Hello, my name is Joanna Stallings, and I'm the Medical ICU Clinical Pharmacy Specialist at Vanderbilt University Medical Center in Nashville, Tennessee, and it's my pleasure to talk to you today about dexametatomidine, a standard of care. Are you the one using dexametatomidine as a first-line sedative in the ICU? The objectives of this presentation are to identify the standard of care dexametatomidine propofol midazolam, examine the cost and resource implications using dexametatomidine in patients with delirium, and to describe the effect of dexametatomidine on the hemodynamics of critically ill patients. So first, we're going to look at what the 2013 PAD, or pain, agitation, and delirium, and the 2018 PADEST, or pain, agitation, delirium, early mobility, and sleep guidelines recommend. So they suggest that sedation strategies using non-benzodiazepines, either propofol or dexametatomidine, may be preferred over sedation with benzodiazepines, semidazolam or lorazepam. This study was conducted by, or I should say led by Pratik Pandiharapandi and was published in Anesthesiology in 2005, and this was really one of the first studies that showed, unfortunately, that there's a 100% probability of being delirious the next day if patients receive more than 20mg of lorazepam, and this was in just under 200 medical ICU patients. So this is a study that was led by Shannon Carson and was published in Critical Care Medicine in 2006. So it looked at intermittent lorazepam versus propofol with daily sedative interruptions. So this was a prospective randomized open-label study that was conducted at two different centers, and it included 132 medical ICU patients who were expected to be on the ventilator for at least 48 hours. So patients were randomized to either intermittent doses of lorazepam, so they received 2-8mg every 4 hours, and they could also receive intermittent doses as well. Or they were randomized to propofol, so an infusion starting at 5mg per kg per minute, and the max dose for this was 80mg per kg per minute, and this was titrated to a Ramsey score of 2-3. Patients did undergo daily spontaneous awaking and breathing trials, and they were allowed to receive intermittent doses of morphine for pain and halperidol for delirium. So the outcomes of this study, as you can see here, looking at ventilator days in all patients, there were more of these in the lorazepam group as compared to the propofol group. Looking at ventilator days in survivors, there were more of these, once again, in the lorazepam group as compared to the propofol group. ICU lymphostate was longer in the lorazepam group compared to propofol, and hospital lymphostate was also longer in those that received lorazepam as compared to propofol. This was really one of the first landmark studies that really indicated that we should not be using benzodiazepines in patients, and maybe we should consider other sedatives, at this time propofol, but eventually dexmedetomidine as well. So let's look at all the data that has compared benzodiazepines versus propofol. So this is a pro-con paper that was led the con to benzos, I should say, it was led by Wes Ely and Tim Gerard. And so this showed all the trials that had better outcomes with propofol as compared to benzodiazepines. So as you can see, there are a number of them. This shows benzodiazepines versus propofol and shows trials finding no difference. So there's a few of them. This shows benzodiazepines versus propofol trials finding better outcomes with benzodiazepines. As you can see, there are none of them, so don't forget that. This looks at benzodiazepines versus dexmedetomidine, so trials with better outcomes with dexmedetomidine. As you can see, there are several of them. Benzodiazepines versus dexmedetomidine trials with no difference in outcomes or better outcomes with benzodiazepines. Remember once again, there are none of these. So moving on, let's look at some of the data specifically that evaluated dexmedetomidine. And this really, the MENDS trial, is really the first study that evaluated dexmedetomidine in adult ICU patients. So this was a prospective randomized double-blind study that was conducted in two different centers and included just over 100 either medical or surgical ICU patients who were on the vent for greater than a day. So patients were randomized to a dexmedetomidine infusion or a lorazepam infusion, and the patients had a RAS score that was set by their medical team, and spontaneous waking trials were not required. So as you can see here, dexmedetomidine improves accuracy of sedation. In other words, more patients were within one point of their target RAS score as compared to lorazepam. So this really increased interest in dexmedetomidine and more people started to use it. So the next study that evaluated dexmedetomidine was the CEDCOM study, which was actually very similar to the MENDS study. So this was a prospective randomized double-blind multi-center study in just under 300 adult ICU patients who were expected to be on the vent for about three days and had a baseline RAS, Richmond Agitation Sedation Scale, of negative 2 to positive 1. And patients were randomized to dexmedetomidine infusion or a midazolam infusion, and their RAS goal was negative 2 to positive 1. And so patients, it's important to note, as compared to the MENDS study, that patients were allowed to receive boluses of midazolam and also fentanyl, because that was one critique that the MENDS study did get, is that the patients that received the lorazepam were thought to be over-sedated, because if they were under-sedated, then you increase the infusion rate versus giving a bolus. So as you can see here, sedation with dexmedetomidine shortened the duration of mechanical ventilation by almost two days as compared to midazolam. So there was no difference between the two groups with regards to time-to-go RAS. There were less days of delirium with dexmedetomidine. There was a less prevalence of delirium with dexmedetomidine, and there was no difference in ICU stay. So once again, this study favored the use of dexmedetomidine, and once again, also improved its popularity of use. So this is a meta-analysis that was conducted as part of the PAD guidelines that we talked about earlier that was led by Gail Fraser and was published in Critical Care Medicine in 2013. So benzodiazepines as compared to non-benzodiazepine-based sedation for mechanically ventilated critically ill patients. So it included six randomized parallel group controlled trials that were conducted between 1996 and 2013. So the inclusion criteria were medical and surgical ICU patients on mechanical ventilation receiving intravenous sedation. So they had to receive a benzo versus a non-benzodiazepine to be included in this, and also have a predefined outcome. So as you can see here with regards to outcomes, looking at ICU length of stay was better if patients received non-benzodiazepine strategies, as was the duration of mechanical ventilation. There was no difference between the two groups with regards to delirium prevalence, and there was also really no difference with regards to short-term all-cause mortality. So once again, really feeding the fire that maybe dexmedetomidine is really what we should be using, or propofol is what we should be using, and not benzodiazepines. So the next studies that we will go over are the MIDEX and PRODEX trials. So this is a prospective randomized multi-center double dummy study, and included adult ICU patients requiring midazolam or propofol infusion for greater than or equal to 24 hours. So obviously MIDEX compared midazolam and dexmedetomidine versus PRODEX compared propofol and dexmedetomidine. So as you can see here, patients were randomized to dexmedetomidine, so 249 of those, in MIDEX versus 251 in PRODEX, and then 251 patients were randomized to midazolam and 247 to those that received propofol, and the goal RAS was zero to negative three. Patients could receive intermittent doses of fentanyl, and they did undergo daily spontaneous awakening and breathing trials. So looking at the outcomes from this study, as you can see here, first we'll look at the results of PRODEX, which is on the left. So the time at goal RAS without rescue was the same in dexmedetomidine compared to propofol. It was very similar in dexmedetomidine versus midazolam. Looking at days on mechanical ventilation, very similar between propofol and dexmedetomidine, and then looking at days of mechanical ventilation between dexmedetomidine and midazolam, it was longer in patients that received midazolam. Looking at ICU lymphocyte, no difference between propofol and dexmedetomidine, and then really no difference between patients that received dexmedetomidine or midazolam. So now we'll move on to the next study, which is the DALYA trial. So this specifically was looking at dexmedetomidine use in patients with agitation. So this was a double-blind, multicenter, placebo-controlled, unparalleled group study that included 74 patients with agitation awaiting extubation in 15 different ICUs. So patients were randomized to either dexmedetomidine, there were 39 of those, versus placebo, and their goal RAS was zero, or the physician's goal, and patients could receive steady drug up to seven days. So let's look at the outcomes. As you can see here, there were more ventilator-free days in the dexmedetomidine group as compared to placebo. The time until bedside nurse thought it was time to extubate was much longer in the placebo group as compared to dexmedetomidine. The time to extubation was also much longer in the placebo group, and time until resolution of delirium was also much longer in the placebo group. So once again, favoring the use of dexmedetomidine in patients with agitation. So it's important also to note here that with regards to the outcomes in the study, patients in the placebo group did receive more antipsychotics and propofol and opiates, actually, than did the dexmedetomidine group, but once again showing how helpful that potentially dexmedetomidine is in patients that have agitation. So looking at the outcomes in this study, the death at 90 days occurred in 569 of 1956, or 29.1% of the usual care group, and 566 of 1948, or 29.1% of the dexamethatomidine group. Also in the dexamethatomidine group, 64% of the patients received propofol, 3% received midazolam, and 7% received both during the first two days after randomization. Interestingly enough, 60% of patients received propofol, 12% received midazolam, and 20% received both in the usual care group. So it's really hard to really make, kind of like, take any outcomes, I should say, from this study, even though there was no difference between the two groups. Both groups received multiple different sedatives, so it's really hard to define, essentially, is dexamethatone being favored versus usual care. So that brings us to the next study, which is MENS-2. So this was a prospective multi-center, randomized, double-blind trial that included 422 ICU patients that were mechanically ventilated and had sepsis. So patients were randomized to dexamethatomidine, so 214 of those, versus propofol, so 280 of those, and the RAS goal was set by the clinical team. So as you can see here, with regard to the results, there was no difference was found between dexamethatomidine and propofol. The number of days alive without delirium or coma was not different between the two groups. Ventilator-free days also were very similar between the two groups, and death at 90 days was also very similar between the groups, so showing that you can use either propofol or dexamethatomidine. So who do you consider using dexamethatomidine in versus who should you use propofol in? So some of the things to consider are, is your patient, do they need to be deeply sedated? So that's someone that you're going to want to consider using propofol on, especially if you have a patient, for example, that has severe ARDS and maybe they need to be paralyzed and you need amnestic effects. That's someone that you're going to want to use propofol in versus, really, you can get light sedation with either propofol or dexamethatomidine. Dexamethatomidine also has the niche area that it can be used in patients that are not on the mechanical ventilator because it does not suppress your respiratory draft. So moving on, the 2013 PAT guidelines suggest that adult ICU patients with delirium unrelated to alcohol or benzodiazepine withdrawal continuous IV infusions of dexamethatomidine, rather than benzodiazepine infusions, be administered for sedation to reduce the duration of delirium. And this is really based on a lot of the evidence that we saw. So let's look at some of the results. So this is a summary of all the dexamethatomidine studies and their effects on delirium. So we looked at the MEN study, which showed the median days alive without delirium or coma was longer in the dexamethatomidine group as compared to the razepam. The CEDCOM study, which we also looked at, showed the prevalence of delirium in the dexamethatomidine group was much lower than the midazolam group. The incidence of delirium in the RUKEM study was actually higher in patients that got dexamethatomidine as compared to standard care. We looked at the MIDAC study that looked at a composite outcome of agitation, anxiety, and delirium, and this occurred in 27% of patients that got midazolam and 29% of patients that got dexamethatomidine, interestingly enough. And then the PRODUCT study looked at the same composite outcome and found that this occurred in 29% of patients that received propofol and 18% of patients that received dexamethatomidine. Trimed to resolution of delirium in the dexamethatomidine group was much shorter than those that got placebo, as we talked about with the Dahlian study. The SPICE 3 study showed the median number days free from coma or delirium was longer in dexamethatomidine group as compared to placebo. And lastly, the MENDS 2 study shows the number of days alive and without delirium or coma really did not differ between the two different groups. So, as you can see here, there was a decreased risk of intubation with dexametatomy. There was also a decreased risk of delirium with dexametatomy. There was a decreased risk of ICU stay with dexametatomy, and there was a risk, an increased risk of hypotension with dexametatomy. There was an increased risk of bradycardia with dexametatomy. So also, they evaluated the safety and efficacy of dexametatomy in acutely ill patients requiring mechanical ventilation. So, once again, a systematic review and a meta-analysis. So this included 77 randomized clinical trials and included almost 12,000 patients. So once again, they looked at Medline, InBase, and the Cochrane Library were all searched from inception through October of 2021 for randomized clinical trials. There was a decreased risk of delirium with dexametatomy, and other outcomes specifically looked at where there was a decreased duration of mechanical ventilation, there was a decreased ICU length of stay, an increased risk of bradycardia, and an increased risk of hypotension with dexametatomy. So secondary to these two systematic reviews and meta-analysis, a rapid practice guideline was published looking specifically at the use of dexametatomy for sedation in mechanically ventilated adult ICU patients, and they made the following recommendation. In evasively mechanically ventilated adult ICU patients, we suggest using dexametatomy over other set of agents if the desirable effects, including a reduction in delirium, are valued over the undesirable effects, including an increase in hypotension and bradycardia. So I think many of us would say that with all the harmful long-term effects that we know are associated with delirium, we know that delirium increases mortality threefold at six months. We also know that delirium increases ICU length of stay and hospital length of stay. We also know that delirium causes long-term, is associated, I should say, with long-term cognitive impairment. And also can increase your patient's risk of pulling tubes, devices, etc. out. So with all these scary outcomes associated with delirium, I think that many of us would be more likely to use dexametatomy in our patients compared to other types of sedation. So the question is, when to use pharmacotherapy for refractory ICU delirium? So we published this recommendation in a review that we were invited to write for Intensive Care Medicine, so myself, Michelle Ballas, and Gerard Shanks. And we recommended that if a patient continues to be delirious despite non-pharmacologic therapies, in other words, you've given the patient their hearing aids, you've put glasses on them, you've done what you can with regards to normalizing their sleep-wake cycle. You're mobilizing the patient. But the patient is still a danger to themselves or the staff, have severe anxiety or fear related to hallucinations or other delusions, and they also have, or they may have, I should say, severe agitation-causing hypoxia. If they have any of these things, then you can consider antipsychotics or dexametatomy. So questions to consider when treating refractory delirium. Does your patient have a history of excess alcohol consumption or any visual hallucinations? So if they're having specific alcohol withdrawal symptoms, then you may want to consider a benzodiazepine or alpha-2 agonist, maybe phenobarbital would be all options that we could consider. Does your patient have a history of psychosis? So this is when you would want to make sure that they're on the appropriate home meds and that also maybe a psychiatry consult would be indicated. Does your patient take psychoactive or opiate medications at home? Is your patient withdrawing? If so, we need to put them back on those medications. Is your patient receiving any opiates, including tramadol? And remember that opiates can cause delirium. There's data out there that if you don't treat someone's pain, then they're more likely to become delirious, but there's also data that if your patient's not in pain and you give them opiates, then they're more likely to get delirium. And then the last question is, has your patient complained from sleep deprivation for the last few nights? Or are there any reports of the patient not sleeping potentially in their chart if they can't communicate? So once again, thinking about sleep induction, so maybe dexmedetomidine or potentially melatonin, but always thinking about doing non-pharmacologic things first, obviously, to promote sleep. So, I couldn't give this talk without talking about the IC deliberation or the ABCDF bundle. So, this bundle has been studied in over 30,000 patients, and essentially it has shown, by doing all the different steps of this bundle, it actually has a dose response effect, which I, as a pharmacist, really appreciate. So, in other words, the more you do it, the better the outcomes your patient has, and outcomes include things like decreasing the incidence of delirium and coma, and decreasing the chance that the patient will be transferred to a facility, decreasing utilization of restraints. These are all positive outcomes associated with this bundle, in addition to decreasing cost. So, what are the different components of the bundle? The first is assessing, preventing, and managing pain, so making sure that your patient is appropriately assessed every four hours, and to ensure that they are receiving appropriate analgesia, if indicated, so thinking about multimodal pain therapy, opiates, and also to not use those if they're not indicated. Thinking about daily, both spontaneous awakening trials and breathing trials, so making sure that your ICU has a protocol for this, and that the nursing staff is indeed turning off their sedation and analgesia every day, if possible, and the respiratory therapists are doing a spontaneous breathing trial. Thinking about the choice of analgesia and sedation, so really what the heart of this talk is, is avoiding benzodiazepines and considering some of our newer sedative agents, such as propofol and dexmedetomidine, and once again, with regards to analgesia, just really trying to decrease the utilization of opiates as possible, and using multimodal pain therapy. Thinking about delirium, so assessing delirium with an appropriate tool, whether that be the confusion assessment at the NICU, or the CAMICU, or the intensive care delirium screening checklist, or the ICDSC, to assess for that, and then using tools such as maybe the Dr. Dre is a mnemonic I like to teach, where the first DR stands for disease remediation, so treating diseases like COPD, or heart failure, or sepsis, and the next DR is drug removal, so stopping benzodiazepines, or meds that they're on maybe for their allergies, that have anti-cholinergic properties that they don't need in the ICU, steroids, benzodiazepines, and then also optimizing the ease times for the environment, so once again, doing things like giving the patient their hearing aids and glasses, and mobilizing them, and help them with their sleep-wake cycle, and then with regards to delirium, not using antipsychotics, since we know from both the MIND-USA and the AID-ICU study, that that is not helpful, but using the non-pharmacologic studies that we talked about, or therapies, I should say, that we talked about. E, early mobility and exercise, assessing patients for this, and doing it whenever possible, and then also involving the family in rounds, and making sure that they know about post-intensive care syndrome, and really just engaging them to help take the best care of their family member. So, you've heard me talk about all the different types of sedatives, how we want to avoid benzodiazepines, and really consider propofol and dexmedetomidine, but the biggest message that you should really take home from this talk is that we don't want you to use sedation at all, if you can get away with that, and that is secondary to some of this research done by Yaya Shahibi, and this was published in the Blue Journal in 2012, and this study showed that deep sedation in the first 48 hours prolongs intubation. Now, historically, everyone thought, like, hey, it's fine, I can deeply sedate my patient for a couple days, it doesn't matter, right, and that's not true. We know it increases their time on the ventilator, and we also know that every four hours a patient is deeply sedated is associated with an 8% increase in the risk of death, so very scary. We need to try to turn off sedation and analgesia every day in our mechanically ventilated patients, and only use it if it's absolutely indicative. So, other key strategies to reduce sedation in the ICU include education. So, what we're doing right now, a lot of people don't know that it's harmful, that it increases time on the ventilator, and that it potentially can also increase mortality, and so just really teaching that, and continuing to provide education to the medicine residents that we all work with, and the nursing staff, to just really empower the nursing staff to do spontaneous awakening trials every day, where the study published by Tim Gerard essentially showed that the number needed to treat if you coordinate your spontaneous awakening trial with your spontaneous breathing trial is seven patients. So, essentially, if a nurse works for a week and turns the sedation and analgesia off on all her patients, then, or his or her patients, I should say, then they have saved a life. Also, providing analogous sedation when possible, so using fentanyl first, not only for its analgesia properties, but also for its sedative properties to avoid the use of benzodiazepines, or propofol, or dexmedetomidine. Restarting pre-hospital medication, so like we said before, so that patients don't withdraw, starting them on their antidepressants or their home antipsychotic to prevent withdrawal. Cluster patient care activities to enhance sleep, so not giving baths in the middle of the night, not drawing wives in the middle of the night, not giving medications unless absolutely indicated in the middle of the night, so your patient can get better sleep. Use your clinical pharmacist. This is a big role that I play in the ICU at Vanderbilt, is that every single day, I'm making sure that on rounds, that the spontaneous awaking trial, spontaneous breathing trial are being discussed, that we are doing essentially like all the different components of the bundle, making sure that patients aren't on deliriogenic meds. I even recommend physical therapy and occupational therapy at times. The reason I say use your clinical pharmacist is, unfortunately, there's a large turnover of nurses following COVID-19, many of our nurses in my institution end up going to nurse practitioner school or going to nurse anesthesia school, and I work with 20 different attending physicians, so they're only in the ICU a few weeks per year, so really using your clinical pharmacist who's always present there, and then promoting staff wellness. You may be thinking, why is this on the list? The reason is, if you're starting this at your institution, once the staff members see the outcomes in just a few patients, and they're going to want to do this on all the patients, because this is going to increase their quality of life, because they're going to see how much better that the patients do when you do these few things to take the best care of them. So now, we're going to change essentially the direction of this talk and talk about cost-effectiveness of benzodiazepines versus a non-benzodiazepine-based sedation regimen for mechanically ventilated critically ill adults. So, a question that I commonly have been asked when I've given talks about this at different places are, isn't it more expensive to use propofol or dexamethasone as compared to benzodiazepines, and let's talk about this. So, this is a cost-effective analysis of a meta-analysis, and included critically ill patients receiving benzodiazepine or non-benzodiazepine sedation who had not undergone cardiac surgery. They used a Markov model accounting for daily mechanical ventilation until ICU discharge. So, as you can see here, so non-benzodiazepines are obviously dexamethasone and propofol versus benzodiazepines, armadizolam, and lorazepam. So, this shows the vial size, the cost per vial, the unit cost, the average dose, the average cost, and the average dose, just to be clear, is the unit cost multiplied by the average dose. It also showed the weighted average cost in 2013, and lastly, the weighted average cost in 2012. So, as you can see here, it was much more expensive to give a non-benzodiazepine as compared to a benzodiazepine, but you have to consider this was conducted a while ago, right? So, this has been 10 years ago. Unfortunately, dexamethasone is now generic and is much more cost effective than it used to be. So, looking, as you can see here, the cost per vial of dexamethasone in 2014 was $95.11 versus the cost today is $3.21. So, the cost of dexamethasone really should not be precluding the use of it for sedation, especially after all the data that we've talked about today. So, now, getting really to the meat of the study, looking at drug cost and cost avoidance. So, first, looking at non-benzodiazepines as compared to benzodiazepines. First, looking at the incremental cost-effectiveness ratio to avoid a day in the ICU. Looking at the incremental cost-effectiveness ratio to avoid a day on the ventilator. So, non-benzodiazepine patients spent two days or less on the ventilator, spent 3.2 fewer days in the ICU. Also, looking at the total cost of ICU care, pretty similar. Mean time to extubation, though this is really where the money is, was much shorter in patients that received non-benzodiazepines, and mean time to discharge was also much shorter. So, is it more expensive to use a non-benzodiazepine? It does not appear it is, and I have further data that we're going to look at now. So, this figure from this study represents the results of each of the sensitivity analysis completed for the two outcomes that a mechanically ventilated patient could experience each day. So, extubation and ICU discharge after extubation, when managed with either a non-benzodiazepine or benzodiazepines sedative regimen. Each individual figure provides expected cost of ICU care over a range of probabilities that were entered into the sensitivity analysis for each outcome. So, the first number one figure, which is the top one on the left-hand side, represents the sensitivity analysis of the extubation rate of the non-benzodiazepine arm. So, if you look at the y-axis, this is the expected cost of ICU care and the extubation probability. So, once again, the higher your likelihood of extubation, then your cost goes down. So, moving to the right, this represents the sensitivity analysis of the ICU discharge rate of the non-benzodiazepine arm. So, once again, your cost of care, your expected cost of care, goes down as your discharge probability goes up. Moving down and to the left, this represents the sensitivity of the extubation rate of the benzodiazepine arm. So, not as impressive as the non-benzodiazepine arm, but once again, your cost of care goes down as your extubation rate improves. And then lastly, looking at the right on the bottom, this represents the sensitivity analysis of the ICU discharge rate of the benzodiazepine arm. So, once again, not near as impressive as the above graph, but once again shows that your cost of care goes down as your discharge probability goes up. So, now we'll look at a second cost analysis. So, this one specifically looks at clinical and economic impact of the use of dexamedetomidine for sedation in the ICU compared to propofol. So, we've talked a lot about like why we want to consider using non-benzodiazepines. And as we looked at SPICE-3, which was difficult because there were a lot of confounders with regards to multiple types of sedation that the dexamedetomidine group and the control group got. And then we looked at MENS-2, which really saw no difference between dexamedetomidine and propofol. The question comes, is it cheaper to use one over the other? So, this was a retrospective single center observational cohort study. So, this was conducted in a single center, including adult ICU patients who were mechanically ventilated and received dexamedetomidine or propofol for sedation for at least 12 hours. So, patients were matched by their sex and also their sober or sequential organ failure assessment score. So, the key economic data associated with dexamedetomidine and propofol-based sedation. So, looking at total ICU costs were lower, not significantly, but in the dexamedetomidine group. The total hospital costs, as you can see, are very similar. Total per patient sedation drug therapy, as you can see, was higher in the dexamedetomidine group as compared to propofol. And total per patient pain and sedation drug therapy was slightly higher in the dexamedetomidine group. So, once again, suggesting that you can probably use either, but it is actually, there is a difference with regards to using dexamedetomidine in your total ICU cost. So, once again, just suggesting that really you can use either of these two agents. The biggest thing to remember is light sedation and, if at all possible, no sedation eventually in our patients. So, this is a summary of studies you can, what leading ways to titrate patients of dexamedetomidine is that I'm sure many of you know in the audience that sometimes if people have been on dexamedetomidine for a while, they can actually withdraw and become very tachycardic if you stop it. So, ways to help preclude that are to use clonidine or oral guanfazine, which are both oral alpha-2 agonists. So, let's look at the data behind it. So, the first study we'll look at was conducted by Terry and colleagues and published in 2015. So, this is a single center retrospective observational study, very small, 26 adult patients. So, they used enteral clonidine to help wean these patients and they found that dexamedetomidine was dc'd in 65.4 percent of these patients. The second study was led by David Gagnon and was published in Pharmacotherapy in 2015 and this was also a single center prospective observational pilot study that included 20 adult ICU patients that were started on dexamedetomidine and then transitioned to clonidine. So, patients that were on less than 0.7 micrograms per kilogram per hour that weighed less than 100 kilograms or that were elderly received clonidine 0.2 milligrams enterally every six hours and everyone else received clonidine 0.3 milligrams internally every six hours and then it was tapered. So, as you can see here, 75 percent of patients were transitioned from dexamedetomidine to clonidine within 48 hours. With regards to cost, there was potential drug acquisition cost avoidance was between $800 and just over $2,000 per patient during the three-month study, so pretty impressive. The next study we looked at was published in Critical Care Explorations in 2020 and this was a single center prospective double bond cohort study in 42 patients that 15 received clonidine lean and 27 dexamedetomidine. So, if patients were on a dose of dexamedetomidine less than 0.7 microns per kilo per hour, weighed less than 100 kilos or were older than 65 years old, they received 0.2 milligrams of clonidine Q6 hours. All others received 0.3 milligrams every six hours and then it was tapered. There was no difference in withdrawal between the groups and the average cost savings was $1,500 per patient who received the clonidine as compared to just the dexamedetomidine. So, once again showing that you can use an enteral alpha-2 agonist to help get patients off dexamedetomidine quickly. So, the last study was led by Fedders and colleagues and this was published in Critical Care Explorations in 2022. Now, this is the only study that I could find specifically looking at guanfacine to help wean patients off of dexamedetomidine. So, single center retrospective study that included 105 adult ICU patients and patients received at least one dose of guanfacine while on the dexamedetomidine and dexamedetomidine was discontinued within 48 hours in 58% of the patients and within 72 hours in 71% of patients. So, once again, just suggesting thinking about cost-effective means, not that dexamedetomidine is that expensive anymore, but you can use enteral clonidine or enteral guanfacine to help wean patients off of dexamedetomidine. So, now we're going to take a different direction with this talk and look at the hemodynamic effects of dexamedetomidine. So, this study specifically looked at the effect of dexamedetomidine on vasopressor requirements in patients with septic shock and this was a subgroup analysis of the SPICE 320 study that we looked at. So, this was a post-hoc subgroup analysis of an international randomized trial that compared dexamedetomidine in usual care. So, it included 83 patients with septic shock receiving mechanical ventilation. So, as you can see here, the noradrenaline equivalent dose in the first 48 hours after randomization, the median norepinephrine equivalent was 0.03 per minute in the dexamedetomidine group and 0.04 in the usual care group indicating no difference and patients in the dexamedetomidine group had a decreased norepinephrine equivalent divided by their MAP indicating lower vasopressors to keep that MAP. When they further analyzed this, they showed an adjusted ratio of noradrenaline equivalence divided by the MAP in the first 48 hours after randomization and they showed that dexamedetomidine was associated with the reduction in the norepinephrine equivalence divided by the MAP ratio indicating they needed less vasopressors to maintain their goal MAP. So, once again, really showing that maybe dexamedetomidine is a little more hemodynamically friendly than some of the other agents that we use for sedation. So, the next study we're going to specifically look at looks at propofol versus midazolam in patients with cardiogenic shock. So, once again, I've definitely gotten this question before and I'm sure many of you in the audience have as well. Propofol is a beta blocker and a calcium channel blocker, so sometimes there's some fear to use this in patients that have cardiogenic shock. So, this study is a retrospective propensity score match patient study that predominantly received propofol to those that predominantly received midazolam and included 174 propofol patients matched to 174 midazolam patients. And as you can see here, patients that received propofol required less catecholamines days one through four of their ICU stay. The mortality rate was 38 percent in the propofol group and 52 percent in the midazolam group after 30 days. And midazolam was associated with ICU mortality. So, I think this, once again, just is kind of a myth buster that I've been trying to show you throughout this talk that, indeed, there are many reasons to use dexametatomidine and that it is safe to use in patients that have cardiogenic shock. So, as we conclude this study, I think it's really important to look at this timeline. And essentially, I put this timeline together to show that we came a very long way. When the first guidelines were developed with regards to giving advice on the utilization of pain and agitation, and these were published in 1995, this was essentially all expert opinion. And we've done a lot of studies, many that we have gone through today, to show that some of the things we used to do historically, like deeply sedating everyone, using benzodiazepines in everyone, have really been proven to be harmful. And that we really should not be doing this to patients anymore, just because we are putting them at risk for delirium. We are putting them at increased risk for post-intensive care syndrome. And the latest set of the guidelines, the PADIS guidelines that we talked about earlier, that were published in 2018, that's why they make the recommendation that we shouldn't be using benzodiazepines anymore and that we should be using non-benzodiazepine strategies. But really, what this also shows is that if we can, we really want to not be using sedation at all. Obviously, once patients are out of the window, they've been paralyzed, we've made sure that their paralytic is weaned off, and that we try to turn off their sedation and analgesia every single day, if possible, so that we can extubate patients faster, just because we know that this is the right thing to do for patients. What this further has shown us is if you have to use a sedative to really consider propofol or dexamethasone. Now, unfortunately, as many of us experienced, most all of you, I'm sure, that are listening to this, and the COVID-19 pandemic that occurred in 2020, 2021, even 2022, and we're still seeing some of these patients, unfortunately, really made us take some steps backwards. And unfortunately, a lot of us did have to use benzodiazepines, whether it be secondary to a drug shortage, or just that we had so many patients with ARDS that had such high triglycerides and high creatinine kinases, that we really were stuck between a rock and a hard place. And so, we've learned some bad habits. And I, once again, I want you to look at this slide and really just reflect and remember why we do what we do, and that we should be if our patients need sedation using dexamethasone or propofol every day, and to avoid benzodiazepines at all costs. So, in conclusion, dexamethasone or propofol is the standard of care for sedation in ICU patients. If dexamethasone and propofol are contraindicated, midazolam should be utilized if needed. Dexamethasone is a cost-effective sedative. Reduction in delirium has been shown with dexmetatomidine. The risk of bradycardia and hypotension can occur with dexmetatomidine, and using the ABCDF bundle or ICU liberation bundle, including daily spontaneous awakening trials, is key in reducing use of sedatives in the ICU. This concludes my presentation, and I thank all of you for listening to it today.

Joanna Stallings

Medical ICU

Clinical Pharmacy Specialist

dexamethasone

benzodiazepines

propofol

ABCDF bundle

sedative use