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By the way, I'm Doctor Deram. I'm the uh Chief of Pulmonary at Robert Ward. And it is my immense pleasure to introduce the next speaker Sais, who I've known for many, many years now. He's at the University of Arizona. And um he's the chief and has a endowed chair for emphysema. He is the Murray and Clara Walker, endowed Chair for Emphysema. He is also the Chair of the Critical Care and Pulmonary Clinical Consensus Group banner Health System and the founding director of the US Center for Sleep and Circadian Sciences and the Medical Director of the Center for Sleep Disorders at Vanner University Medical Center. Um like all our previous speakers, um he is an extremely accomplished person and his uh CD is like a book. So I really uh don't think I can cover all of this in the next minute or two that I have. But just to say that he is an incredible speaker, very well respected as uh to grants over 100 and 50 publications. II think I may have undercounted that. And um he uh I think his early studies were in sleep in the ICU if I remember correctly, almost 2025 years ago. I think he was the first person to actually look at uh sleep in the ICU. So, so I great pleasure. Come on out, right. Uh Thanks Jack. Uh I hope I can uh grow up to uh uh deserve that kind of uh introduction, but I appreciate it uh very much and I appreciate the programming committee, Greenstein and for the invitation and the New Jersey Thoracic Society uh for this uh kind of introduction. Um So I'll be talking to you about sleep in the ICU. So it's sort of bench to the bedside and back. Um But I know that uh my charter is to talk to you about the various interventions that can be used um in peripheral patients to improve their sleep. I'm gonna use the word sleep in a broader sense of sleep and circadian rhythms. Um These are my conflicts of interest. Um And I will not be speaking of any off label uh indications or usage of any of them. And my talk doesn't overlap with uh any of these. So it, it is interesting that, you know, we um depending upon which philosophy of life um uh that you belong to, that we happen to be on this earth. Uh uh And it also, it just so happens that we adapt to this environment with the rhythm. And it's interesting that our sleep time is slightly longer uh than the spin of the earth maybe closer to that of Mars, you figure. Um But the um uh have a problem with regards to how that can affect us if we are this um organized or if we are not in sync with the spin of the earth. And um I wa I wanted to start off with this uh you know, um uh slide because it was the 2017 Nobel Prize uh that went to circadian rhythms. Uh If you talk about the entire field for pulmonary critical care and sleep medicine, um what is the fundamental finding that led to a Nobel Prize? Um The fundamental finding, the only fundamental finding that's led to a Nobel Prize is actually in rhythms, in terms of care and sleep. So, even though my lab is right next to that of uh some acute lung injury researchers um who uh would make a, a little, you know, jab at me uh sometimes about sleep research. Um when this happened, I got the good opportunity of going, knocking on the doors and giving them this uh information about circadian S winning the Nobel Prize, but there is a clock that's going on inside of the cell between the period gene and timeless gene that they both are working much like this little uh you know, toy that you see on top of the office desk, uh where it's essentially keeping time by going tiktok, tiktok and that's essentially what's happening in the cell. Um But it is usually is affiliated with that of the brain because you have this circadian rhythm that's happening in the supra asma nucleus. And um all of the hormonal pathways and systems that ensue from that are gonna create this oscillation in the body. And so to the point that in cave experiments, if we end up in a cave with the white solid lines, meaning you're awake and the dotted lines, meaning you're asleep. And once you go into the cave on the 10th day, you can see that your sleep starts shifting. That's because the circadian rhythm of our body and the brain and the place is slightly longer than the spin of the earth. So if you start free shifting or drifting or undergoing delayed phase, which is the technical term uh until to the point that in about, you know, another uh 20 days or so, you will be exactly in the opposite phase. In other words, it almost be you'll be keeping time in China or India. Although you're in the same cave in Colorado. Now, you are keeping the, the wake and sleep times of someone in China or India. That's because your sleep a has drifted. Now, why does that matter? Uh Well, it does matter when you're talking about sleep in the ICU is, is that when you look at the cellular missionary, these are cell based experiments in animal studies and you have the, you know, uh gene expression that's shown in the small insect on the right side at all 600 hours in this animal experiment which is published in the preceding National Academy of Sciences and 0 600 hours is when the inflammatory responses and the gene expression is the highest for some of these uh you know, NF Kappa B, which is, you know, a precursor to interleukin cysts, which is the precursor to your cytokine storm. And so for the same insult, the time of day matters with regards to what would be the response. So if someone uh you know, there are my studies with the li puncture sepsis models and the time of day for opposed to 600 hours is associated with the highest chance of mortality. So what gets even more uh crazy is that every cell in your body keeps time, keeps a clock. So you have a circadian rhythm going on in each and every cell in your body, including your skin cell. So there have been experiments that have been done, which is published in C where they show that nude mice, some mice without an immune system when exposed to UV radiation have a higher likelihood of developing skin cancer when they're exposed to this radiation. So essentially cancer producing model and they have a higher chance of developing cancer if you expose them to um uh the UV radiation, when their rhythm is put by keeping them completely bright light for a 24 hour period, as opposed to having light and dark cycles like we have in a traditional animal facility suggesting that circadian rhythm is important for cancer, you know, formation. That's why the wh O is classified shift work disorder as a procarcinogen. So, um let's say it's uh pretty profound when that news came about that. Uh people who do shift work um are more likely to develop solid cancers in the body. And why is that important? Because cancer is tied to inflammation and inflammation can be affected. As I showed you in the previous slide, depending upon how light en trains the eye and how it, you know, signals to your, you know, your, your, your genes and the transcriptome and the proteins that ensue can actually set someone else for inflammation and even cancer production. And that's important because that's the last thing we pay attention to in an ICU which is fully lit uh during the entire period of time. And there are still questions about why we developed inflammation. And this is Mike Urban from UCLA. And he, you know, he had this publication in each review in Immunology. And, you know, he came to Tucson and you know, as a keynote speaker and I was talking to him and uh and he's like, yeah, no, I came up but there's really nice, you know, hypothesis for how, you know, your adrenergic system gets turned on and how it's proinflammatory and it signals the enough coa B but I really don't know why sleep ruction is proinflammatory and we really don't know why. So there are questions about why this inflammation is happening in people with sleep interruption. I mean, just imagine you're in an ICU, the patients in the ICU, they already have a cytokine storm going on or inflammation going on and then we expose them to light, create more inflammation and then you cause perturbation of their sleep, not just the circadian rhythm, which can also cause inflammation. And so, what are we doing? And so what is really the circadian rhythm in these people? Uh because sleep is part of circadian sleep is one of the manifestations of one of the components of circadian rhythm because there can be a circadian rhythm of everything including core body temperature. Um And so this is cr measurement by six sulfoxy and in the urine back when uh you know, everybody had an in welling catheter. And you can see patients with uh who are controlled patients who have mild uh infection, maybe some, you know, pneumonia that didn't warrant them being on a ventilator, which is down at the bottom. And you can see there's a circadian rhythmicity to the melatonin where there's a rise in melatonin after the light onset, quote unquote um late evening rise in Melatonin, which is what happens in uh the normal situation. Whereas in a nonseptic uh sicker patient, as opposed to the sickest patient, which is a septic patient, you can see that it's flat line, there's absolutely no circ rhythm. And so we were like, well, what is sort of the process that's going on here? And why would circadian rhythm, you know, be related to inflammation? We think that it actually is a bidirectional relationship. If you make the circadian rhythm, uh if you disrupt it, you're gonna cause inflammation. But if you cause in, if there's inflammation, inflammation can make the second rhythm go away. That is essentially, there's enough animal data to suggest that it's a bidirectional relationship. So this is actually a, a new work that we just published. Um you know, last month, uh these are mice and there are control mice and then there are mice that are face shifted. Um Essentially each one of these blocks is a week and you can see that these mice uh in the control condition are having the same week, each week. I mean, this is about 10 weeks. You can see after a two week period of aroma in the animal facility. Whereas down, you can see a sort of a checkered box there. So these mice in that group are actually having one week in the daylight condition in one way and the other week, we just turned the light system in the animal facility. So now day is night for the mice and night is day for the mice. Our light dark cycle is being flip flopped. So it's almost like they're living in China, all of a sudden they got transported and they were induced jet lag and we euthanize these mice so that we can actually look at the lung. And uh what we found is in mice which were exposed to LT S, the jet lag mice shown as CPS, which is the gray columns at two weeks or 10 weeks, we essentially did uh uh you know, b on these mice. So I know Abby presented talks and doing cool bronchoscopy in humans. Uh But uh but I don't think he's done a bronchoscopy in a mo mouse. So this is actually a mouse bronchoscopy. It's too bad that Abby is not here to show him this. Um And we showed that there is actually increased amount of B cell count in BL proteins suggesting that just the fact that these mice have circadian rhythm disruption can actually increase with both the cell counts and the protein. And this is a well known indicator for lung permeability, which is what happens in acute lung injury. Is, is that right? You have leaky capillaries that, you know, actually lose protein and cells into the BA L. And so we found that there was elevation. So we were like, well, what, why is that happening? And so this is essentially by taking these mice and Mary's groups and looking at uh the ontogeny and they're looking at some of the uh uh pathways that are overexpressed. And, you know, I'll just quickly show you is is this MLK, which is uh Myosin light chain kinase, which is actually part of the cellular cytoskeleton. And so if you look at the tiles up on the ceiling here, these tiles are all flat and they are abutting the wall, which is what the endothelial cell inside of a blood vessel will look like it's abutting the wall and there's no gap between these tiles. And, but when MLK is overexpressed, which is what we showed. Even with quantitative immuno histochemistry, we found that there is increased amount of MLK. What happens is these flat tiles start becoming globular, they retract and they become globular which creates gaps in the in the junctions between the cells, the intracellular junctions. And that causes the fluid from if we have the blood loss, all it'll cause the plasma to extrude out into the periphery. So we're seeing that there is, we haven't done scanning electron microscopy or anything like that. But all we we we are postulating is that there is an over expression of ML. OK. And it's probably the reason why there's a leakiness of the capillaries and greater amounts of inflammation. So, sleep and inflammation are closely tied to each other. And if you disrupt sleep, you know, there's an increased risk for mortality. We think inflammation is in the mediation pathway for why that is happening. And if, if that is true, I mean, this is essentially um in patients with insomnia participants. It's a community based population called the study of the two study of a disease where participants, thousands of participants, I mean, uh it's about a 1000 participants in this data set that also had some blood sample with them that were recruited by going door to door in a true community based sampling without any bias of getting a clinic or hospitalized patient sampling. In 1971 they were pulled and their blood samples was collected and stored minus 80 degrees of of refrigerators. And so you can see people with never insomnia was just as shown in green versus persistent insomnia shown in red. That's because when you say persistent, but because we followed them five years later and went and pulled them to find out if they had insomnia and we administered the A s undefined criteria for insomnia definition. And this was done in the late 19 eighties, uh 8988 for the second visit. The first visit was prior to that. And you can see the people with persistent insomnia are dying at a faster rate than folks in green who had never had insomnia and people with intermittent insomnia, either it was remittent or incident, either they developed insomnia five years later or they had insomnia, but then it went away five years later. So they are more unstable as opposed to the phenotypes where the trait was that they have persistent insomnia. You can see that people with insomnia more likely uh to die quicker. But remember we had the samples in these people that was banked from before. So this is essentially a 20 year follow up period. And so when we look at the over 20 years, if you look at the dark dots, those are the CRP levels, c reactive protein levels at baseline in 1970 1971. And then the fog ones are in the open circles in people with never insomnia, intermittent or persist with insomnia. What you can see is that as we age, we have a little bit of inflammation, not so much for never or intermittent, but for people with persistent insomnia. Your c reactor protein tremendously goes up and it actually goes up beyond a level of three in at least uh 50% of them. And as you know, three is some of the cutoff, why we start statins uh in these people because they are at increased risk for plaque rupture and cardiovascular event related deaths. The majority of deaths in this cohort were cardiovascular related. So it sort of ties in that poor sleep is pro inflammatory and pro inflammation can actually increase all cause mortality. True cardiovascular death, which is probably due to um atherosclerotic vascular disease. So you can only imagine if this is happening in community based community dwelling residents. You can imagine what sleep ruction would be doing to a critically ill patient with acute lung injury or sepsis that's hospitalized on a ventilator. And we have lights, we have noise and we have action going on all the time. Um, because we're going and poking and prodding them every few hours, giving them bronchodilators and doing nursing or respiratory therapy intervention. And so what I wanted to show you is the context, this is actually, um, you know, Parson's, um, Polly Parson's work that overlaid on top of the art that study for low tidal volume ventilation, the armor trial. And so you can see that there was a 25% reduction in interleukin six when you did low tidal ation. So if you're practicing low tidal mon in because you wanna do lung pressure strategy with the idea that you wanna reduce mortality as was observed in the art study, that means you believe that you wanna reduce the inflammation and you wanna reduce the lung injury. Whereas what we're doing on a day to day basis is actually based on the mouse study. You know, other studies that I'm gonna share with, you can actually perpetuate or aggravate the inflammation and aggravate the risk for death in these individuals. And so in this particular study, with Il six and Il eight levels were associated with morbidity mortality. But this is the amount of Il six and Il A that you can actually reduce by doing lung productive strategy. So we just wanna share with you that sleep disruption is not different from disruption. And so, you know, um th this is actually a murine study that Chris Sinton who was at Southwestern did. And this is essentially a, a mouse sleep lab. And you know that we have where we're measuring sleep in mice and we have an actuator cable. This is a mouse cage, you can see the mouse outline over there and this is the actuator, they undergo survival surgeries. So the wires and electrodes are implanted both in their brain as well as in the knuckle area. I mean, these are pretty sophisticated surgery because the mouse's scalp is like it's like paper, it's like paper thin. So you gotta get it past the paper, but before the dura, so that you're not penetrating into the CSF and, and then you put these wires into their uh neck muscle. So that's your chin emg. So you get some eeg s and you get some EMG S and you can actually do sleep staging. And so what Chris did is essentially did sleep interruption after control condition. You can see that the mice for them day is night and night is day, right? Mi mice forage during the night. And you can see that there's a nice circadian pattern on the control day. Uh you know, and they are essentially the minute or hour of sleep is lower during the day, day, which is our night and then it's higher during, you know, their night, which is our day um And so that's for control day one. But then sleep instruction day 12, and then there's a record day one and two, you can see what happens to their circadian rhythm. You can see that there is a rhythmicity in their sleep to the point that you have that there is a disruption uh of their circadian rhythmicity. And there's also a reduction in the amplitude of sleep in day two of sleep traction. Before you go to the sleep recovery phase. You can see that the amplitude of the circadian rhythm reduces, which is what happens to all of us as we go through life. When we, when we are babies, we have an ultra circadian strong rhythm. And these babies, you know, sleep and wake, you know, multiple cycles during the day. And then, but then as you lengthen them out, a young adult has a very strong circadian rhythm and being able to sleep and spontaneously wake up. But as we age, you know, go past the age of 60 seventies, they develop insomnia because they're sleeping during the day or napping or dozing during the day and they are sleepy at night. And so the circadian rhythm rhythm is important for uh health or is associated with youth and uh health. And this is, you know, essentially Cooper and colleagues and Pat Hanley in Canada showing that the amount of time you, you know, critically ill patients sleep during the night and day are not very different and their sleep is fragmented in terms of arousals and awakenings during this time. So, very similar to the previous graph, in terms of the proportion of time that's been sleeping during the day, the proportion of time during sleep, you know, wake at night stops, flip flopping in these people, which is what happens in the ICU patients. So we're actually visibly aging these individuals in our ICU by doing the instructions and exposure. But this is actually Randy Free, uh who's a trauma critical care surgeon who came from UT Southwestern to Tucson. And he did the study and published in general of trauma because a trauma critical care guy and um and showed that in a cecal acupuncture model for sepsis in animals, sleep in mice, all of the mice in this group were underwent um you know, seal and puncture, single ligation and puncture, but all of them had sepsis. But you can see that the sleep in mice shown in dash lines were dying at a faster pace suggesting that sleep interruption can actually increase mortality. And these are essentially uh actigraphy based um circadian rhythms that we looked in survivors of critical illness. And you can see that there is actually a reduction just like I showed you previously of circadian rhythm amplitude. The peak is lower and the trough is higher shown in green as opposed to blue that individuals with greater amount of sickness are critical illness, which is essentially the green one with a higher Apache score during the hospitalization as compared to blue, which is a lower Apache score because they are more comparable with each other suggesting that their circadian rhythm is not only amplitude is reduced, but there is a shift or a phase delay. And that's what happens in the cellular machinery. If you have high levels of inflammation, it causes a delay in the circadian rhythm of face, which actually goes to the same slide that I showed you, which is associated with high levels of inflammation and a higher chance for mortality. So, the whole purpose of these slides is to tell you that it's just not sleep, but it's also circadian rhythm and they are very internally tied to the upstream pathway of inflammation in the body. So that's why sleep loss or sleep ry or circadian rhythmicity can actually increase cardiovascular disease and can also increase cancer. And the question here in critically outpatient is it can increase the chance for death. So chance for that tangible patient, you're not talking about 0 25% higher by all 60 a half a day, less of delirium or 1.5 days less of hospital stay. Those are endpoints, they're tangible. Um But the big big picture, this is Paula Watson and Mandible. Uh you know, showed that there is a huge mortality difference in people with eeg birth suppression. Um meaning eeg burst suppression is associated with increased risk for mortality. You know, people with greater burst suppression have it. There was a tendency at ICU but not significant, but it was significant for hospital mortality after they got discharged from the ICU and six month mortality for birth suppression. It as a matter of power, I'm sure that if she did a multisite study, it would clearly show um that um disrupted eg in these people is associated with mortality. And then this is actually a very cool study. And I continue to decide this because this is a sleep organization pattern in people with blunt head injury to the head and um and their chances for neurological outcome. Um and you can see that people with organized sleep patterns and I see this in our new IC. So we do cover about 80% are in your ICU and all of them get the monitored. Um But if people have organized sleep patterns, you know, there's a question in our institution, I don't know about your institution about who's really monitoring these eeg s we do it monitoring. I swear to God, we, you know, there are some of us who aren't eeg experts. You know, I like to show during rounds to my house staff and fellows saying, you know, this is what this is and they're like, oh wow, that's very suppression because you know, that's not something you look for. Look for a, you know, spike and wave activity. You have a seizure. We had a lady with status and, and I was able to see that and call and that's when I realized nobody's really watching the head in the house a different manner. Now they're talking about artificial intelligence monitoring and everything. But, but there was a patient that they wanted to withdraw care on. And um you know, this is a young woman who had overdosed and the husband was actually in, in the war theater, he was in, in the Middle East. Um This is a, a while ago and they, he got special permission to be, you know, flown back in because his wife, uh you know, had and uh was quote on quote in the ICU and the question about the state of state and end of life conversations were happening. But I looked at the E eg and she had r that I could see and I was like, wait a second, this is, you know, this is not time for us to be having these conversations. Uh because I think there's a good chance of a hurry, but the guy flies in and four days later, augmentation starts improving and we took her off the blower and she was discharged home. Um So, uh you know, that's anecdotal, but this is actually from the trauma ICU and this is an Italian study showing that the sleep pattern at that time was more predictive than neuroradiological findings age or Glasgow coma scale in predicting uh recurrence. So you see the sleep in, in terms of RC curve, which is shown with the open diamonds, she goes all the way up to the left top corner as opposed to any of the then available. Uh As you can see, there is uh neuroimaging was um you know, sort of broad and it wasn't necessarily a, you know, three T MRI uh that we do not, that they are very predictive or indicative of uh the neurological outcomes down the road after a patient gets discharged. So there's a lot of work being done in the TBI space. Now, in terms of looking at sleep correlates with traumatic brain injury, these are tangible outcomes and this comes from uh the French group by, you know, Ro Ro Camp, uh prospective observational study, ha respiratory failure, proportion of people with abnormal sleep where had a greater likelihood of noninvasive ventilation failure. So I know this is neurological. There are other ways of predicting N IV failure. You really don't need to look at the E eg. I'm not saying you should measure the eeg all I'm saying is that there's an association, the tangible bad or poor outcomes in people who have bad P eg patterns. So it's just not in the community. Lots of hospitalized patients going home with insomnia have a higher risk for mortality. You go further out. This is 25 years ago, they were just asked a simple question and um you know, but whether they had insomnia or not. And we did a biomarker array. Um We found that for each level of insomnia, there are two kinds of people. There's two endo types, people who have high levels of inflammation and people who don't have high levels of inflammation. So we think it is an inactive effect between the genomics of the uh the genetics of an individual and the, the exposure to the level of sleep uh problems that they have. So, not everybody is equally susceptible and that there is a interindividual difference that can probably be explained using some biomarker studies. Um but um but that is left to be determined. But before we start talking about how we can improve someone's sleep, we really need to know how you measure sleep. And that's part of the problem is we believe that it should be by eeg and a lot of us would agree that EEG is the way to measure sleep. But the problem is conventional uh sleep uh scoring methodologies don't apply in these people. I mean, these are the various five stages that was done in the val study that was indicative of prognostication for neurological outcomes. After a nonpenetrating head injury, you see this monophasic pattern or it it's not a flat line, but you see these low uh monophasic activity that's going on and that is the worst um that you can actually see um besides the flat line, then you have something called cap or cyclic alternating pattern where you see sudden burst effectivity and then it hardens down and then it bursts effectivity and then you have parts down and it happened in a cyclical way. So if you just stand there and you reduce the speed of the screen rate, you can actually start seeing that pattern. It's amazing guys on fentaNYL and propofol breath. But you can see the cyclical activity, burst suppression is, is when you have that burst activity and then you have a flat line. So that's burst suppression. It's like burst factory and a flat line. That means two things. Either you're terribly or sedating a patient that would be useful if the patient is paralyzed for R DS or something. It could also mean that the person has had a neurological catastrophe, you know, such as severe brain injury would be a whatever cause that you have that birth suppression. Um or you may see some rudimentary non rem sleep, you know, poorly from K or you can see well structured non sleep, you know, with the K complex with a spindle writing that, that you can see in those arrows down in the bottom, it shows the spindle and you can see AK complex right before the third spindle there. And that is actually, you know, better sleep, uh or organization pattern. And then of course, if you see rem sleep, that's the best situation because most of these people don't have rem sleep. There's a smattering of people that don't have rem sleep. And that lady that I was telling you about, you know, she odd and they didn't wanna give her any sedatives. She wasn't waking up. And so she was not on any narcotics, narcotics immediately suppressed the rem sleep. And so you're not gonna see rem sleep. None because of disease, but you're gonna see it because it's genic because you're giving someone a fentaNYL drip and it's gonna go away immediately. And so what we did was a comparison and I know the flight is uh busy um in the lack of what we would determine a gold standard, we did Interobserver intraobserver agreements or co you know, cos Kappa and suffice to say that, you know, we found that the fast for your transform, reliably measured sleep in these people sleep, organization pattern, there was some under agreement but the rush and chaos then a some criteria now did the worst uh in terms of inter rater and intrarater observer reliability. In other words, assuming that you don't assume this or that as the gold standard. If you just look at inter inter observer reliability as a measure of what is the way to measure sleep because you wanna be able to reproduce your findings. If you can't reproduce your findings, that's probably a bad measure right there. It's out the door. You can see that the faster your transform did did the best. And so we decided, well, we have to be looking at F FT and not looking at sleep staging in ICU patients. And you could even take it so far as to say that you wanna do that in hospitalized patients. And so how to measure sleep? I hope, uh, you know, I've told you what my bias is and how to measure sleep in critically ill patients. But we know there are various factors that can affect sleep in these critically ill patients. I've already talked about light, we talked about noise. Uh, we talked about, um, uh, me medications like, uh, you know, narcotics that can suppress rem sleep. Um, but then norepinephrine and, you know, essentially, if you're giving adrenergic compounds, you're giving someone Norepi or epi or you're giving them dopamine or, you know, uh, you are gonna be disrupting your sleep because you're giving adrenergic, you know, agents which is going to cause sleep disruption also how you set the ventilator. And so this is some early work that we did where we showed that, uh, as, as controller, as pressure support. Um, there are patients with pressure support that were having the central apneas. I, it was actually interesting because as a fellow, as a third year fellow, um, I was rounding with, uh, the chairman of medicine who's also a pulmonologist who personally had, had an status asthmaticus and ended up on a ventilator, uh, because he's allergic to some dye that's in commonly available food drinks and he ended up going to status and then he was intubated and this is an old, uh, s 900 ventilator. Some of you would know the silver nine and ventilator with the knobs on the side of the, the machine. And, uh, famously, he was told, he was told that, uh, he asked for the ventilator to be pulled closer to him so that he can try out which modality of ventilation works for him. So, um and he found pressure support to be the most comfortable. So whenever I around with him, you know, as a fellow, I'd be like, oh, he's putting everybody on pressure support. So you go around in the CCU do vents in the CCU and change everybody to pressure support because he personally knows that that that's the most comfortable. And I agree with him because it's comfortable when you're awake. But what happens when you're asleep? And the next morning we came back and the, the, one of the nurses gave him a piece of his mind and here's the chairman of medicine, the chairman of medicine, but she was just raining on him. So I think the apnea alarm kept going off and the CC and these patients and I was like, wait a second, these people are probably having the same central apnea as if you over titrate in the sleep uh lab. And so that's why I did this randomized controlled trial and, and interestingly, three quarters of the patients that had central apnea. There are a few that didn't, one of the people that had some apnea had underlying either hip or hip pa uh that was underneath uh uh underneath it all which tells you that the game is and they really should not be on pressure support without a backup rate. So the what we found in that study is we found that 67% of someone's sleep interruption was not explained um by anything I could not tie it to a nurse visit because we did synchronized polysomnography with the video, we did polysomnography. If someone woke up, if uh the respirator therapist went in the room, I would attribute that as a healthcare intervention. Uh if someone had uh apnea and then it's an apnea related. But then I found that two thirds, nearly two thirds of the sleep fragmentation that I was observing was just happening spontaneously. So to this day, I'm convinced that a, a vast majority of the sleep interruption that we're seeing is inherent to the patient's critical illness. You know, because they're sicker, they were critically ill because they have their own adrenergic system, you know, that's all revved up and cranking out. And so I was thinking, well, what is something that we can do to improve sleep? So, are only two medications that can actually um induce sleep that doesn't affect cognition, everything else uh can affect cognition and in the acute setting, um can actually a delirium. So your pa guidelines, what not you want to avoid benzodiazepines, you wanna avoid gabaergic medications, right? Why, why did dexamine come up to the forefront when Marin May in UCSF brought metomidine, which were being used in animal studies into human world. In Dex. Metomidine was he has done studies with using functional magnetic resonance imaging as well as mice studies showing that in our brain. The reason why we worry about giving people sedatives long term is because of something called spine formation. It's because neurons actually form spines and they find each other, make new connections, make new memories and the more connections you have, the more computational power that your brain has. So there is the spine formation, there's a budding budding uh like budding and they bud and they become little tentacles and they ST form new connections. That's what's happening constantly. Your memory that's forming on right now is on the basis of you having that network and creating a new memory of what I'm saying right now. Hopefully, uh if I'm not bored to death, um but that's how you form these, you know, memories, but sedative agents reduce spine formation and that they're gonna affect memory, they're gonna affect cognition and what is cognition, memory in the acute setting and the effect and increase the risk for. Er so the only medication that doesn't ae one of two medications that does not affect cognition is also the one that does not limit the spine formation. And that's a dex of ho explan doesn't, you know, uh, reduce your spine formation. Anyone know, what is the other drug? Everything else? Benadryl is that everything reduces spine inflammation. That's why eventually, if you did a study where you wanna follow these people and give them daily, uh, sedative medications, you're gonna see that they're gonna be cognitively impaired as opposed to the control group. The other medication is yes, Xenon. So there's, you know, Xenon is the only other one that can actually sedate you. But of course, you have to go around the very complex armada of tubes and hoses that actually administer xenon. So Xenon can actually sedate you. It's an inert gas, but it stabilizes the lipid membrane and causes sleep and it, and it does not affect spine formation. So if you wanna sedate, I see your patients, I'm just throwing it out there, you know, maybe, you know, it's not de but as you know, study was also run, uh done, which showed that there is a reduction in number of days of delirium in people who are on DEX. So we did the study to see, well, what is really happening to these people's sleep. We randomized people and cross them over uh to Dexa Land and, and we did fast for your transform and you know what the output of a fast failure transform is the spectral analysis which is a delta or beta ratio. And we found that the same patient with ne on me, as opposed to Midazolan have a higher delta or beta or delta or alpha ratio. The delta or beta ratio. How you interpret it from the fast for transformers is that the better the delta or beta ratio? That means you get more slow sleep, slower sleep delta, you get more delta sleep and that is actually better for your brain. And so you can see the is associated with a higher amount of delta and therefore greater amount 25% greater amount of delta beta power in the very same patients. And um and then the delta alpha is about 20% greater. But then what's happening to the circulating levels of inflammation? And you can see that you know, this is essentially a busy slide, but I'll just bring your attention to il six reduced by 26% for the same patient on the night that they use this uh medication. When you're using omadine, you're actually reducing inflammation of both Il six and soluble receptor one and two of human necrosis factor TNF alpha solid receptor. And remember the partly parson study showed a 26 25% reduction in il six levels by low T volume in. So our thinking is just that, you know, this is a comparable amount of level of reduction in inflammation. But then the question becomes, this is a direct action of the DEX is the DEX directly anti-inflammatory. So for that, we actually had grabbed cells and from these people, a peripheral blood mononuclear cells and put it in a Petri dish intubated overnight and exposed them in ex vivo to DEX or which is also another essentially acting alpha adrenergic agent like dexamine. And we found that there is no difference in uh in their cytokine levels. There was a slight uh difference in um in il 10 levels. But after correcting it from one for adjustment, we found that there was, you know, change. So at least now there is uh you know, evidence suggests. Uh then Karen Bosma from Kr also published studies showing subjective sleep in people getting de was better. She had not measured objective sleep in that. Um But um that was actually published uh in the blue journal. So can you really improve sleep in correctly your patients? You know, it's about this, you know, we wanna do this but can you, you dex auto can you know, improve sleep, you know, as we showed. But when we put all the interventions together, we did a meta analysis and there are others, two other groups that have done meta analysis. Since then, we found the pool um odds ratio there, you can see a slight improvement in sleep efficiency in terms of the total amount of time that they spent asleep. And if you break it down into studies that adjusted the mechanical ventilator, um if we found that there was the pool, uh, rates were better and then, but then medication and environmental interventions, at least at that time there was a tendency, uh, it wasn't statistically significant but it was getting close to being significant, um, in saying that medications can make a difference. But, you know, this is why I wanna take a step back and, and I will be, I have a slide on pad. Yes, in terms of medications. Um But the question is, and you know, I just wanted to say that, you know, Chitra was a fellow, she did a meta analysis with me, but there are two other meta analysis that are available in the literature. I wanna make sure that I share that with you. Um And uh you know, Wilcox from Australia, you know, they looked at another, you know, scoping review, 50 studies with care bundles, uh you know, five with uh you know, uh training with care bundles, five with the light therapy, five with ear plugs and masks and 19 with Melatonin. And they found that these findings were mixed and uh there's, you know, uh they positive that you, you know, more research is needed in terms of how we improve sleep uh in these individuals. And then there, there's, of course, the pa you know, guidelines. So the idea is to help improve pain, reduce agitation by reducing the amount of sedatives that we administer. Um and uh paying attention to delirium delirium and improving mobility and making sure people sleep better at night. All of these has been shown um to reduce mortality and duration of mechanical ventilation and length of ICU stay. Um but there are not, you know, studies that have been done that has looked at what is the contribution of sleep destruction to that. And so this is why I wanted to take a pause is that we did a study, I mean, a bunch of us were interested in sleep in the ICU across the country, including, you know, J A and, you know, there's a recent review paper that, you know, came out and the American General respirator care medicine, you know, and our father, but when we, you know, take a step back and look at how are we helping people sleep in the ICU because they have this no stimulus. But then there is the sedative, there, there was a paper by Gordon Rubenfeld and some of you may know, uh Gordon, um um which was essentially 20 years ago and look at what is the most common sedatives given in, in ICU S across the country. And it was uh gaba medications. It was either Ativan or Midazolam or Propofol. And then 10 years ago and you know, Nancy Reder at Yale got together, we did a survey, we send it out on the same proportion of ICU S and doctors giving s and I'll submit to you if we did the same survey now, you know, just 20 years from the original Garden Rubenfeld study, we find the same pattern because we wanna limit sedatives, but we really don't have an alternative for how we can keep people comfortable. And so you end up either giving propofol or end up giving, you know, some medication that is going to cause harm or you end up giving Eliquis of Midazolam for breakthrough agitation or I don't know what your folks are doing, but at least I don't know what we are doing because we talk about it a lot but limiting, we're still giving the same classes of drugs. The drugs may be different. When I was a resident, we had people on Ativan infusion and then forget about it and they would just be snowed until J PS work came out about you doing daily. We were just putting people on a drug which is a longer halflife, much longer halflife than Midazolam. So we changed that but there are still ICU S in the US that are using Ativan for sedation and there's a health disparity into it. We find that um hospitals in lower socioeconomic uh status, um zip codes are more likely to be using Advant Dex economy is being used more likely in higher socioeconomic zip codes in terms of the hospitals. So there's a huge uh health disparity gap in terms of the sedative choices in terms of what the hospital that you're working with. It's a county hospital or it's a Coronary Ivory Tower as to what sedatives that you can use. So I'll just let you, you know ponder about that thought. Um I just want to conclude by saying that are severely disrupted during clinical illness. Uh sleep disruption is associated with systemic and lung inflammation. And there's the cellular missionary that's been well elucidated in terms of how this inflammation is secondary to sleep derangements. And so there's a lot that we can do in terms of the ventilator or um uh noise or you know, where there's bundle care that can be given, but none of them in meta analysis or when you look across studies are having a uniform signal, that's because the fidelity with which the consistency with which we can prevent a nurse and a respiratory therapist and a physician going at different times. But waiting until they all could go in and see the patient in order to consolidate the intervention. So you reduce all of that constitutes only a third, a minority of sleep destruction. The majority of the sleep destruction is happening in the due to critical and just like how the Mrna vaccine protected us, you know, you know, against, you know, the scourge of the COVID pandemic. We need to really understand the cellular mechanisms by which sleep derangement is happening in critical critical illness. And we are literally scratching the surface of that. So we can come up with a new way to sedate people and keep them comfortable rather than talk about how, you know, we as caregivers, um, have to somehow wait outside so the three of us can go together to go disrupt the patient. That's just not gonna work. That's behavioral intervention for healthcare providers. And we all know that healthcare providers are the worst when it comes to behavior. I'm just kidding. Right. That's, that's essentially it. And just thank you, uh, for your attention and uh I appreciate you having me here. Yes. In the IC most of IC patients are exposed to use in. It's like that's gonna be very few patients are going to be there for months. So, can you like is it affecting them that, that clear or sleep dis if I can? So that was one question. Um If that makes me more worried about the US as physicians and provide more than the patient right now, they are there for one week, we are there for months and years. So it makes me more worried about the provider. Uh the patient is there only for maybe maximum and then they move on that. Um And the second question I had was, is this the effect of right? Uh or is it the fact of sleep or is it the fact of not having Melatonin? So there are some studies and data showing that the Melatonin ciic and they have used exogenous melatonin to help to prevent um cancer. It has been used. Yeah. No, there's, there's a lot of, and hopefully I kept track of that. So the first question I do think that there is, um, changes that happens in the acute setting. That can, at least in our studies the last, where we studied their sleep in the ICU and then six weeks out, we find that even six weeks out their sleep and circadian rhythm is not normalized. And that's one of the reasons why a problem with the long COVID definition or past definition, which is 28 days, four weeks and beyond. Because for some of us who have been studying ICU survivorship before then we feel that anyway, IIC, it's gonna take them six months to get back to baseline. So I do think that that's happening there. But how much of that is due to the sleep interruption versus the uh underlying critical illness that also cause that and sleep is an EpiPen. Menon is actually unclear. Um But at least six weeks that at least our, our data. And if you look at some of the survey data that is done looking at ICU survivorship, you're talking six months uh with the caveat that it cannot distinguish from underlying disease. Um the healthcare provider stuff. There's a whole lot of people that are doing research in that area. Um Interestingly, the studies that led to wo categorizing shift work um as being a pro carcinogen because of the increased risk for breast cancer came from the nursing, the nurses study and essentially the participants were nurses were doing nighttime shift work. And so how do you tackle that? Uh There is someone at least one if, if the practice of medicine doesn't require physicality, you know, because that's tele radiology, tele radiology is a perfect example because it can be 100% displaced right from there. But there is the practice of the IC where you can be 100% displayed and displaced. And there is a concept by someone in the business world in Harvard who has coined this concept of 24 hour workshop. In his theory, no one should work when they are suboptimal. In other words, you should not pull a ship longer than eight hours. You work for eight hours, hand it off to people in Poland or Israel and they hand it off to people in India or China and they hand it off back to people in the US. So no one is burning the midnight oil. But for that, you should have an area of specialty of medicine where it doesn't require physicality that you are actually right next to the patient's bedside. So uh uh outside of that, I do think that we uh by doing nighttime shift, forget about the effect on sleep, medical hours, cognition. We are doing some irrepairable or repairable damage to our body. Well, the good news there is is that the susceptibility of ends is different, you know, I may be more susceptible than you are and we may be inherently resilient due to various poly, all the omics reasons where uh that difference may be due to your susceptibility versus mine. So that's the good news. But the bad news is, is that we, we are not skinning this cath. Right. We, we have not figured it out and I can't remember what your third question was. Oh, yeah. Yeah. Melatonin her in in mouse studies where they expose these mice to LPS and induced acute lung injury and looked at the transcriptome just like we looked at it. Uh it's been shown that Melatonin is actually antiinflammatory and antioxidant properties fairly shown in terms of the transcriptome. But does that mean we take a lot of melatonin? No, you know, uh there are studies of Melatonin in the ICU to help improve sleep, not uh you know, good design uh suggesting that sleep has improved. Um But I don't know if studies uh where there are studies that have been contemplated and abandoned of giving intravenous melatonin because surprisingly, you can take 50 times the amount of melatonin and still have no side effects from it. Um And uh there are some people who considered that we have it and some people have used remo instead as a meg receptor agent but has its baggage on the liver. Uh you know, uh disease, idiosyncratic hepatotoxicity and I have never prescribed remo to my outpatients. And so because of that, because I don't wanna, they come and see me with irregular sleep circadian rhythm cycle and I knock out the liver. That's not a fair trade. So II don't end up prescribing but, but yes, Melatonin would be uh something that's worth rigorous study. Um But um animal data, yes, human data. There's a paucity of that. Yeah. Uh Thank you. That was a great time. Uh I love that you. II see you in um I there's a recent debate in our department. Um A few of my colleagues have brought the uh uh um care and they came back with uh this opinion from uh they said that was based on the spice. I don know when they talk about uh they had when they use up front, um they have more side effect uh adverse effects uh these other agents as well, whereas in the process, they have better control over their. And um and so they saw a worse or so there are not at all and our was when you look at the trial um that is in the and so maybe that kind of uh but you know, what is the, you're using all the time? We almost use it as um you know, like you use it like a steroid sparing agent. Uh You know, you know, you use methotrexate for someone, you know, let's say sarcoidosis who's on predniSONE and you wanna reduce um the amount of predniSONE that you're giving them. It's almost like a sparing agent. So we use it as a garage sparing agent. So many patients who are on continuous infusion and this, I wanna say is that, you know, um I didn't um despite uh a study is, is that even with the Secom study, um they gave bolus uh you know, and giving loading dose is actually a, a problem in our study. We expressly decided that we're not gonna give a loading dose. So we started an infusion and we didn't exceed the FDA uh limit of points, uh 0.7. Uh whereas most studies go up to 1.5. Um what we uh what we found or what we heard, the reason why we did the protocol that way is, is, is that there's an increased risk for both tachyarrhythmias and arrhythmias. First of all, when you actually give pre uh to these uh individuals, there's also a complex intra in the peritoneal space with macrophages depending upon the state of infection in high levels of septic face. It seems like there may be a totally different reaction of macrophages in, in the predal space, especially in people with intraabdominal infections. Um This wasn't done in humans, it was done in, in murine models where they showed that um it ends up being excess amount of adrenergic stimulation at low doses can be anti-inflammatory. Um But at high doses, we can give a lot of no uh epi it's actually proinflammatory. Um and then you're adding dextroid, which is an, you know, adrenergic, you know, it's a sympatholytic agent. So that low effect of inflamma aggregating infl inflammation in milder versions of infection or sepsis via they actually having a lot of circulating around is actually a good thing because it sort of chills in the system paralyzes the system and reduces the inflammation. So it's quite possible, some of the adverse consequences that were observed were a due to short term loading dose level of dose that can cause cardiac arrhythmias, tachy brady arrhythmias because it can also cause blocks and it can. So I've seen patients who get a bolus loading dose of dexamine and they go in density. So not just in my research protocol, but even in the regular ICU all are noticing never ever give a loading dose. Um We just started as an infusion and we try not to exceed 0.7. All of there are times when they exceeded that, but we definitely don't go up to 1.5. And then there is this situation like what is the state of the infection if it's early on in the infection? If you have a high adrenergic state, maybe the high adrenergic state is actually helping sort of freeze everything, you know, kill the immune system. Um but the the vomiting goes in and probably interferes with that
