Good afternoon, everyone, or I suppose it may still be late morning for some of you. I'm Kirsten Wilkins, I'm a geriatric psychiatrist who works at the VA in West Haven, Connecticut, and I'm professor of psychiatry at the Yale School of Medicine. Really pleased to be here today to talk to you about delirium. I have no conflicts of interest to disclose. So what I hope you all get out of this talk today is an ability to, if you don't already, have the ability to define delirium and explain its importance, thinking both about short-term and long-term outcomes. Hope you'll also be able to describe the epidemiology of delirium, predisposing and precipitating factors, explain the diagnosis and evaluation of delirium, including screening tools and investigative studies, and finally discuss non-pharmacologic and pharmacologic management of what are the most distressing aspects of delirium, the behavioral and psychiatric manifestations. So what we can look forward to here in the next 45 minutes or so, again, a rundown of definitions and epidemiology, I'll talk a little more about the impact and outcomes of delirium, how delirium presents, because I think the various different ways that it can present can make it challenging to diagnose at times, the etiology, of which there are often many causes of delirium, how do we assess delirium, how do we prevent it, perhaps most importantly of all, and there have been a lot of, you know, a lot of research looking at this aspect of prevention in the literature lately, and I think that's really worth covering maybe in a little more depth than I know I've covered in the past. And then lastly, we'll talk about management, non-pharmacologic and pharmacologic management. So first, some definitions. What is delirium? What does DSM-5, you know, require the criteria to be met to diagnose delirium? First and foremost, delirium is a disturbance in attention, and I think that's just one of those really key factors we have to keep in mind, especially as we think about distinguishing delirium from dementia. So a reduced ability to direct, focus, sustain, and shift attention is a really key component of delirium, in addition to a disturbance in awareness or level of consciousness, a reduced orientation to one's environment. And importantly, we know the criteria must be met that it develops over a short time, and again, this helps distinguish delirium from dementia, which takes place on the order of months to years of developing. Delirium tends to develop more on the order of hours to days, and it tends to fluctuate even within the course of a day. We do see additional disturbances in cognition, memory deficits, disorientation, perceptual disturbances, and lastly, we must know that the disturbance is the direct physiologic consequence of a medical condition and not due to a preexisting dementia. I think that one's particularly important, that we really need to get the timeline straight so we can determine delirium versus dementia. Delirium has many other names that it tends to go by in our healthcare settings, and I always think it's just important to review the different names that we may hear other specialists, what we in psychiatry refer to as delirium, sometimes it's called altered mental status or acute mental status change, maybe by our colleagues in the emergency room. Sometimes our hospitalist colleagues may use the term toxic or metabolic encephalopathy. Hepatic encephalopathy is often a term that's used brain failure, but all of these we know as delirium. So why is delirium important? Why is it something that's really essential to include in a gerocyte review? Delirium is very common. In fact, it's the most common psychiatric syndrome that's seen in the hospital setting. Unfortunately, it's often unrecognized. Studies suggest anywhere from a third or two thirds or more cases of delirium go missed by doctors and nurses. Delirium has a lot of complications associated with it, and we'll go into those in some detail. And it can be challenging to identify a single etiology because so often delirium is multifactorial. We have to really consider what are the predisposing and precipitating factors that may confluence together here to cause delirium in an individual. And lastly, it's important because, as I mentioned earlier, it's preventable. We now have studies telling us there are things that we can do that can reduce the likelihood that somebody will get delirium. And so educating and familiarizing ourselves with how we can prevent delirium makes it a very important topic as well. We can't always say that for a lot of illnesses, that we can prevent them, but this is one where we really can make some difference. So I mentioned delirium was common. I said it was the most common psychiatric syndrome that you see in a hospital setting. But it's not limited to the hospital setting. And in fact, prevalence rates in the community are estimated at about 1% to 2%. I think this is important to recognize because I know for many years myself, certainly as a trainee and early in my career, would associate delirium with the hospital. This is something I would see in the hospital. And so it wouldn't even necessarily be on my differential for a patient that I saw in clinic. But it really should be any time we have an older adult who presents with memory changes. And many of them do present to the outpatient setting first. And so be aware that delirium could still be in your differential for an older adult who walks into the clinic for a cognitive evaluation. Among hospitalized patients over 70, rates range from 11% to 42% having delirium. About half of those will have it at admission, and the other half will develop it during the time of hospitalization. Post-operative rates range from 15% to 60%. And they are particularly high for cardiovascular surgeries, emergency orthopedic surgeries, and vascular surgeries. The ICU is, of course, a very common setting in which to see delirium. Over 70% of patients in the ICU are estimated to have delirium. And we know that there are many environmental factors about the ICU that can perpetuate or exacerbate delirium. We don't think of the ICU itself as being the cause, because certainly the people in the ICU are very ill and have enough metabolic, toxic, and otherwise processes going on to contribute to delirium. But the poor sleep-wake cycle that's often happening in an ICU setting, the unfamiliarity, the lack of visitation, et cetera, can make it a place where delirium really tends to fester. And lastly, even in nursing home settings, we see fairly high rates of delirium. And this was something that I would see when I was doing nursing home consultations. Similar to an outpatient clinic, you would get a consult for dementia. And it would be a patient that had been discharged from the hospital recently, had been diagnosed with delirium while in the hospital. And it would have been easy probably to say this patient has dementia if we had not known that there was a recent episode of delirium and that it was likely that the delirium had yet to fully resolve. And we know that delirium sometimes lags behind the treatment of the underlying conditions. So we will still see it in people that are in nursing home settings and outpatient clinics who are still recovering from a recent hospital stay. So delirium has many impacts and complications. People with delirium have poor functional recovery. They tend to have more protracted medical illnesses and increased morbidity. So folks that have delirium are at higher risk for pressure ulcers, aspiration pneumonia, pulmonary emboli. They tend to need more walking devices on discharge. They tend to stay in the hospital longer, and they tend to cost the health care system much more. Estimated costs anywhere from about $40 billion to $150 billion. So a lot of money goes into the care of individuals with delirium, you know, in the country, in the world, really. Those that have delirium are more likely to be placed in a rehab or nursing home at the end of their hospital stay. And again, I think that raises that point earlier to be made that for those that work in nursing home settings, keeping delirium in your differential any time you get a request for a cognitive eval is really important because many of those individuals that have just been placed from the hospital will be, again, still resolving their delirium. And lastly, delirium leads to a high amount of caregiver burden. And we know that our caregivers of patients with dementia certainly have higher rates of depression, anxiety themselves. And delirium can be something that can be very frightening for the patient, of course, but it can be very frightening for family as well to see a loved one completely confused, hallucinating, perhaps delusional, agitated. And so there's a great deal of caregiver strain and burden as well. We used to think of delirium as something that was wholly reversible. That was the, that was the training that I got, you know, when I was in medical school, delirium is reversible, dementia is not reversible. What we know now is that unfortunately delirium increases one's risk of future cognitive decline and dementia, and that the cognitive impacts of delirium are not always fully 100% reversible. Especially in older adults who have a lot of risk factors anyway, it may be the case for maybe a younger, previously healthy adult. But in our older veterans, excuse me, older patients work at the VA, it's hard to shake that term, in our older patients, we do see those with delirium have increased risk of future cognitive decline, twice the rate of decline compared to older adults that are not delirious in the hospital. And this rate of decline can actually extend out five years. So again, a far reaching impact. And we know that people that have delirium have a 12-fold likelihood of developing dementia compared to people who do not. And it's not entirely clear yet what this relationship between delirium and dementia is. Some theories that have been postulated include, is delirium some sort of marker of an underlying vulnerability that one's brain has to developing cognitive decline or impairment? They have similar precipitating factors. Certainly we know vascular risk factors, strokes and TIAs can lead to delirium. Those also can lead to dementia. Or may there be permanent neuronal damage that happens during an episode of delirium? So different theories as to what that relationship is, and it likely is multifactorial. So who is at risk for getting delirium? Obviously because we're talking about this today, you know, older adults are a large, you know, age itself is a large risk factor. We see that in young adults, young children, I should say also do get delirium, but our today focus is obviously older adults. Those with dementia. So anyone that has an underlying vulnerable brain, if you will, or injured brain in any way post-stroke, dementia, et cetera, is a higher likelihood of developing delirium. Even mild cognitive impairment can place one at risk. Other risk factors or predisposing factors for delirium include functional disabilities, multi-morbidity, visual and hearing impairment, substance use disorder, and depression. And substance use disorder, I think deserves a special note because this is often neglected in our older patients. It's easy to sort of make assumptions about substance use in older adults that this is something that if they did have it, it's probably not happening anymore and, you know, is not likely to be happening in an older adult anyway. But I think we really have to challenge ourselves and make sure we're asking about substance use, talking to collateral, if we're not able to get a good history from the patient themselves. Now what about precipitating factors? What are the kinds of things that tend to tip delirium off? The more predisposing factors somebody has, the fewer precipitating factors it takes to trigger a delirium. And we'll go into some of these in a little more detail, but just briefly, medications. I mentioned earlier post-operatively, surgery, anesthesia that's used in surgery, pain, all these things that often take place after a surgery can be quite challenging for folks for a variety of reasons and can precipitate an episode of delirium. Infections, many causes of infection can lead to delirium. The use of restraints, which is a very challenging problem when you have somebody who may need restraints for their own safety. But we know that restraints are associated with delirium and can perpetuate confusion, paranoia, disorientation, not to mention be uncomfortable for people. Dehydration, falls, many more. The list of precipitating factors is quite long. I think these are some of the more common ones we see in our older adult population. So how does delirium present? As I mentioned earlier, it's often unrecognized and missed. The hyperactive component, where as the name implies, an individual is more likely to have the agitation, resistance to care, maybe more of the quote positive symptoms of psychosis. These are the patients that come to clinical attention. We hear from our healthcare colleagues that work in nursing and so forth. This patient is behaving unusually, they're problematic, they're impairing their own care, they're endangering staff. Those are the folks that actually get recognized because they come to our attention and therefore we can begin to investigate what's going on. Because of that, the hyperactive subtype of delirium actually has an improved outcome and a better prognosis. The hypoactive form of delirium, where patients tend to be more apathetic, withdrawn, maybe resistant to care, but not in an agitated way, more of an apathetic withdrawn way. These folks are often missed because they may appear depressed or they may just appear to be sleeping, resting, and it may not be apparent until someone does a little bit more of an evaluation that there actually is a hypoactive delirium going on. And then certainly mixed type where you see features of both can be common as well. Delirium presents with a variety of symptoms and some clusters of symptoms I think that are worth visiting here. Cognitive symptoms first and foremost. I mentioned earlier the inattention really being that core symptom, memory impairment and disorientation being common, but not necessarily distinguishing it from dementia. With regard to behavioral symptoms, again, could be agitated, hyperactive, could be hypoactive. Resistance to care is often common as people are confused and they don't understand why is somebody coming at me that I don't recognize wanting to give me a medication that I'm not sure what that is. And so that can be, that can then manifest in some resistance to care as somebody struggling to comprehend what's going on, where am I and who are these people that are trying to give me medications or trying to change me or trying to bathe me that I don't know. Psychiatric symptoms, paranoia, delusions, visual hallucinations. What I think is worth mentioning, if you all haven't seen, I'm just going to put a plug in. There's a really wonderful video that the Atlantic put out a couple of years ago and the title of the article was COVID is a delirium factory, COVID-19 the delirium factory, something like that. And it actually shows some interviews of people who had delirium due to COVID and the way that they describe their experience, I think is really compelling. And it's not something I've forgotten since I saw that. And having not gone through delirium myself, it really helped me to really empathize with how confusing and utterly frightening it must be to experience delirium. So just encourage that if you haven't seen that video, I think it's very helpful for learning purposes for your trainees, colleagues, et cetera. How about delirium versus dementia? I keep referring to those together because it's important that we distinguish the differences because many of our non-psychiatric colleagues and a lot of lay people will get these two confused. They do share some things in common. So things in common that they have written in black here, impaired memory, disorientation, the sleep wake cycle, sometimes hallucinations, both can experience psychosis. Both can experience lack of insight or impaired judgment, but truly delirium is distinguished by again, clouding of consciousness, a major attention deficit, fluctuations, and that acute onset. So what are the causes of delirium? Delirium can be secondary to another medical condition. It can be secondary to substances, whether you are in a state of intoxication or withdrawal. And most commonly, it is secondary to multiple etiologies. I really like this quote by delirium guru, Sharon, anyway, who says, rarely is delirium caused by a single factor, rather it is a multifactorial syndrome resulting from the interaction of the vulnerability on the part of the patient, either predisposing conditions and hospital related insults, i.e. medications and procedures. And I think we'll, as we think about the hospital potentially being a precipitating factor in its various insults, we can think about prevention, you know, how can we as a healthcare system and a hospital prevent delirium? So what are the can't miss etiologies of delirium? These are the things that we like to tell our trainees that are really important. If you get that call in the middle of the night that a patient's having an abrupt mental status change, what are the things that I want to be thinking about and asking about so that I don't miss these very urgent etiologies? Some folks use the mnemonic WIMP, that's W-H-H-H-I-M-P, or Wernicke's delirium due to thiamine deficiency, hypoxia, hypoglycemia, hypertensive encephalopathy, intracerebral hemorrhage, meningitis or encephalitis, and then poisoning, which could also include obviously medications, substances, etc. So these are the kinds of things that we want to think about urgently and really not miss if they are present. The differential diagnosis going from then on is quite broad. Again, many, many medical conditions can lead to delirium in the right patient with the right predisposing factors. Infection is a huge cause of delirium in our older patients. And this one may be challenging for our family members, our caregivers, to understand. How can something as seemingly benign as a urinary tract infection cause so much havoc to someone's behavior and psyche? And so really explaining that, again, in a vulnerable person, it doesn't take a lot to tip somebody over into delirium. But different types of infections certainly have been associated with delirium. The use of intoxication or withdrawal from a variety of substances. And again, I think keeping in mind, it could be both states. So just because someone's not using now, or maybe not in the past 24 hours, doesn't mean that a substance couldn't still be playing a role. Metabolic and endocrine etiologies, including hypoglycemia, thyroid abnormalities, anemia, certainly trauma, cerebrovascular etiologies could include stroke, seizures can also be an etiology, vitamin deficiencies, I mentioned thiamine earlier, vitamin p12 also, cardiac, and other conditions as well, including but not limited to hyperthermia, hypothermia, but it really helps whether one uses a mnemonic or whether one has a systematic kind of approach that they think about kind of systems system by system in an individual patient, but to have an approach that allows you to sort of think through all of the different body systems that could be involved and that are worth investigating and which ones might be more likely given an individual given their past medical history, etc. I mentioned medications earlier and I think that's especially worth noting because again so often we see iatrogenic causes of delirium in a hospital setting. Anything that has anti-cholinergic properties that might include our tricyclic antidepressants, anti-spasmodic agents, some of the anti-parkinsonian medications, you know, anything that has the ability to decrease or limit, you know, availability of acetylcholine is going to contribute to delirium. Opioids, benzodiazepines, and sedative hypnotics are still prescribed, you know, despite all we do, we've done a lot of education and I think appropriately so. We've cut back on prescribing a lot of these medications, but we do still see many older adults being prescribed these medications and often being misused, maybe not purposely. Again, if somebody already has a vulnerability, maybe a mild cognitive impairment, it might not be too difficult to think about the possibility that a dose could be taken extra if one was forgotten and then doubling up or accidentally tripling up, you know, can certainly contribute to development of delirium. Steroids, we know, have a host of mental health side effects and delirium can be one of them as well. Antihistamines and certain antibiotics, I think it really speaks to the value of a thorough medication inventory, including prescription and over-the-counter medications and supplements anytime that we're evaluating a patient with delirium. So while the pathophysiology of delirium has not been fully elucidated, but it certainly seems likely that it is a kind of a common pathway. It's the end result of a common pathway of multiple factors that result in impaired brain function. And some of these factors likely include, I think again we're still figuring this out, but likely include neuroinflammation and oxidative stress, neurotransmitter imbalances. Again, as mentioned earlier, decreases in acetylcholine are associated with delirium. Meanwhile, folks with delirium are seen to have potentially increased increases in glutamate, norepinephrine, and dopamine, which can contribute to some of the psychosis that we see, some of the hallucinations, delusions. There can be dysfunction in the reticular activating system, which can lead to some of the difficulty with maintaining a stable level of consciousness. Cerebrovascular dysfunction, impaired network connectivity, and altered brain metabolism have all been theorized as playing a role in the neurobiology of delirium. So moving on to diagnosis. So history and physical always goes without saying, but I think just a couple of points to mention about it. One, the timeline of symptoms, so essential. And I think that's where we really will rely on our collateral informants, because an individual with delirium probably by definition is not going to be able to give us a very thorough history of when did these symptoms start, you know, what was the premorbid cognitive and functional ability like in this individual. And that's where we really, really need input from our caregivers to find out, you know, what this patient was like before. Is there a history of dementia? Is there a history of cognitive impairment? Any new medications? You know, obviously getting medical history, mental health history, et cetera, substance use history are all really important aspects of a delirium history. And as I mentioned, a thorough medication inventory being part of that as well. Physical exam with special attention to vital signs, looking for any evidence that somebody might be in withdrawal or potentially have an infection going on. The mental status exam, obviously that's part and parcel of what we do. But again, thinking about level of alertness, ability to focus and maintain attention. And then screening tools. And there are validated screening tools specifically for delirium that I'll go over that I think are very helpful and perhaps more beneficial in terms of actually making a diagnosis of delirium than our old faithfuls, the mini cog, the mocha, the mini mental state exam. I do think there's a role for cognitive evaluation using tools like a mocha or a mini cog. But I think it's important that we not consider those tools diagnostic of delirium. They are diagnostic of cognitive impairment, or I shouldn't say they're diagnostic, they're screening for cognitive impairment. But they don't tell us if somebody has delirium versus dementia. They may be helpful in tracking cognition over time. So let's talk a little bit about the confusion assessment method or CAM diagnostic algorithm for delirium. If you look up the CAM, you'll see that there are many different versions and there are different depths of detail that the different tools go into. So depending on your needs, if you look up CAM, you'll find many different versions. You'll likely find something, there's a CAM ICU. And then there is this most brief and I think succinct diagnostic algorithm. And this algorithm requires in order to diagnose delirium, that one have had an acute onset and fluctuating course and the presence of inattention. And then they can have, or they should have, I should say, they must have either disorganized thinking or altered level of consciousness. So one plus two and either three or four equals delirium. And this has been found to have very high sensitivity and specificity for delirium. And again, will certainly help rule out folks that have dementia because we typically do not see that acute onset and fluctuating course with dementia. And usually, maybe until severe stages, attention will be retained in those with dementia. An alternate screen, if you wanted to go even briefer, might be the ultra brief two-item bedside screen. And this was developed by Fick and colleagues a few years back. They found that using two items, one, what is the day of the week? And two, name the months of the year backward. That if a patient couldn't do either of these, that they were able to diagnose delirium in 93% of the cases. And actually, if they only used one of them, name the months of the year backward, they picked up about 83% of cases. And they found that this two-item bedside screen worked well, even in patients who had preexisting cognitive impairment and whom delirium is often missed. So this may be another option for folks if you're looking for something that's a very, even briefer, just something you can do at the bedside. What's the day of the week, name of the months, the year backward. They can't do those two, high likelihood of delirium. Moving on to investigative studies. Again, I don't think any surprise to folks in this audience, but certainly we're going to want to do a thorough evaluation once our history and physical is complete. We're going to want to get those usual labs, CBC, basic metabolic panel, urinalysis, very important in older adults. As I mentioned earlier, urinary tract infections being a particularly common cause of delirium. Don't forget a urine tox screen. Again, we don't want to make assumptions about our older adults and substance use. Other labs listed here, chest x-ray, electrocardiogram, and then other tests as indicated, LP, neuroimaging, certainly depending on the patient's presentation, exam findings. And if there were any kind of red flags in the history that might indicate trauma or other stroke, et cetera. EEG, I would say is not something that is typically used in the workup of delirium. If you do an EEG in delirium, you typically find generalized slowing, which is not very specific. And it's certainly not going to tell you what the cause of the delirium is or the causes, I should say. Some specific findings that one may see in hepatic encephalopathy include triphasic waves and alcohol or benzodiazepine withdrawal, may see low voltage fast activity. And I have seen times where EEG was used to differentiate between a hypoactive delirium and depression. And certainly if seizures are at all in the differential, one would get an EEG. Okay, so how can we prevent delirium in our older adult population for whom we know and we've made a case here that delirium has very significant impact and complications? How can we prevent that from happening in the first place? Well, Sharon Inouye and colleagues in a very seminal study published back in 1999 looked at something that was then called the Hospital Elder Life Program or HELP. And I recently discovered that this has now been renamed CO-CARE, and it's available on the American Geriatric Society website if anyone is interested in learning a little bit more about that. But basically what they did was they developed standardized protocols for six known risk factors for delirium. And those risk factors, I don't know if I'll be able to remember them all, but they include things like cognitive impairment. So providing, so maybe the protocol might include providing regular reorientation, having familiar objects in the room. And another risk factor might be immobility. So the protocol might include efforts to get somebody mobile as soon as possible, you know, once they're finished with surgery or once they're admitted to the hospital, you know, trying to keep them mobile. Another risk factor, poor sleep. So they would implement a protocol to promote sleep hygiene. So these were just some examples. So they identified the risk factors, developed some standardized protocols, all non-pharmacologic, and they found that implementing these protocols for the risk factors reduced the incidence of delirium, decreased the total number of days and episodes, reduced cognitive and functional decline, and decreased cost. Less sitters needed to be used, less falls. And so it really was a very powerful study to show that there are things that we can do in our environment, you know, in a healthcare setting that can make a difference in preventing delirium. Other studies that have looked at ways to prevent delirium non-pharmacologically include use of proactive geriatrics consultation. And many of you may have this available to you at your hospital. We do in our VA, where surgical patients who are known to be at risk for delirium are asked to be served, you know, asked to be seen by the geriatrics consultation service. And they will interview the patient. They might perform a baseline cognitive assessment, mocha or slums, do a medication inventory, and make recommendations for the team based on that individual's needs, letting them know what their risk of delirium is. Maybe they want to give, maybe they want to recommend giving standing Tylenol orders for pain. Maybe they want to reduce, you know, the patient, maybe the patient now has three PRN medications for sleep, and they might recommend to the team, let's try to just minimize the sleep medications, maybe just one medication, maybe trying melatonin instead of temazepam, PRN. And in this case, they found the number needed to treat to reduce the incidence of delirium was 5.6. So this, the proactive geriatrics consultation, I recognize is not always a resource that all people will have. But when it is available, it certainly can help prevent delirium. Another study looked at home rehabilitation versus hospital rehabilitation. After acute inpatient admission, they found a reduced incidence of delirium when folks were allowed to rehab at home. And again, I think we can certainly all appreciate that sleep might be better at home, you know, confusion might be improved at home if you're around familiar faces and objects. And so that may be something to keep in mind as well. And then another interesting study looked at computer assisted identification of delirogenic medications. So the computer would sort of identify, you know, from a list of meds that were known to be delirogenic, the patient has these kind of red flags, and then a pharmacist might review the meds and make recommendations for the team. This to reduce the incidence of delirium. How about medications for prevention of delirium? Well, very helpfully, Owen and colleagues in 2019 did a systematic review of 14 randomized controlled trials looking at this question. They were looking specifically at whether antipsychotics versus placebo would make any difference in the incidence of delirium, hospital lengths of stay or mortality. And they really found there were no differences in terms of, again, being used for prevention purposes. And they summarized, and most delirium guidelines that I'm aware of at this point do not recommend current, do not recommend the use of antipsychotics for prevention of delirium. We'll get to treatment in a bit, but maybe, maybe a different story. How about preventing delirium with cholinesterase inhibitors? Not a lot of luck here either. Five randomized controlled trials, including denepazil and ribostigmine, were used to attempt prevention of delirium in surgical settings. Four studies found no difference in the intervention versus placebo. And many authors have concluded that the current evidence does not support the routine use of cholinesterase inhibitors for prevention of delirium. How about melatonin? Melatonin may be a different story. So in 2016, a meta-analysis looked at four randomized controlled trials with about 670 elderly patients, and they did find a reduced incidence of delirium in the melatonin group versus placebo. Interestingly, a subgroup analysis found this reduced incidence of delirium in medical settings, but not surgical settings. Just something to consider, and I think maybe reinforced in this trial as well. So the Healthy Heart and Mind Trial, published in 2019, looked at 210 adults, 50 and higher, so they're being quite generous with the older adult term here, scheduled for cabbage or valve replacement. And they randomized them to either melatonin, three milligrams at bedtime, or placebo for seven days, starting two days prior to the surgery. Of those 210 patients, 42 developed delirium, and there was an equal distribution between the melatonin and placebo group. They found no difference in length of stay, mood symptoms, or cognitive symptoms. And they concluded that this study did not support the prophylactic use of melatonin for delirium prevention, at least in post-cardiac surgery patients. So again, interesting that there was maybe some question of benefit for medical settings, but not surgical settings, with regard to melatonin for the prevention of delirium. Unclear if that's really a signal or not, but sort of an interesting finding. So how about management now? I think we all know identifying and reversing the underlying cause really is the definitive management. Delirium is brain failure, and so we have to be thorough in our search for the underlying etiology, as we would with any other organ system failure. Of course, this includes the basics of good care, monitoring one's vital signs, ins and outs, good oxygenation, and again, really thinking about those non-essential medications. We talked about some of those deliriogenic medications, and this is where I think our pharmacy colleagues can also be tremendously helpful to us in the hospital. And again, geriatrics consultation, if available, to really go through and think about, you know, what are the essential and non-essential medications that we're going to be using and what are the essential and non-essential medications? Sometimes, you know, I'm hesitant to say, but sometimes I think we see that psych meds may be considered non-essential when they actually are essential. And so I do think it's helpful to have, you know, psychiatry involved in that medication inventory as well to maybe help provide some clinical context for which of these medications would it be wise to consider holding while the patient's in the hospital with delirium, and which ones might actually make things worse if we were to stop them abruptly due to their propensity for delirium as a component of withdrawal. So again, I think working together with primary teams, pharmacy teams, psychiatry, and or geriatrics, I think can be particularly helpful when it comes to older adult medication review. And again, we will often need to go back and repeat the workup if we still can't identify what that underlying cause is. So non-pharmacologic management of delirium is not altogether different from non-pharmacologic prevention of delirium. So as I think about some of those risk factors that the hospital elder life program targeted with these standardized protocols to reduce the risk of developing delirium, many of those same strategies would apply for the management of delirium as well. And I've referred to some of these already, really promoting regular reorientation, the presence of calendars and clocks, doing our best to mobilize patients as soon as they're able so they're not lying in bed for days and days, providing some familiarity and comfort in the form of family visits, pictures, items from home, making sure that one has the optimal sensory abilities. So making sure they have their hearing aids, their glasses, their dentures. Again, I think sometimes, unfortunately, ageism is prevalent and it may be just sort of easy to assume that somebody doesn't hear well and that's just their baseline. But the reality is they actually hear just fine if they have their hearing aids with them. And so making sure that we're giving patients all the tools they need to recover as quickly as possible, avoiding restraints, as I mentioned earlier, which can be very frightening and contribute to confusion and paranoia, and making sure pain is adequately addressed. I'm certainly not a pain management expert, but I think we know that opioids and some of our pain medications can certainly exacerbate delirium. And so being mindful about staying on top of pain, adequately assessing for and treating pain, but trying to do so with medications that would be least likely to impact one's cognition. And again, promoting sleep-wake as much as possible. That's hard to do in the hospital anyway, we know this, but as much as we can to keep the lights off at night and try to minimize the number of times people are being interrupted at night for medications or blood draws, et cetera, will behoove our patients. Okay. How about pharmacotherapy for delirium? Important to mention that there are no medications that are FDA approved for delirium. This is a very similar refrain to what I imagine you have heard or will hear about behavioral disturbances of dementia. So when it comes to older adults with behavioral dysregulation from delirium or dementia, we really don't have a lot of options. Although I suppose we do have one new medication approved for that in dementia, but I'll let Dr. Tampe tell you about that. But not for delirium. I think an important principle in general is that we will try to avoid meds for the treatment of hypoactive delirium. So again, if folks are already somnolent, hard to rouse, apathetic, we don't really want, this is probably not the best time to give them something that's going to potentially sedate them further. And we know that all medications that we might consider are going to carry a risk of side effects. So it really is always going to be a balance of that risk benefit ratio and trying to figure out what makes sense for an individual patient. You know, incorporating their choices and preferences when they're able to provide them or their caregivers. We know that antipsychotics are the most commonly used medication for severe agitation, secondary to delirium, which compromises one's care or the safety of the patient or others. Antipsychotics may be particularly helpful in patients who have psychotic symptoms and aggressive behavior. However, recent meta-analyses have questioned their efficacy and we'll talk a little bit about what some of those studies have shown and maybe some ways that we might think about how to interpret that literature. And finally, just a reminder, as I'm sure everyone is aware, that the antipsychotics as a class do carry a black box warning for an increased risk of cerebrovascular accident or event and death in people with dementia. Again, that risk is not, the black box warning does not specify delirium, but I'm mentioning that as we are talking about older adults with delirium, many of whom will also have dementia. So let's talk a little bit about some of the studies here. So in 2007, a meta-analysis of three randomized controlled trials of haloperidol versus some of our second generation antipsychotics found that all of the active drugs were effective in reducing the severity of delirium and there was no difference between haloperidol and the atypicals. A 2008 systematic review evaluated the efficacy of atypical antipsychotics in delirious older adults and they found that risperidone and olanzapine were effective in more than 70% of cases and that they were better tolerated than haloperidol in terms of neurologic side effects, extrapyramidal symptoms. Many of you all probably saw this study come out in 2018 by Gerard and colleagues. This was a multi-site randomized controlled trial of 566 patients identified by CAM as having delirium. Their median age was 59 to 61. Of note, 89% of them were hypoactive in their delirium presentation. But despite that, these patients were still randomized to IV haloperidol, IV zeprazidone or placebo and they found no differences among the groups in duration of delirium, mortality, time they spent in the ICU or the time that it took for them to get to hospital discharge. And so they really concluded that, again, antipsychotics efficacy in the treatment of delirium was questionable. They did note that, and I think many people noted afterward that this study was limited just because of the nature of having so many patients in the treatment groups that were of a hypoactive delirium. And I think, again, we discussed earlier, antipsychotics probably not ideal to give in somebody who is hypoactive. So a more recent 2019 systematic review of 16 randomized controlled trials and 10 observational trials also found no differences between haloperidol or second generation antipsychotics versus placebo in sedation status, delirium duration, excuse me, delirium duration or severity, hospital length of stay or mortality. And I think what, sorry about that. I think what I found interesting and what I have read in the literature and I think is a helpful perspective to consider is that it seems clear. We can likely agree that antipsychotics don't change the pathophysiology of delirium in a sense that they will impact necessarily the cognitive symptoms and maybe not even the course, the duration or course of illness. But I think what is hard to measure and has not been consistently measured in many studies because they are very heterogeneous in their study design, their patient populations and their measures is the symptom relief that people may get from using medications like antipsychotics and the distress that untreated symptoms and safety concerns that untreated symptoms can cause. So while I think this literature is very important and I think we need further studies to help us determine who are the best candidates to receive antipsychotic medication or are there other alternatives that might be safer or better than antipsychotics that I think these studies can appear quite discouraging. But again, I think we have to keep in mind that they weren't all looking at symptom relief and the behavioral symptoms we know carry a lot of distress and a lot of, in some cases, safety concerns too. And I think that too needs to be considered. So just something to keep in mind, I think, as we interpret these studies. So as we think about medications, what would be kind of our ideal approach to pharmacotherapy for delirium? Time-limited trials of antipsychotics are probably reasonable for patients who have certain conditions with their delirium, psychosis, or pretty significant behavioral disturbances that compromise care or safety and don't respond to that first line non-pharmacologic treatment. We would then select the medication based on target symptoms and side effect profile. At this point, no real suggestion that any one medication is better than the other, but we may need to take advantage of sedation as a side effect, or we may need to avoid certain side effects, which I'll mention here in just a minute. As we always do with our older adult population, we start low, we go slow, and we continue to reassess that risk-benefit ratio and need. And then of utmost importance is to taper and discontinue when appropriate. I often tell our trainees that I had a patient who came to see me in my outpatient clinic, this was several years ago, and he was on Paxil and Risperidone, and we talked about his history of anxiety and the Paxil, and then I said, what is the Risperidone for? Do you know? And he said, you know, I don't know, and kind of looked at his wife, and he said, I think I've been on that since I remember a couple of years ago, I was in the hospital with pneumonia. And she said, oh yes, remember you were really anxious during that hospitalization. You were kind of out of your mind, you were confused, you were hallucinating. And it appeared that this gentleman had been on Risperidone for delirium and had just never come off of it two years later. And we were able to successfully get him off of that medication. So I do think, you know, being clear with our outpatient colleagues when we make that warm handoff to the receiving team in the community, especially if the patient's in a new area and maybe getting new primary care teams or other care providers, that this is a temporary medication and this is a plan, you know, the plan for tapering should be as follows. So haloperidol has the longest track record, as you all know. Many of you have been working in psychiatry for a while. This is something that we've been using for delirium for a long time now. It's nice because it does come in various routes of administration, including PO, IV, and IM. And we find that the extracranial side effects are rare when the IV route is used. However, the IV route does carry greater risk of QTC prolongation. And the risk is greatest with higher doses over short periods of time in patients who already have a QTC greater than 450. So always good to get a baseline electrocardiogram and then monitor, you know, when we're using antipsychotics in the case of delirium. Atypical or second generation antipsychotics have also been used. Those are listed here. No one med has been found superior to my knowledge. And I think all, as I said, all of them carry some potential risks or benefits. Some of them do have an IM or oral disintegrating tablet available, which may be a helpful modality if somebody is not able to take PO. Quetiapine is the preferred antipsychotic for patients who have Parkinson's disease or Lewy body dementia due to that decreased risk of extrapyramidal side effects. We know that those folks can be particularly sensitive to the extrapyramidal side effects of antipsychotics. So using something like quetiapine would be advisable in those cases. As I mentioned earlier, starting low is helpful with either PRN or standing dose at bedtime. And then if one is needing a PRN medication rather frequently, giving a standing dose of whatever that effective dose of the antipsychotic was. And then again, when symptoms improve, and after a few days of improvement, gradually taper. We don't want to cut them off abruptly, but we do want to make clear in the plan, especially if they're being discharged to a facility of rehab or nursing home, the plan to continue to taper the medication as follows. Usually that last dose to go would be our bedtime dose, kind of hang onto that one last and then taper that one at the end. As I mentioned, monitoring for QTC prolongation, that can range anywhere from seven milliseconds to maybe 20 or so, but certainly worth keeping an eye on as well as making sure that potassium and magnesium are within normal range. And again, monitoring for extrapyramidal symptoms, in particular akathisia, which can sometimes be mistaken for worsening of agitation and then therefore a need for more antipsychotic, which may then exacerbate the akathisia. So if there's a clear timeline that one's agitation actually increased, shortly after the initiation of an antipsychotic, particularly if one appears to be restless and having difficulty sitting still, thinking about could this be an extrapyramidal side effect, not just the delirium itself. Okay, so just a table here of the different antipsychotics recommended starting doses for consideration, and then the available routes that they come in. I won't read the table, but I'll keep it here just for a minute and maybe just mention a couple of things. Certainly some of these medications are more sedating than others, particularly quetiapine, olanzapine. So these medications may be helpful for folks who really need more sleep-wake regulation. Aripiprazole is one that can be activating and can contribute to akathisia. So always monitoring for that, for potential for increased activation with aripiprazole is important. Risperidone being obviously the most typical of the atypicals would be important to monitor for extrapyramidal side effects, which again would obviously be important in haloperidol as well. So moving away from the antipsychotics and thinking about other treatment options, cholinesterase inhibitors. Again, limited number of randomized controlled trials, most revealed no difference from placebo in the severity or duration of delirium, and American Geriatric Society guidelines at this point recommend against starting in delirium. So I think we would say, again, cholinesterase inhibitors really have not found a role for either prevention or management of delirium. Benzodiazepines. I think with a lot of concerns about the antipsychotics and their black box warnings, people understandably went looking for something that was potentially maybe a less risky intervention. I think when it comes to delirium, as well as dementia and behavioral disturbances. So benzodiazepines, I think are something that we've long relied on for their sedative properties. However, we know that they are really delirogenic and can really exacerbate delirium. So we would like to limit the benzodiazepines to cases of alcohol or benzodiazepine withdrawal delirium. Sometimes they may be used as an adjunct to neuroleptics if somebody is severely agitated or if somebody needs sedation for a procedure or a test. And if it is needed, we, as you all know, use lorazepam. This is always preferred in our geriatric population given reliable absorption from multiple routes and no active metabolites. But again, generally you're going to avoid the benzodiazepines as they may worsen delirium. Melatonin. I mentioned that one earlier that it's had a few studies for prevention. You know, maybe effective for insomnia as well. Again, I don't think we've seen anything that suggests that it, you know, changes the duration of or severity of delirium once delirium has developed. But I think if we are looking for something in the hospital setting for insomnia, you know, certainly trialing melatonin is generally low risk, may be helpful to restore that sleep-wake cycle and generally is pretty well tolerated. Dexmedetamine, those are hard times saying that word, I apologize. An alpha-2 agonist has been studied in ICU settings for prevention and treatment of delirium. Not something I personally have, you know, had experience with, but in reviewing the literature did see that this is a treatment that's been explored, you know, in the ICU settings and may have a role in some cases of delirium. So what about the prognosis? As I said, I think for a long time, the conventional wisdom was that people would recover fully from delirium, that it was a reversible condition. I think we know now that full recovery from delirium in older adults is pretty unlikely at the time of hospital discharge. And in fact, almost half of patients at discharge with delirium are still delirious. About a third may still have symptoms at a month post-discharge. So I think this is really important for a few reasons. One, because again, we know these patients are now at greater risk of having a persistent cognitive deficit or a new baseline. So they may have come in here, you know, sort of declined from delirium and they're better, but they may never quite get back to where they were before. And this, I think is particularly helpful as we discuss cases with our caregivers. So expectations can be clear, you know, wait a minute, you know, dad, mom, spouse, you know, still confused. I thought we already treated the pneumonia. We treated the infection. We treated the infection. They had the surgery. They're doing better physically. Why are they still so confused? So letting people know that it may take some time. It may be on the order of weeks before their delirium fully resolves, you know, some of the cognitive and psychiatric side effects and that, you know, in the meantime, we need to continue to monitor them and, you know, have them be reevaluated, you know, a few months down the road. As I mentioned earlier, for many patients with delirium, they will go from hospitals now to institution, may not be able to be discharged back home. As I mentioned earlier, increased incidence of dementia and increased mortality as well. So in conclusion, delirium is very common and unfortunately still goes under recognized in the geriatric population. It does have significant short and long-term impacts on cognition, morbidity, functional recovery, mortality. Recognition is key. Screening using a validated tool like the confusion assessment method or the ultra brief two-item bedside screen can be helpful to rapidly identify delirium. Consider that delirium often is a result of a number of etiologies. So just because we find one, doesn't mean we shouldn't continue to explore and look for other etiologies and try to intervene to address all of those. The non-pharmacologic interventions should be employed early and often. And again, can be used for both prevention of delirium as well as management of delirium. Melatonin is very reasonable to consider for insomnia, for folks that are delirious. Again, pretty low risk and may be helpful, especially if they're having insomnia before the surgery or whatever, maybe their potential precipitant may have a role for prevention. Reserve medications such as the antipsychotics for severe agitation, compromising care or safety, psychotic symptoms, aggressive behavior. In the case of the antipsychotics, not any one probably that's going to be more effective. Consider the side effect profile, consider the patient's medical history and e-contraindications, et cetera. And limit benzodiazepine use to cases of alcohol or benzo withdrawal. Okay, I've got some select references here and certainly happy if anyone would like more information or references, I'm happy to share that. And I think now we're ready to do our Q&A. I think I'm able to, let's see, I think I have a chat. And I know we have to start the next one at 4.45, so we may just have to do a couple. Okay, thank you. It looks like Violet shared the slides. Thank you, Violet. Oh, great question about catatonia and delirium. So this is a really fascinating topic that has been getting more attention in the literature because, so we have a question, what is the relationship between catatonia and delirium? Sorry to not be clear. So catatonia, interestingly by definition in the DSM criteria, there's an exclusion for delirium that the symptoms cannot occur exclusively during the course of delirium. But many people, many experts, more expert than I, certainly in the field, I think have really kind of challenged this. And they have identified that catatonia can be secondary to medical conditions. And some of those medical conditions too can cause delirium. So I think that there is, I think the old either or mutually exclusive notion that's sort of indicated in DSM-5, folks are really kind of calling for that to be reevaluated because I think they're saying there actually may be more overlap than we see, but yet it's important because the differences in treatment are quite significant. So we wouldn't want to treat delirium with benzodiazepine, but that is the treatment of choice for catatonia. We really wouldn't want to treat catatonia with antipsychotics, but that is the treatment often for managing behavioral issues of delirium. So I think that's where our validated screening tools can be helpful. So using something like the Bush-Francis catatonia scale, you know, using the CAM to really tease out, you know, which of these symptoms is the patient, you know, exhibiting to kind of help me think about which treatment arm I might want to go down. But yeah, great, great question. And just quickly a question about remeltion. Yes, so there have been some studies looking at remeltion. Hey, I apologize, I can't remember now. I believe it was a prevention study and there was some suggestion that remeltion too, like melatonin could be helpful in prevention of delirium. So I think that could be, I don't have a lot of experience with remeltion, but from my reading of literature, that would be a very reasonable choice. You know, I think, I know that risperidone in particular, I think is one that's to be avoided in severe renal disease. And this may be a time where maybe an IV, you know, heloperidol, you know, again, very low dose might be the best route. We were maybe able to take advantage of, you know, utilizing one of our old standbys. Thank you all for being patient. Sorry, we got a couple minutes late start, but it looks like you'll be able to start the next one on time.

delirium

geriatric psychiatry

health outcomes

diagnostic approaches

Confusion Assessment Method

non-pharmacologic interventions

Hospital Elder Life Program

cognitive decline

healthcare professionals