Dr. Kate Madden - What’s the Big Deal About Delirium

Good morning. We have the privilege of having Dr. Kate Mann and speak to us today. Dr. Mann did some of her training out at WashU as well as Brown, but all of her pediatric training including critical care was done here at Children's. We've been fortunate to have her on staff since. She has several clinical research interests that she pursued after her master's in medical sciences here at Harvard. Much of her work is involved in sepsis, but today we're actually going to hear a little bit about some of the work she's doing with ICU sedation and delirium management, which is something we really struggle with in the ICU and as well as we've really learned a lot more about how to manage sedation, but there's a lot more we can do. So we're thrilled to have you, Dr. Mann, and I'm excited to hear what you can teach us today. Good morning and thanks so much to you guys for the invitation. I'm really happy to be here and thanks to the Department of Anesthesia and Dr. Hickie for allowing the Anesthesia Department to join this morning. I'm really happy to have you guys here as well. And this is a huge topic that I could talk to you guys, not that you would enjoy it for hours about. I'm going to try and cram a lot into this short period of time. Please excuse my mild disnea, which if I get really excited, maybe that I have to stop to catch my breath. I'm totally to theologic. So we're going to talk a little bit about sedation and delirium and really they're very closely married and very hot topics in ICU and pediatric ICU of late and something I'm really interested in. I don't have any financial relationships to disclose. I will be talking a little bit at the end about treatment options and those are off label. And here's a roadmap for some of the questions I'd like to cover today. They're big questions, so I'm not pretending that I'm going to have all the answers. But what are we trying to accomplish with sedation in the picture? I think that's a question we've come back to. I think that's a time and again and recently have revised our approach in ICU. What are the medications to help us best achieve these goals? And what role does delirium play in our management of sedation and vice versa? I think like I mentioned, I'm going to try and convince you they're very closely married. How are we assessing picky patients for delirium? That's something we've started doing and it's not without its little flaws. That's something that has really become standard of care. And how are we assessing all the different factors in the ICU that are contributing to delirium in these patients? In the operative world, you guys have a lot of delirium. You pretty much have a discrete exposure and I get folks past that and we are dealing with a very complicated milieu and trying to distinguish what's going on. And then a little bit about are there effective treatments for ICU delirium? So sedation that pick you like in other locations in the hospital, where our indications are primarily to reduce patient pain, anxiety and agitation. This is something that again we've sort of changed our approach to it. I'm going to come back at the end and talk to you and hopefully convince you that we're trying to assess pain specifically a little bit more accurately. The induction of amnesia in ICU patients has been also a controversial topic. I was taught when I was a fellow, you know, it's best if they don't remember anything about their ICU experience. And I think, you know, they're still an argument to be made for that, but we're certainly re-vising that a little bit. And then of course facilitating the life-saving treatments that we need to offer in the ICU and preventing this placement of, you know, these critical tubes and devices. In some cases, we're trying to decrease cellular metabolism in certain conditions. And so that's another indication we may be using for sedation for. And then for you guys out there and for some of the operative programs in particular, we're really trying to, you know, maintain a certain position or to maintain a patient's operative repair for some period of time after their procedure. And that adds its own as you're aware, a little complications in ICU. So what do we have in terms of consensus about ICU sedation? Well, right now it uses that we don't have that much. This is from 2006 and this really our most recent kind of consensus guideline about sedation in the ICU. And you can just scan through here and see that all of these are grade of recommended recommendation D. So not great grade of evidence. Obviously, all children have the right to adequate relief of their pain, local and regional anesthetic, anesthetic, anesthetic techniques should be considered, you know, consider a PCA. There is a stronger evidence for, you know, assessment of sedation level with a validated scale, which in our ICU, you probably know we use the SPS, the state behavioral scale, and that this kind of the goal for your level of sedations should be assessed on a regular basis. So pretty basic. I think we can all kind of agree on those tenants. But again, not necessarily that helpful in terms of how we're going to manage sedation and what agents we're going to choose. And back in 2006, this was the grade C recommendation of this group. Because that medallion was a recommended agent for the majority of grade, we all children requiring IV sedation to be given by continuous infusion. So we're going to revisit this and hope to convince you that our attitude about this has changed somewhat in recent years. And I'll tell you why. And so then since these guidelines came out, we've had some studies looking at specifically sedation protocols. And whether having a protocolized approach to sedation is helpful in terms of, you know, ICU outcomes, minimizing exposure. The one, the largest one, sort of the really seminal multi-center RCT in this area was a restore trial. And maybe aware of, we participated in our cardiac ICU here, which was almost 2,500 children ventilated in about 30 ICUs, 17 used an intervention, which was a nurse led, excuse me, sedation protocol with, you can see here, you know, the SBS goal was, was decided upon and it was targeted. There were arousal assessments. The exhibition readiness testing, which we do, and then adjustment and weaning, but a lot of control given to the bedside nurse. And they compared it to 14 control sites who use quote unquote, usual care. And this is their enrollment diagram you can see. And in the end, about 1200 patients in each arm were included in the analysis. And I think it's interesting to look specifically at the agents that they found were used both in, you know, the protocolized arm was, you know, pretty well prescribed. So those patients were getting usually morphine and medallion. You can see here that morphine was much higher in the, in the protocolized arm than in the usual care where there was a lot more fentanyl. But both the protocolized and usual care arms were predominantly using medallion's use. So just like we saw with the guidelines, this is at the time of the restore study was done. This was absolutely standard of care for ice use evasion. Really a small proportion using longer acting, Benzos. And then in here, the secondary sedative category, we just see a, a hodgepodge of different agents. So a good number of places using DEX metatomating, interestingly more in the usual care arm because it wasn't really included in the restore protocol. You see here, ketamine, conidine, variety of different agents. So just shows you kind of the, you know, heterogeneous approach to this practice, especially for, so in the cases where there's not a protocol, kind of a variety of approaches. And the results of this study, especially in regards to the primary outcome, which was duration, mechanical ventilation, were negative. So there was no effect of the protocolized situation, duration of ventilation, and also on the adverse outcomes like withdrawal or safety events. Interestingly and importantly, I think for our discussion today, they didn't look at delirium in either arm or in any of the populations. So that's unfortunately something that we don't have from this study. There's another study, just a single center pre-post implementation that did show that the implementation of a standardized protocol reduced the dose of sedative infusions, but also didn't have any impact on the length of ventilation here. And you can see the infusion duration and the doses here for both morphine and medazlaminist study. And then finally, for those of you who have practiced in adult ICU recently, may be aware of at, I wonder about the daily sedation interruption. This is something that's really, again, standard of care and adult ICU's that has been adopted very widely across the country in the world. It's been shown to be effective at decreasing delirium in adult patients, as well as decreasing duration of ventilation. There was one multi-center RCT in the Netherlands of a few ICUs that used daily sedation interruption with a protocolized sedation approach versus just protocolized sedation. Unfortunately, they terminated prematurely, but they didn't see a difference at all and really no signal even in the number of ventilator free days in either arm. And it's an interesting topic to talk about is something that has not been adopted in PICU's and in PICU approach to sedation, largely, I think, because of sedation concerns, but also we just don't have compelling evidence that at this point that it would make a difference in outcomes. So all that being said, what do we have to guide us with the use of sedation? Well, there is some evidence that having a sedation protocol probably reduces variability in practice and may less an overall exposure, but there's certainly a lot of variability in agents by center and certainly by individual provider. And we don't really know that that's a bad thing, I think, in terms of evidence, we have good number of negative studies, but really nothing powerfully convincing us. And then so we get to the question of what's the problem with doing the wrong sedation or or not using the right agents. And so that's really where I'm going to focus the rest of my talk and really try to highlight ICU delirium and PICU delirium specifically, which has been a topic of a lot of discussion and publication in recent years. As you all know very well, I don't have to tell you that delirium is just described as acute brain dysfunction that's related to an organic cause, so underline medical condition of which we of course have many in the ICU, and then Iatrogogenic exposures on top of that, as well as some environmental factors in the ICU, which again we have many. So the DSM-5 describes it specifically as a disturbance in attention. And this is of course something that we see is much much easier to measure in an adult patient than in a pediatric patient. I'll tell you in a few minutes about some of the measurement tools that we have, but this is kind of the holy grail is to be able to assess a child's attention when they're on a ventilator and awareness of their environment and then additional cognition disturbances. So it's a very general description and of course can include a lot of different presentations. I think we think of it much like this comic depicts delirium, right? So this is and this is certainly much more a hallmark of emergency delirium, right, which is much more commonly identified in this kind of very hyperactive agitated phase. This picture is actually from an emergency delirium publication on the web. Just the very, very activated patient, you know, a lot has increased motor activity. We think about the patient who has restlessness, who's combative. We need to treat them in order to protect their devices and their lines. They likely have hallucinations associated with this, whether we can elicit them or not, in a baby or a young child, it may just be in consultability. And so this is kind of, I think, been a collective understanding of what delirium looks like. And more and more lately, we've come to appreciate the hypoactive presentation of delirium, which is much more difficult to appreciate, much more insidious. These patients may just be lethargic. Again, they may be inattentive, but in an ICU environment, this may be very difficult to elicit. And their response times may be decreased or they may have a longer response time. In adult patients, this has been associated very strongly with a poorer prognosis than the hypoactive type. And these may just be the patients who seem like they're good patients in the ICU, right? So they're not doing much. We're not giving them a lot of sedation voluses. And we have, they had a great night, you know, everything's good. But we may not be really picking up on what's going on in this surface. And then we have the mixed type of delirium, which is also quite common, along with hypoactive in our ICU cases. And these patients are the ones who vacillate between hypoactive and hypoactive presentation. These are patients who, classically, might be described as sundowning. So people say, I don't understand what happened. She had a great day. You know, she was really calm all day, and then totally wild at night. And we had to give her a ton of sedation. And so these are, these are really challenging patients to manage. And so I think, you know, in terms of description, you know, I think a picture is worth a lot of the type of patient we're dealing with very often is this type of patient, and it's to be the flu patient from a news article. But, you know, this is much more commonly how we're addressing a patient and trying to assess what's going on for them underneath. So how do we make that assessment? I'm going to tell you briefly about a few tools. The Cornell Assessment of Pediatric Delirium, you may recognize some components of it if you have used the pediatric anesthesia emergency salarium scale of a PAD, for which this is very heavily borrowed. So five of the eight components are from the PAD. And it speaks to interaction with the caregiver. This is administered after the nurse's shift based on their assessment of the patient. Do they seem to have purposeful actions? Do they seem to be aware of the surroundings? Are they restless and consultable? But then you can see they've added in some of the hypoactive features here. Are they underactive? Very little movement? Does it take a long time to respond? And this has been validated compared to psychiatric assessment and multiple studies. This is probably the most commonly used pediatric ICU delirium scale. Certainly you can already looking at these questions and the always-to-never responses. You can guess that there is some degree of subjectivity associated with this and certainly some challenges. And I'll talk a little bit about some of the challenges. There's also the Vanderbilt group has come up with a more interactive scale. Those of you who have worked in adult ICU settings are familiar with the CAM ICU by far the most common delirium assessment tool in adults. This is a pediatric version of that. You can see that's four components but very basically they have to have a acute excuse me acute change in mental status. And then the second and the fourth feature is both require interaction with the patient. The patient has to be able to follow a command for feature two and they also have to answer questions for feature four. Questions like is sugar sweet, things like that. You can this is validated for patients five and older. You can imagine and in the ICU setting with a sedated and to be the patient this can be very challenging. It's been one of the issues with implementation of this scale on a wide you know wide basis is that it's challenging for bedside nurses to be able to you know assess this and have this degree of interaction. There's also a preschool CAM ICU which similarly is down to six months and they have for feature two really just paying attention to pictures and for feature fours sleep, wake cycle disturbance. So I'm actually going to show you a video from this group hopefully to work of an infant who is being administered the picture portion of this. You really see just for the basic requirement here is that the patient focuses on the picture that's some tracking things interact with the patient. So you can contrast this with very similar patient similar age. You can see not really having any interaction with the picture. You might say this is just the way this patient is we have a lot of patients who don't necessarily this is the same thing later on. So I think that highlights pretty well how it can be difficult to assess the patient and how the patient as you saw in the middle with really the hypoactive delirium may just be unless you're specifically looking for this attention maybe very difficult to pick up and the ICU environment. So in terms of doing these scores for ICU patients we just have a recommendation from the European Society of Pediatric and the Inatal Intensive Care that the CAPTEE specifically should be the instrument used to assess the pediatric delirium that it should be done every shift at least and starting at least 24 hours after admission. And so this is really the only guidance we have about screening tools as I mentioned there are some centers that are using the PCAM and the PSCAM in some cases in addition to the CAPTEE and in some cases instead of. And so we're thinking about a patient who is delirious in the ICU if we've been able to identify them. I really like this diagram from the New England Journal. It's based on a lot of adult work that really is applicable to a pediatric as well and it really kind of depicts this what they call the ICU triad. So here you have delirium here and you have a lot of things contributing to delirium but certainly agitation and pain we know also contribute to delirium. And I've circled a lot but there are probably more here that I could circle that we have in the ICU. We have a lot of patients who have neurologic immunologic injuries or history of neurologic problems. We certainly have withdrawal unfortunately from sedative medications. We certainly have sleep deprivation. We have noise so all that we're trying to cut down. We have sedatives of course and then physical restraints and ability to communicate. These are all things we're trying to work on even ventilator synchrony, vascular access. And then certainly the underlying things that patients come in with tissue injury so trauma, other types of tissue injury and just the routine ICU care all contribute to both pain agitation and to delirium. So really dealing with a very heterogeneous milieu here and trying to understand. And then in terms of the mechanisms that we know of that contribute to delirium, these are all based on some basic science and some other translational work. You can see here we have the services in the colonurgic system. I'm going to talk a little bit more about that. We have the services in GABA, of glutamate, certainly cortisol excesses, something that we see serotonin dysregulation. So all of these things are also implicated in the development of delirium in different ways and we have different amounts of data supporting these. But you can imagine all the different both underlying conditions and also Iatrogenic exposures that you see benzodiazepines showing up here. But other things that we're doing in the ICU that may be contributing. So specifically in terms of a colonurgic deficiency, this is something we've been interested in. And the impact of anti-colonurgic medications on delirium, but also the underlying just dysregulation of the colonurgic system. And there's some basic science evidence that there's changes in the receptors that can affect cognition in the rousal. There's evidence of decreased acetylcholine synthesis. There is a lot of work being done on colonesterase activity right now. And we Dr. Ataskar and I have been working on a study that is funded by trailblazer looking at the acetylcholine esterase levels in our ICU patients. This is an area that hasn't really been looked at. But colonesterase activity is of course very important in regulation of the effective acetylcholine ethystenapses. So this is an area of active work. And then looking at kind of proxies for anti-colonurgic activity. And serum anti-colonurgic activity is one that's been looked at and mostly adult patients and has been correlated with delirium. And it's going to talk to you more about how we measure anti-colonurgic burden or the amount of exposure to anti-colonurgics that we're in the history in the ICU because it's another area of a lot of interest for us. And so really I mean I like this slide a lot thanks to Nadine which you have to see about sort of a multiple multiple factors hypothesis with some underlying predisposition to delirium based on age or other underlying features. High severity of illness. And then the precipitating factors that we know we're administering the ICU and the colonel of itself talk more about it. I'll mention benzodiazepines, immobilization, other metabolic derangements. And then you know the additional hits we know in some cases there is definitely neuroinflammation. These neurotransmitter abnormalities and dysregulations all contributing to the outcome of delirium. So what do we know about the manifestations of delirium and critically ill children and really the topic of my talk today. Why should we care about the fact that this delirium is happening in our patients. So this group at Cornell has put out a couple of series looking at the epidemiology and outcomes in a single center study of over 1500 patients. The prevalence was 17% and interestingly almost half were hypoactive and the other almost half were mixed. So you don't see a lot of the pure hypoactive form at all in this series. And there was a higher rate of delirium in the developmental lead delayed patients. They did see that patients who are delirious were more likely to be on anti-colonergic medications. Although the burden of anti-colonergic medications is high in all patients. And then in terms of outcomes they saw that delirium diagnosis was associated with an increase ICO and to stay increased duration mechanical ventilation and strikingly an increased mortality which for them had an odds ratio over four. And you know we can talk more certainly at the end. It's a controversial topic. I think you could argue there are some component of increased underlying morbidity, severity of disease and these patients. But this is the kind of evidence that makes us stop and think you know this is not just a diagnosis that makes it difficult to manage sedation for these patients. It's not just a diagnosis that maybe extends the ventilator time because we can't get them excavated as quickly maybe you know even if we're you know not focused on the experience as a patient of being delirious and what impact that may have in the long term. There really this may be something and has been has been shown an adult ICU series over and over again to be a diagnosis that is associated with increased mortality. And again whether that's causal or something that we're picking up I think it really gives us pause and makes us think you know mortality of 5% versus less than 1% you know certainly grabs your attention. The same study also did a multi-center point prevalence study of almost a thousand patients we participated in this year and they found a prevalence of delirium of 25% and 13% patients were deemed to be in coma so too sedated to assess but they found associations between physical restraints and you know high odds ratio whether this is positive or not this is a point prevalence study so we can't show causation but an association also with sedatives narcotics and other supports. And then we we want to also come back to in these studies that are using things like the CAPT to us to a diagnosed delirium to the scores that we're using and this is work that Robert Hasker and I did looking at the scores themselves the components of the scores and what are we picking up on in terms of the behavior of the patients and how that may interact and overlap with effective anti-coolenergics and overdoser or toxic dome of anti-coolenergics. And you can see here for the domains like motor alteration so uncoordinated repetitive movements things like that there's a fair amount of overlap here between the CAPT are withdrawal score that we commonly use we can see these get picked up with withdrawal score and also with anti-coolenergic toxic dome certainly with changes in state so time to sleep and consolability things like that. So you know just to add even more complexity to an already complex topic when we're dealing we're dealing with a multitude of different contributors and then we're also trying to weed out what's going on with the patient but we're administering the CAPT and looking at all these domains but we want to make sure that we're not diagnosing withdrawal as delivery or something excuse me like anti-coolenergic toxic dome and this is just excuse me then diagram showing overlap of these different symptoms and that there may be some symptoms that are more specific to to a syndrome so for withdrawal we're thinking more specifically about the gastrointestinal symptoms there's a fair and geol symptoms whereas things like you know behavior state those things likely to overlap with other things that may be going on versus you know constipation antidrosis and more of an anti-coolenergic picture in delirium we really have the interaction and attention feature that we're trying to pick up on. So in terms of anti-coolenergic burden is a busy slide but it just gives you a sense of some of the medications that based on validated anti-coolenergic drug scale which has been used in a lot of adult populations not so much in pediatric but it assigns a level of 3 being the highest to or one to a variety of medications based on what their anti-coolenergic activity is and you can see here Benadryl is a level 3 unsurprisingly so the polymineatropane um things that we maybe use less commonly in the ICU but certainly in the level level 2 we use we're knitting a lot and in the level 1 drugs you can see there are a lot of medications here that have some low level anti-coolenergic activity based on a variety of data and that are deemed in the literature about the ADS and other anti-coolenergic burden to be additive. And so these are all you know Bank of Mice and Barosamide I don't know if you can read these all very common medications that we use in the ICU and give you a little pause to think are we really tracking what medications we're administering and whether they may have a risk of anti-coolenergic effect. So Dr. Jasper and I looked at just this question what are we giving patients in the ICU in terms of the potential for anti-coolenergic effects we just looked at retrospective cohort of patients who were on a prolonged mechanical ventilation and we measured this ADS scale. We found that the median daily score was 5 in these patients and that the most patients had ADS over 3 so 11 out of the 15 days they had a score very in theory. This is in contrast with a similar adult study for adult ICU patients had a median ADS score of 2. So you know really something I think even just if you're thinking about awareness this is something that adults have been aware of for some time and are thinking about in the care of their ICU patients and I think we just haven't really been aware or thinking about the anti-coolenergic burden so maybe another thing to look out for this just shows you the medications that contributed to the highest scores and working in medazlam unsurprisingly because they're ventilated patients but also ferro-semide, winenadeem, and so on. So let's get to medazlam and medzadayazepiens this is a very hot topic and I'm sure we'll bring some controversy from the crowd and you know this is again we're a little bit later to this data than the ICU folks, it's you the adult ICU folks who have you know shown a correlation with between benzoes and ICU delirium for many years and have been moving away from using benzoedazepiens but we after seeing a bunch of sort of correlation studies showing that you know patients with delirium was always correlated with administering benzos of course we know there's a lot of reasons why patients may receive benzos so there were a couple studies here that looked specifically at benzoedazepiens and take you delirium and I think you know what's also compelling about benzoes is to say you know based on this work is that there is there is mechanistic validity to a correlation between benzos and and delirium both through the gabba pathway through you know some some evidence of impact on the colonergic pathway as well and the low level anti-colonergic effects of medazlam so I think it's both mechanistically plausible and also there's been mounting evidence so this is a series from Vanderbilt of excuse me 300 younger patients so one to three years they had a high rate of delirium over 40 percent and again showed that it was associated with a decreased likelihood of ICU discharge and they found really just two risk factors for delirium in their multi variable model and that was administration benzos and higher prism score or our risk of mortality score on admission and they didn't all the other things that they looked at sepsis need for oxygen opioid exposure fell out when they did the multi variable model so a little bit more compelling I think even more compelling was this paper from the Cornell group where they really tried to tease apart the timing of benzo exposure and the onset of delirium and they look specifically at the days of benzo exposure and the days of delirium and so in this model looked at the risk the outcome of this was a risk of delirium on the subsequent day so you can see if they had delirium on the prior day their risk of delirium and subsequent day was eight times higher so that's not surprising right but if they had any benzo day at the pain exposure on the day prior and they had two times ratio of delirium and that wasn't true for opioids it also it was true for the mechanically validated patients which has been seen in a lot of studies so a little bit more compelling here in terms of potentially more positive relationship or at least a sequential relationship right and they did this complex modeling where they looked at the dosage of medazelam equivalents received on the day prior to the onset of delirium and showed this pretty compelling dose response curve with an effect on delirium incidence after this medazelam exposure so again this is one study but in I think conjunction with a lot of evidence from the del ICU world has really had an additional impact in terms of our questioning our use of benzodiazepines really as a first line agent medazelam especially as the go-to for sedation and these patients you guys are much more familiar with sex amount of time even than I am and you could tell me all about its benefits does it seem like it's better for specifically ICU a delirium you know you know you guys use it all the time for emergency delirium a lot of effect there this is one series from about 10 years ago but a big study and RCT of almost 400 adult ICU patients and they did show that the dexmanituminin group had a lower rate of delirium than those who received medazels their primary sedative agent and if you're all where there's multiple other adult ICU and keep the anesthesia studies looking at the benefit of dexmanituminin this I thought was a pretty compelling graph showing that at baseline the delirium prevalence is pretty equal although high in this cohort and then you know with the advent of dexmanituminin use you see it you know pretty impressive decrease in the rate of delirium so things like this have been you know pretty effective at changing practice both across the US and and in the in the world and just in the last little bit here I want to talk about really kind of a cohesive approach and how this evidence has impacted our overall theory and and our practice around sedation and delirium and I really like this from Patel at all because you know there's a lot of there's a lot of components here I think it lays them out nicely you know that you know identifying delirium doesn't stop there as we're trying to educate everybody in the unit about if you have a patient who you think is delirious you need to assess for things that that may be causative so is the patient infected certainly you know an organic cause for delirium do they have gaff exchange issues is there untreated pain that is contributing to delirium they have metabolic abnormalities do they have a new neurologic injury that we need to identify that may be presenting as delirium and so you know the the cappede or whatever screening tool is used is not you don't just stop there when you get your score back but you go through and I'll show you what our unit-wide list is done but we're we go through the contributing factors factors in the patients themselves and then you think about the eye-astrogenic factors are we able to minimize sedation so we can better interact with the patients and assess their pain can we give them more cognitive stimulation you know are we treating substance withdrawal adequately can we avoid restraints is not always possible and the evidence in pediatrics again is is coincidental and not necessarily causative but I think we're trying to address restraints and whether that may be a contributing feature and then our weon medications that we don't necessarily need to be exposing the patient to more anticholinergic or other delirigenic features and then we're also trying to do a lot of environmental stuff and again for those of you who have been in an adult ICU recently their way ahead of us on this stuff but you know thinking about is there a way we can or mobilize patients we're doing a pick you up initiative in our unit and on a south but can we get patients moving earlier this has been shown in adult studies to be associated with decreased salirium cognitive stimulation although it seems like maybe counterintuitive you should leave the patient alone if they're delirious there's been evidence that you know reorienting and as you know reaffirming the patients where they are and doing those kinds of activities is beneficial plusard care something that we have been horribly guilty of in the pediatric units of weighing the patient and giving them a bath at three o'clock in the morning right so and and that's not great for sleep hygiene it's not great for day night cycles and so thinking about trying to cluster things when the patient is awake and really trying to enforce patients awake during the day this is not very popular with tired patients and families who want the lights out during the day but these are the kind of things we're trying to you know get the sleep patterns reinforced and then at the very at the end here are the considerations for pharmacologic treatment of delirium and dexamitatomy if they're not already on it and then I'm going to talk a little bit about antipsychotics in terms of the sedation approach what's called a now-go sedation has you know taken on wings as a popular approach in recent years and what this basically is is really is the approach that preferentially uses opioids IV opioids before using sedative agents like enzymes or a proper fall and whereas before I think our practice is much more to use them in concert and to use them at the same doses estlally in the same doses now I think there is much more focus on ensuring that the patient's pain is adequately treated this lighter level of sedation which allows you to assess the patient better so whereas before you might have just you know assume that patient was fine if their SPS score was in range and they were pretty much asleep all the time except when we were doing things to them this lighter level of sedation you know the thought is that it allows us to get more accurate pain scores and one study by Faust at all that looked at just 144 patients you know sort of pre post intervention study did show that there was improved pain management and the patients who had this type of sedation approach and really sort of dramatically reduced the amount of sedative infusions that they were using and so this is something that again it's been sort of a hot topic it's taken on and a lot of pediatric ICU's we recently and the MSI's you and on 11th self have adopted a similar approach this is very busy but just to basically show you that for an intubated patient who comes to the unit or who's intubated in the unit you really have a initial initiation of dexameta tomning as the first agent but very quickly you're distinguishing whether the patient is in pain did they have a painful operation we know they're going to have a lot of pain they go down this left side we do enhancement and maximization of standing in algegia you know in patients where diathopam is appropriate can we get a regional or do we already have regional blockade that would be helpful so maximizing pain control if those you know if those things are maximized them going to IV and then I'd be continuous opioids if there is an expectation of pain or the test the patient they're not in pain then we're leaning more heavily on dexameta tomning and then adding on intermittent opioids and opioid infusion with really the addition of benzodiazepines and preferentially out of the end but you know in general using benzodiazepines as a sort of third or fourth line agent after maximizing dexameta tomning and opioids and then in terms of our delirium initiative this has been between seven south eight south and eleven south and shout out to eight south folks who came up with the pink elephant logo and this nice branding and our our acronym for the multiple causes contributing to delirium is mopez which only makes sense if you think about the elephant on a mopez because otherwise like why would mopez have anything to do with delirium but it does is I prefer it to the other common pick you acronym for delirium which is ic death which you may have heard which I just find to be a little bit too intense but so we go through the different contributing features to delirium do we have decreased mobility do we have an ability to optimize mobility is organ function disturbed oftentimes we can't do anything about this but it helps us kind of investigate again going back to investing in the causes and really having the holistic approach to the delirious patient pain management you know really trying to assess the patient may seem like they're asleep but are we really getting effective pain control we're doing a lot of environmental modifications and interventions and this is in in conjunction with the pick you up initiative and again it's not always the most popular to come in turn all right open up the shade but you know the you know very much that sleep is very disturbed in the ICU and that there's some signal in adult ICU series that these kind of interventions alone impacts the risk of delirium what drugs are we giving and you know oftentimes it's not possible to avoid a medication with anti-cool allergic effects but sometimes it is and is there an opportunity to review the anti-cool allergic burden from the medications that we're giving and then can we do things to enhance sleep I haven't talked a lot about sleep sleep is a talk in and of itself but we are doing things to try and enhance sleep like melatonin earlier in the ICU course to try and get again these day night cycles established so that we may be able to eliminate that cause of delirium what about treating with anti-psychotics this is a controversial topic and I'm not going to talk about I'm just going to tell you about two RCTs that I think in adult ICU literature have been pretty compelling in terms of a couple of questions with anti-psychotics this one recently published in JAMA a large RCT of almost 2000 patients where they tried to prevent delirium with halidol versus placebo and short answer is no effects so it doesn't seem like there's any benefit to trying to prevent delirium in these adult ICU patients and then another big series looking at halidol versus an atypical anti-psychotic versus placebo or patients with delirium in the ICU these are sick patients with you know arDS or shock and they didn't find any difference in their primary outcome which was days alive without delirium or coma in any of the groups and you can see that half of my occurs here they had a very high rate of hypoactive delirium and so the kind of prevailing with the now is if you have a lot of hyperactive features that are needed to be treated for safety you know we're still using these agents for safety but in terms of impact on the bad outcomes we see from delirium we don't have any evidence that treating with anti-psychotics makes a difference for those and may change the experience of the patients it may be be necessary for safety of lines and tubes or ICU care but we don't really see any benefit in terms of the outcomes we're interested in so hopefully leave a few times a few minutes for questions where do I think we are right now I think as a field we're trying hard and it's it's a difficult task to move slowly towards a lighter approach to sedation with really more emphasis on assessing and treating pain whatever possible we are understanding more that delirium is at least associated with increase morbidity in the pick you these patients have a higher risk of not doing well and there's some evidence that it may actually be causative for increase morbidity and it's linked to higher mortality and something you need to really be aware of there are eye-atrogenic causes of delirium that we can modify we can't modify everything obviously as I hopefully have shown you there's there very complex patients with a lot of exposures but there is an opportunity to do better these benzodiazepines bearing regimens are gaining popularity I think are becoming more and more kind of a standard and we're not really sure that treatment with anti-psychotics has any benefit where do I think we're going I think there's a lot of questions to answer if anyone's interested I think it's a great field to to be in now in terms of also translational and basic science research we have really a huge problem with managing sedation under chemical paralysis that we really don't have our brains wrapped around yet and how we can assess those patients biomarkers of delirium and delirium risk I think are coming and maybe helpful in terms of categorizing patients and what exposures we should be focusing on yeah I think this is obviously a syndrome with heterogeneous causes and further categorizing these patients by mechanisms and ideologies I think will be useful going forward and you know I think hopefully down the line there'll be treatments other than just kind of removing exposures that may be effective but currently we don't really have any evidence of that I just like to end on this I won't read it out to you but these kinds of stories that unfortunately almost always come from adult ICU patients have a big impact on me when I'm thinking about this work as we very commonly can't understand what our patients are experiencing even after they're excavated they can't tell us the types of things they're experiencing but if they're experiencing anything like this with delirium if they're thinking that they're being set on fire they're being put into an oven those those things that really have an impact I think I'm thinking about prevention of this of this experience and for this patient especially he had the symptoms for months after his ICU discharge we know kids are incredibly resilient but I think this question of what works those in our kids too in the ICU what impact they have on long term and how we can be better I think is a good one to tackle by going forward and thank you very much for your attention she did yeah Kate thanks so much for a big topic lots of information or incomplete information which is really the challenge and I want to thank our anesthesia and critical care pain management teams for joining us in surgical ground rounds and short notice this morning having had such a key speaker to us all open this up for questions Kate your passion for this subject and your leadership here comes through thank you for that great overview as you noted this is an awfully difficult area to study there's so many exposures that are overlapping and to know actually what is causative you pointed out I noted that there's a large absence of serum studies examining whether in fact the exposure leads to serum levels that may be more associated with what we're seeing why is that the case and is there anyone working on that yeah I think most of that work has been done excuse me in the sort of colon or jick field so and one of the problems is that there have been a few things that have been tried that haven't worn out anything so for a while people are measuring this serum in the colon or jick activity and and tying that to a delirium presentation but it's really been fraught with a lot of issues and fundamentally I think people are concerned that the the peripheral measurement of anti-colonage activity probably doesn't really reflect what's happening centrally and so that's why there's been more interest in this colon esterase I think that's where a lot of the kind of biomarker stuff that's happening now is a levels of colon esterases in post operative and other delirium and there you know they have been studies looking at CRP and other inflammatory markers as but of course we know there was a very non-specific and I think that you're always comparing the issue is I think what Robert would probably say is that you're always comparing these levels to an imperfect tool like the CAPTI which is kind of the standard of measurement of delirium but that is likely capturing the stary heterogeneous group and that's why I think being able to drill in on patients who have a specific risk or specific exposure that may be more amenable to a specific biomarker tracking would be more more fruitful but I think you know this that's why I said sort of categorizing these patients a little bit better as versus just like their CAPTI score is elevated but it could be a million different things is probably the most important thing to happen next. Okay that was a great talk so the most of the focus has been on things that we do to patients that cost delirium but as you know a lot of these patients are long-stay patients if you think about what are the categories of long-stay patients they they're often infected or ARDS or something what gets a patient on the ventilator a long time or some surgical very inflamed patient with a long healing time and so and and septic patients can present the lyr with delirium and cognitive changes is actually now the part of the definition for adults so I'm just wondering how much of this you know people haven't focused on the disease process and is inflammation systemically that's also inflaming the brain and maybe these drugs they have a role because there's but they also are you know commonly used and these are long-stay patients with a lot of inflammation. Yeah it's really interesting and I think you know we're we're hopefully publishing soon a look at our septic patients because that you're getting the septic septic associated and septal apathy patients are really interesting and a lot of cases they're an adult ICU is they're actually diagnosed by delirium scale so there's so much overlap between sort of ICU delirium and septic associated and septal apathy there's a fair amount of evidence again translational and and animal evidence about colonurgic dysregulation and the in the four brains specifically in subcissus and in these in these inflammatory syndromes and so I think you know I I think it makes sense to kind of focus on what we can do something about and you know the under these like patients who present with septic or ARDS so we can't necessarily address the underlying mechanism as well but I do think that for example specifically with the colonurgic dysregulation that's been seen in some animal models of septic that you know we certainly don't want to be adding fuel to the fire by further dysregulating the colonurgic system by giving antichonurgic medications and other things and so you know there's I think the interplay between like with the diagram I showed that you know you have the underlying disease process which in a lot of cases we can't necessarily address those specific mechanisms but we can at least modify the degree that we're we're sending that with other exposures yeah I agree. Kate it seems odd that we're not trying to monitor the brain more in assessing this problem and its treatment it's early recognition the need for medications can you comment on the state of EEG monitoring or other neurologic monitoring to help I really wish Robert was here because whenever I talk to him about EEG's like it's not as doctorate be helpful I think you know one of the issue the major issue that we have with EEG specifically in these patients who especially are undergoing pharmacologic sedation and are you know we're trying to distinguish between a fair amount of chemical sedation versus delirium those patterns on EEG are just very difficult to assess you know because you see so much dysregulation of the EEG with sedation alone and that's my very non neurologic assessment of why EEG is not used more commonly there have been studies looking at EEG patterns in patients with a clinical diagnosis of delirium and nothing has really come through as being a hallmark of like okay we can we can look at this and say for sure this patient meets criteria based on EEG I think it would be really helpful it mirrors would be another great thing to be able to use and that hasn't really been looked at I think it's an area that's when I I said you know especially for the patients who are chemically paralyzed who we can't assess or who are very deeply sedated for other reasons that we really can't do a delirium assessment those are the patients I think we really need some other kind of monitoring and hopefully one of you guys will come up. Well I think we're we're at the hour it is a tremendously important and fast-thanks topic seems like a little bit of a black box with all this class the evidence in the what all the areas where the adult world is a little bit ahead of the pediatric world we have challenges particularly we get to the nicoids even the sort of a more difficult challenge because there's no even hope of them communicating to us in an verbal or meaningful way as we're sort of evolving from having been taught and some of our era that pain actually some of us were near where it was still not clear whether babies had pain or the baby's experience pain I don't know if some of you can't believe it but that was actually a question to now of course babies feel pain and we went through and hear some of us where if a pinky finger moved we needed to give more narcotics and sedation to now we're understanding that narcotics are opioids are being overused and we're creating a problem all the interaction with this is fast-thinning so I'm expecting a decade from now that you're going to have it all clear and explain it to us. Thank you very much.