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INFORMATION FOR

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

February 10, 2023
  • 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.