"Sleep Apnea Endotypes: Implications for Precision Sleep Medicine" Danny Eckert, PhD (01/18/2023)

February 10, 2023

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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.