"Sleep Deficiency in the ICU: Beyond the Brain" Melissa Knauert (11/17/2021)

December 09, 2021

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00:00Something is making a very weird
00:02noise in this call room. Oh no.
00:05Will have a disclaimer
00:07will be like when I run
00:08out of the screen just.
00:13Alright, so good afternoon everyone.
00:16So as usual I'm going to start
00:18with a few announcements before I
00:20introduce our speaker first that
00:22these sleep seminar lectures are
00:25available for CME Credit Wendy.
00:28In real time and to receive
00:29credit you do need to text the
00:31ID for the lecture to Yale Cloud.
00:33See any by 3:15 PM today and
00:35there will be more information in
00:36the chat on his lecture goes on
00:38recordings of the lectures are
00:39available in approximately 2 weeks
00:41and the site will be in the chat.
00:42There is no CME credit
00:44available for later viewings.
00:45If you have questions please type
00:46them into the chat and we'll get
00:48to them at the end and otherwise.
00:50Please keep your microphone muted so
00:53today it is my pleasure to introduce our
00:56seminar speaker who's one of our own.
00:58Doctor Melissa Canaller Dr Can Art is
01:00an assistant professor in the Yale
01:03School of Medicine with a secondary
01:05appointment in the L School of Nursing.
01:07She received her pH D and her
01:08medical degree from Yale School
01:10of Medicine and then she moved to
01:12Philadelphia for Internal Medicine,
01:13internship and residency at the
01:16University of Pennsylvania.
01:17She returned to Yale to do her
01:18pulmonary and critical care and
01:20her Sleep Medicine fellowships,
01:21and then she Subs when we stayed
01:23on here as faculty,
01:24she is active clinically in
01:27education and research.
01:28She attends in Sleep Medicine.
01:30And in the medical ICU she's currently
01:32on jeopardy and working as we speak,
01:34so we give her a lot of credit
01:36for doing this talk.
01:37Today she served as the associate program
01:40director for the Yale Sleep Medicine
01:42Fellowship program from 2013 to 2021,
01:44and she's been an inspirational
01:46mentor and role model for multiple
01:49trainees during this time.
01:50She's lectured,
01:51know locally and nationally,
01:53on topics and sleep in circadian science,
01:55and she's regularly participated in
01:57the American College of Chest Physicians.
01:58Sleep four to review course.
02:01Her research centers on sleep and
02:03circadian disruption in critical illness.
02:05She is a recipient of numerous grants,
02:07including from the NHLBI,
02:09the National Center for Advancing
02:11Translational Sciences,
02:12the National Institute on Aging,
02:14American Academy of Sleep Medicine,
02:15and other agencies.
02:17She is currently principal investigator
02:19on three ongoing clinical trials,
02:21including circadian rhythm as
02:22a novel therapeutic target in
02:24the intensive care unit.
02:26Randomized control trial of daytime bright,
02:28light, circadian abnormalities and delirium.
02:31In medical ICU patients and a
02:33randomized controlled trial of
02:34intermittent feeding in mechanically
02:36ventilated ICU patients.
02:37She wasn't invited.
02:38ASM representative at the recent
02:40Sleep Research Society Workshop on
02:42Sleep and circadian rhythm disorders,
02:44so we are really pleased to have
02:46Doctor Canal.
02:46Join us today and she's going to
02:48be discussing sleep deficiency
02:49in the ICU beyond the brain.
02:51Welcome,
02:52thanks so much Janet.
02:53Thank you everyone.
02:54It's really a pleasure to be here.
02:56I am over in the hospital and if I
02:59for some reason get disconnected.
03:01Or frozen, I'm just gonna jump back on
03:03or or pause and wait for it to keep going.
03:05It seems like the connection is pretty good,
03:07but I apologize for the logistics.
03:09It really is my pleasure today to
03:11talk to you about safe deficiency
03:13in the ICU beyond the brain.
03:16This is a new talk for me in a really
03:18fun talk and sort of scientifically,
03:20really exciting that there's there's
03:22something a little bit to talk about
03:23because I think this is something that's
03:25been emerging for much of my my career,
03:27and so glad that we've
03:30taken some steps forward.
03:32Uhm?
03:47I have nothing to disclose.
03:56I'm sorry, who is that work?
03:59OK sorry, sorry nothing to disclose
04:02and also the CME code is here on
04:04this slide and will also be in the
04:06chat as doctor Hilbert mentioned.
04:13OK, so today we're gonna do a little
04:14bit of work on definitions and
04:16background so that you know where
04:18I'm coming from with sleep and
04:19circadian disruption in the ICU.
04:21Well then go into the functional
04:23consequences of these disruptions
04:25and all scattered in through that.
04:27I'll talk about some possible
04:29interventions that are emerging
04:30for our critically ill patients.
04:33And so sleep deficiency is a construct
04:36proposed in more recent years by any
04:38by the NIH as an attempt to really
04:42define the domains within what I would
04:44call a syndrome of ways that sleep
04:47and circadian rhythms can go awry.
04:49There's mentioned,
04:50and these these things I think,
04:51are still evolving,
04:52and there's been some very thoughtful
04:55efforts to formalize these domains
04:57and to really try to come come
04:59to a common nosology a bit.
05:01At this time.
05:02You know what we're really talking about.
05:03Or abnormalities in sleep duration
05:06in the chronic literature.
05:07This can be short or long.
05:08In the ICU we most typically
05:10talk about short sleep.
05:11Also issues with sleep quality that
05:13encompass changes in sleep architecture,
05:16notably differences in REM and slow
05:18wave sleep increases in arousal
05:20that can be quite dramatic to the
05:22tune of 30 to 40 arousals per hour
05:24of sleep and also very importantly
05:26patient perception of sleep.
05:27And so there is this real disconnect
05:29between what we can measure with our
05:31objective tools and what patients perceive,
05:33and both of those.
05:34Entities can be linked to outcomes.
05:36We also know that sleep timing is an
05:39important part of sleep deficiency,
05:40and in this case we're talking
05:42about sleep that does not occur
05:44during the biological night or
05:46the time that melatonin is high.
05:48Try to keep that term consistent.
05:49I sometimes call that circadian
05:51night as well,
05:52and So what I mean and that is the
05:54time that melatonin is high and
05:56that your body is really cute to
05:58be sleeping and also in and sleep.
06:00Deficiency is some aspect of
06:02daytime function I think.
06:04For the ICU I most readily think of
06:06things like alertness and cognition.
06:08This can be more expanded in
06:09the outpatient setting and all
06:10of us are most of us are or.
06:12Sorry,
06:12I'm sure many of us are familiar with
06:14the many cognitive domains that have
06:16been tested in sleep deficiency and.
06:18And how those can be impacted by
06:20short sleep or slow sleep quality?
06:22I think it's important at this
06:24juncture to to say that we really
06:27don't know what is normal,
06:28and therefore it's very hard to
06:30define what is abnormally ICU.
06:32There is some consideration that
06:34especially disruptions in circadian
06:36rhythm might both be an innate aspect of
06:39acute critical illness and brain injury,
06:41as might sleep disruptions,
06:42but also that some of it may be adaptive.
06:45So,
06:45for example,
06:46it may be that loss of circadian rhythmicity
06:48is in fact adaptive during acute infection.
06:51There is very little evidence in this regard.
06:53It really is not known.
06:55But I share with you really this
06:58fundamental question of the field.
07:00But I think there is.
07:01On the flip side,
07:02a sense that we know acute sleep
07:04deprivation can be quite detrimental,
07:05and while some of this might
07:07be innate to critical illness,
07:08it can't possibly be good to be waking our
07:11patients up purposely several times an hour,
07:13and so there's a balance there,
07:15and a lot to be untangled.
07:16But that's the context that
07:18we're working in today.
07:20We know, so that was a general description
07:22of the domains of sleep deficiency.
07:25We know when the ICU that patients in
07:27general have a shorter sleep duration,
07:29and even if their duration approaches normal,
07:32it does not occur occur in a
07:35consolidated time or generally considered
07:37occurs across the 24 hour period.
07:40We also know that patients
07:42have problems initiating sleep.
07:43They have the increased number
07:45of arousals that I mentioned
07:48decrease REM and slow wave sleep.
07:50Sleep occurs equally during
07:51the day and night.
07:52So while patients maybe get get
07:53six or even in some studies,
07:557 hours of sleep,
07:56they're getting three or four at night
07:58and three or four during the daytime
08:00and we daytime function is also abnormal,
08:03and I think all of all of those who have.
08:06Being providers in the ICU or who
08:09have visited friends or family in the
08:11ICU can see that this is quite clear.
08:14We also know that.
08:17ICU patients are generally have a
08:19delayed phase of circadian alignment
08:21and this is a very nice early study
08:24by Brian Gehlbach and his group
08:26and what he has demonstrated for us
08:29here is is really just a simple.
08:31Illustration of alignment and so on.
08:33The X axis he's placed clock time.
08:36He started in the evening at 1800
08:38and then preceded to the next evening
08:40of 1800 and then in that solid
08:41black rectangle that you see at the
08:43bottom of the screen with radiating
08:46dashed lines that I confess I added.
08:49He has just drawn and what he
08:51thinks is a normal sleep time,
08:53and so he's trying to Orient
08:54us to when the sleep period,
08:57and also when the melatonin elevation should
08:59be or the biologic night as I called her.
09:01Earlier in this talk,
09:03and then each of these striped
09:04record rectangles represents a
09:06subject that he took urinary,
09:08excel,
09:08photography,
09:08melatonin and made an estimate of
09:10when their biologic night would be
09:12when their time of high melatonin
09:14would be and what he's illustrating
09:16and then excuse me and then he
09:18put him in in order of estimated
09:20dim light melatonin onset.
09:21So what he's illustrating really is
09:23that these bottom two individuals are
09:26perhaps slightly advanced compared to normal.
09:29The next few,
09:30the next two or three.
09:32Maybe four if you're generous,
09:34are normally aligned,
09:35and they have a dim light melatonin
09:38onset not too far away from that
09:40first vertical dashed line,
09:41but then the remainder of the
09:43subjects as you go up further on
09:45the graph are really delayed all the
09:46way to the last subject,
09:48who is almost eight or nine hours delayed.
09:50And So what he's trying to convey is the
09:53spectrum of of circadian alignment in ICU.
09:56In this small study, and also to demonstrate,
09:58as I said at the start of this slide that
10:00most patients in the ICU have a delayed.
10:02Phenotype and this makes a lot of sense
10:04when you think about the light patterns and
10:07exposures in the ICU in the fact that it is
10:10easier to delay humans in circadian phase.
10:13This is another study done by Kyle
10:15goes in them at all these studies.
10:17Patients have been in the ICU for quite a
10:20bit of time on average of 20 or 30 days,
10:22but they looked at core body temperature
10:25and so I've just have a descriptive table
10:27here on the left telling you a little
10:30bit about the patients whose 21 subjects.
10:33They were.
10:34About roughly half and Half Men and women,
10:38they were in their 60s.
10:40They had a Apache three score around 49.
10:45And at the bottom here,
10:46the first day of core body temperature
10:48recording was an average day.
10:50Twenty of their admission.
10:51So a bit of a different population from
10:53with Doctor Gehlbach shared with us.
10:55But what they show on this right
10:56hand panel that I've included is
10:58that on the X axis is the Apache
11:01Three score 0 being low acuity,
11:03low severity of illness and 100
11:05being high severity of illness.
11:08And then on the Y axis degree of
11:10circadian displacement in hours and
11:11what the authors want to impress
11:13upon you is that the more severely.
11:15Our patients have much more
11:17circadian displacement,
11:18so this attempt to to look together at
11:21how circadian delay may be associated
11:24with increased severity of illness.
11:26And since that time,
11:27these are two of the earlier studies.
11:29There's there's been a fair amount
11:32of work really demonstrating that
11:33in a wide variety of ICU patients.
11:35Neurologic, critical illness,
11:37surgical critical illness,
11:38medical critical illness,
11:39that there is considerable loss of
11:42circadian amplitude and rhythm,
11:43but also delay and misalignments.
11:47I included this slide just to remind
11:49us of the fundamentals of the two
11:51process model and so this is a cartoon
11:53along the again along the X axis
11:55is time starting the even boxes we
11:57starting in the morning going into
11:59the evening and then double plotted
12:01so repetition we have the homeostatic
12:03sleep drive in purple coming up,
12:06peaking right at bedtime and then
12:09decreasing during the the illustrated
12:11period of this patient sleep and
12:14then underlying that we also have.
12:17Process see the circadian process
12:20and the reason I like to see the two
12:22process model in this illustrated
12:23way is that I can really imagine
12:25that this arousal drive from the
12:27circadian system is tagging along
12:28with a homeostatic drive and fighting
12:30it all along the day so that there's
12:33no sense of sleep pressure or no
12:35gap between the two.
12:36And it's not until the circadian
12:38system cycles off close
12:40to habitual bedtime at that dim light
12:43melatonin onset that you lose that alertness,
12:45and all of a sudden there's
12:46this very big difference.
12:47Between homeostatic Dr and circadian
12:49driving that that creates an opportunity
12:52for sleep and what I really want to
12:54say here is that in the ICU it is
12:57very difficult to predict when when
12:58this is happening because it's very
13:00difficult to know in real time with
13:02the person circadian phases and it's
13:04therefore hard to know when to promote
13:06sleep and it's also therefore hard
13:08to coordinate a number of biologic
13:10functions such as eating and exercise
13:12that will talk about a little bit
13:14later and make these things happen
13:16during the right biologic time.
13:19And finally, you know,
13:22I I show this slide often in my talks.
13:24Just a reminder at the things that
13:26drive the circadian system and so the
13:28site gamers are incredibly important,
13:29and so inasmuch as circadian health
13:31is important for sleep health,
13:33azeite keepers are important
13:34for circadian health.
13:35And we know that light is the primary side.
13:37Gave are traveling in the
13:39eye to the master clock.
13:41The central clock that then
13:43promotes synchronization across
13:44the bodies peripheral clocks,
13:46but also that there are non voting
13:48site cavers. Or sleep wake itself.
13:49Physical activity,
13:50social time and meals that
13:52are very important.
13:53And with all of that said,
13:55I don't think it's very surprising that
13:57we have sleep deficiency in the ICU.
13:58We have a real lack of sleep opportunity.
14:01We have incredible interruptions,
14:03sound, light.
14:06Painful stimuli lab draws and so on,
14:08but we also have all these abnormal
14:11side keepers feeding light exposures.
14:13This particular picture that is not
14:16our ICU notably doesn't have a windows.
14:19There's no natural sunlight even,
14:20and so it's not something that
14:22that is counter intuitive.
14:24But there's a lot of opportunity here
14:27to improve sleep for our patients.
14:29And so I'll circle back to a case.
14:31And again,
14:32this is a case that I have presented
14:34quite a bit in my talks and I
14:37remember this patient distinctly.
14:38He was one of the first patients
14:39I enrolled as a fellow,
14:41but I think his story tells so
14:43many so many of the lessons of
14:45sleep deficiency in the ICU.
14:46So he was an elderly gentleman.
14:48He came in with a critical care.
14:49Chief complaint of Shock
14:51and respiratory failure.
14:52He presented to the emergency room because
14:55of an altered mental status and fever.
14:57His evaluation.
14:58Was not super abnormal.
15:00It showed that he had low blood pressure.
15:02He did for some medical reasons have an
15:05indwelling Foley that there was clear
15:07there was evidence not clear cloudy
15:09urine and also an elevated White County.
15:11A lactate in a positive urinalysis.
15:14Ultimately he was admitted to make
15:16you around 3:00 in the morning.
15:18The team's assessment was at his
15:20euro sepsis and this was complicated
15:22by respiratory failure.
15:24He was mechanically ventilated.
15:25He went, unfortunately,
15:26required renal replacement basis,
15:28suppressor vasopressors,
15:30support antibiotics,
15:31continuous sedation,
15:33continues to feeding,
15:34and software Swiss wrist restraints
15:37out of concern that he would
15:39discontinue his medical equipment.
15:41His hospital course was notable
15:43for nursing reports of poor sleep.
15:45Family reports that the
15:46patient was sleeping all day,
15:48delirium a delay mobility because
15:50of his medical severity of illness.
15:53He had a fib with RVR.
15:55Uhm, he had hyperglycemia prolonged
15:58mechanical ventilation course
15:59and ultimately was discharged
16:01to skilled nursing facility.
16:03And often when I talk about
16:06sleep deficiency in the ICU,
16:08my early work and I think I
16:10mean I agree a major target,
16:12a sleep efficiency in the ICU is delirium,
16:14and what what happens with
16:16sleep deficiency and cognition?
16:18But what I'd like to talk about today
16:20is some things that are that are
16:22important to us as ICU clinicians and are.
16:25Also probably related to sleep and
16:27circadian disruption in the ICU,
16:28and so he also had delayed
16:30mobility atrial fibrillation,
16:32rapid ventricular response,
16:33hyperglycemia,
16:33the prolongation of his mechanical
16:36ventilation and was discharged to sniff.
16:37And I would argue,
16:38and my thesis for this talk that these
16:41are also related to his sleep deficiency.
16:43I certainly am not going to trip attribute
16:45all of this to sleep deficiency,
16:47but I do think there are some associations
16:49here that we should keep in mind.
16:51So I'll end my background session
16:53with would just touching on a little
16:56bit of what's known about outcomes,
16:58and I'll pick the the ultimate MCU outcome,
17:00which is mortality.
17:01And still I have two studies that were
17:04done at Yale with my group showing
17:06that an association between sleep
17:09deficiency and and mortality in the hospital.
17:11The first we did meet significance
17:13and so I can formally say that
17:15the second I it was a trend.
17:16But I'll share with you that work
17:18and then we'll dive into some of the
17:20things that I think are going on.
17:22So first was a study of sleep loss and
17:24specifically abnormal sleep architecture,
17:27and this was a study in which I was
17:29assessing patients for what is called
17:30atypical sleep and then make you the
17:32most cardinal feature of which is a
17:34loss of stage and two sleep features,
17:36and so this was a 93.
17:3993 subject cohorts.
17:40It was from apparent cohort of
17:42medical ICU patients who got
17:44who receives continuous EEG as
17:46part of their routine care.
17:47So a very unique.
17:53Shouldn't we excluded acute brain injury
17:55such as folks who are post cardiac
17:58arrest and we looked at the EG. For EG.
18:02And cephalad encephalography encephalopathy
18:05features as well as her sleep criteria.
18:09And what we found I thought was
18:11pretty interesting. One was.
18:14Excuse me, just gonna move my here.
18:16We go. One was the length of MCU and
18:19hospital stay was quite different between
18:22patients who had retained K complexes.
18:25So as a marker of stage two had retained
18:27their K complexes and those who had not.
18:29So this is an association,
18:31not causation.
18:31We don't know the directionality,
18:33but we see that our patients who
18:36maintained their sleep architecture or
18:37in the MCU and hospital for much shorter,
18:40and that is the red highlighted box that I've
18:42shared with you and then on the flip side.
18:45Quite remarkably,
18:46all of the deaths in our cohort
18:48segregated to the folks who had
18:50lost their sleep architecture,
18:51and so we had 36% of those folks who
18:55had in hospital in hospital death,
18:57whereas 0% of the folks who maintain their
19:00safe architecture died in the hospital.
19:03When we used logistic regression
19:04techniques to model this and to look
19:07in control for other covariates,
19:09we found that this retained
19:11significance and that had,
19:12while a very broad confidence interval
19:15and odds ratio close to 19 for folks
19:17who are who are no longer maintained,
19:19typical sleep architecture.
19:20So we thought this is very important,
19:23very interesting,
19:24and we're very happy to follow
19:26up on this with subsequent work.
19:28Uhm?
19:28Looking at the other side of the coin,
19:31the circadian side of the coin,
19:32we've been able to leverage continuous
19:35heart rate data here at Yale.
19:37This is data that is.
19:38This is hardly data taken every five seconds
19:42automatically via our telemetry monitors,
19:43so it's very nice inasmuch as it's
19:45available for essentially all
19:47patients in the ICU have telemetry
19:49as part of their routine care,
19:51and this small sample when this
19:53technology became available.
19:55That we had some clinical
19:56characterization of due to a ongoing
19:58biorepository were able to look at
20:00these patients and ask the question.
20:02Are there clinical clinical outcomes
20:05associated with with patients who have
20:08their circadian diurnal variation of
20:10heart rates that have maintained it in
20:13an aligned manner in a misaligned manner?
20:15Or patients who have really
20:16lost that diurnal variation?
20:17We're very pleased to see that regardless
20:20of vasopressors and other arrhythmias,
20:22patients we were able to see these signals.
20:25We were able to do cocinar analysis
20:27and see if this variation maintained
20:29and so here I have three samples
20:32and so in panel a I'm sharing with
20:35you a patient who had normal aligned
20:37diurnal variation of their heart rate.
20:40Reflecting but not directly telling
20:42us the alignment of the central clock,
20:44I don't want to overstate what
20:46we're looking at here,
20:47but certainly hopefully
20:49associated with in panel B.
20:50I have a patient who is misaligned,
20:52so they've maintained that diurnal
20:54variation in this particular example.
20:56Their amplitude is a little bit lower,
20:58but that was not true across
21:00all misaligned patients,
21:02and this was the majority of our patients.
21:04So of the 53 we had,
21:074039 patients who are misaligned and then.
21:09Actually, a minority,
21:10only eight of the 53 with who had no no.
21:14No detectable cocinar pattern,
21:17and no detectable diurnal variation.
21:20Again, when we looked in this group,
21:22another striking segregation,
21:23and so the patients who had
21:25diurnal variation that was
21:27aligned had no deaths in hospital,
21:29whereas we saw all of our
21:31desks in the misaligned,
21:32and the lacking variation groups,
21:33and so this was a trend.
21:35It missed significance.
21:36But again, as we are able to gather
21:38more patients in a larger cohort,
21:40we look forward to following up on this.
21:43And so this is, I think,
21:45hopefully adequate background to
21:46Orient you to what I think about.
21:48When I think about sleep
21:49deficiency in the ICU,
21:51but also that this is significant and
21:53something that is at least associated
21:55with poor outcomes in in much of
21:57of the work that I look forward to
21:59doing is trying to figure out what
22:01the directions and causalities are.
22:03So I want to talk now about some
22:05of the functional consequences.
22:06Setting aside the very important and
22:08I think very real problem of sleep,
22:10deficiency and cognition,
22:11but just setting it aside.
22:13For the next little bit,
22:14and looking at some of the
22:16other functional outcomes.
22:17So I'll touch on these three areas.
22:20There are many areas so metabolic
22:23respiratory and cardiac function
22:25seems to be pretty clearly,
22:26at least in healthy populations
22:28affected by acute sleep deficiency,
22:30mostly acute sleep deprivation models.
22:33There's some very nice
22:35misalignment models as well.
22:36Looking at metabolic function,
22:38I'll share with you this early sort
22:42of classic definition or excuse me.
22:45This early classic work by Spiegel
22:47at all in even Cutters Group
22:49looking at 11 healthy men who
22:52came in for some baseline nights
22:54and had some recovery nights.
22:57But the core of this experiment was six
22:59nights of four hours of sleep opportunity.
23:02They did maintain circadian alignment by
23:04keeping the sleep midpoint at the same time.
23:07Uhm,
23:07and they looked then at glucose tolerance.
23:11Sorry,
23:11just they looked at glucose
23:13tolerance and what the authors
23:15want to share with you in these
23:17panels that I've selected is what
23:20happens in the sleep debt and in
23:21the sleep recovery conditions and
23:23so in the top panel they're showing
23:26an intravenous glucose challenge.
23:28I apologize for the image quality.
23:32And what they want you to appreciate?
23:33I think it is.
23:34It is subtle, but the glucose is
23:37higher and the at this the slope.
23:40Under the Sleep conduct,
23:42sleep debt condition is a is more shallow,
23:46representing a slower glucose taught
23:49me a slower glucose tolerance,
23:51and that's the second bullet point
23:53that glucose clearance with Ivy glucose
23:56challenge is 40% slower after sleep debt,
23:59and happily this resolves
24:00after sleep recovery,
24:02but is certainly present in that condition.
24:04And then in the lower panel that
24:06I selected to share with you,
24:07they are looking at a standard meal
24:09and so going via the GI tract.
24:11Just have some difference.
24:14Different signaling and usually
24:16is better at addressing glucose
24:18challenges and what they want you
24:20to appreciate in the second panel is
24:22that in the sleep debt condition.
24:23The area under the curve that
24:25they defined as the first 90
24:27minutes after the meal is greater
24:29in the sleep debt condition.
24:40OK, so that was sleep that alone and
24:42they authors took care in those cases to
24:45maintain circadian alignment by keeping
24:47the sleep midpoint at the same time.
24:49In this experiment we look only
24:51at circadian misalignment.
24:52So sleep is maintained and looking here again
24:56at glucose intolerance rather than tolerance.
24:59And this was six healthy adults and they
25:02were exposed to a shift broke protocol that.
25:05The goal of which is to have sleep
25:07and circadian processes together
25:08during the beginning of the protocol.
25:10Then there is a forestway period
25:12and then a separate and then 88.
25:17The last period there's sleep that
25:19occurs and during biologic days and then
25:23circuits Arcadian process continues.
25:25During the night.
25:26The point being that in that first
25:28testing period sleep in certain
25:30processes occur together.
25:31There's the transition and then in
25:32that second period the statement
25:34circadian process are separated so
25:35that you're able to look at things
25:37that are related to sleep.
25:38Things that are related to Kenyan
25:40and you're also allowed able to in
25:42this case put time meals in a way
25:45that you can ask questions about
25:48circadian misalignment.
25:49And so in this case the author is used,
25:51fixed meals and challenged their
25:53subjects with it and what they show
25:56here on the left hand panel a as
25:58glucose and on the right hand panel
26:01B is insulin and they want you
26:03to appreciate that in both cases
26:04with circadian misalignment,
26:06the glucose area under the curve is
26:08much greater and the insulin area
26:11under the curve is also much greater.
26:14And not only are these values higher,
26:17but you would seem that with greater
26:19insulin you should actually get
26:21better glucose levels,
26:22and so they also want you to
26:24understand that this is also there.
26:25Is there an insulin resistance,
26:27or an insensitivity that's going
26:29on in this case?
26:30And finally,
26:31I wanted to show you an experiment
26:34that put these together and so.
26:36These authors put together a short
26:38sleep in misalignment and again
26:40looked at glucose intolerance,
26:42so this was 26 adults.
26:43I apologize, healthy adults,
26:46healthy adults.
26:47They did sleep restriction with and
26:49without misalignment and then looked
26:51at insulin sensitivity and they
26:53concluded that insulin sensitivity
26:55was decreased by sleep restriction
26:57and the effect was exaggerated under
26:59circadia misalignment and so here they are.
27:06Skip, sorry. Here they're showing
27:09in the far left hand panel. Again,
27:11these are glucose and the far left is the
27:15arrested condition and we have a profile
27:17of glucose in an area under the curve.
27:20They would like you to appreciate.
27:21The authors are likely to appreciate under
27:23sleep restriction with circadian alignment,
27:25that this area under the curve is is
27:27greater and that this is emphasized.
27:29So I do think it's subtle with circadian
27:32misalignment and sleep restriction,
27:33and because it's it's visually complicated.
27:35I included here as well.
27:38Then the numeric.
27:39The numbers behind those curves,
27:41and so this is as I,
27:43which is a measure of insulin sensitivity.
27:47And in this case,
27:49they're showing only patients who
27:51are sleep restricted and then
27:54comparing circadian alignment
27:55versus circadian misalignment.
27:56So you can have some hard numbers to look
27:58at that and so here in all subjects.
28:01When folks were circadian aligned,
28:04they had eight 834% decrement
28:07in insulin sensitivity,
28:08which will worsen to 47% in the
28:12case of circadian misalignment.
28:13So you can see that that hard change
28:15from one to the other and then they
28:17had mostly men in their cohort,
28:19and so they did take.
28:20They did pull out that single sex and
28:23showed that there was very similar data.
28:25A 32% decrement in circadian alignments,
28:28and maybe a little bit exactly a
28:30little bit more exaggerated effects of.
28:3258% decrement under circadian
28:34misalignment conditions.
28:37And so, with this in mind,
28:39all of these are all these experiments
28:41I told you about are in healthy adults.
28:44To to then frame that onto how
28:46we feed patients in the ICU,
28:48or at least how we feed into
28:50baited patients in the ICU.
28:51We do 24 hour continuous feeding.
28:55And so really,
28:56we're overlapping sleep deficiency,
28:58circadian misalignment and
28:59feeding all the same time.
29:01And so one thing that we're interested
29:04in looking at is time restricted feeding.
29:07And so as you may or may not be familiar,
29:09it is a general practice.
29:10May I ask you to feed patients
29:12continuously over 24 hour periods?
29:14This involves giving them food at
29:16very low and very low constant rate.
29:19There was concern and there is historical
29:23concern about bolus feeding or feeding.
29:26Meals at intermittent times,
29:27but really at that time with that meant
29:30was putting in food at quite a rapid rate,
29:33and so there was concern for
29:35aspiration and sort of in this move.
29:37With the advent of feeding
29:38pumps to continuous feeding,
29:40and so there's sort of this
29:42logistic and historical construct
29:43that has LED us to do what we do.
29:45There's not a lot of if you look through it,
29:47there's a a decent literature
29:49of meta analysis.
29:50There's not a lot of safety concerns,
29:52and so folks are starting to swing
29:54back towards intermittent feeding.
29:56Mostly based on concerns around how
29:59the gut works and strap the need for
30:01stretch and the need for feeding and fasting.
30:03What I would add to this or
30:05what I would advocate for,
30:06is that this should not just be
30:08intermittent feeding as I've drawn
30:09in the middle here with meal
30:10space around the 24 hour period,
30:12but that this be time restricted
30:14to what we estimate is circadian
30:16daytime or biologic daytime,
30:18or when the melatonin is low.
30:20So this is something that I and
30:23other groups are interested,
30:24and so we have a.
30:26Randomized controlled trial ongoing
30:27and I will be very excited in a
30:30few years to tell you the results
30:31are hopefully shorter than that,
30:33but I think this is a really important
30:35Ave to improve glycemic control in
30:37the ICU and it may also I've put that
30:39little picture of the site gathers
30:41up on the top of my slide just to
30:43remind us that it may also have
30:45beneficial effects in terms of orienting,
30:47underlining the peripheral clocks
30:49that are responsive to food to
30:51food intake and food schedule,
30:53and so it may have more than
30:55one beneficial effect.
31:00This is one small study that they
31:02did were able to look at continuous
31:04versus intermittent feeding.
31:06It was a nice crowd.
31:07It was a randomized crossover study
31:09and what the authors report here is a
31:11little hint at what I'm hypothesizing
31:13is that they are able to reduce glycemic
31:15need by doing intermittent feeding.
31:18This was not timed time restricted,
31:20intermittent feeding,
31:22just intermittent feeding alone.
31:24And so they did a pilot trial.
31:26They as they show here in
31:27the left hand panel,
31:28randomized patients either to continuous
31:32goal goal feeds or intermittent goal feeds.
31:36They let the patients attain,
31:37attain a steady states.
31:39They take their four hours
31:41of data collection.
31:42How much insulin do they need
31:43during this period of time?
31:44And so on.
31:45And then they crossover.
31:46So the folks who are continuously fed are
31:49now intermittently fed and vice versa.
31:51They repeat their data collection
31:53and then end the study.
31:55And the right hand panel in more detail.
31:57They've showed each of their 15 patients.
31:59So the small study,
32:01and they've again ranked the patients
32:04from most from the patients who
32:06needed more insulin during the
32:09intermittent feeding period to the
32:11patients who needed them the most
32:13during the continuous feeding.
32:15And so the idea is that.
32:17You can ask the question visually
32:20how many of the patients needed
32:21more more insulin during that that
32:23intermittent feeding and really
32:24it was just these.
32:25First these first few in which you
32:27can say well you know what during
32:29that intermittent feeding period they
32:31really required more insulin units.
32:33Patient five is equivocal and
32:36then really an impatient 6 through
32:3915 appears to need clearly more
32:41more insulin during continuous
32:43feeding rather than intermittent.
32:45What I don't know,
32:46and I think what we would be interesting.
32:48What was the circadian phase
32:49of these patients?
32:50And so this was not the focus of this study,
32:52but I think there's a lot of work to
32:54do here and a little hint that if we
32:56can guess correctly when biologic day,
32:57as we can make some strides in terms
33:00of how we're feeding our patients.
33:02OK,
33:03I'm gonna switch gears to respiratory
33:05function and sleep deficiency
33:06and this is also.
33:07Uhm, there's there's road to go,
33:10but I think one of our more
33:12developed areas of sleep deficiency
33:15and organ function in the ICU.
33:18So again,
33:19we're going to go back to healthy controls.
33:22And in this, in this case,
33:26our authors right at all did
33:28this very nice study,
33:29in which they took 19 subjects.
33:32Healthy volunteers again and had
33:35them breathe against resistance
33:37for up to 60 minutes.
33:39But they were to breathe against exist
33:41against resistance until exhaustion.
33:43And So what you see on the X
33:45axis is the sleep,
33:46normal sleep and sleep deprivation condition,
33:49same subject, and then on the Y axis,
33:51how long they were.
33:52Able to last and so these three
33:54parallel lines at the Tippy Tippy top.
33:55Here are folks that were able
33:57to go the full
33:58hour and then everyone else are.
34:00These are paired plots of how much
34:02filter would be able to do in
34:04the normal sleep condition versus
34:06how much they were able to do
34:08and sleep deprivation condition.
34:10It was a single night of sleep
34:12deprivation and they showed that
34:14there's really a significant difference,
34:15and it's significant decrements
34:16and what what subjects are able
34:18to do with sleep and without so
34:21very important implications.
34:22I think for ICU patients with
34:24a single subjects here towards
34:26the middle who was able actually
34:28just to have an improvement.
34:33The author is then followed
34:34up in the same cohort,
34:36but they were able to include twenty
34:38subjects and they looked here at
34:41subjective feelings of air hunger,
34:44but also subjective feelings of breathing
34:46efforts, and this is very interesting.
34:49But what they found was that in the
34:51case of questions around air hunger
34:53and the sensation of air hunger,
34:55the patients again in general had
34:59increased perception of error.
35:01Hunger after sick deprivation.
35:02There are a few exceptions with it,
35:05but overall this difference was significant,
35:07but they did not perceive a
35:09difference in breathing effort,
35:10and so this is also,
35:12I think, important.
35:13It's a little hint about how
35:15we perceive sleep today,
35:17how we perceive breathing
35:18and worker breathing,
35:19and to consider folks who are maybe
35:23evolving respiratory failure or evolving
35:25their illness to then become sleep deprived.
35:29This may have significant
35:31impact on their care.
35:33Now transitioning into the ICU,
35:35we also know that eight to focal
35:37sleep predicts late failure
35:38and non invasive ventilation,
35:40and so if you'll recall I had
35:41presented my own work on patients who
35:44had lost their stage two features.
35:45They looked lost their K complexes.
35:49And that this was part of a syndrome
35:50that we called atypical sleep that
35:52was inclusive of losing spindles and
35:54having very very little slow wave
35:57sleep and very very little REM sleep.
36:00And so in this group in this study,
36:03excuse me,
36:04the authors separated folks who
36:06came in and respiratory failure and
36:08required non invasive ventilation.
36:10They did Poly sonography on these
36:12patients and then ask the question
36:14which of these patients graduated and
36:16then became independent of ventilation.
36:18Which of those?
36:19Failed,
36:20which they definitely defined as needing
36:22to be intubated in the in the 24 hour.
36:25The subsequent 24 hours,
36:27the success versus failure
36:29was pretty evenly balanced,
36:31and what they identified is that the
36:32folks who had this atypical sleep
36:34that I've touched upon a few times
36:36during the talk really a much higher
36:39proportion of the late failures
36:41had a typical sleep in and and in a
36:45related matter at differences in their sleep.
36:49Timing is so different.
36:50In their night versus day,
36:52total sleep ratio.
36:53And so.
36:53If you can imagine night is the denominator,
36:57day is the new excuse me,
36:59night is the numerator in today.
37:00Is the denominator,
37:01a higher number means more nighttime
37:03sleep and less daytime sleep,
37:04so more normal.
37:06And again in our failure group
37:09that ratio is decreased,
37:11suggesting that these folks are
37:13not getting naked time sleep but
37:14rather daytime or abnormal sleep.
37:16So I think those pieces of evidence
37:18hang together very well and then again.
37:20Highlighted in yellow down here one
37:24of the phenomenon of atypical sleep
37:26is a very low round proportion,
37:28and again you see that those.
37:30Those folks were able to liberate
37:32from the base of ventilation were
37:35had a higher proportion of RAM,
37:37had a higher proportion of RAM.
37:39It should be not proportionate
37:41to minutes of RAM,
37:42whereas those who had failure
37:43had lower minutes of RAM.
37:48And then this is even more different.
37:51So this is the odds ratio products,
37:54which is an automated EEG metric
37:57reflecting alertness with higher
38:00numbers in the threshold being 2.2,
38:02indicating a sensually wake.
38:05And I'll, uh, I'll beg.
38:08Forgiveness of experts in the crowd
38:09with that very crude explanation of RP.
38:12But basically the authors in this study
38:15are asking, what if it's not sleep?
38:17Or what if the domain of sleep?
38:18The important is is the wake
38:21domain so functional alertness,
38:23ability to be vigilant, and so on.
38:27That's very important,
38:28so they use the odds,
38:29odds ratio product as their proxy.
38:31For this they divided their
38:34patients into those who spent.
38:37Less less than point less of their time.
38:40Above that alertness threshold that I told
38:43you about a middle amount of their time.
38:46Sort of an average RP if you score
38:49if you will and then the group
38:51that spent their highest proportion
38:52of their time with those higher,
38:53more alert or peas and then
38:55they asked for each of those.
38:57What was the probability of success
38:59that they would be passed a spontaneous
39:02breathing trial followed by extubation,
39:04and so really the the gold
39:07standard of success from from a.
39:10Vent dependent respiratory failure
39:12perspective and they showed that
39:15the alertness as as defined by
39:17the RP predicted your ability to
39:19be excavated from the ventilator.
39:21I can imagine a lot of ways that
39:23this could be interpreted. Is this a?
39:25Is this something about sedation?
39:27Is this something about sleepiness?
39:28Excuse me,
39:29is this something about drug induced?
39:32Lower levels of consciousness?
39:33Or is it really the domain?
39:35Awake is important as we are beginning
39:37to suspect it is and are starting to
39:39study in our healthy populations.
39:42I am going to continue to switch gears
39:45still in the respiratory domain but
39:48now breezing through a really rich,
39:51very meticulous literature of how we
39:54can adjust the event to improve sleep
39:58and so that there's been some very
40:01careful tracing with PSG and ventilator
40:04reporting to look at what aspects of
40:06the ventilator can interrupt sleep.
40:09And usually we look at elements as.
40:12Ventilator events like
40:14asynchronous and arousals,
40:15but we also look at things like architecture,
40:17RAM, proportion, slow way,
40:19sleep proportion and so it seems
40:22true at this point that there's three
40:24main themes that lead to ventilator
40:27or the related sleep deficiency.
40:29In the ICU one is increased work
40:32of breathing so under support if
40:34you will and other is ineffective
40:36triggering of the ventilator.
40:37So what we call a synchrony and then
40:40also ventilator over assistance in this.
40:45Sees me. OK, the ventilator over assistance,
40:50which needs several more more steps,
40:52but that leads to hyperventilation.
40:54Decreased carbon dioxide and then central
40:57apneas which ultimately lead to arousals.
40:59And so these are the three main
41:01buckets that we think a lot about
41:03when we think about adjusting the
41:05ventilator for the benefit of sleep.
41:06It's a one line of evidence supports
41:08that if we can increase arrest,
41:10so we address this first problem
41:14of increased work of breathing,
41:16and so an acute hypercapnic respiratory
41:18failure or sleep quality was improved
41:20when patients were supported with NID,
41:22noninvasive ventilation versus not.
41:24And then also,
41:26if pressure control ventilation was
41:27titrated to the point that patients
41:30became passive on the ventilator,
41:32that also improved sleep sleep efficiency.
41:34So this idea that folks, if they need it.
41:38Taking away their effort of
41:39breathing may improve sleep,
41:41but I remind you of the dangers
41:42of the third bullet point,
41:44which is we cannot over
41:46ventilate these patients.
41:47It also seems clear that
41:49increased Synchrony is helpful,
41:50and that proportional modes of
41:52ventilation such as PV and NAD A can
41:55which have been shown to decrease,
41:57decrease asynchrony.
42:01May be helpful, and so in one
42:03study PV improves sleep quality,
42:04view VR fewer arousals,
42:06which is what we would imagine would
42:09happen as there have been links between
42:11those distinct asynchrony events
42:13and linked arousal as well as fewer
42:15awakenings per hour and greater rent sleep.
42:18But this is this result
42:19has not been consistent,
42:21so the Bosma reference I've
42:23included here did have success,
42:25but Hux uploaded not and then Na BA
42:27has also been associated with increased
42:30RAM and lesser sleep fragmentation.
42:35And so. This also I think.
42:39Is not ready for primetime if you will.
42:41Much like the feeding literature,
42:44we have a lot of small studies
42:46and inconsistent studies.
42:47The direction of causation
42:48remains unclear and I think.
42:52At the end of the day,
42:53it will be bidirectional,
42:54and so we'll know that respiratory
42:55failure can contribute to sleep
42:57deficiencies and sleep deficiencies
42:58can worsen respiratory failure,
42:59and so untangling that will certainly be a
43:03challenge for the novel ventilator modes.
43:05I just have some logistic concerns.
43:06We really need provider familiarity
43:08with some of the newer modes.
43:10Some of the algorithms are proprietary,
43:12so hard to know what's under the hood
43:14and we just need to integrate these
43:16with our lung protective strategies and
43:17so some logistic hurdles to overcome.
43:19And finally, I think the question is.
43:22As with other issues with
43:24mechanical ventilation,
43:25is is it the mode or is it
43:27what we're doing with it?
43:28So do we really need to predict
43:30select the correct mode or do we just
43:33need to achieve the Physiology of?
43:36Matching the patients need but not over
43:39ventilating and improving asynchrony, it's.
43:41So those questions remain there.
43:44OK, one last switching of gears and I
43:46wanted to touch just on cardiovascular
43:49function and sleep deficiency and so this is,
43:52I think a step behind the metabolic
43:55and respiratory data that I've
43:58shared with you and so here.
44:00This is short sleep duration,
44:02but this is even chronic and in
44:04outpatient populations and so I
44:06think we know this as a as a group,
44:08right?
44:08We know that sleep duration short sleep.
44:12Is bad for health outcomes and so
44:14this very large meta analysis that
44:16I picked out shows that short sleep
44:18was associated with mortality,
44:20diabetes relevant to cardiovascular bucket
44:23hypertension, cardiovascular diseases,
44:24corner heart disease, and obesity.
44:26So this really is not a surprise
44:28to any of us.
44:29But this is chronic and so I think
44:31what's important to ask is what
44:33about acute sleep deprivation?
44:34Is that one night that few nights
44:37of short sleep have real?
44:40Impact on cardiovascular events
44:41and certainly.
44:44When I asked this question I,
44:46I think of the daylight savings time
44:48literature because it really is an
44:50acute several nights of short sleep,
44:52not dramatically shorter sleep
44:54for it's usually you know,
44:55associated with an hour or two and change
44:58in sleep duration for that spring forward.
45:02But I think there's it's suggestion there,
45:04and so I I bring that literature up
45:06just to say that I do think in that
45:09outpatient epidemiologic setting.
45:10We're seeing some hints at this.
45:11And there's there's more data out there.
45:14Didn't then this just?
45:16So I think we can move forward into
45:19ICU population saying that acute sleep
45:22deprivation does matter in terms of
45:25cardiovascular and arrhythmia risk.
45:27I present here a nice echo Echocardiographic
45:31study of 32 healthy individuals.
45:34They had two echocardiograms in a row.
45:37One was after regular sleep
45:38and was after short sleeve.
45:40Short sleeve was quite short just 2
45:421/2 hours and what they saw was changes
45:44in the mechanics of the heart and so
45:46this one was focused on left atrial
45:48mechanics so they had a prolonged
45:50deceleration time and increased 80 prime.
45:53And I mean ally passive the amine passive.
45:57Yep, was lower.
45:59I know these terms are not
46:01super familiar to a lot of us,
46:03so I appreciate the author's conclusion.
46:05This is really consistent with
46:08subclinical diastolic dysfunction.
46:09The LA and so it's a stiffer hard.
46:11It's a heart that's not gonna work as well.
46:13And in fact there's a very similar study
46:16that looks at the at the LV and again says,
46:19you know,
46:20this is along the lines of left of left,
46:25ventricular dysfunction
46:26and diastolic dysfunction.
46:27But when we think about the patients
46:29were seen in the ICU, this is.
46:30This is clearly relevant to us and these
46:32are the sorts of issues that we battle
46:34as we struggled to control volume,
46:36respiratory failure and so on.
46:39And then in terms of arrhythmia risk,
46:42we know that sleep deprivation is
46:45a high sympathetic tone condition,
46:48and there's concern for arrhythmia.
46:50And I thought this study.
46:53Was was very elegant and very interesting,
46:55so this group just looked at
46:57the number of nocturnal overhead
46:59announcements in their hospitals,
47:01or an acute acutely ill population,
47:04not necessarily in the ICU.
47:06And they said.
47:07Depending on how many overnight
47:09overhead pages happen at night,
47:11what do we see is terms of PDC's per hour?
47:14And what do we see in terms of
47:16cardiac arrests during the following
47:18day and looked at this over?
47:21A three year period?
47:23Excuse me in three months period.
47:25Uhm,
47:25excuse the typo and so they looked
47:28at 2600 hours of telemetry.
47:30Was almost 90 patients that they
47:33looked at and they looked at
47:34nights that had less than less than
47:36or equal to two announcements.
47:38And they said with low number of
47:40announcements the number of PVCS per
47:43hour decreased during that night.
47:45And then remained 30% lower during
47:48the following day time period,
47:50which I found remarkable the
47:53nights that had more
47:54equal or more than four announcements
47:57had an increased by 23% versus.
48:0223% and then it was further increased
48:0485% the next day and sorry I should
48:07mention the reference was three
48:08announcements per night so that
48:10the number that's missing for.
48:12Furthermore, uhm.
48:13If they looked at cardiac arrests and they
48:18looked at daytime hours from 6:00 AM to 2200,
48:20so this is not come.
48:24Staff distraction this is not,
48:25you know, something going on with the
48:27announcements during the night time.
48:28This is the following day that
48:30the nights that had for whatever
48:32reason 0 announcements the cardiac
48:34arrest rate per day was .3.
48:36If it was one announcement.
48:38It was .339 almost .4 and if it
48:42was two announcements it was .47.
48:44And this was significant.
48:47And then they had a natural experiment
48:50in which they added an additional
48:53criterion for overhead pages and
48:54it resulted in announcements.
49:00They look looked at periods when the average
49:05increase from one per day to sticks per day.
49:07Due to this change in hospital protocols
49:09and they saw that the frequency of cardiac
49:11arrest went from an overall global average
49:14of .46 to .62 with a very significant P.
49:17I think it's a very, you know, there's
49:19a lot of questions is observation ULL.
49:21This is certainly not conclusive and
49:23mechanisms are a little unclear, but it's
49:25very interesting and a very convincing.
49:27It hangs together as a pattern.
49:30However, I'm not really sure what to do.
49:31I mean, that hospital should definitely
49:34stop their overhead announcements,
49:35but I'm not really sure other than
49:38sleep promotion. What we can do?
49:40They imagine mechanisms are
49:42inflammation and sympathetic tone.
49:43I mean going after those medically
49:45seems quite dangerous in terms
49:47of unintended side effects,
49:48but I think it's an interesting
49:51area to explore.
49:52With that,
49:53I'll summarize and so you know many
49:55functions are affected by sleep deficiency.
49:57I've alluded to this throughout the talk.
49:59I think there's been a lot of
50:01appropriate focus on cognition,
50:02mood, and vigilance for our patients.
50:04In our case, ICU delirium.
50:07And we are seeing some strides in
50:10which sleep promotion interventions
50:11are decreasing delirium in our
50:14in our ICU patients.
50:16As I presented them and I,
50:19I think it's it's a reasonable statement.
50:22I think the metabolic and respiratory
50:24domains of decreased function in the
50:26setting of sleep deficiency are probably
50:28the closest store prime time we have
50:31active randomized controlled trials.
50:32We have a pretty robust.
50:36Healthy volunteer disease models to look at.
50:39And really some some concrete things
50:41that we can do in the ICU to test.
50:43Really in the next few years and figure out
50:45if we can help our patients in this way.
50:47I think what's coming down the Pike is the
50:50cardiovascular data that I touched upon,
50:51which we really just have hints.
50:53That is important,
50:54but it's a little unclear how
50:56to move forward.
50:57There is also some very interesting.
51:00Bidirectional relationships
51:01with sleep and immune system.
51:03We know that in the setting
51:05of sleep deprivation we have
51:07worsened vaccine response.
51:08We have higher clinical
51:10vulnerability to colds,
51:11but we really have a lot to explore
51:14in the ICU in terms of how supporting
51:17sleeping circadian function can maybe
51:19boost immune function and then also this,
51:22there's a fair amount of interaction
51:24between skeletal muscle strength
51:25and sleep and sleep deficiency.
51:27And we can imagine how important
51:29that can be for recovery.
51:30Come from critical illness and so
51:33I think that's that's the future.
51:35With that, I will think as always,
51:37my mentors and my funders,
51:39who have been phenomenal supporters
51:42of me and really willing to step
51:45outside the box and ask some
51:47unusual questions in the ICU.
51:49And I'm also happy to take questions.
51:50Thanks so much.
51:55Thank you very much.
51:56That was terrific, really.
51:58A great overview and I certainly
52:00learned a lot. I am going to.
52:02I got well I got a fantastic talk
52:04already but I had one question.
52:06While people are thinking of their
52:08their questions so you know your study
52:10that you're doing with the feeding
52:12in the ICU where you want to do the
52:14time restricted intermittent feeding.
52:18Of course you want to feed these
52:19people during the circadian day, right?
52:21And you're going to try to do that,
52:23but you, previous to that,
52:24explain that patients in the
52:26ICU you know they're not they.
52:28It's hard to predict when their circadian
52:30day is and some are on a advanced
52:32schedule and some on normal schedule,
52:34and the majority are delayed.
52:35So how are you deciding
52:37when circadian day is?
52:39Are you doing salivary melatonin?
52:43You know core body temperature,
52:45just guessing what's your?
52:46What are you going to be doing?
52:48Yeah,
52:48so fantastic question.
52:50So we come. There's there's
52:54currently no real time solution.
52:57I think the real time solution
52:59ultimately will hopefully be
53:01something like real time heart rate
53:04detection of diurnal variation,
53:06but for this study it is a guest
53:09and I am basing it on that.
53:10Most of them are delayed and so.
53:14I have arranged it that.
53:17Uhm, we start.
53:19Don't correct me, we started eight.
53:23We do formulas eight we started
53:25first meal at 8:00 AM and we end
53:28our last meal at 8:00 PM and so
53:30it's actually a 13 hour period.
53:32I debated it.
53:32We debated it for a long time.
53:34I was very tempted to do
53:37a much more constricted,
53:38like three meals,
53:39just to sort of guarantee that
53:42I was in that biologic date.
53:43But for logistic reasons it made the meal
53:46volume very big and made folks more nervous.
53:48'cause it was.
53:49You know, pretty big,
53:50and so on.
53:51So right now we have what is
53:53essentially a 13 hour feeding
53:55period 888 AM to 9:00 AM to 9:00 PM.
53:59Alright, terrific thanks, thanks.
54:00Alright so I'm getting some questions.
54:02Add question here it says so it should be
54:05fair to say that the New England Journal
54:07paper a few years ago about holding
54:09sedation in the ICU had physiologic
54:12sleep architecture improvement.
54:13What is the basis for that?
54:16I think that is what I meant to see.
54:20Does that make sense?
54:21Do you know about this New England
54:23Journal paper? A few years old?
54:25Yeah, I'm I'm not clear about
54:27what the question is. Sorry,
54:29OK, maybe I can.
54:30I can try to unmute this person
54:33asked to unmute, let me see.
54:35It's William Rodriguez.
54:38Are you able to clarify?
54:40Oh hi, can you hear me?
54:41Hi yes yeah perfect no.
54:43Basically that that are that
54:45the manuscript went over about.
54:48I mean having patients being off
54:50sedation I mean benzodiazepine's etc.
54:53And we know the effect of the events of
54:54the last episode on the architecture.
54:56So it was sort of I was protecting.
54:59I am taking it as we were
55:01by holiday situation. We
55:03are sort of protecting the patients from
55:05having a different sleep
55:07architecture.
55:08I mean trying to make more normal.
55:09I don't know if you can get my.
55:11My message what I'm saying.
55:13So. I don't. I don't know the
55:16paper that we're talking about,
55:18but I think the so yes.
55:19So benzos and narcotics are
55:21terrible for sleep. That's it?
55:23That's a technical description.
55:27And so. Sedation holidays should benefit it.
55:31But we it what? Is unclear as if that
55:35sedation holiday like daily station
55:38holidays are generally brief, right?
55:41So either they're brief and the patient
55:43fails and they need to be re sedated
55:45or lightened or whatever it is,
55:47or they liberate and and so there is not.
55:52That should benefit sleep.
55:53In in the global sense,
55:55but there have not been studies to date
56:00saying does the sedation holiday of an
56:03hour so improve sleep is that yeah,
56:05but I'm saying at the time what?
56:07What show the study was that patients
56:09were weaned off the band easily
56:11earlier. They come off the bench better
56:14so, but the article did
56:16not analyze any aspect
56:18of sleep architecture. So in a way
56:20they were right, but they reach a
56:22conclusion through a different way.
56:24That's fine. So yeah, so I don't.
56:26Yeah, so I think all of these are,
56:28you know, that's a great question, you know.
56:31The It's the same though
56:33for the feeding right?
56:35So the feeding the intermittent
56:37feeding also has benefits for
56:39protein synthesis and gut you know
56:41all the normal functions of the
56:43gut and so so on and so forth.
56:44And so I don't and mobility,
56:46which I think is going to be really
56:48important for sleep promotion and
56:50is and I think also is going to be
56:52bidirectional that getting your skeletal
56:54muscle strength back is going to be
56:56important for sleep and vice versa,
56:58but I'm certainly not going to assert that
57:00sleep is the whole story of the situation.
57:03Holiday rates sedatives have many effects.
57:05Sleep is one of them,
57:06and so I think a lot of the early
57:09mobility studies the sedation studies.
57:12Some of the time restricted feeding studies
57:14are going to have not looked at sleep,
57:16and it's going to turn out that
57:18that was part of their mechanism.
57:20Great
57:20thanks, there is another question and this.
57:25The question is, can you talk about
57:27the difference between peripheral
57:28clocks and central clocks and what
57:30some of the intervention and what
57:31are some of the interventions that
57:33can be leveraged to target these?
57:36OK, so I think that the best example
57:39for that is is certainly the peripheral
57:42clocks that are associated with feeding
57:45and so stepping back very big picture
57:48central clock brain tide to light
57:52peripheral clocks everywhere else in
57:54the body and they certainly get signal.
57:56From the central clock melatonin,
57:57certainly a coordinating signal,
57:59but they also have.
58:01I can't, I think of them as functionally
58:03relevant peripheral clock signals,
58:04and so the gut the pancreas and liver
58:07are tremendously influenced by feeding
58:09schedule and so you could imagine
58:12that in shift work for example.
58:15You have one set of signals from light
58:17and maybe you eat a big meal in the
58:19middle of the night of your biologic night,
58:21'cause you're up and your gut saying it's
58:23a different time than your brain saying,
58:25and so you can get these internal
58:27desynchrony and so one thing that we think
58:31about in the ICU is if we try are trying.
58:35Uhm, to target these things we want
58:37to do it in a in a organized manner,
58:41and so the feeding the time restricted
58:43feeding that I suggested certainly is
58:45going to have the effect of orienting
58:47the gut and the liver and the pancreas
58:49to my feeding schedule and hopefully
58:51that is the same because I'm also
58:54promoting sleep during the night and
58:56and I'm doing mobility during the day
58:59and so hopefully a kinda Janet question.
59:02I'm guessing right,
59:02but I'm also hopefully giving
59:04coordinated signals and so the time.
59:05Doing the same signal through a
59:07different messenger to the peripheral
59:09clocks as I am to the brain.
59:10Hopefully that makes sense.
59:14Thanks, and I think we have time for
59:16one more question and this is I think
59:18a difficult one to in the COVID era.
59:20There are many patients requiring high
59:22levels of sedation for a long period of time.
59:24How do you approach sleep management
59:26in these types of patients?
59:28I have no idea, so you know at the Clover
59:30things the kovid issue has been really
59:32hard 'cause we've had drug shortages,
59:35so we've picked a lot of drugs that a lot of
59:38us would not take off the shelf otherwise.
59:40Lot of lot more use of benzos,
59:43especially in the surge one
59:45because that was all we had.
59:46And so the question is sort of academic
59:49in terms of the major said it is.
59:51I think the there's a little teeny bit of
59:53propofol evidence and probably more robust
59:55Dex medata mediene evidence that that is
59:58the best thing if you need a sedative.
60:00That is the best thing you can do
01:00:02in terms of sleep architecture and
01:00:03so it's not so much the COVID era.
01:00:05I think that the question can
01:00:08just be rephrased.
01:00:09To what do you do when you need
01:00:11deep sedation to keep the patient
01:00:13safe and one is I challenged you?
01:00:15Do you really need to?
01:00:16Do you really need deep sedation
01:00:17to keep the patient safe?
01:00:18There's certainly a subset of patients
01:00:20that that's true for for those folks,
01:00:22I think you start with Dex,
01:00:23Medata, mediene and you,
01:00:24and then you end up following the
01:00:26PADIS guidelines of using the minimal
01:00:29necessary narcotic sedation that you can
01:00:31because there's no other good choice.
01:00:33There's nothing and there's
01:00:34nothing else you can do, and,
01:00:36and I think this is.
01:00:39This is one of our great challenges is
01:00:41what do you do when when your desire
01:00:44to promote sleep runs up against
01:00:46other ICU needs and that's just that,
01:00:48you just have to compromise,
01:00:49but I would start with DXM in automating,
01:00:51then go to narcotic and avoid benzos.
01:00:54But that's more based on that based
01:00:56on the decks management is based
01:00:58on sleep architecture.
01:00:59The rest is based on PADIS guidelines.
01:01:01'cause that's where the evidence is
01:01:03great. Thank you. Thank you.
01:01:05Gotta thank you for that.
01:01:06Well, this is really been terrific.
01:01:08I really I've learned so much.
01:01:09I think everyone in the audience has
01:01:11learned a lot and it's in great talk
01:01:14and under extreme circumstances.
01:01:15Being in the ICU yourself.
01:01:16So really we appreciate it.
01:01:18So thanks everybody for attending everyone.
01:01:20We don't have conference.
01:01:21Next week is Thanksgiving so happy
01:01:23Thanksgiving everyone and will
01:01:24convene again in a couple of weeks.
01:01:26Bye bye everyone
01:01:27sounds good. Take care everyone.