,
- 02:57costly and it's really
- 03:00failing too many patients.
- 03:02I won't go through all the
- 03:05various steps here as.
- 03:07Framework, I've just turned my video
- 03:09off because it's a little unstable,
- 03:10so I I hope, hope that that will
- 03:13make the audio a little clearer,
- 03:15but not obvious to say that first
- 03:18you have to suspect you have sleep
- 03:20apnea primary care referral,
- 03:21recognizing that there's
- 03:22different models of care.
- 03:24But also very true that
- 03:27it's quite convoluted.
- 03:28Every step along the way there's
- 03:31there's delays we're relying on
- 03:33on this technology for for our
- 03:35diagnosis often in a single night
- 03:37and it's and yet despite these
- 03:40different causes of sleep apnea as
- 03:42I'll talk about well over 90% of
- 03:45patients are initially prescribed
- 03:46CPAP half of whom will fail
- 03:49with our measures out to a year.
- 03:52And and this is despite our
- 03:54emerging evidence that you know
- 03:57things like oral appliances.
- 03:59And this is now you know this
- 04:01clinical trial conducted here in
- 04:03Australia over 10 years now showing
- 04:05similar health outcomes with
- 04:07oral appliance therapy to CPAP.
- 04:10More recently if we look at other therapies,
- 04:13this was a study led by Mika Antic
- 04:16and Doug McAvoy and our team showing
- 04:19you know the the the potential
- 04:21benefit for multi level surgery
- 04:23for many patients and yet you know
- 04:26this is again another development.
- 04:29In Australia, CPAP.
- 04:31Developed here in in Sydney,
- 04:34you know, many years ago now,
- 04:36but for many patients,
- 04:37despite the images like this,
- 04:39we can see all the sorts of the
- 04:42multiple sleep hygiene issues
- 04:43going on with this with blue light
- 04:46there and not sure you'd be having
- 04:49your CPAP machine on my.
- 04:50Nonetheless,
- 04:51for for many patients it
- 04:52feels more like this.
- 04:53So so whilst CPAP is a fantastic
- 04:56therapy and literally benefits
- 04:58millions of people around the planet,
- 05:01you know for many it's it's you know,
- 05:03they just cannot tolerate it or or are
- 05:06unwilling to do so or find it invasive.
- 05:09So as as I'll show you
- 05:10in the next few slides,
- 05:11you know sleep pattern is very
- 05:13much a heterogeneous disorder
- 05:14and as such the optimal therapy
- 05:16or therapies as the case may be
- 05:18likely varies between patients
- 05:19and this is where these precision
- 05:22medicine concept come into play.
- 05:24So really I'm just going to talk about
- 05:26three things in this presentation
- 05:28I'm going to briefly describe the
- 05:30four key pathophysiological traits
- 05:31or or and or types that contribute
- 05:33to OSA and highlight how that's
- 05:36the foundation for precision
- 05:37or personalized Sleep Medicine.
- 05:39I'll then talk about implications
- 05:41for targeted personalized therapy
- 05:43for this common respiratory chronic
- 05:45condition and then finally I'll
- 05:48I'll share some
- 05:49of the more recent highlights
- 05:51in terms of simplified tools.
- 05:53Steps into the clinic.
- 05:57So I guess just to begin we we
- 06:00know that well we now know that
- 06:02sleep apnea you know fundamentally
- 06:04this interaction between indeed
- 06:06the upper airway anatomy but also
- 06:08these non anatomical contributions.
- 06:10And so if we're just to take a
- 06:12static image of the upper airway,
- 06:14it really does not show the full
- 06:16picture of what's going on in this,
- 06:18in this very common disease here.
- 06:21If we look on the on the left,
- 06:23we would just say yes,
- 06:24this individual does not have sleep apnea,
- 06:25we'd look on the right.
- 06:27This crowded individual who is a base,
- 06:29we can say the adipose tissue
- 06:31throughout the genioglossus muscle and
- 06:33surrounding the upper airway would say
- 06:35yes this person does have sleep apnea,
- 06:38but actually you know ultimately
- 06:40it's this interaction between
- 06:41pharyngeal dilator muscles and
- 06:43the anatomy and these other non
- 06:45anatomical traits that I'll highlight.
- 06:47So this person again if we just
- 06:49look here narrow crowded airway,
- 06:51but actually because this
- 06:53individual despite being obese
- 06:55having an anatomically compromised.
- 06:57Either way is able to be protect
- 06:59themselves from sleep apnea
- 07:00because the muscles are working
- 07:02so well to protect that airway.
- 07:04Now,
- 07:04recognising that this is
- 07:05awake in this imaging,
- 07:06but we've also done studies to show
- 07:09that these individuals who are
- 07:10these who don't have sleep apnea
- 07:12have about three or four times.
- 07:14Get a muscle activation of the
- 07:17dilator muscles during sleep
- 07:18compared to their counterparts.
- 07:20Obviously this is not always the case.
- 07:22In some people they have this
- 07:25counterproductive motion where
- 07:26initially at the start of inspiration
- 07:28the tongue moves anteriorly,
- 07:30but here we can see the UVA
- 07:32falling back on the posterior
- 07:34wall and this individual's got
- 07:36moderately severe sleep apnea.
- 07:38And in other individuals,
- 07:41we've we've,
- 07:43we've got examples more like this
- 07:46where really there's no motion
- 07:50whatsoever of the dilator muscles,
- 07:52at least in terms of opening up that airway.
- 07:56And in, in those cases,
- 07:59this actual individual's got
- 08:02very severe sleep apnea.
- 08:04Yeah.
- 08:06So this is really our framework
- 08:08and how we think about it now.
- 08:10So yes,
- 08:10people will sleep and you've got some
- 08:12degree of sleep of anatomical compromise,
- 08:14but it varies dramatically
- 08:16between patients as I'll show you.
- 08:18And then of course there's that
- 08:20interaction between whether or
- 08:22not the muscles are able to
- 08:23keep that airway open or not.
- 08:25Other traits such as how easily they
- 08:27wake up to airway narrowing or this
- 08:31respiratory arousal threshold try and
- 08:33finally their control of breathing
- 08:34or or what we often refer to as.
- 08:37As Luke can.
- 08:38So let me just talk through
- 08:39the Physiology briefly here.
- 08:41That sort of lays out the
- 08:43foundation for what we've been
- 08:44doing and we and others in terms
- 08:46of these Ender typing concepts.
- 08:48So initially when we're trying
- 08:50to figure all this out,
- 08:51we inserted these fine wire
- 08:53electrodes just after a bit
- 08:55of lignocaine into the upper
- 08:57airway dilator muscles and in
- 08:59this case tensor palatini and
- 09:02genioglossus to get these,
- 09:03you know, very nice recordings of
- 09:05the upper airway dilator muscles.
- 09:07Uh, during sleep,
- 09:08there's an airway pressure sensor,
- 09:10uh just above the epiglottis,
- 09:12so we can measure respiratory effort,
- 09:15nasal mask,
- 09:16animatograph to measure accurately,
- 09:18measure airflow and then standard sleep
- 09:20staging and arousal scoring equipment.
- 09:22The participant breathes through a modified
- 09:25CPAP device that's goes to the room,
- 09:28the control room where we're sitting
- 09:30and then we we we manipulate the
- 09:32pressure throughout the night with
- 09:33this device and and I guess the.
- 09:37This device that enables us really to
- 09:40give anyone, even healthy individuals,
- 09:42sleep disorder breathing events and
- 09:44very controlled way where we can measure
- 09:47all these physiologic parameters.
- 09:49So here we've got the mask pressure.
- 09:51This is actually a healthy individual.
- 09:53We're starting them about four
- 09:54or five centimeters of water.
- 09:56We flick them switch on our
- 09:57PCRP machine and in this case,
- 09:59we've actually delivered about minus
- 10:012 centimeters of water to the mask.
- 10:03So now here's their breathing effort as
- 10:05measured by that epiglottic pressure swings.
- 10:08We can see that they've had gone
- 10:09from very nice air flow to a
- 10:11mild hypopnea in this instance.
- 10:12And overtime they're building up some CO2.
- 10:15Every blood pressure or those
- 10:18negative airway pressure deflections
- 10:20are increasing as it does in a
- 10:23hypopnea and indeed an apnea event.
- 10:25And this allows us to sort of very carefully
- 10:28measure these traits that are interested.
- 10:30And obviously the most important
- 10:31thing that we want to figure out is
- 10:33how collapsible is that airway or how
- 10:35bad is their anatomical compromise.
- 10:37So we look at these.
- 10:38Yes,
- 10:38you breaths immediately following a
- 10:40pressure reduction and we can see and
- 10:42most people they don't generate much
- 10:44muscle activity in these first few
- 10:46breaths until we they start to build up
- 10:48some CO2 and and and negative pressure.
- 10:51So we really are mainly looking at that
- 10:54interaction with the passive anatomy
- 10:56in these first few breaths and what we
- 10:59see in these three different examples.
- 11:00So here we've just dropped the
- 11:02pressure level at varying different
- 11:04levels throughout the night in
- 11:06these individuals again and again.
- 11:08And here's an individual,
- 11:09some of that sort of mild
- 11:10anatomical compromise.
- 11:11So what we've plotted here is the peak
- 11:14inspiratory flow versus the pressure
- 11:15we've delivered in the mask on the X axis.
- 11:18And then we can construct these
- 11:19curves to figure out where the
- 11:21Airways closing for each individual.
- 11:23So for this individual,
- 11:24they actually require that minus 4
- 11:26centimeters of water to close off the airway.
- 11:28This individual,
- 11:29it's more like atmospheric pressure.
- 11:31And this individual was severe
- 11:33anatomical compromise.
- 11:34Their airway is actually collapsing
- 11:36at about 5 centimetres of.
- 11:38So severely anatomically
- 11:42compromised individual.
- 11:44OK so there's there's the range of an
- 11:46enemy issues we then look at you know
- 11:49can these muscles actually recruit and
- 11:51and and dilate the airway during sleep.
- 11:54It turns out that that that
- 11:56cannot be done in all cases.
- 11:57Many people with sleep apnea
- 11:59this mechanism isn't working.
- 12:01But here is more of an example
- 12:02of the first image that we saw,
- 12:04that dynamic image where that
- 12:06individual had a narrow crowded
- 12:07airway and yet they were protected
- 12:09from sleep apnea because they had
- 12:11fantastic dilator muscle responses.
- 12:13So. Here's an example of this
- 12:15person during sleep.
- 12:16We've narrowed off the airway.
- 12:18We can see here in the first few breaths
- 12:19the airway is almost completely closed.
- 12:21But look at what happens within.
- 12:23A few breaths are able to
- 12:24recruit the dilator muscles.
- 12:25This is tensor palatini,
- 12:27this is genioglossus.
- 12:28They restore air flow very quickly
- 12:30and the Airways protected from
- 12:32from sleep apnea and you can
- 12:33see that there's no arousals.
- 12:35I've done this all whilst maintaining sleep.
- 12:39Unfortunately, many patients cannot do this.
- 12:42Here's the office that excrete
- 12:44extreme pressure drop.
- 12:45We've gone from about 10 centimetres
- 12:47of water down to, you know,
- 12:49four or five centimetres of water,
- 12:51mild hypopneas occurred.
- 12:52We can see those negative
- 12:54epiglottic pressure increasing.
- 12:56So CO2 is building up and yet there's
- 12:58no activation on the genioglossus
- 13:00or tensor palatini muscle.
- 13:02And for this individual,
- 13:03it's not until I have an arousal
- 13:04from sleep that they can get
- 13:06robust by later muscle activation
- 13:08and and reopen that airway.
- 13:09So there's the extreme example
- 13:11of what we see.
- 13:12So here's that first example of
- 13:14very good muscle responsiveness.
- 13:16So with increasing negative pressure,
- 13:18muscle activation is increasing.
- 13:19And here's that second example
- 13:21of of someone where it really,
- 13:23despite the fact they're getting lots
- 13:25of negative pressure in the airway,
- 13:27there's no activation of the muscles
- 13:29until they wake up from sleep.
- 13:31Next trait is how easy they wake
- 13:33up when that airway narrows off.
- 13:35And,
- 13:35and this is really at least a good
- 13:37surrogate of what's waking people
- 13:38up during these respiratory events,
- 13:40how hard they're working to breathe.
- 13:42And the reason this trade is important.
- 13:43You can imagine if an individual
- 13:45was waking up right here,
- 13:46so just a relatively low arousal threshold,
- 13:50waking up at maybe 10 or 15 centimeters
- 13:53of negative pressure in the airway.
- 13:55If this were the case,
- 13:56then they were not having enough time
- 13:58to actually activate the muscles,
- 13:59assuming they were able to do so and.
- 14:01Build up that CO2 and negative pressure
- 14:03that's required to recruit the muscles,
- 14:06and they're also not able
- 14:07to get into deeper sleep.
- 14:08We know for reasons that are
- 14:09incompletely understood that you know,
- 14:11sleep apnea is very rare in slow wave sleep.
- 14:13So if people can get off and have
- 14:15those deeper stages of sleep,
- 14:16the airway is somewhat protected.
- 14:18And then finally, every time you wake up,
- 14:20you take a deep breath and that
- 14:22blows off your CO2.
- 14:23And that can not only turn off
- 14:25the dilator muscles,
- 14:26but it feeds into this final
- 14:28trait which is really all about
- 14:30the control of breathing and.
- 14:31Really it's,
- 14:32it's all we're measuring here is
- 14:34when we do these pressure drops
- 14:36as shown in this schematic,
- 14:37we're reducing the minute ventilation
- 14:39and we can quantify this.
- 14:44So here we can reopen the airway and
- 14:46measure the ventilator response.
- 14:48And this really just gives us a ratio of
- 14:50their ventilator response to disturbance.
- 14:52Some people, they have
- 14:54very exaggerated responses.
- 14:55So in this individual,
- 14:56it's not too bad for any one liter minute
- 14:58per reduction in their minute ventilation,
- 15:00they have a 2 litre per minute overshoot.
- 15:03Some people it can be more like
- 15:051011 liters per minute overshoot.
- 15:07So that's really unstable and it
- 15:10feeds into that cyclical pattern
- 15:12of sleep disorder breathing.
- 15:15So hopefully that's sort of laid out
- 15:16the foundation of those those different
- 15:18Ender types that contribute to sleep apnea.
- 15:20And now I'm just going to switch
- 15:22a little bit to, you know,
- 15:23I'll talk a little bit more detail
- 15:25here about the functional anatomy or
- 15:28peak credit and then how we can use
- 15:31that information to target therapy.
- 15:33So firstly what we see here,
- 15:34so this is the peak create the
- 15:36collapsible ability of the airway
- 15:37and firstly the red dots we can see
- 15:39are our people with sleep apnea and
- 15:41immediately we can see those ranges
- 15:43and pressures some people airway.
- 15:44Requires you know negative pressure
- 15:46to close off, you know,
- 15:47in the order of minus four or
- 15:48five centimeters of water.
- 15:49Others there Airways closing at
- 15:51+5 centimetres of water or more.
- 15:54These folks down here probably
- 15:55doesn't matter if they're dilator
- 15:57muscles aren't working because their
- 15:59Airways really not an anatomically
- 16:01compromised airway.
- 16:02So these people,
- 16:02you know,
- 16:03they require some of them minus
- 16:0515161718 centimeters of water
- 16:07to close off their airway.
- 16:08As you can see here on the X axis,
- 16:10these people do not have sleep
- 16:12apnea because they got really
- 16:13no anatomical problem.
- 16:14Here's the other extreme,
- 16:16these folks got very severe
- 16:17sleep apnea Airways closing at
- 16:19plus 5 centimeters of water,
- 16:21and invariably they've got
- 16:22very severe sleep apnea.
- 16:24With 40.
- 16:27But then there's this group,
- 16:28about 20% of all people sleep apnea,
- 16:30their Airways closing off at a similar
- 16:33level to many people without sleep apnea.
- 16:35So whereas, you know,
- 16:36some of these folks were sleep
- 16:38apnea have got mild disease,
- 16:39others moderate, others very severe
- 16:41sleep apnea and yet they their anatomy
- 16:44issue is really only quite mild.
- 16:46So they they're in the order of minus
- 16:48two to minus 5 centimeters of water.
- 16:49So they require that suction pressure to
- 16:52close off the airway and yet you know,
- 16:55marked differences in terms of their.
- 16:57The pattern is severity.
- 16:58So in these people it turns out that
- 17:00they've all got a problem with one or
- 17:02more of those non anatomical traits.
- 17:03Either the muscles aren't working,
- 17:05they're too sensitive to CO2,
- 17:06or they're waking up too easily,
- 17:08or multiple factors and those
- 17:10non anatomical traits.
- 17:11So in these people we should be able
- 17:13to give them an intervention to fix
- 17:15those issues and and treat their
- 17:17sleep apnea to get them over to this
- 17:19side with these other people that
- 17:20don't have sleep apnea for the same
- 17:23anatomical compromise however if we
- 17:24just gave a non anatomical intervention.
- 17:27These people were,
- 17:27you know, terrible anatomy.
- 17:28Yes, we might lower the HR a little bit,
- 17:31but unless we deal with the anatomical issue,
- 17:34they're still going to have
- 17:36major sleep apnea.
- 17:38Yeah.
- 17:38Here,
- 17:38if we don't go after the anatomy issue
- 17:41as well or or indeed exclusively.
- 17:44So the goal I guess here physiologically
- 17:46at least with all these therapies is
- 17:48either to get them over here into
- 17:50this pocket here or really get them
- 17:52below minus 5 centimeters of water.
- 17:54So whether it's CPAP surgery,
- 17:56mandira advancement,
- 17:57splendor or combination thereof,
- 17:59we're trying to make that airway
- 18:01less collapsible so that we can
- 18:04stabilize breathing during sleep.
- 18:05Right, so it turns out that yes,
- 18:07as I highlighted everyone with sleep apnea,
- 18:08it's got some degree of
- 18:10anatomical compromise,
- 18:11but the range varies minus 5 + 5
- 18:14centimeters of water per credit and beyond.
- 18:173rd of patients wake up too easily or
- 18:19have this lower arousal threshold.
- 18:22Certain patient groups,
- 18:24others are too sensitive to see.
- 18:27A little gain, at least 1/3 of
- 18:29patients and 1/3 of patients just
- 18:30cannot activate those dilator
- 18:32muscles during sleep and have a
- 18:33have a problem with their muscles.
- 18:3770% or more of all patients have have one
- 18:39or more of these non anatomical factors
- 18:42that start feeding into their sleep apnea.
- 18:44OK. So now we know a little
- 18:46bit about the pathophysiology,
- 18:47what are the implications for
- 18:49targeted personalized therapy.
- 18:51So I'm just going to talk
- 18:53about three things here.
- 18:54Firstly, if we're going to
- 18:56deliver non CPAP therapies,
- 18:57we need to know how much they improve,
- 19:00the things that we're trying to modify here
- 19:03and of course anatomies the major factor.
- 19:06Where our current therapies
- 19:08are are targeting.
- 19:10I'm also going to talk about how we
- 19:12can improve outcomes with existing
- 19:13therapies if we know about these traits.
- 19:15And finally how we can use this information
- 19:18for developing new therapies including
- 19:21pharmacotherapies and combination therapies.
- 19:23So here's that framework again,
- 19:25anatomy and these non anatomical
- 19:28traits in person.
- 19:30Existing interventions,
- 19:31we've got oral appliances,
- 19:34we've got upper airway surgery,
- 19:36position therapy, weight loss.
- 19:37So I'm just going to talk through,
- 19:40you know,
- 19:40what is the effect on the collapsibility
- 19:42of the airwave when we put one
- 19:44of these interventions in place.
- 19:45So here's a study we did with Ahmad,
- 19:48a PhD student in the lab and we
- 19:51used that rather detailed Physiology
- 19:53setup again and we took advantage
- 19:56of this device developed by John
- 19:58Remmers in Canada where we can.
- 20:00Actually sit in the control
- 20:01room and move the jaw remotely
- 20:04whilst the participant is asleep.
- 20:05And that enables us to look at,
- 20:07you know,
- 20:08what is the effect of moving that mandible.
- 20:10And here we did a randomised design
- 20:12where we left it at baseline.
- 20:14We advanced at 50 percent,
- 20:15100% of their maximal protrusive range,
- 20:18and looked at the collapsibility
- 20:20of the airway along with some
- 20:22other other components.
- 20:23And essentially what we found the more you
- 20:26move that jaw forward here at baseline,
- 20:2950 percent, 100%,
- 20:30here's our P crit,
- 20:31the less collapsible the airway became.
- 20:34And you can see that this at baseline
- 20:36the collapsibility of the Airwave
- 20:37varies again as I showed you before,
- 20:39anywhere from minus five and in this
- 20:41case up to above 10 centimeters
- 20:43of water collapsibility.
- 20:44And there is that inter individual
- 20:46variability.
- 20:47But overall you get a pretty good
- 20:49improvement in the collapsibility
- 20:50of the airway with mandibular
- 20:52advancement splint.
- 20:52So when you move it about.
- 20:5450% of the productive range,
- 20:55it's, you know,
- 20:56two or three centimeters of water.
- 20:58But when if you can go to 100%,
- 21:00you're more like 5 or 6 centimetres
- 21:02of water and improvement.
- 21:03And this was a small Physiology study,
- 21:05but there was a bit of a hint
- 21:07that the people that had a less
- 21:08collapsible airway to begin with
- 21:10tended to do better when we followed.
- 21:16What about upper airway surgery?
- 21:17Now there's a bit of a gap in
- 21:19in knowledge here, but this was
- 21:21some early work by Alan Schwartz.
- 21:23There's now, you know,
- 21:24we've moved beyond the the sort of
- 21:26traditional U triple P and are onto
- 21:28model level surgery and things.
- 21:29So there's an like this, but you know,
- 21:32Alan's early work showed us that
- 21:35with the old new triple P techniques,
- 21:37you improve the collapsibility of the
- 21:39airway about minus 3 centimeters of water.
- 21:41And remember the goal of treatment is
- 21:42to get everyone at least below that
- 21:44minus five and then you're basically.
- 21:45You know, get rid of their sleep apnea.
- 21:48What about putting people on their side?
- 21:51Three studies that I've highlighted
- 21:53here show us that again you get about a
- 21:56two to four centimetre water improvement
- 21:58in that airway collapsibility.
- 22:00When you move someone from the
- 22:02supine to the lateral position,
- 22:04that airway becomes less collapsible.
- 22:06So you've got,
- 22:07you've got a bit of improvement
- 22:09there in there in the airway just
- 22:11moving people off their back.
- 22:13Finally, weight loss.
- 22:15You know, roughly half of all
- 22:17patients with sleep apnea,
- 22:19in fact not overweight or obese,
- 22:21but but many of course are.
- 22:23And and indeed when you are successfully
- 22:26able to get rid of that weight,
- 22:28the airway becomes less collapsible
- 22:30as shown here.
- 22:32So here they had a usual care group
- 22:33and A and a Weight Loss Diet group
- 22:35and you can see what's happening in
- 22:37terms of collapsibility of the airway.
- 22:39It varies here.
- 22:40Here's the reduction in BMI on the X axis.
- 22:44But the more weight you lost in these,
- 22:46you know, morbidly obese folks,
- 22:47the less collapsible the airway we can.
- 22:51OK. So that's just showing,
- 22:52you know, a few examples of how
- 22:54much our existing interventions
- 22:56can improve the collapsibility
- 22:58or that that main anatomy tray.
- 23:00I'm now just going to move on a
- 23:02little bit to this next question of
- 23:04how can we use information if we knew
- 23:06about what these different entity
- 23:08types were and a given individual,
- 23:10how can it help us inform treatment?
- 23:14Just that this palm scale concept
- 23:16which is really just again reiterating
- 23:18that if we knew what the peak credit,
- 23:21arousal threshold, loop gain and muscle
- 23:24responsiveness is, how can we use
- 23:26that information to inform therapy.
- 23:28So as a whole ideally roughly 20%
- 23:31of all patients really only have a
- 23:33mild anatomical issue and for them
- 23:34it's really driven by a problem
- 23:36with these non anatomical traits.
- 23:38So for these folks we should be able
- 23:40to get one or more non anatomical
- 23:41interventions and and and get
- 23:43them treated the opposite.
- 23:44Scream, you know, 2025% of patients have,
- 23:47you know, major anatomical
- 23:48problem Airways collapsing at +2
- 23:50centimetres of water or beyond.
- 23:52So these people are really going
- 23:53to have to go out of there after
- 23:56the anatomy to get them treated.
- 23:57The, you know,
- 23:58the largest group of patients and
- 24:00most patients are Airways closing at
- 24:02about atmospheric pressure between
- 24:03minus two and +2 centimetres of water.
- 24:05And again,
- 24:06if we knew what the anatomy was first
- 24:09that it could help us inform our secondly,
- 24:11if we need to just go after
- 24:13the anatomical issue,
- 24:14or indeed we also might need
- 24:16to consider them.
- 24:17Patients is present in about 2/3 of
- 24:20of the patients with an airway that's
- 24:24collapsing at about atmospheric pressure.
- 24:26So that's the sort of conceptual framework.
- 24:28Now obviously lots of information
- 24:31on this slide really.
- 24:34As highlighted in the heading there,
- 24:36if we know what all these studies show,
- 24:38if we know about the Physiology,
- 24:39if we know about these traits,
- 24:41it can help us.
- 24:42Instead of it being a 50% success
- 24:44rate with an oral appliance as
- 24:45it currently is and recognizing
- 24:47that many of these patients have
- 24:49already gone through CPAP therapy.
- 24:51So they may be already somewhat
- 24:54disgruntled with the process.
- 24:55If we use the information about
- 24:57these end of types and these
- 24:59sort of proof of concept studies,
- 25:00turns out that people with a less
- 25:02collapsible airway to begin with.
- 25:04And that don't have major non anatomical
- 25:06issues such as high loop gain.
- 25:08They're the ones that tend to do better.
- 25:10So we looked at this at various ways,
- 25:13but the, the, the,
- 25:13the,
- 25:14the story really is if we know
- 25:16about these enterotypes instead
- 25:17of being a 50% success rate,
- 25:18we could probably get it up to north of 80%.
- 25:24The same is also true
- 25:26with our railway surgery.
- 25:27So here's, here's some of the
- 25:29initial findings that again much
- 25:31like our appliance therapy,
- 25:32if you've got a, you know, if you do,
- 25:34if you improve the anatomy a little bit,
- 25:35but you've still got these residual
- 25:37issues with these non anatomical
- 25:38traits and you haven't got them
- 25:40below that minus 5 threshold.
- 25:41Recognizing that these therapies might
- 25:43improve your anatomy in the order of
- 25:46three to to five or six centimetres
- 25:48of water depending on how much move,
- 25:51how far you move the jaw forward and
- 25:53what type of surgery you do and so forth.
- 25:55If you've still got a loop game problem,
- 25:56your anatomy hasn't been completely resolved,
- 25:58not surprisingly.
- 26:01So things like Luke gain are very
- 26:04strong predictor of surgical success
- 26:06as shown in this study whereby people
- 26:09with respiratory construction control
- 26:11instability give them surgery,
- 26:14they still will have sleep apnea.
- 26:16So this is a pretty.
- 26:18Want to look at the anatomy?
- 26:20And much like oral proliance therapy
- 26:22for the Airways less collapsible at baseline,
- 26:24they tend to do better.
- 26:25And and also other studies showing
- 26:28that if you know about the muscle
- 26:30activity as well,
- 26:30that can also help predict who's going
- 26:33to do well at Upper Iowa surgery.
- 26:36More recently with hypoglossal
- 26:38nerve stimulation, we again,
- 26:41if we all these traces show is
- 26:44basically if you know all four,
- 26:45if you have estimates of all four traits.
- 26:47And in this study it was done just
- 26:50using estimates using the technique that
- 26:52developed in Boston of these enterotypes.
- 26:54Again there's various clusters that
- 26:55you can use to predict who's going
- 26:58to respond to hypoglossal nerve
- 27:00stimulation and who you should really
- 27:02avoid this therapy in or or at least
- 27:03you might need to combine it with
- 27:05other therapies if you want to.
- 27:07Gets full therapeutic effect.
- 27:11And and finally looking at these
- 27:13sort of existing therapies and again
- 27:16this is Alan Schwartz's earlier
- 27:17work and you can see these sort
- 27:19of individual differences here.
- 27:21So if we if we look at this sort
- 27:22of cut off of A0P credit,
- 27:23so here's everyone with sort of
- 27:25positive P credits, negative P credits,
- 27:26you can see that the ones that did
- 27:29best on weight loss are within a
- 27:31weight loss intervention tended to
- 27:32have a less collapsible airway to begin with,
- 27:35whereas those that had higher
- 27:36peak credits to begin with, yes,
- 27:38they might have got some improvement
- 27:39in their sleep. Load of breathing.
- 27:40But you know it wasn't enough to
- 27:42overcome unless they were able
- 27:44to get down here, you know,
- 27:46below this sort of minus five critical
- 27:49threshold as I highlighted earlier.
- 27:51Alright, but what? What about CPAP?
- 27:53You know,
- 27:53how can we use the information from
- 27:56these end of types to perhaps predict or
- 27:58figure out who's who it will and won't.
- 28:01On cpap up front,
- 28:02so here's a study we did you know
- 28:04five or six years ago now where
- 28:05we took people that were coming
- 28:07through the clinical service and
- 28:09our in our public hospital and in Sydney and
- 28:12we particularly liked from these folks with
- 28:14these non obese people with sleep apnea.
- 28:16So now the rationale being that yes some
- 28:18might have retrognathia and anatomical
- 28:20issues but many of people who are not obese
- 28:22you know what was driving their sleep apnea.
- 28:25If it's not a major anatomical issue we
- 28:27figured it must be at least non anatomical
- 28:29traits and indeed we we estimated that.
- 28:31About 85% rather than it being a third
- 28:34of the overall population, you know,
- 28:3685% of these people who are not obese
- 28:39actually had a lower arousal threshold trait.
- 28:42And when we followed them up,
- 28:43they did particularly poorly on CPAP.
- 28:46And that kind of makes sense.
- 28:47If you're waking up very easily,
- 28:49you're going to be more sensitive to these
- 28:51pressure changes and perhaps less likely
- 28:53to tolerate that CPAP physiologically.
- 28:55So they're much less likely to be using
- 28:57CPAP at all when we followed them up
- 29:00and their objective compliance was.
- 29:01That was lower at that at that
- 29:03follow up with.
- 29:05Yeah, Andre and the team there at
- 29:08Yale have gone on to show this in
- 29:10other cohorts now both in the in the
- 29:12veteran cohort as well as people
- 29:14with coronary artery disease and
- 29:16effectively found the same thing.
- 29:18People with that lower arousal
- 29:20threshold including those non obese
- 29:22folks really did not do well on CPAP.
- 29:26So I'll get to what can we do about that.
- 29:29I'll highlight that as we move forward.
- 29:32So I might now.
- 29:35Maybe I'll just before I get to that uh,
- 29:38here's a review article that we wrote,
- 29:40recently wrote just so trying to I
- 29:42outline how can we use this information
- 29:44about end of types to better deliver
- 29:47targeted therapy with John Lewis,
- 29:49Peppin and Perrywood.
- 29:50Obviously very small font here,
- 29:53so I don't expect you to read it,
- 29:54but just to say that we went
- 29:55through the advantages,
- 29:56disadvantages of these therapies
- 29:57and and how we might be able to use
- 30:00this enter type information to move
- 30:02towards her a personalized approach.
- 30:04So encourage folks.
- 30:05To take it,
- 30:06take a look at that one if if of interest,
- 30:09alright, so development of new therapies.
- 30:13Off the back of this,
- 30:14this conceptual endotype framework,
- 30:16if we know about these four traits
- 30:20what can we do to develop therapies.
- 30:22So just to recap a bit,
- 30:25we first looked at use that model
- 30:26to figure out how much they are
- 30:29non CPAP interventions,
- 30:29noting that most of them are
- 30:32focused on anatomy at this time.
- 30:34Then we've looked at if we have
- 30:36information about the end of
- 30:38types how can they help us improve
- 30:39outcomes with existing therapies.
- 30:41So again trying to avoid people.
- 30:43With with major non anatomical
- 30:45issues really trying to hone down
- 30:47on the people with minor anatomical
- 30:49compromise perhaps people with CPAP.
- 30:50Sorry people with lower arousal
- 30:52threshold might need some more
- 30:54help getting on to CPAP or indeed
- 30:55look at other therapies for them.
- 30:57But and what are these new therapies
- 30:59you know what can we use to develop you
- 31:03know based on this framework develop the.
- 31:06They're going to switch to you know
- 31:08looking at these these non anatomical traits.
- 31:11So what can we do down here?
- 31:12As I've alluded to,
- 31:13you know these people that where their
- 31:15muscles really aren't working during sleep,
- 31:17you know we've got things like
- 31:19hypoglossal nerve stimulation,
- 31:20upper airway muscle training potentially
- 31:22can help some patients and I'm really
- 31:24going to focus in on you know the
- 31:26role of potential pharmacotherapy here.
- 31:28And and so you know theoretically
- 31:30this should be pretty straightforward.
- 31:32You know we've got out there later
- 31:35muscle function working nicely
- 31:36whilst awake and here's an alpha
- 31:38Theta transition where you know
- 31:40they've gone off to sleep.
- 31:41We see this profound reduction in
- 31:43tensor palatini and genioglossus muscle
- 31:45activity and a reduction in breathing.
- 31:47And so theoretically if we knew
- 31:48sort of neurochemically what was
- 31:50driving these reductions,
- 31:51these brisk reductions that occur with
- 31:54the transition transition of sleep,
- 31:56we should be able to give a drug
- 31:58and theoretically
- 31:58if we can. Going down on this
- 32:00upper airway motor neurons,
- 32:01we should be able to crank up
- 32:03these muscles and, you know,
- 32:05restore airway patency by giving
- 32:07a drug intervention.
- 32:09And here, you know,
- 32:10we and others have been looking at this
- 32:12for a long time and initially they were
- 32:14sort of looking at serotonergic agents.
- 32:16But thanks to, you know,
- 32:17beautiful animal work from Richard
- 32:19Horner and colleagues in Toronto
- 32:21have really LED us to believe that
- 32:24the noradrenergic and the muscarinic
- 32:26systems are very important both in
- 32:28R.E.M and non REM sleep for driving
- 32:31these reductions in muscle tone.
- 32:33So with this in mind,
- 32:34Luigi and the Boston team took
- 32:37these two agents, atomoxetine.
- 32:39Oxybutynin that had these properties
- 32:41and noradrenergic reuptake inhibitor
- 32:43and A and an anti muscarinic put
- 32:46them together measured upper
- 32:47airway Physiology and HIV in this
- 32:49initial proof of concept study.
- 32:51And what they found was that about
- 32:53a three or four fold activation
- 32:55of the Virginia glossus muscle
- 32:56response to those negative pressure
- 32:58swings when the drug intervention
- 33:00was in place compared to placebo.
- 33:03And you know this result in quite
- 33:06major reductions saying a single night
- 33:09acute Physiology study in in in HIV
- 33:11is shown here and improvements in
- 33:14oxygenation and in this particular
- 33:16study these improvements occurred
- 33:18both in non R.E.M and REM sleep.
- 33:21Akia Ashar and in our group PhD student
- 33:24who's just finished her PhD studies,
- 33:28you know went on to study these
- 33:30atomoxetine and oxybutynin at different
- 33:32dose regimes over a one month period
- 33:35to see what happens over a month.
- 33:38Recognizing that initial study
- 33:39was a single night study,
- 33:41she's actually just commenced to
- 33:44a postdoc studies over in Boston
- 33:47there and what Acura found was
- 33:50roughly a halving of the HIV.
- 33:53With the with the same dose
- 33:54that was in the original study,
- 33:55the lower doses that were not as efficacious,
- 33:58we had like 1/2 dose of atomoxetine
- 34:00and 1/2 dose of oxybutynin compared
- 34:03to baseline in this in this case.
- 34:06And there was also those improvements
- 34:09in hypoxic burden and these study
- 34:11and these findings are now impressed
- 34:14in the annals.
- 34:15We also in parallel this is Richard
- 34:18Lim's PhD work in the Sydney lab
- 34:21and what he did was take.
- 34:23Another jar, a drug in this class.
- 34:25So um, reboxetine, you know,
- 34:26not particularly good any antidepressant,
- 34:28but a pretty good NRI.
- 34:31And a different a muscarinic higher scene,
- 34:35beautiful bromide.
- 34:36And what if we looked at the upper
- 34:39muscle activity and what he found
- 34:40was indeed the tonic component of
- 34:42genioglossus improved in this small
- 34:44randomised Physiology study and again
- 34:46saw pretty consistent reductions in HIV.
- 34:50Gave this reboxetine
- 34:52combination with high seen,
- 34:54beautiful bromide and again you know
- 34:58quite marked improvements in oxygenation.
- 35:01Independently group in Italy went
- 35:03on to look at Reboxetine on the
- 35:06back of our work with Oxybutynin
- 35:08and you can see here,
- 35:09you know quite major improvements in HIV.
- 35:12This is now one week trial and they also saw
- 35:15improvements in the PvP.
- 35:16That's a psychomotor vigilance
- 35:18performance task next day and again they
- 35:21saw improvements in non R.E.M and REM
- 35:23sleep in this small randomized trial.
- 35:27We we were all singing this question.
- 35:29So when in that study,
- 35:30this is Tom Altree, he's a pulmonologist
- 35:32who's just finishing up his pH.
- 35:34D In the lab in Adelaide.
- 35:35And what we're interested in here was when
- 35:38we did those earlier studies with high aroma,
- 35:40not particularly good at crossing the blood
- 35:43brain barrier that particular muscular in it.
- 35:45So here we did a 3 way crossover
- 35:47to really answer the question.
- 35:48You know is it the noradrenergic
- 35:51agent that's largely leading from.
- 35:53Yeah.
- 35:54As well as Reboxetine alone in
- 35:55this 3 way crossover study and
- 35:57effectively what we found was really
- 35:59it was the Norwegian education that
- 36:01was driving the improvements in
- 36:03in sleep disorder breathing.
- 36:04And you can see you know similar
- 36:07improvements in oxygenation and ODI
- 36:10343 as shown here with Oxybutynin
- 36:14and REBOXETINE alone.
- 36:17And think about the end of type approach,
- 36:19the other thing that these these
- 36:21noradrenergic agents do is they lower
- 36:23the loop gain by about 10 or 20%.
- 36:25And in this particular study it seemed
- 36:27that the people with high look going
- 36:29to begin with and this study was
- 36:31mainly men that had the high loop game
- 36:34tended to have the greatest reductions
- 36:36in the HIV with reboxetine. OK.
- 36:39Uh, just to change tax a little bit.
- 36:41So he, he's a, he's a different target.
- 36:45We've got these robust reflex responses.
- 36:48So here if you deliver a negative
- 36:50pressure pulse to the airway you get
- 36:52marked activation of genioglossus
- 36:53and tensor palatini via these,
- 36:55you know,
- 36:56pressure sensitive McKenna receptors that
- 36:58are located throughout the upper airway.
- 37:00And so really what we wanted to ask
- 37:02are the question here was you know,
- 37:04rather than giving lignocaine which
- 37:05we know is knocks off these these
- 37:07reflexes and makes your sleep disorder.
- 37:08Getting worse.
- 37:09Can we give a a topical application
- 37:12that enhances this mechanism and so
- 37:15colleagues at Bayer had developed
- 37:18this agent and we did I guess the
- 37:211st in human Physiology proof of
- 37:24concept studies that I'll show you
- 37:26here that's just been accepted for
- 37:28publication and we delivered this agent.
- 37:30It's a potassium channel blocker
- 37:33in this sort of randomized.
- 37:39Sebo and then we went on to deliver
- 37:41it in different forms, nasal drops,
- 37:43half dose nasal spray and then finally
- 37:46we actually put an endoscope down
- 37:48and used an open channel to spray it
- 37:50directly in the area of interest.
- 37:52Here's our group.
- 37:54They were predominantly severe
- 37:55sleep apnea as shown here.
- 37:57They all came back from multiple peak
- 37:59visits and this is really this was
- 38:01our primary outcome and the study
- 38:03can we change the collapsibility of
- 38:04the airway by spraying this topical
- 38:06agent into the airway prior to sleep.
- 38:09This is Amal Osman's work.
- 38:11She very talented postdoc in the in the
- 38:13lab that's been doing a lot of this
- 38:16Physiology work and effectively that
- 38:18the summary findings are shown here
- 38:20delivering this spray we're able to.
- 38:22Decrease the collapsibility of
- 38:23the airway on average about two
- 38:25or three centimetres of water.
- 38:26So about about equivalent to
- 38:27what we saw with you know,
- 38:29position therapy if you like and
- 38:30and so here are the individual and
- 38:32group findings as shown here with the
- 38:34various interventions and it didn't
- 38:36seem to matter whether we go for high.
- 38:40Try the drops or the endoscope application.
- 38:44All the applications tended to improve
- 38:46the collapse of believe the airway,
- 38:48although it varied between
- 38:49individuals as shown here.
- 38:51So these findings are now impressed at chest.
- 38:56What about,
- 38:57you know these folks that
- 38:58are that are light sleepers,
- 38:59what can we do to help them?
- 39:01Here's an initial study I did while
- 39:03I was in Boston with the team and
- 39:06we just gave Eszopiclone and these
- 39:08individuals who did not have profound
- 39:10hypoxemia to begin with because
- 39:11the risk there of giving hypnotic
- 39:13to people with already have a high
- 39:16arousal threshold as you'll make the
- 39:18events longer and oxygenation worse.
- 39:19So excluded them to begin with and
- 39:21we're left with people with sort
- 39:23of moderate respiratory arousal
- 39:24threshold and low and what we found
- 39:26is an improvement in the HIV.
- 39:28In those people with lower arousal
- 39:30threshold without worsening the oxygenation,
- 39:33we've since gone on to do lots of
- 39:34work looking at the Physiology and
- 39:36looking at lots of different agents.
- 39:37I don't have time to sort of go
- 39:38into those now,
- 39:39but if you're interested in this,
- 39:40Sophie and I again,
- 39:42another PhD student in the lab,
- 39:44wrote a review on all of this.
- 39:45These recent finance was really challenged.
- 39:47Some of those sort of preconceptions
- 39:49you might have about the role of
- 39:52hypnotics and sleep disorder breathing,
- 39:53but potentially you can also get
- 39:56there without drugs. So this is.
- 39:58Alex Sweetman's work,
- 40:00uh again a talent postdoc in
- 40:02the Adelaide lab.
- 40:03And and what he's gone and done is
- 40:05actually in these people with comorbid
- 40:07sleep apnea and insomnia is actually
- 40:10give them cognitive behavioral therapy.
- 40:12And when you just give them cognitive
- 40:14behavioral therapy and bring them back
- 40:16and measure their their HIV turns
- 40:17out that that improves their sleep
- 40:19apnea across all stages of sleep.
- 40:21So we think that what's going
- 40:22on there is the
- 40:23therapy is you know behaviorally
- 40:25and improving their arousal
- 40:27threshold and improving their.
- 40:28Have to sort of breathing with
- 40:31this intervention. So, you know,
- 40:32and and and just wanted to, you know,
- 40:34here's 2 epidemiological studies that
- 40:35we've done looking at their sleep health,
- 40:37heart sleep, heart health start.
- 40:41And it turns out, you know,
- 40:42people with insomnia and
- 40:43sleep apnea symptoms,
- 40:45mortality risk is you know, not so good.
- 40:47So we really do have to look after
- 40:49these patients and think about them.
- 40:51And so potentially no cognitive
- 40:53behavioural therapy if they do have a
- 40:55bit of insomnia going on or perhaps,
- 40:57you know, short period of of a
- 40:58hypnotic to help them get on CPAP
- 41:00in these people that you know,
- 41:01probably also have a lower arousal threshold,
- 41:04maybe a sensible path forward.
- 41:08Finally,
- 41:08what about combining all of these therapies?
- 41:10You know,
- 41:11we hopefully have now shown you
- 41:13that there's these different causes
- 41:15that vary between individuals.
- 41:17You know, can we,
- 41:17can we go after one or two of these,
- 41:19sorry,
- 41:20at least a couple of these traits
- 41:22to deliver therapy and these people
- 41:25that have got multiple issues
- 41:27are driving their pathogenesis.
- 41:28So here just a couple of examples
- 41:30quickly to show this study that Brad
- 41:32Edwards did when he was in Boston.
- 41:34And so really he's doing nothing to the
- 41:36anatomy, just giving oxygen therapy.
- 41:38To lower the loop gain and
- 41:40hypnotic dystopic line again so
- 41:41increase the arousal threshold.
- 41:43These were unselected patients.
- 41:44So we didn't know about that endo
- 41:46types ahead of time and you could
- 41:48see that overall just with these
- 41:50two interventions of combination
- 41:51therapy roughly half the hi you
- 41:53know with that intervention
- 41:54alone and many patients were you
- 41:56know now in the sort of what we
- 41:58consider the treated range.
- 42:01Last few years we've been working
- 42:03with these oral appliances.
- 42:04Amal and Ben Tong have been doing this
- 42:07work across the Adelaide and Sydney
- 42:08sites where we've brought you know
- 42:10a large group of people over 100.
- 42:12We've instrumented them with all the
- 42:13equipment we've then brought them back.
- 42:15We've we've seen if we've worked
- 42:17with the dentist and giving
- 42:19them oral appliance device,
- 42:21roughly half of them you know had a.
- 42:26After therapy and so
- 42:28they're they're all done.
- 42:29But the question is and you know
- 42:30again a big clinical problem
- 42:32recognizing that many of these people
- 42:34might have already failed CPAP,
- 42:35now we've brought them through roughly
- 42:37half of them don't get a full therapeutic
- 42:40response on an oral appliance.
- 42:42We use the phenotype information and
- 42:44use this sort of stage protocol to
- 42:47deliver targeted therapy and this kind of
- 42:49proof of concept study also led by Aqua.
- 42:52So here's we specifically brought
- 42:54back these people that didn't have
- 42:56resolution with their ISA just
- 42:58with oral appliance therapy alone
- 42:59and mass therapy is shown here.
- 43:01So they've all gone HF 10, yes,
- 43:03they've had some improvement and
- 43:04then we just added on things like
- 43:07position therapy and so just adding
- 43:08an additional anatomical intervention
- 43:10roughly half of these people.
- 43:12Weren't treated beforehand.
- 43:13Now where?
- 43:14And then again if that didn't work,
- 43:16we added on either oxygen,
- 43:18the lower the lip gain or some drug
- 43:20therapy to activate the muscles.
- 43:22And then finally we added a bit
- 43:23of CPAP to the oral appliance
- 43:24device if nothing else worked.
- 43:26And Long story short,
- 43:27aside from this individual who really
- 43:29could not tolerate CPAP and wasn't,
- 43:31it wasn't a candidate for drug therapy.
- 43:34We managed to treat all the
- 43:35patients with this sort of targeted
- 43:38combination therapy approach.
- 43:39So hopefully we're building up
- 43:41this toolkit off the different.
- 43:43Therapies, yes,
- 43:44traditionally we're focused
- 43:45on the the anatomy side,
- 43:47but now we're building up this toolkit
- 43:49of the of the sort of non anatomical
- 43:51approaches that we can combine.
- 43:53So rather than I guess using
- 43:55largely this sort of single night
- 43:57hi measures to inform our treatment
- 43:59decisions which we know aren't
- 44:01aren't particularly good at working
- 44:03out who's going to respond to which
- 44:05therapy and who's going to have
- 44:07an improvement in their symptoms.
- 44:08Uh with the various treatments
- 44:10we have available today it's very
- 44:11much a trial and error.
- 44:13Process if we could use this sort of
- 44:15more Physiology or palm scale approach.
- 44:17Firstly,
- 44:17if we know how bad the anatomy was,
- 44:19that won't help us initially decide
- 44:21whether we need to go for CPAP
- 44:22or one of these other.
- 44:25That's position therapy and so forth.
- 44:28Uh, we could hopefully get to the successful
- 44:30treatment upfront rather than this,
- 44:32you know, trial and error approach.
- 44:34So I'm just gonna spend a few minutes to
- 44:36to finish now to just whiz through some
- 44:39simplified approaches for translating
- 44:40these concepts to the to the clinic and
- 44:43then allow some time for questions.
- 44:46And and really you know this is obviously
- 44:48the big question you know all well and
- 44:50good to figure out this Physiology but
- 44:51how can you actually use it in the clinic.
- 44:54So here's a little test that we've
- 44:56further developed again our mouse
- 44:58LED much of this work where you know
- 45:01rather than doing a sort of looking at.
- 45:07And uh, awakened oscopy, uh,
- 45:09we can do a little test here,
- 45:1115 minutes in the lab where we just
- 45:13deliver brief pulses of suction
- 45:15to the airway with this device
- 45:17here and we can get a pretty
- 45:19good estimate of the P credit.
- 45:20So in this study,
- 45:21we did these little pulses to the airway,
- 45:23about 1/4 of a second pressure.
- 45:25We do about 50 pulses or?
- 45:29The difference throughout the airway
- 45:31to see how collapsible that airway is
- 45:34and that's simple awake testing lines
- 45:36up very nicely with the overnight
- 45:38peak as shown here in a mile study.
- 45:41And here's our sort of receiver
- 45:44operating characteristic curves.
- 45:45So very good if that first thing,
- 45:47if all you want to do is
- 45:49differentiate between who has a + a
- 45:51positive P credit and a negative,
- 45:52this technique is pretty good at doing that.
- 45:54Or if you want to go further minus
- 45:57two versus you know that minus 2.
- 45:59Threshold, so that 20% of
- 46:00patients that really don't,
- 46:02you only have a mild anatomical problem.
- 46:04And here's the area under the curve as
- 46:06shown here for those different approaches.
- 46:08But if you know obviously
- 46:10that's work in development.
- 46:11Many of these patients have
- 46:13already had a CPAP trial.
- 46:14Turns out that information gives you a pretty
- 46:16good idea of their peak credit as well.
- 46:18So people with a pity credit,
- 46:19you know,
- 46:21above atmospheric pressure
- 46:23tend to be on require CPAP.
- 46:26That you know 10 centimeters of water
- 46:29and again we've shown this in a follow-up
- 46:31study as well here in a couple of
- 46:34follow up studies as well as that ratio,
- 46:36if you got more apneas compared
- 46:39to hypopneas than you're likely
- 46:40to have a more collapsible AOI,
- 46:42which also kind of makes sense.
- 46:45We've also got tools,
- 46:47and Andre and the team have been
- 46:49using these over there in Yale.
- 46:523 measures from a standard sleep
- 46:53study can give you a pretty good
- 46:55idea of whether or not with pretty
- 46:57good sensitivity and specificity.
- 46:58So you just look at the HIV Nadia sat
- 47:00and the fraction about the hypotenuse
- 47:02and that can give you a pretty good
- 47:05idea of who's got a lower arousal threshold.
- 47:07And the type Boston team,
- 47:09as I mentioned,
- 47:10we've done a great job at trying to do
- 47:12some signal processing techniques where
- 47:14they look at the end of the PSG recordings,
- 47:17the flow signal in particular,
- 47:19and estimate each of those traits
- 47:21as outlined in these various.
- 47:23Type is here now.
- 47:24Trouble with that of course is you need
- 47:27an engineer and it's not automated yet.
- 47:29Standard Sleep study reports.
- 47:31But just to finish on,
- 47:32here's some work that we've
- 47:34done with my colleague really.
- 47:35Bandata,
- 47:35who's a data scientist and
- 47:38a machine learning expert,
- 47:40works with our government
- 47:41agency called the Csro.
- 47:43Basically what we did was just take
- 47:45simple variables from a sleep study age,
- 47:48plus clinical outputs,
- 47:49age, BMI and and develop a
- 47:52machine learning algorithm.
- 47:53And effectively what we're able to do was
- 47:56estimate the traits using this approach,
- 47:59just plugging this information
- 48:00into the algorithm.
- 48:01And this can help us predict who's
- 48:04going to respond to oral appliance
- 48:05therapy as shown in this paper here.
- 48:08And we've also gone on,
- 48:10we've just presented this stuff
- 48:12at these findings at our recent
- 48:14sleep meeting in Australia in a
- 48:16prospective cohort of 90 people.
- 48:18Here's the sort of success
- 48:19rates that we got when
- 48:21we applied the, the algorithm
- 48:22prospectively in this cohort here.
- 48:25Similarly, we've been working on
- 48:26different therapies using this,
- 48:28in this case children with
- 48:30removal of adenoids and tonsils.
- 48:32Work with Jordan in in Hong Kong.
- 48:34He's now doing a postdoc in Toronto
- 48:36and he is the success rates in
- 48:39this initial proof of concept work.
- 48:41Using the model that we developed,
- 48:43we've also built an interface
- 48:44that we can sort of apply this
- 48:46so you can securely log in,
- 48:48put in the information and
- 48:50make predictions not only about
- 48:52whether their ender types are,
- 48:53but also whether or not they're going to
- 48:56respond to these various non CPAP therapies.
- 48:59So just to summarize,
- 49:00what can we do immediately?
- 49:02Clinically to implement this car,
- 49:05our palm scale category or
- 49:06OSA under typing concepts,
- 49:08so just to summarize,
- 49:09it can help with improving outcomes
- 49:12of existing therapies.
- 49:13Fabral characteristics for non CPAP
- 49:15therapies tend to be mild to moderate
- 49:18collapsibility without major problems
- 49:20with these non anatomical traits.
- 49:22People with a lower alcohol threshold
- 49:24endotype do not do well on CPAP and general
- 49:27and as I've highlighted we can also.
- 49:31New fair piece.
- 49:32But in terms of translations,
- 49:34some of these approaches can be
- 49:35applied in the clinic right now.
- 49:36So for example,
- 49:37that happened to hypopnea ratio gives
- 49:39us an idea of how collapsible the
- 49:41airway is or your CPAP therapeutic
- 49:43pressure talked about those 3 parameters
- 49:45that you can use to estimate the
- 49:47lower arousal threshold end of type.
- 49:49And hopefully I've shown you some of the
- 49:51work that we're doing to move forward for,
- 49:53you know,
- 49:54being able to get these tools readily
- 49:56available and simply in the clinic
- 49:59to inform clinical decision making.
- 50:00OK, very big.
- 50:01Thank you to my team and collaborators
- 50:04at Neuroscience Research Australia
- 50:05and my my lab in Sydney,
- 50:08as well as our fantastic team at
- 50:09the LA Institute for Sleep Health.
- 50:11Over 60 people in the team
- 50:13and they're a fantastic group.
- 50:14So thank you very much.
- 50:18Amazing. Thank you so much Doctor
- 50:20Eckert for this excellent presentation.
- 50:23Was very thought provoking
- 50:25and super informative.
- 50:26If anyone has any questions you
- 50:29can either put it in the chat
- 50:32or feel free to unmute yourself.
- 50:35I have a question.
- 50:35So as you mentioned,
- 50:36you know we do have all these
- 50:39alternative meds approved for OSA,
- 50:41but you know these are as we
- 50:43all know less frequently used.
- 50:45Any thoughts on what would help
- 50:47clinicians in day-to-day practice
- 50:49to utilize these alternatives
- 50:51on patients who meet criteria
- 50:53these alternative treatments?
- 50:56Yeah, look, hopefully just applying some
- 50:58of these concepts so you can get close.
- 51:01Just looking at the sleep studies
- 51:03as I've alluded to at the end,
- 51:05you know, in terms of what's going on
- 51:06in terms of their pathophysiology,
- 51:08how collapsible is this airway? You know,
- 51:10are they predominantly having hypopneas,
- 51:12in which case the Airways probably
- 51:14not going to be so collapsible.
- 51:15So you can start to just look at
- 51:18the recordings and that way if you
- 51:20do happen to have a CPAP trial,
- 51:22you can look at what pressures they require,
- 51:24so you can start to map this out.
- 51:26Like OK, this person may be a candidate
- 51:28for for some of these non CPAP
- 51:30interventions just from looking at
- 51:31information that we're already collecting
- 51:33and you know potentially plug some
- 51:35of those variables into that simple.
- 51:37Whether or not they gonna lower our
- 51:39threshold in terms of the readily
- 51:41available or the availability of
- 51:43these non CPAP therapies particularly
- 51:45pharmacotherapy and others.
- 51:47Of course the the work workup
- 51:49needs to take place.
- 51:51You know we need to see those trials
- 51:52through make sure all they're safe and
- 51:54efficacious in the long term and so forth so.
- 51:56You know unfortunately that's
- 51:57that'll takes time but you know we
- 51:59and others are working hard to try
- 52:01and try and make that the case.
- 52:02But you know I think it is as I
- 52:05showed you know we're quite excited
- 52:06about those targeted therapy ones
- 52:07where we you know you start with
- 52:09an oral appliance doesn't work.
- 52:10You can add on some of these other
- 52:12things you know just adding position
- 52:13therapy alone we've got most of the
- 52:15people treated there and these were
- 52:16people that would otherwise be left
- 52:17you know kind of done you know if they
- 52:19if you didn't get them treated with
- 52:21CPAP or oral appliance then what do you do.
- 52:23Well just adding a bit of and this is
- 52:25regardless of whether or not they'll.
- 52:26Position dependent because you
- 52:27know you're still getting about 2
- 52:29centimetres of water improvement there,
- 52:31collapsibility like that.
- 52:31So I think just thinking about
- 52:33these concepts,
- 52:34you know,
- 52:35using what we've got and as more
- 52:37of these things come onto line
- 52:39and a sensible strategic way,
- 52:41we'll be able to get more solutions
- 52:43for these patients that otherwise
- 52:44fall through the cracks.
- 52:47So much.
- 52:50We have a question here.
- 52:51Excellent talk updated in the theme,
- 52:54maybe I failed to listen.
- 52:55Is there any data in terms of
- 52:58ethnicity and peak Ridge variability?
- 53:02Yes, they look, there is and in
- 53:06particular they've studied the, you know,
- 53:09the airway anatomy traits in in Asian
- 53:12populations where there tends to be
- 53:14a little bit more retrognathia or,
- 53:16you know, skeletal differences going on.
- 53:19But what I will say in terms of this,
- 53:22you know, in terms of the ethnic
- 53:26differences ultimately, you know,
- 53:30racist social constructs.
- 53:32So this is not, this is not anatomy,
- 53:34so, so or Physiology.
- 53:37So if we can measure the Physiology
- 53:42in the way that I've described,
- 53:45then yes, certain features as I
- 53:47just highlighted in the Asian
- 53:49population might be more prominent,
- 53:51but there's much more physiological
- 53:53variability than there is, you know,
- 53:56race driven variability in the
- 53:58physiological traits that we see.
- 54:00So I think it comes back to you know.
- 54:03Regardless of race,
- 54:04you want to know what is their Physiology
- 54:06and then you can use that information
- 54:08and treat them as an individual to
- 54:10target their therapy in this case.
- 54:13Great.
- 54:14Thank you. And we have a question
- 54:16from Doctor Yagi to one on
- 54:18you to yourself. Doctor yagi.
- 54:21Sorry, Danny. Thank you so much
- 54:23for taking time out of your
- 54:24schedule to talk to us today.
- 54:26It was really clear
- 54:28presentation I put in the chat.
- 54:31How we might be able to use data
- 54:33from home sleep apnea testing and
- 54:35whether the clinical prognostic
- 54:37system that your group has developed
- 54:40whether data from HSAT could could
- 54:42inform in the in the types and
- 54:44and treatment decisions. Yeah.
- 54:46Let me look thanks very much for the
- 54:49question it it's really important
- 54:51obviously there's that balance
- 54:53between huge burden of disease
- 54:55and what I've talked about is very
- 54:57much relying on these more more
- 54:59detailed measurements or in lab PSGS.
- 55:01But of course the world is moving on.
- 55:02We've got to diagnose and and and and
- 55:04do this in in in more efficient ways.
- 55:06Now it turns out that in some of the.
- 55:13And when you do get those neurophysiological
- 55:15information with the egg and so forth,
- 55:17but actually there's probably a
- 55:19few drivers that you can get.
- 55:22So if you can get that as oxygen
- 55:24measures and in the home as well as the
- 55:27key parameters from the SLEEP study,
- 55:29you can probably still get pretty good
- 55:30estimates of what their endo types
- 55:32are from those home sleep studies.
- 55:33And very importantly I think that there's
- 55:36information in multi night testing.
- 55:38You know we know that if we do a single
- 55:40night sleep study 20 to 50% of the time.
- 55:43They're going to get the
- 55:44diagnostic category wrong.
- 55:45So, so using this technology in the home,
- 55:48even if it's simplified,
- 55:49but we could start to do
- 55:50it over multiple nights,
- 55:51we might be able to get as good
- 55:54or in fact in some cases better
- 55:56information to inform these sort
- 55:58of targeted therapy approaches.
- 55:59So absolutely that's the way of the future.
- 56:05Great. Thank you.
- 56:09If we don't have any other questions,
- 56:12we will wrap it up here and.
- 56:15Thank you Doctor Eckert again,
- 56:17and thank you everyone.
- 56:19She looks like Andre has a question. Oh.
- 56:24Is he?
- 56:27Andrew, can you unmute yourself?
- 56:33I don't see the question.
- 56:42Hi, I have a question
- 56:43that's there. You see it?
- 56:50I am. I can't see the question myself, but.
- 56:57No, here was the question does
- 56:59the use of oxygen and hypnotics.
- 57:02Likely lead to increasing the
- 57:05duration of the apnea events and and
- 57:08is O2 available through
- 57:10insurance in Australia it's.
- 57:14Pretty difficult for us to
- 57:16use O2. With sleep
- 57:18apnea. Yeah, yeah, yeah.
- 57:21Good questions.
- 57:22Look, we we have not if you take out,
- 57:24if you do not study people with
- 57:27profound hypoxemia to begin with,
- 57:29we have never seen you know.
- 57:32Major worsening in terms of
- 57:35prolongation of respiratory events
- 57:37or oxygen dips with a, you know,
- 57:40common dose of of standard hypnotics.
- 57:42The same obviously is true in
- 57:45terms of prolongation with oxygen.
- 57:48Again we have not seen that when we
- 57:51combine the two either in in those cases.
- 57:54So and to your second question,
- 57:57no, you know there there lies
- 57:59the practical issues.
- 58:00Yes, there's oxygen concentrators
- 58:02and things that are available.
- 58:03But it's not particularly um,
- 58:06yeah, well, you know,
- 58:07the costs are somewhat similar
- 58:09to a CPAP machine, but.
- 58:11We're still in this position of
- 58:13not knowing who's gonna respond,
- 58:15what the long term outcomes with it
- 58:16is with oxygen therapy and I mean
- 58:18we know it does a pretty good job
- 58:19of you know roughly halving your
- 58:21loop gain and and and can roughly
- 58:23half your sleep apnea severity.
- 58:24But in terms of that translation
- 58:27question insurance and rolling.
- 58:30As a viable uh and and economically
- 58:34yeah viable therapy you know that
- 58:36remains to be done but you know these
- 58:40this technology is always improving
- 58:41these concentrators against smaller
- 58:43and smaller and lighter and lighter.
- 58:44So conceptually you know it it
- 58:46it could be possible down the
- 58:48line but no not at the moment.
- 59:00Any more questions, Andre?
- 59:01I still can't see your question.
- 59:31Look, I know Andre said he was
- 59:32in the ICU this week, so he,
- 59:34he may have had to fly off.
- 59:35So he sent me, sent me,
- 59:37he sent me a note.
- 59:38Yeah, yeah, yeah.
- 59:40OK. Alright then. Thank you again
- 59:42so much Doctor Eckert, and thank
- 59:44you everyone for joining in today.
- 59:47You're very welcome. Thanks so much.
- 59:49Thank you. Bye, bye.