Thank you so much for that kind introduction. I have no disclosures. And today, my section is going to talk about the analogous sedation for better for worse. And we'll get into some of the controversies and details. Some of the kind of laying the groundwork stuff, you know, critical care patients, as we all know, are prone to pain during their critical illness. Inadequate pain management is associated with some poor outcomes. And one of those important poor outcomes is chronic pain post-ICU. And so the question is, you know, we need to consider our therapeutic goal for treating the pain. And then what is that going to do for our patients? But we need to think about the individual patient, whether it's a routine surgical patient versus a medical patient, ERDS, et cetera. So I think those patients are a little bit different and a little bit nuanced. So the ideal pathways, you have patients that are critical ill or acute surgery. They come down. They recover quickly. Everything's fantastic. The trouble is, is like, you know, inadequate pain management can lead to perhaps uncomfortableness, therefore maybe less rehabilitation. And that pain may also be leading to chronic pain down the line and have that chronic vicious cycle that we see sometimes in some of our patients, not all, obviously. As a pharmacist, I think it's important to point out that I really feel strongly that there is not a single medication that's going to solve the problem. And I think that I call it the top nine, if you ever heard me talk about pain, agitation, and delirium. I have the top nine kind of modalities that we can do to improve hard clinical endpoints. And the hard clinical endpoints is what we have to think about focusing on. So those things like setting a goal, assessing, sedation interruptions, opioid rotations, analogous sedation, which is one of the ones I want to talk about today, and opioid rotations, and et cetera. So quickly, the PAT-X guidelines very clearly says that we should have pain assessment-driven protocols, which are driven mostly by gold standard self-report. Self-report's not always going to be possible, so we'll do the behavioral pain scores in those patients. The key, though, is that we try to get that patient self-assessment as it's a subjective thing. And we all know the numeric rating scales and the subjective pain scores, which are the gold standard. But I think it's also important to note, and we all know this, but just to remind ourselves, the pain score goal is going to be dependent on the patient. For example, if they live at a pain score of five for one reason or another, we're not going to get them to a pain score less than three. So we need to think about that rather than trying to drive our patients to adverse effects to these unrealistic goals. On the observational pain scores, I think I just want to make two big points. One is that they're essentially a positive and a negative score. So for the CPOT, anything that's greater than two, so three to eight, is considered to be likely in significant pain. By the way, it doesn't mean that they're in pain. It means that they're likely in significant pain. And a score of zero, one, and two means they're likely not to be in significant pain. It does not mean they're not in pain. Also, they're not a linear scale. It's not an intensity score. So a CPOT of eight is really no different than a CPOT of four. And I know for a fact, because I've seen them at many hospitals, that there are intensity scores for the CPOT. That's not validated practice, just so we're aware. Observational pain scores are positive or negative. And it doesn't mean that they are in pain. It means they're likely to be in pain. It's such a subjective thing that we're trying to put into an objective pain score. So here we get into the controversies of analogous sedation. And within the pain group in the PADS guidelines, we had a lot of discussions about this. So I'm going to go over the slide with a little bit of nuance. But I think it's extremely important. So using an assessment-driven, protocolized-based, analogous sedation, stepwise approach for pain and sedation management in critically ill patients is recommended with the conditional recommendations of moderate level of evidence. And analogous sedation was further defined as analgesia first, usually in opioid, but not necessarily. It's used before sedation to reach a sedation goal. I want to say that again. An analgesic is used before sedatives for a sedation goal. So clearly, we're going to be treating pain as well, but also to the sedation goal. And there's more of the classical definition of analogous sedation, which is analgesic, typically an opioid, is used instead of a sedative for the sedative goal. So the nuance there is that the first approach, which I'll go into first, is that we try the pain-first approach, and that we call that analogous sedation if we're trying to then use that analgesia to treat to a sedation goal and a pain score. And so then when these things get rolled out in protocolized fashion, we've seen thousands of these. I just picked out a few. You start seeing observationally that we have many differences in clinical outcome, such as duration of mechanical ventilation, hospital, and ICU lengths of stay. But also, I think it's equally important is in many of these studies, in most of these studies, we see massive reductions in sedatives, which makes sense. We're giving an analgesic instead of or before we give a sedation. But what's even more important in many of these studies, in most of these studies, we actually see a reduction in the opioids as well. Because it goes back to my top nine assessments, right? Assessment and driving to that assessment. So we're not just giving analgesics, whether it be opioids or otherwise, to a sedation goal. We're targeting what our sedation and pain goals should be, and we're targeting these things. So we're not throwing willy-nilly opioids, for example, at patients. And so I think that's what sometimes gets missed in this concept. And again, there's tons of studies looking at hard clinical endpoints, reduction of mechanical ventilation, decreased ICU length of stay, and other morbidities. Almost universally see reductions in sedatives, and at least no difference in opioids prescriptions. Occasionally, of course, you'll see some patients with a little bit of an opioid increase, so it's important that we really closely monitor that. And in these studies, we actually have seen no difference in that a lot of these are smaller, but no difference in opioid-related adverse effects, which I think is important. What I also think is extremely important is that I can guarantee pretty much all of you all at your institutions have some sort of stepwise approach. Treat pain first. We're talking really basic stuff. But the question is, are we doing it? And I'm going to be very straightforward and blunt. At my institution, we're not always doing it. We have it written down in the protocol. We feel good about ourselves when we put it in the protocol. But in practice, we're getting tugged for the propofol infusions. And so not to say it's a bad thing. I'm just saying, if we're being honest with ourselves for a few minutes. But what we know is when we have these protocols, we look through the A through F bundle, that when we have compliance with the protocol, outcomes are better. So you can have these protocols, which is great. But making sure you're assessing compliance and how that is working in clinical practice is really the key to all of this. Again, another one of the studies we're treating in a protocolized fashion, pain first. See reductions in pain and agitation. Reduction in continuous infusions of opioids and decrease in continuous infusions of sedatives. But this is one of the earlier signals that we saw other analgesics. It's not all about opioids. Maybe the reason why we see reduction in opioids is because we have an increase in some of the adjunct medications. And we know that adjunct medications are so vitally important, multimodal. And I'm not telling you anything you don't already know. But here's the reality. If you're looking at for pure ICU trials, there's very, very few studies looking at these multimodal therapies. Epidural infusion, there are studies out there, but only subsets of those patients are critically ill. And so in the PICO questions for the grade criteria for PAD-IS, the number one thing is patients. Right, it's gotta be critically ill adult patients. And so if they weren't critically ill patients, we really can't include them in the guidelines. So it's a paucity of critical care literature specifically on the multimodals. And the risk of that is that we just think that multimodals is the greatest thing ever. But we know that multimodals have their own adverse effect profile as well. So it's not as simple as just adding things on. We need to do it in a very protocolized way. A couple more nuances of the PAD-IS guideline I want to recommend. We pretty much all use acetaminophen in one way, shape, or form in many or most of our patient populations. Important to note here that it's a very low quality of evidence for the PAD-IS guidelines because the study is specifically of randomized control trials in patients, in the critically ill patients, is actually, again, paucity of data. When you look at things like ketamine, which we probably all use in our practice, I think it's important to look at the nuance. The PAD-IS guidelines was kind of hand-strung to surgical patients specifically for the reason of decreasing opioid doses. It's very specific. It's surgical patients. And here's one of the reasons why, for example, the acetaminophen recommendations is very low quality of evidence. It's a randomized control trial, extremely small number of patients. There was a reduction in pain, a modest reduction in opioid use, even though it wasn't statistically significant, and specifically in cardiac surgery. And there's only a couple of these studies. There's been a few more since PAD-IS has gone out. The point is it's a very, very low quality of evidence because of the paucity of evidence. When we look at ketamine, this is an extremely old study, but this is the only randomized control study that we could have used for ketamine because it was the only randomized control trial and the grade criteria sort of makes you use this. So this study saw a reduction in pain, I'm sorry, a reduction in opioids, but not a reduction in pain in a surgical patient population. So a tale of caution that I like to mention with ketamine. So again, one of those, we can't just add things on, right? So we think about the patient population. When we're adding ketamine to a patient who's coming up on the higher end of opioid dosing post-surgical, and maybe they get in respiratory depression, add ketamine, stimulate the respiratory drive, come down to the opioids, it makes sense. But what about the patient who's getting higher dose opioids because they have ARDS and getting to the point of maybe needing ECMO support? A tale of caution here is that we might be driving the respiratory drive up with ketamine and therefore needing to go up on opioids, which we've seen in some of the medical patient population with ketamine. So be very clear on why we're adding drugs and what the good effects and the bad effects that may be. We're not always gonna see a reduction in opioids if it's not specifically for treatment of pain and opioid reduction. The question is, what about dexmedetomidine for analogous sedation, right? And the reality is, based off the studies, it depends. If it's a pure surgical study, the reality is it probably does spare you opioids, particularly if it's cardiac surgery. However, in a mixed medical surgical patient population, likely not, there was no difference in CEDCOM, Prodex, Mydex, or Spice 3. And in fact, the men's trial had three times more opioid consumption in the dexmedetomidine arm. Why? Well, probably because those patients were a little bit more awake and alert as opposed to the lorazepam infusion, but they received more than three times the dose of opioids in the medical population. So be clear that what we're talking about here in patient populations. Going to the other side of analogous sedation where we're sort of replacing infusions with an infusion, so like the remifentyl infusion, the classic example, critically ill patients, usually for these studies, it was shorter term. We had remifentyl plus or minus propofol. The competitor group in almost all these studies was some sort of opioid infusion with usually a benzodiazepine. And the outcomes were you were more likely to come off mechanical ventilation, but we know this because it's benzodiazepine infusions, which hopefully none of us really use unless it's really necessary for four or five reasons that we might need them for individual patients. And there's a newer feasibility study looking at the analogous sedation versus more conventional therapies, but there's no hard clinical endpoints with that. So really, in 2023, giving remifentyl infusions to replace midazolam is not really a thing. And so it's really something that needs to be studied more. So then what about the kind of nuance that probably is the Paul Zemeter approach at analogous sedation is the no sedation groups. And so we have a little bit more studies than that. So we all know the Strahm analysis, which now is getting a little bit older. So the Strahm analysis was no sedation versus sedation. And the patients who quote unquote received no sedation received an injection of morphine if they were agitated. In other words, analogous sedation, right? So this is great. Hard clinical endpoints, reduction in mechanical ventilation time, get them out of the ICU. This is fantastic. Massive reductions in propofol, midazolam, and no difference again, no difference in opioids. So this is great. The trouble is extremely small, really feasibility trial. And it showed that it was probably feasible. When we roll this out to the no sedation, bigger randomized controlled trial, we see that they're cut to the chase. No difference in all cause mortality, time and mechanical ventilation. The hard clinical endpoints that we wanted to see, that we saw in this Strahm analysis, we did not see here. I do think though it does show at least partial feasibility because less than 40% of the patients at any point during their ICU actually required sedation. So a portion of patients, think about your patients just for a minute. What portion of your patients that are mechanically ventilated in the ICU for a long period of time, don't receive any sedation at all? So this study did, so it is feasible, not in all patients, but in a big number of patients. And in the no sedation arm, no surprise, the RAS scores were slightly lighter. The patients were less sedated. Now, does it matter between, you know, somewhere around negative two to negative one? We don't really know. And the hard clinical endpoints in the study know, but it's things that we try to reduce the amount of drugs that we give patients and reduce the amount of badness that we can give through medications. But in the subgroup, again, you know, all the things that go along with subgroup populations and, you know, theory finding things, in the patients who were actually successful at the no sedation, they actually did have, modest albeit, but statistical reduction in some of the important clinical endpoints such as ICU free days, coma free days. And again, the patients who did not receive sedation had lighter levels of sedation. Makes sense, right? And there was no difference in the opioids in these groups. So kind of a shot in the arm, kind of like the downside is that there was no difference in all grommers. It was probably feasible in many of these patients and the patients that you could actually achieve it on, again, going back to the compliance part of things, then it actually was probably beneficial in a subgroup analysis. So we've talked a lot about like replacing things with morphine injections, but we know there's a ton of opioids and they have their own profiles. They're all very different. So it's not as simple as just saying, let's just replace with a opioid. We know there's class effects. And I always put respiratory depression as the top of the class effects because being me when I staff my days, I'm staffing the medical intensive care unit, a lot of critically ill patients with ARDS, et cetera. And we have to be honest with each other. Is that side effect of respiratory depression something that we want or don't want in some patients? You know, if we're trying to suppress the respiratory drive to get the patients complying with the mechanical ventilator and ARDS net ventilation, sometimes even if we're not saying it out loud, sometimes we're using these drugs to these toxic effects on purpose, right? And so we have these class effects of respiratory sedation, but we know with the opioids that there's all the individual class specific adverse effects such as serotonin syndrome, chest wall rigidity with fentanyl, with remifentanil with the ammonia levels and quick tachyphylaxis. Morphine we know has its histamine and neurotoxicities. We don't really use miparidine a lot, but it has its issues with seizure. And we know we have the QTC prolongation with methadone. So oftentimes we'll have to rotate opioids. We've done it all the time. We do it in critically ill, we do it in non-critically ill patients. And we gotta think about what is the goal of opioid rotation? And so, you know, better analgesic effects, maybe a better side effect profile. That's why sometimes I think opioid rotation is important, but also maybe being a little bit more proactive upfront to say what's the better opioid for this patient right now, given the things that we're trying to do theoretically and therapeutically in the patient and try to avoid the adverse effects. For example, fentanyl has many limitations with pharmacodynamics and kinetics. Why? Because it's extremely lipophilic. And so in patients with liver disease and patients with heart failure and the different weights of patients, it's going to be very heterogeneous of what the result of the patient's levels are. So in patients in ECMO, for example, patients, again, observational studies, but looking, you see reduction in delirium with hydromorphone versus fentanyl, ECMO specific, reduction in patients with lighter sedation and had decreased morphine equivalence in the hydromorphone group. So again, some things to think about, maybe upfront in the certain populations, maybe there's certain drugs that are better. We looked at this at the Brigham and we saw patients who are on fentanyl infusions and we switched to hydromorphone. We saw the sedative requirements of morphine, of propofol in very few midazolam patients, but we saw the massive reductions in the amount of sedatives that we needed for our patients when we transitioned. So thinking of transition, it's not just from IV to IV, but think of another opioid rotation as being from IV to enteral if you needed to. And one of those drugs is methadone. Methadone has been shown to decrease the length of fentanyl infusions, which by itself isn't fantastic, but the other observational studies saw that it might be associated with a decreased length of mechanical ventilation and getting patients off of infusions is sometimes very helpful. Important point here, there isn't all the answers. There's probably more questions than anything else. Will certain patient populations benefit from certain strategies and certain drugs? We can say that pharmacodynamically, kinetically, maybe, but we don't actually know this without randomized controlled trials, which are missing. What medication for what type of patient? Multimodal pain management with outcome trials, and what combinations of, you know, a lot of times we're looking at the addition of acetaminophen, but what combination? We know through ERAS protocols, et cetera, we're given three or four different multimodal medications. What PICO questions should be prioritized? What are the wording of the PICO questions? I know John Devlin's sitting here in the second row. We talked at length about the PICO questions during the Patience Guidelines. It's so important, which ones want to be prioritized? It's a huge burden on us as critical care clinicians to come up with that right question. Will multimodal pain cause less chronic pain? We think that if you're treating pain, they have less acute pain, maybe they'll have less chronic pain, but that's a stretch, so I don't really know that. And the data for the techniques that we use mostly in the surgical patients, we need to get some more data for critically ill patients. Of note, to be very important, kind of close out the talk, opioid prescriptions lead to misuse. That misuse leads to heroin, right? This is a straight up fact. So when we're leaving, we know that patients who leave the ICU don't even come down to their pre-ICU opioid requirements until 12 to 24 months after. This is a huge burden on us as clinicians, whether we're in the ICU or part of the post-ICU care. So when we transition to care, we need to think about upfront in the ICU, what can we do to decrease this patient's opioids? Assessments, right, adding a multimodal for the purposes of decreasing opioids, weaning these drugs before they get out of the ICU. We know that we've seen tons of studies that continue antipsychotics, stress ulcer, prophylaxis, sedatives as patients leave the ICU. We all, as an ICU community, need to do better at getting rid of these drugs and aligning these things from ICU to ward, and then ward to home. It's on all of us. It's gonna take a collaborative approach. All of us in this room, no matter what your subspecialty might be, needs to take a hand in this. So my take home points are critically ill patients are often in pain, analogous sedation is complex and isn't simply replacing one med for another. Several strategies to treat pain in critically ill patients, including multimodal approaches. Opioids have therapeutic benefit, however, efforts should be taken to minimize overexposure to these meds, focus on transitions of care and refocusing whether we need these drugs, and further research is needed to address the best optimized use of analogous sedation through the phases of care. I appreciate your time. Thank you so much. Thank you.

analogous sedation

pain management

therapeutic goals

opioid rotations

multimodal therapies

clinical outcomes