Hello, and welcome to the ABCs of analogous sedation. My name is Paul Zamita. I'm the Director of Clinical Pharmacy and the Director of the PGY2 Critical Care Pharmacy Residency Program at Brigham and Women's Hospital in Boston, Massachusetts. I have no disclosures relevant to this presentation. The objectives of this presentation are to describe the pharmacological considerations for analogous sedation in critically ill patients, discuss the evidence-based outcomes to support analogous sedations compared to other sedative strategies, and recommend supportive care regimens for patients receiving analogous sedation. Pain is complex in the critically ill population, but one thing that's very clear is that pain is common in the ICU. Up to 80% of patients experience moderate to severe pain. That will vary depending on the type of ICU subgroup, such as medical, surgical, or trauma. The type of pain might also vary depending if the patient is at rest, with routine care, or for procedures. There's a correlation between inadequate pain management and the association with increased morbidity and cost for inpatient care. But maybe even more interesting is the correlation between chronic intensive care-related pain associated with the pain that patients receive in the ICU. Therefore, the development of chronic pain is reported in up to 50% of ICU survivors post-ICU stay, but can be as high as 80% in certain type of surgical procedures. But I wanted to just mention, when we talk about pain, that it's not just necessarily about the drugs that we use to treat the pain. And we need to think about the therapeutic goal on an individual patient. For example, does the patient come in with pain needs and constantly lives at a pain score of, say, 6? Or is this a classic post-op patient in the ICU? Or are they in the ICU with a chronic or acute issue, such as ARDS, which patients may require high doses of medications to support the respiratory system, but the dosing of that medication isn't necessarily for pain in that individual patient? So it's important to think about the individual goal for individual patients. The role of analgesia in the pathway to recovery, the ideal pathway where the patient is acutely ill or has a surgery, is optimal pain management, whether that's through medications or other modalities, supportive care, rehabilitation, and discharge. The undesirable pathway would be patient is acutely ill or has surgery, has inadequate pain control through different modalities, therefore has poor recovery and rehabilitation, which leads to increased ICU length of stay, which then leads to iatrogenic complications such as delirium, falls, hepatostarmosidopenia, infection, and then the patient circles around the undesirable pathway. And this pathway is thought to perhaps be the biggest risk for things like chronic pain and prolonged length of stay and post-discharge based off the complications that patients can get while in the ICU. The difference in heart clinical endpoints in critically ill patients has not been correlated specifically with medications. It has been more closely aligned with non-medication specific strategies. So in other words, there's not one drug that's going to be right for all patients or even most patients. The strategies that have actually had the biggest impact on heart clinical endpoints are listed below, such as setting a goal and continuously discussing that goal. Assessment, assessment, assessment, and discussion of that assessment based off of what the goal was. With the non-pharmacological strategies, vent adjustments, massage, music therapy, we have having the default be awake and alert RAS of zero, for example, whenever possible. Also having the patients, particularly during the waking hours, be awake and alert. Symptom triggered or preemptive boluses. So if patients have turns or critical care needs, that does prevent preemptive boluses, but not necessarily just continuous infusions. If a patient happens to be on a continuous infusion of opioids, the sedatives that there's a sedation holiday or spontaneous awakening trial. Analogous sedation or no sedation. Patient-specific pharmacotherapy, which is oftentimes considered to be multimodal. And the rotations of medications to avoid accumulation. So we'll focus on the goal, the assessment, analogous sedation, patient-specific pharmacotherapy, and rotation of medications during this presentation. The 2018 SCCM PAD-AS Guidelines recommends management of pain for adult ICU patients to be guided by routine pain assessment and should be treated before the sedation agent is considered. This is a good practice statement. Among critically ill patients who are able to self-report pain, the numeric rating scale should be administered and the patient should self-report pain. That should be considered to be the gold standard. And among patients who are unable to self-report pain, then a behavioral pain score or the critical care pain observational tool have demonstrated the greatest validity and reliability in the ICU. So as mentioned, on the hierarchy of pain assessment, self-reporting is preferred. It really should be really 1A, 1B, 1C, 1D, just continue down. Self-reporting is preferred. However, when that's not possible in the ICU, then we could search for a potential cause of pain. Then you have the observed pain behaviors, which would be the observational pain scores that we have. Next is becoming more popular in the literature, a thing that needs to be sussed out a little bit more, but the concept of a proxy report, particularly a family member who knows the patient's behaviors and patient's past medical history. And the very last in the hierarchy would be to attempt an analgesic trial to see if it works. Again, for the patient self-reporting in the ICU, we're looking at the numeric rating scale or the visual analog scale. The thresholds for acceptable pain typically are less than 3 to 5 on a scale from 0 to 10. However, not all pain is avoidable, making individual goal-oriented therapy vital, as well as the patient's past medical history, where they may have different pain scores at baseline to begin with. There's many limitations to this, but one of the bigger ones in the ICU is the patient unable to communicate. Now, of course, we should be having our patients awake and alert and be able to have patients self-report pain as much as possible, but it's not always going to be possible, as we know. So in that case, we have the patient assessment of patients who are unable to communicate. So these are the behavioral pain scores, which essentially look at facial expression, movement, muscle tension, and ventilator interaction. The guidelines recommend scales generally not considered to be linear pain scores. So, for example, a CPOT score of, say, 3 have more intensity than a CPOT score of, say, 4. They're considered more to be on or off. So, for example, a CPOT score greater than 2 is considered to be likely to be in significant pain. This does not, however, mean that a CPOT score of 0 or 1 or 2, that the patient is not in pain, it means that the patient is likely not to be in significant pain. For a patient with a CPOT score from 3 to 8, that patient is likely to be in significant pain. However, again, it's not a linear pain score, so a score of 3 does not necessarily mean the patient is in more pain than a score of, say, 5. The same is true for the behavioral pain score, where it's a score from 3 to 12, and the inflection point is typically greater than 5, that those patients are likely to be in significant pain. So, again, a BPS score of 6 or 7 likely to be in significant pain. A BPS score of 3 or 4, the patient's likely not to be in significant pain, which does not necessarily mean the patient is not in pain. There's many limitations to this, such as the diverse languages as well as cultures that not necessarily validate in all patient populations, such as traumatic brain injury in patients in paralysis, et cetera. What I think it's interesting to note is that the PATAS guidelines very specifically mentions the use of assessment-driven, protocol-based, analogous sedation, stepwise, approach to pain and sedation management in critically ill patients as a conditional recommendation. In addition, what I think is fantastic is that the guideline further defines what analogous sedation is, and it defines it really in two different ways. One is analgesia-first sedation, analgesia, or an analgesic, usually an opioid, used before a sedative to reach the patient's sedative goals. And then you also have the analgesia-based sedation, where analgesic, usually an opioid but not always, is instead of a sedative to reach the sedative goal. So the concept here is that we're treating pain first either way, typically with an opioid, although it doesn't have to be, only with an opioid, and is used before we do a sedative strategy, or we use it completely in place. So it's not necessarily remifentanil infusion as analogous sedation. It's really any protocolized approach to the management of patients that prioritizes pain before sedation is the concept of analogous sedation. So with that, the impact of pain assessment on ICU globally, if we look at the studies, you see that there's more frequent pain assessment using validated pain assessment tools, which is also accompanied with a protocol or education, has been associated with improvement in pain scores, a reduction in the length of mechanical ventilation, ICU length of stay, reduction in mortality. Almost always has been associated with a decreased prescription or consumption of opioids, which is interesting when we think about analogous sedation, where you might think, well, that would just increase the amount of opioids. If done correctly and with proper pain assessment, actually has been associated most of the times with a decreased consumption of opioids. Almost universally has been shown to have a reduced consumption of sedatives, which we know can be dangerous in the ICU. Reduction in the need for boluses and analgesic in the patients who are non-communicative, mostly based off of the behavioral pain scores that we can use for patients. Increased the use of non-opioid analgesics. And interestingly, has no effect on opioid-related adverse effects, probably associated with the fact that we don't really see an increase in opioids in these patients. One of the problems, though, is that compliance is often low with protocolized care in the ICU. We know this. And we need to continually focusing on having our bedside providers compliance with these protocols. And one study that looked at the A through F bundle and looked at compliance, looked at as compliance went up with the protocol, so did survival in a linear way. So I'll review just a few of these analyses presented in the previous slide. So in this case, they implemented a protocol, which was pain-first approach in patients who had pain, treating pain, or patients who had agitation and we treat pain first. And protocolized that. And we saw a large reduction in the length of mechanical ventilation, ICU length of stay, and hospital length of stay. A reduction in some subsyndromal delirium, which is likely associated with the pretty large reduction in benzodiazepine equivalents. And in this case, a very large reduction in opioid equivalents. So even though we're looking at pain assessment and pain-first approach, we actually see a pretty large reduction in opioids. And again, I just want to stress that the PAT-IS guideline for best practice really should be approached with the bundle of the A through F bundle, with the goal of liberation from the ventilator, getting out of the hospital, getting out of the ICU, returning to normal brain function, independent function, and survival. So really, these do combine. And again, if we can increase the bundle compliance, then we're likely to see a reduction in mortality. Another key finding that we have when systematically implementation of pain and sedation tools, such as the assessment tools and pain-first approach, you see that we have a reduction in the pain and agitation, which makes sense. But we also have a significant increase in non-opioid analgesics that are being utilized in these patients. And this only makes sense when we're looking at pain-first approach. And this only makes sense. We know that the chemical mechanism of pain is complex. And there's many chemical mediators that interact with nociceptive neurons, such as pulmonoformatized cytokines, et cetera. And there are just a countless number of them. So it makes sense that you wouldn't be able to manage pain just with one different mechanism of action. We've seen this with many different types of things in the world of medicine. So we know that if we could potentially hit different mechanisms of action, that you're likely to decrease the need for one of the individual agents. And perhaps we can hone down for an individual patient with the best medication to treat that particular pain. Which leads us to the concept of multimodal analgesia, which is defined by the combination of different analgesics that act by different mechanisms and different sites in the nervous system, resulting in additive or even synergistic analgesia with lowing adverse effects of the sole administration of an individual med. Anesthesiologists have been doing this for many years, and they call it balanced analgesia. It was established many years ago and is recommended by perioperative practice guidelines and is standard for the ERAS protocols that we have. One of the problems, however, is that the literature in the ICU for this is somewhat limited. So I'll go through what we currently have in the literature. And again, I want to mention that for effective ICU analogous sedation, it's not just opioids and it's not just a different combination of different drugs, but it's also perhaps different mechanisms of where drugs work or even perhaps even different ways of delivering medications. Multimodal pain management, again, incorporates many different mechanisms of actions. Some of the ones that are endorsed by the 2018 PEDAS guidelines include acetaminophen, NMDA receptor antagonists such as ketamine, anticonvulsants such as gabapentin pregabalin, and non-pharmacological strategies. However, there are other multimodals which aren't necessarily supported or endorsed by the 2018 PEDAS guidelines, such as NSAIDs, COX-2 inhibitors, alpha-2 agonists such as clonidine, dexmedetomidine, corticosteroids, and local anesthetics. For many of these, the reason why they're not endorsed by the 2018 PEDAS guidelines is because they're not supported by the 2018 PEDAS guidelines. For many of these, the reason why they're not endorsed in the guideline is because the literature specific to critically ill patients is missing. We don't necessarily have a lot of local anesthetic literature specific to critically ill patients, so one of the cries or the calls would be to have more literature specific related to critically ill patients so that future guidelines can address these in a systemic way. So briefly, let's look at adjunctive acetaminophen and ketamine. The 2018 PEDAS guidelines gives conditional recommendations to acetaminophen to decrease pain intensity and opioid consumption for pain management in critically ill patients, and for ketamine, using low dose, one to two micrograms per kilogram per minute as an adjunct to opioid therapy when seeking to reduce opioid consumption in post-surgical adult patients. So it's a very specific conditional recommendation. This is low dose, in this case, very low dose, as an adjunct to opioid therapy when patients seeking to reduce opioid consumption in post-surgical patient populations, and we'll go through why that's the case. Even for acetaminophen, the literature in the critically ill patients is somewhat lacking, but things that we have seen relatively consistently is that the pain score has been reduced, and you see a general reduction in opioids, even though sometimes it's not statistically significant, it is clinically significant reduction in the amount of opioids. In the one randomized controlled trial of ketamine in surgical ICU patient populations, actually saw a reduction in opioid consumption, but actually no difference in the pain scores. So when seeking to reduce opioid consumption, ketamine at a very low dose can decrease opioids, not necessarily decrease the pain scores. This is where that recommendation comes from in the guideline. Although I think we all know that ketamine for sedation has potentially some other benefits besides just opioid consumption, such as improved time to sedation goals, decreased frequency of agitation, allow for reduction in discontinuation of other sedatives, and is relatively well tolerated. Unfortunately, these are only been shown in the ICU population in observational trials, so that one randomized trial would overweigh this, but important to note that the observational trials have seen other benefits. However, there's a caution of tail here with ketamine in the ICU. In this pilot randomized controlled trial, the test of hypothesis that the administration of continuous low dose ketamine infusion to patients receiving VV ECMO would result in lower opioid and sedative requirements with improved wakefulness. It was interesting that we saw in this analysis a pretty large increase in the amount of opioids that patients required in the VV ECMO. Not 100% sure why, but in the patients in the ketamine arm did receive much more analgesics. Of note, it's not generalized to standard surgical and medical ICU patient populations. Again, this is VV ECMO, where the patients likely had respiratory problems, but the patient Again, this is VV ECMO, where the patients likely had respiratory problems, therefore likely given the opioids to decrease the respiratory rate and need, and therefore ketamine might then counteract that and therefore then give more opioids. Who knows? But it's important to have patient specific goals in understanding why we're giving these individual meds, and understanding that some of the risks may be associated with very specific patient populations. So how about adjunctive neuropathic pain medications for surgery for patients with non-neuropathic pain? In relatively, again, a low number of literature, in this case was cardiac surgery trials, the pooled data saw a small reduction in opioid consumption and no difference in any other outcomes. Which leads us to our adjunctive neuropathic pain medication recommendations in the PADDAS guidelines. So for patients who have the presence of neuropathic pain, which is typically assessed by past medical history prior to the patient being in the ICU, there's actually a strong recommendation for the use of neuropathic pain medications with opioids to treat the neuropathic pain in the ICU. In patients without the presence of neuropathic pain, using neuropathic pain medications such as gabapentin and pregabalin with the opioids for their management in ICU patients after cardiac surgery, there's a conditional recommendation for the use of these in cardiovascular surgery patients. How about adjunctive lidocaine? How about adjunctive lidocaine infusions in the ICU? Again, limited randomized control trials, the PADDAS guidelines utilized one randomized control trial, which gave 1.5 milligrams per kilogram of IV bolus times one over 10 minutes at the time of surgery followed by an IV infusion of 30 micrograms per kilogram per minute for 48 hours. This saw no significant difference in self-reporting of pain, opioid requirements, ICU length of stay or hospital length of stay. Therefore, the recommendation for IV lidocaine as an adjunct to opioid therapy is a conditional recommendation to not routinely use IV lidocaine in this case. Now I think that this is important here. One is that it's not routinely used, and two, that it's a conditional recommendation. So perhaps there's a patient population, call it GI surgery, at your institution that you have a protocol. That's totally fine because it's not routinely in all ICU patients. It's maybe that one population. And again, it's just a conditional recommendation against, but it's important to note that in the one randomized control trial in the ICU, the cardiac surgery patients, that actually was no significant difference, which leads to that conditional recommendation to not routinely using in the guideline. Again, IV lidocaine does have some advantages. In fact, in the abdominal surgery meta-analysis, which again is not specific to the ICU, the IV lidocaine was associated with a decreased duration of ileus, length of stay, postoperative pain intensity 24 hours after operation, and incidence of nausea and vomiting were decreased. So there are some potential advantages. The trouble is that critically ill patients can oftentimes be complicated, and so it's hard to translate these studies to be specific to critically ill patient populations. But just want to note that there are, as many know, different utilization of these meds outside of the ICU literature. And very similar with adjunct NSAIDs in the ICU. Believe it or not, the randomized control trial data is limited. There really have been two small randomized control trials in the ICU, which saw no significant difference in pain scores. There was a small reduction in opioid consumption and no significant difference in ADRs. So with that, the PATACS guideline to recommend suggests not routinely using NSAIDs as an adjunct to opioid therapy in critically ill patients with a conditional recommendation. Again, it's the concept of not routinely using and a conditional recommendation, and this is based off of the randomized control trials that we currently have available in critically ill patients. But again, and you point this out in many different situations, but this is one example. For orthopedic or abdominal surgery, again, non-ICU, you see reduction in opioid requirements in patients who are receiving NSAIDs. So we know that there likely is a reduction in opioid requirements, it's just that the literature isn't there for critically ill patients. But we have to also balance the adverse effects that you can get from NSAIDs as well, which helped lead to that recommendation for not routinely using NSAIDs in the management of patient and critically ill patients. The PAT-IS recommendations we had up until this point are just general management of pain in the ICU, but there are specific procedural pain in the ICU recommendations in the PAT-IS guidelines. And interestingly enough, I'll hit the NSAIDs first, there's actually a conditional recommendation for the use of intravenous oral or rectal as an alternative to opioids for pain management during discrete and infrequent procedures in the ICU. So although there's a general recommendation against the use of NSAIDs in patients in the ICU, if it's for the management of a procedural pain, there's actually a conditional recommendation for. There's a recommendation generally against the use of topical NSAID gel in the ICU for procedures, and for procedures suggest not using local analgesia or nitric oxide for pain management during chest tube removal based off of the evidence that we currently have, again, as a conditional recommendation. So that's procedural. So earlier I mentioned that the alpha-2 agonists, such as dexmedetomy, for example, does not have a specific recommendation in the PAT-IS guideline about the use of them for analogous sedation. And I think a point of that is we all know that alpha-2 agonists have analgesic properties. The question, though, I think is, does dexmedetomy or other alpha-2 agonists actually have opioid sparing properties in the ICU? And I think the answer to that is depends. In the pure surgical trials, the answer is maybe, or even likely, particularly in the early post-cardiac surgery trials. However, in the mixed medical-surgical, the answer is likely not. There's really been no difference in the CEDCOM, PRODEX, MIDEX, SPICE-3. In fact, the first men's study had over a three-time consumption of opioids in the dexmedetomy arm, which is here. So the first men's was the first trial here looks at the fentanyl consumption was over three times increased in the dexmedetomy arm. Now, that could be for a number of reasons. These patients were very ill, and many of them had acute respiratory illness, so likely giving those opioids to help respiratory suppression, which does not happen routinely with dexmedetomy. But again, too, if you look at the men's 2 analysis, which is much more recent, you see that there was a non-significant, but an increase in the amount of fentanyl equivalents used in the patients in dexmedetomy compared to the propoform. So does dexmedetomy decrease the need for opioids? I think, again, the answer depends. In the mixed medical-surgical patient population, I think that it might have increased analgesic properties, but it doesn't necessarily decrease opioid consumption in the studies. So multimodal pain management, there's a lot to choose from, but limited ICU data. I think we have seen why the PAD-AS guidelines recommend acetaminophen, ketamine, gabapentin pregabalin, and non-pharmacological therapies. However, there's potential for NSAIDs, alpha-2 agonists, corticosteroids, and local anesthetics as well. The choice of agent, route, dose, and monitoring is often patient-specific and limited by resources that are available. We'd be remiss to say, though, that multimodals aren't without their adverse effects. So we know that each one of these drugs has their own adverse drug reaction profile. So we need to make sure we're balancing that with our individual patient. We know, for example, that dexmedetomy can potentially lead to bradycardia and hypotension. We also know that ketamine may cause hallucinations and tachycardia. And there's sedation and withdrawal issues with some of the other meds. So we just, as we all know, need to make sure that we don't just throw meds on, that we're looking at a goal-oriented, and we're looking at the balance of the individual patient and their adverse effect profile. What I think the PAD-AS guideline does a great job on is looking at the literature, looking at multimodals that's more than just medications. So looking at cold therapy, which is a conditional recommendation. Relaxation techniques, conditional recommendation. Massage therapy, conditional recommendation. And music therapy for conditional recommendation. So when you look at analogous sedation by replacing benzodiazepine infusions largely with opioid infusions, some of the oldest studies, you see that the patient population is typically short-duration and mechanical ventilation. The intervention typically is remifentanil plus or minus propofol infusion. The comparator was typically a midazolam plus or minus an opioid infusion. And the outcome is more likely to achieve a light sedation and faster time to extubation in the opioid group, which makes sense. Newer feasibility studies support the feasibility versus more contemporary comparator arms. So again, remifentanil versus a midazolam infusion, really in 2023, 2024 doesn't really make sense. We need to have outcomes trials to support widespread use of this strategy with things like comparator arms like opioid, for example, propofol, for example. However, what about no sedation strategies? Is that analogous sedation? Is it feasible? And is that beneficial? So in the first drama analysis, you see non-sedation feasible? The answer is probably yes. No sedation versus propofol or midazolam infusions with daily interruptions. We saw that the no sedation group, if the patients were agitated, received a dose of opioids for their agitation, as opposed to continuous infusions of sedatives. And you can see that the patients in the no sedation arm, or really the concept of analogous sedation, those patients were off the vent faster, out of the ICU, and out of the hospital faster. This saw massive reductions in the need for sedatives. And interestingly, no difference at all in need for opioids. However, it's important to note that there was no increase in the accidental extubations, but there was a greater rate of agitated delirium, which required an increased use of sitters in the no sedation arm. So that pilot analysis suggested that it was feasible. Analogous sedation by management of agitation with an opioid was feasible in a pilot manner. When then that trial was brought to a larger multicenter randomized controlled trial, we saw that it wasn't always feasible. In fact, 38.4% of patients in non-sedation arm actually required sedative medications during their ICU stay. And overall, there was no difference in all-cause mortality, time to mechanical ventilation, ICU length of stay. There was slightly higher RAS scores in patients in the sedation arm compared to the sedation group, but really no difference in those other clinical endpoints. If you look at the non-sedation subgroup, looking at the non-sedation success versus the patients, the non-sedation failure, to the patient that was successful had a reduction in ICU length of stay, as well as a reduction in coma and delirium scores. And again, you see the patients in the non-sedation group had lighter RAS scores. Our patients are more awake and alert. Therefore, hypothesis generating, but in the patients so that you could actually achieve the non-sedation, those outcomes are potentially there. Again, something that we'll have to see in further randomized controlled trials. We would be remiss to talk about analogous sedation and not talk a little bit about the comparison of opioids. I don't want to go into complete detail because I'm sure everyone listening to this lecture has a pretty good understanding and appreciation for the difference in opioids. But I think it's important to sometimes just put it down on a slide. To see what the major differences are. So for example, for fentanyl, we know that it's more lipophilic. It actively goes to the cytochrome P450 system. We know that fentanyl has potential risks such as accumulation over the course of time. We know that it has the rare potential for stiff lung syndrome. We know that things like hydromorphone go through more of a passive glucuronidation, hepatic metabolism. We know that morphine has the histamine release issue. And we know that remifentanil is very short acting. It gets broken down by plasmasterases, but has a high risk of tachyphylaxis, for example. So very briefly, just looking at opioids metabolism, you can see that the phase one phase one active metabolism for things like fentanyl, it's really important, cytochrome P450 system. But we also know that there's many different reasons why the cytochrome P450 system might be compromising the ICU, such as drug interactions, blood flow, etc. Therefore, the phase one is a little bit unpredictable. As opposed to the phase two or glucuronidation, for example, which say the hydromorphone goes through. So you might have a little bit more predictable pharmacodynamics and kinetics associated with hydromorphone than something like that goes to the cytochrome P450 system, such as fentanyl. And again, if we're talking opioids, we know there's many potential unwanted effect. Many of them are class effects, such as respiratory depression. And I kind of put respiratory depression at the top because, you know, sometimes I think that we don't say this out loud enough, but respiratory depression may be one of the therapeutic benefits of using opioids in certain patient populations, such as ARDS in patients trying to get a low tidal volume strategy. You know, again, it is a side effect. Sedation, constipation, nausea, vomiting, pruritus, withdrawal, hypotension, delirium. These are all things that are a class effect. But I think it's important to note on an individual opioid that there's, again, this class-specific effects. Again, fentanyl has a chest wall rigidity, the serotonin syndrome. Remifentanil has increased ammonia levels and tachyphylaxis. Morphine has that histamine release and hypotension. We know it's issues with the CNS system. And methadone we know has acute prolongation issues as long as a very long half-life. Therefore, I think it's important to discuss an individual patient population, individual patient opioid rotation, which is defined as a change in opioid drug or route of administration with a goal of improved outcomes, whatever those outcomes are in the individual patients. And again, we have to be clear that the goal of opioid rotations are established in opioid regimen that is more effective than the prior therapy. But I think it's important to note the indications for rotation might not necessarily be something that you'd have to try one first and then rotate to another. It's that perhaps it's simply, is there a benefit from the beginning? So not to belabor the point, but we know that fentanyl, pharmacokinetics, and critically ill patients can be influenced by many things, such as liver disease, heart failure, as well as different weights. You see that the blood levels of fentanyl vary widely depending on the differences in liver disease, congestive heart failure, and the patient weight. So there's just inconsistencies we'll see with fentanyl in general. So is there a signal with fentanyl versus hydromorphone? Let's look. Patients requiring ECMO on either fentanyl or hydromorphone for at least six hours, you see that the patients had decreased amount of delirium, ICU length of stay was decreased. You see that the patients actually had a higher rate of CVVH in the hydromorphone group, which is kind of interesting because a lot of times they'll say, well, I don't have CVVH, I don't have delirium. the hydromorphone group, which is kind of interesting because a lot of times they'll say, well, what about the renal clearance of the metabolites, et cetera. But again, massive reductions in opioid equivalence when you look at hydromorphone and no difference in the sedative doses statistically in these two groups. In an analysis that we actually did here at the Brigham and Women's Hospital, we saw that patients would transition from fentanyl to hydromorphone. You can see that the sedatives were actually pretty markedly reduced once we transitioned from fentanyl to hydromorphone. We actually did a pretty aggressive incomplete cross-tolerance dose reduction in the hydromorphone group. But in these patients, when we transitioned from fentanyl to hydromorphone, the actually sedative requirements went way down. You see the rationale for why we transitioned these patients was captured at the time of transition. Improved ventilatory compliance, tachyphylaxis pain control, opioid rotation, just generally speaking, reduction in sedatives. So you see that there was kind of this concept that there was a reason why we transitioned patients. There were a wide variety of reasons, but we saw that's a pretty big reduction in the amount of sedatives that patients received post-transition to hydromorphone. But of course, there's other analysis looking at rotation of meds, such as giving enteral methadone, shown in observational trials, and even in a relatively small randomized control trial, saw a reduction in time to extubation in patients off the fentanyl infusion and transition to an enteral methadone, even for a relatively short period of time. In the 2016 Management of Post-operative Pain Guidelines, which is endorsed by many different societies, there's some general recommendations that I think make sense, but we need to be clear this isn't specific to critical care. Recommend oral over IV opioids for post-operative patients when tolerated, using PCA medications without a basal rate if a patient is opioid naive, recommends multimodal analgesia, recommends use of a variety of analgesic medications and techniques, recommends non-pharmacological interventions, all which are within the concept of analogous sedation in the ICU as well. Of note, that guideline goes on to talk about patients who are on chronic opioids, and just highlight a couple of these recommendations. Recognize post-operative opioid requirements are typically greater, and pain may be more difficult to control in these patient populations. Consider non-pharmacological interventions, consider non-opioid analgesics, consider PCA with a basal rate in these individual patients, and provide education and instructions on tapering opioids to target dose after discharge. I think it's important to note that we need more robust data on the following, and probably more. Will certain patient populations benefit from certain strategies? What medication for what type of patient? Multimodal pain management outcome trials with different combinations of therapies? What outcome in the PICO questions should be prioritized in the next version of the PATI-S guidelines? And what type of patient should be prioritized in the next version of the PATI-S guidelines? Will multimodal pain management lead to less chronic pain? We think by treating pain that we can prevent chronic pain in these critically ill patients, but we don't actually have that in a randomized control fashion. And we need data recommendations for regional or neural axial techniques in patients in the ICU. These are prevalent in the anesthesia literature, but not necessarily in the critical care specific patient population. But again, there's likely even more questions that need to be answered when it comes to management of pain in the critically ill patient population. We would be remiss if we talk about opioid use in the critically ill population and not talk about opioid use in general, as there's a current epidemic of opioid use in the United States. Some general statements that just unfortunately are true is that prescription opioids are misused. Prescription opioid misuse leads to heroin use. And opioid overdose is a societal issue. Post-ICU, the mean opioid consumption continuously decreases 24 months after ICU stay, but does not return to baseline with a pre-ICU. Patients with chronic opioid use, mortality was increased 6 to 18 months after ICU admission. And chronic opioid use after discharge from ICU is complex and multifactorial. Concerted efforts need to be made at the transitions of care considerations in the ICU population and pre-transition. Multimodal therapy while in the ICU may be beneficial, including the reduction and development of tolerance and dependence on opioids in the ICU. So the concept of decreasing the amount of total opioid equivalents in the ICU by early multimodal therapy potentially could help. Weaning of opioids for patients who have required high doses and or prolonged infusions during the ICU to have them get off of those infusions prior to leaving the ICU as much as possible. Reconsider medications that are initiated during the ICU stay. And remember that oftentimes these medications are continued post-ICU stay. We've seen this time and time again with things like antipsychotics, opioids, sedative, stress ulcer prophylaxis, and many, many more. So efforts need to be aligned for the use of medications with an active problem list at the transitions of care as warranted. And this includes from the ICU to the wards. Therefore, the wards to the home or rehab facility would have even less of an issue. So this work has to start on admission into the ICU, trying to decrease the amount of opioids that patients are receiving, weaning them off before they leave the ICU, and then aligning these efforts at transitions of care to make sure it's clear what the plan is to get these patients manage their pain but not on these opioids at discharge. So the key takeaways. Critically ill patients are often in pain. Analogous sedation is complex and isn't simply replacing one class of medications for another. Several strategies are used to treat pain in the critically ill patient population. Opioids have therapeutic benefit. However, efforts should be taken to minimize exposure or even overexposure as much as possible while in the ICU and then the hospital setting and during transitions of care. And we need further research to address how to best optimize the use of analogous sedation through all phases of care in the critically ill patient population. I want to thank you for your time and attention. Have a fantastic day.

analogous sedation

critically ill patients

pharmacological considerations

evidence-based outcomes

supportive care regimens

pain management

multimodal analgesia

opioid epidemic