I'm Joanna Stallings, and today I'm going to present to you about the letter C, so the choice of analgesia and sedation. So, most of you probably already know this, because this has already been somewhat discussed this morning, but I wanted to put a couple intro slides in there in case that you were doing this slide set by itself, but really the difference between the 2013 and 2018 guidelines were that the PIDIS guidelines that were published in 2018 were just the addition of the two letters, so incorporating early mobility and then also incorporating sleep, which you're going to learn about later today. So, with regards to methods, they used the GRADE methodology, and then they had a group of individuals that met and they decided with respect to specific recommendations with regards to each of the different statements that I'm going to tell you with regards to pain and sedation. Okay, so I've highlighted in yellow which specific statements from the pain part and the sedation part of the PIDIS guidelines that we will be looking at today. So, first we're going to look at the choice of analgesia. So, you all have already heard some of this today, but it's pain and agitation and delirium are not individualized. They affect each other. It's no coincidence that the PAD guidelines are called the PAD guidelines because you always have to think about pain first, because if you don't treat pain, someone might become agitated and they can become delirious. So, when we think about opiates for treatment of pain, IV opiates should be the first-line agent that we use for treatment of non-neuropathic pain. Now, all IV opiates are equally effective, however, there are certain side effects with different IV opiates that will make us use one versus the other that we will talk about in a few moments. And then the PIDIS guidelines, we're going to talk about this in depth, specifically make a lot of recommendations with regards to non-opiate analgesics, how to use those in addition to opiate analgesics. So, how to optimize opiate regimens. First you need to consider is the pain acute? So, if the pain is acute, then this is where you'd want to give a bolus dose of something. You're not going to want to give somebody a patch or something that's going to take a while to work. You need to give something that's going to work fast. With regards to route of administration, once again, you're going to want to give an IV agent if you need something to work quickly. And then, with regards to hemodynamic instability, morphine, as I'm sure many of you all already know in the room, has an active metabolite 6-morphine glucuronide, which will accumulate in patients that have renal dysfunction, so that's why you don't see this agent a lot in ICU patients because of this, and also the large amount of histamine release that occurs with this agent, which can cause hypotension. Moving on, we know that opiate tolerance can occur quite quickly in the ICU, and because of this, it should not be surprising that our patients require increasing doses of opiates while they're in the ICU. Like I've said before, there's not really a role for patches. There is a role for patient-controlled analgesia in certain patient populations, but not a lot of intubated patients. And lastly, we really want to think about multimodal analgesia, so essentially this is just using different types of analgesics, so not only using opiates, but using some of the other non-narcotic options that we're going to describe in a few minutes. So, multimodal analgesia, like I said, is just using agents, not just opiates, but also using things like maybe acetaminophen or gabapentin, and different agents like this that work differently to get the best effect on someone's pain. So, first we're going to look at using non-narcotic analgesics. So, first we're going to look at adjunctive acetaminophen. So, I'll start at the top here, and as you can see, if you specifically look at acetaminophen, it does decrease patients' pain scores if you use this in addition to opiate agents. And then on the bottom here, you can also see that by using the adjunctive acetaminophen, it also decreases the amount of opiates that patients receive. However, you have to consider these were both single-centered studies. They were specifically in patients that had cardiovascular surgery or abdominal surgery, and you have to consider side effects of these agents as well. I, via acetaminophen, honestly have no experience with it. We don't have it at Vanderbilt. It causes a lot of hypotension, and I think a lot of people forget about it. It is quite expensive. The last time I looked, it's about $10 a dose. And from what I'm told by other pharmacists and physicians at other institutions, it actually quite often gets misused because patients that are able to tolerate enteral acetaminophen quite often get IV acetaminophen, which can be quite costly. So, it is recommended in the PIDIS guidelines to consider this as an adjunct agent to decrease the use of opiates, but you do need to consider the potential for hypotension if you use IV and the cost that would result from using that. Moving on, now we're going to look at low-dose ketamine. So, there's actually only one study, randomized controlled trial, I should say, that's in critically ill patients. And so, this was a single-centered prospective randomized double-bond trial in about 93 patients that had major abdominal surgery that were in the surgical ICU. And if you look on the left, so this once again shows pain scores. And these vary. Sometimes it helps if patients got ketamine as compared to placebo. Sometimes it doesn't. And then also over here, you can look at with regards to morphine. It does decrease the amount of morphine that these patients required if they got ketamine as compared to placebo. But like I said, this is really only one study specifically in critically ill patients. This recommendation really came from a lot of studies that were in non-critically ill patients. The biggest concern with ketamine is really the side effects. I'm sure a lot of you all have heard or know, I should say, that ketamine is a PCP analog. So, in other words, it can make patients very delirious. And even the studies in non-ICU patients have not thoroughly looked at all the side effects that can be associated with it. So, we really need specific studies in critically ill patients that are not only looking at the right dose, potentially for pain or for sedation, but also specifically looking at side effects such as maybe delirium, hypotension, or hypertension as well. So, the specific recommendation from the PADIS guidelines is we suggest using low-dose ketamine as an adjunct to opiate therapy when trying to reduce opiate consumption in post-surgical patients. Now, we'll move on to IV lidocaine. As you can see here, there is no difference in the one available ICU randomized controlled study. So, because of this, the PADIS guidelines suggest not to use IV lidocaine as an adjunct to opiate therapy for pain management. So, if you came to Vanderbilt, I'd be lying to you to say that our pain service pretty regularly will recommend to use IV lidocaine in patients. So, I think that it's not necessarily harmful. We just don't have the data is why this received the recommendation that it got. With regards to adjunctive NSAIDs, there's really just two small randomized studies that were in the ICU. Now, as you can see here, there was no difference in pain scores at 24 hours and really only a small reduction in the amount of opiates that these patients got. So, the problem with these agents is the side effects. You all already know this. We worry about giving these to people that have renal dysfunction since it can worsen that. We also worry about the huge risk of GI bleeds with these agents as well. And because of this, and because of the lack of data in COX-2 specific agents, hepatoskeletons suggest to not use these agents as adjuncts to opiate therapy. Next, we'll move on and we'll look at adjunctive neuropathic pain meds. So, as you can see here at the top, with regards to opiate consumption in 24 hours, looking at all the different studies that have specifically looked at this, if you give somebody neuropathic pain meds, it will decrease the opiates that these patients receive. So, specifically, the PADIS guidelines made two suggestions. They recommended using a neuropathic pain medication with opiates for neuropathic pain management in critically ill adults. And then in cardiovascular patients, they recommended to use this after CV surgery for pain management in general. Notice that they didn't specifically say neuropathic pain. So, once again, you just have to consider the risk versus benefit of these agents. If you look up how long it should really take for these agents to work, pregabalin, gabapentin, it really should take about a week for these agents to really show benefit. But as you see here, these agents are showing effects much, much more quickly. The other thing to consider is, in some of our ICU patients, some of them actually aren't going to be able to give you a lot of information to help you determine if it actually is neuropathic pain. So, that might be okay in the cardiovascular surgery patients, like we said, because you're specifically supposed to use that in all of them, potentially. But in some of our medical and surgical patients, that might be more tricky to determine. So, it's important that if we think the patient does have neuropathic pain, or if there are all of these agents at home, that we do restart it. So, multimodal analgesia, thinking about the evidence gaps with this, we really need more specific studies in critically ill patients. As I just told you, there were only a few studies that were specifically in critically ill patients. Unfortunately, there's very little data on medical patients. As you noted with the ketamine study, that recommendation was only in surgical patients. So, we also need to look at medical patients, too. There are specific safety concerns. Once again, giving you ketamine as the example, the delirium, the hypotension, the hypertension that we more specifically need to evaluate. And in critically ill patients with their large volume and distribution, we don't know the optimal dose or the route of administration. So, and lastly, we want to figure out what the optimal combination in this patient population is, too. So, just further studies specifically in this patient population. So, next we're going to move on, and we're going to look at procedural pain and what the PATIS guidelines specifically said with regards to these recommendations. So, first, as you can see, they suggest using an opiate at the lowest effective dose for procedural pain. So, the important things to consider with this, you can use any opiate, but you're going to want to use an IV opiate, and the most important thing is to figure out timing. You want to make sure that you give that close enough to the procedure that it's still going to be working when the procedure happens, but you need to give it far enough before the procedure that you give it time to work so that this will actually be on board when the patient gets the procedure. Also, looking at IV lidocaine for procedural pain, they suggest not using this or nitric oxide because there is no data specifically to look at this. There's no evidence that lidocaine is beneficial at all with regards to procedural pain in ICU patients. Volatile anesthetics, they also recommend not using inhaled volatile anesthetics for procedural pain. There's no randomized controlled trials comparing volatile anesthetics to opiates for procedural pain. So, what about NSAIDs for procedural pain? So, there's one randomized controlled trial that found pain scores that were similar when somebody had a chest tube removed between comparing morphine to Ketorolac. So, because of this, they suggest that a non-steroidal agent administered IV orally or rectally as an alternative to opiates for pain management during procedures is okay to do. However, they do suggest not using a topical non-steroidal agent because this has not been shown to be effective. So, just a general approach to treating acute pain in ICU patients. So, like we said, if somebody has acute pain, this is when you're going to give a bolus dose of an agent. If it persists or recurs, this is when you're going to want to use an infusion and then you're going to give bolus doses on top of this when someone has additional signs of pain. And then, what about a chronic opioid user? You need to account for if someone is on prior opiates in the dose that they're currently getting in the ICU. And something that we need to work on, particularly as pharmacists, is if people transition out of the ICU, we need to get rid of the IV pain medications and transition them over to oral medications if they are still indicated. So, now that we've talked a lot about different analgesics that we could consider in the ICU, we're going to move on and we're going to look at choice of sedation. So, what are the properties of an ideal sedative agent if we were going to design one? So, we want it to have quick onset. We want it to have quick offset. We want it to have a predictable dose-response relationship. We want it to be really easy to administer. We don't want it to accumulate if somebody has liver dysfunction or renal dysfunction. You want it to have minimal side effects. You want it to have minimal drug interactions. You want it to be cheap, and you also want it to promote natural sleep. Now, wouldn't it be wonderful if we had a drug that met all of these qualities? So, when we think about our different sedative agents that we currently have, so we have benzodiazepines, we have propofol, we have opiate agents, and we also have alpha-2 agonists such as dexamethasone. And as you can see here, they all obviously work for sedation. With regards to anxiety, some of them are better than others. You could question whether or not dexamethamidine, the alpha-2 agonist, really does have beneficial analgesic effects. But as you can see here, so all of them but dexamethamidine does suppress the respiratory drive. Dexamethamidine may be beneficial with regards to delirium, and they all, except for dexamethamidine, do disrupt sleep. So, as you can see, with regards to the one that's most likely to have all the ideal properties that we think about, it really is dexamethamidine. Looking at adverse effects, so prolonged emergence. So, all of these agents can accumulate with dexamethamidine being the least of that. They can all cause respiratory depression except for dexamethamidine. It is the one that you can use in a patient that is not intubated. They can all cause hypotension. With regards to bradycardia, anyone that's ever used dexamethamidine can tell you that is significant with that agent. And then there are specific side effects with each of those. The bradycardia that we already talked about, the dexamethamidine, if you have to use lorazepam at high doses, you worry about the propylene glycol toxicity. Midazolam and lorazepam cause a ton of delirium. And then we think about propofol and the risk for propofol infusion syndrome, and we think about the increased triglycerides with this agent as well. Some of them, or they all have different benefits to them, with obviously propofol and dexamethamidine being the best agents to consider, and they all have specific side effects that we have to think about as well. So the 2013 guidelines as compared to the 2018 guidelines, so really with the PADIS guidelines that were published in 2018, what their goal was, they wanted to look at more long-term effects with these agents. So now we're going to look at level of arousal assessments. So Kathleen went over some of this, so I'm going to talk a little bit about it again. So the RAS and the SAS are the two tools that are recommended by the PADIS guidelines in 2013. So when we teach people to do the RAS, what we recommend is you either put your hands in your pockets, or you put your hands behind your back, and that'll make sense in just a minute. So in general, we want most people to have a goal RAS of either 0 or negative 1. So the positive numbers are the degrees of agitation. A RAS of 0, someone is alert and oriented. Negative 1, they'll make eye contact or voice for greater than 10 seconds. Negative 2, they make eye contact or voice for less than 10 seconds. Negative 3, they'll respond to your voice, but they will not make eye contact with you. Negative 4, they only respond to touch. Negative 5, they don't respond to anything. So if we're friendly people and we go in and you're like, hi, Ms. Smith, and you pat her on the hand and you're like, how are you doing? Then you don't give her the chance to respond. You only know that she'll respond to touch. You aren't finding out if she'll respond to your voice and if she'll make eye contact with you. So try not to touch the patient until you determine what the RAS score is to get the best estimate of that. So as you all are learning to teach this to other people, I would recommend to always tell them that. The other sedation assessment scale that we use is the SAS. And as you can see, the higher numbers here are the degrees of agitation. And as you get into the lower numbers, this would be like 1 would be when someone is unarousable. So the ideal number that you would want people to be with regards to the SAS would be 4, which would be calm and cooperative. So now we're going to look at light versus deep sedation, which we've already talked a little bit today about with Kathleen and then with Wes as well. So once again, the PADIS guidelines gathered information with regards to whether we should be using light or deep sedation. And as you can see here, time to extubation was better with light sedation, as was times in three randomized controlled studies and in three observational studies as well. The tracheostomy rate was lower in patients that had light sedation versus deep sedation. However, light sedation was not associated with a reduction in delirium, post-traumatic stress disorder or depression. Looking at long-term outcomes, we think about 90-day mortality was not significant and also self-extubation was not significant between light and deep sedation. So their recommendation was to suggest using light versus deep sedation in critically ill mechanically ventilated adults. So unfortunately, as we already talked a little bit about, there's no consensus in what's the difference between light, moderate, and deep sedation. If you're going to ask me, in general, I would say a RAS of 0 to negative 1 is generally what we think about or a SAS of 4 is what we think about as having light sedation. So we also need more specific data on long-term outcomes in this patient population, looking at light versus deep sedation as well. But in general, as you all are teaching this, we need to encourage everyone to use light sedation in their patients. So now we're going to look at daily sedative interruption versus a nurse-protocolized sedation. So you all have seen this picture a few times today already. What happens at Vanderbilt, I'll just give you a specific example, is that our night shift nurses are actually responsible for doing the safety screen for the spontaneous awakening trial. So they will do this, and then as soon as the day shift nurse gets there and they've given them the report, then once the day shift nurse gets settled, then they, assuming the patient doesn't meet any of the exclusion criteria, then they will turn off the sedation and analgesia. At that time, they will contact the respiratory care therapist, and they will come and they will assess the patient and determine whether or not it's appropriate to do a spontaneous breathing trial. And if it is, then they will do the spontaneous breathing trial. And so we do all of this, this is about 7 o'clock in the morning, and so it's not by chance that our nurse practitioner rounds start at 7 a.m. every day, but our house staff rounds start at 8.30 every day. So our fellows, when they're on nurse practitioner rounds, Emily can attest to this, are stepping away and are extubating patients quite often, and the same thing at the beginning of the house staff rounds, they're stepping away. So it's really important, and Kathleen also emphasizes this when she was talking, that when you're setting this up in your ICU or teaching others to, that you really consider the timing of all of this. And like I said, when we thought about doing this at Vanderbilt, then we thought it was best to do it in the morning, and I think that seems to work best for us. So with regards to the statement that was made by the PADIS guidelines, they say that daily sedative interruption protocols and nurse-protocolized targeted sedation can achieve and maintain a white level of sedation. So I think all of us know this, and I would encourage you to definitely recommend that everyone does daily awakening trials when patients can tolerate this, and to also develop a sedation protocol at your institution if you do not have one. We have examples of both of these on our website, www.icudelirium.org. If you all need examples of this, we would be happy to share with you. So they specifically, when they were writing the guidelines, looked at a subset population cardiac surgery. So let's look at the choice of sedation that they made in this patient population. So the question was, should propofol, as compared to benzodiazepine, be used for sedation in mechanically ventilated patients after cardiac surgery? And as you can see here, time to extubation was shorter if patients got propofol as compared to benzodiazepine. Time to light sedation was also shorter in patients that got propofol as compared to benzodiazepine. So they did suggest using propofol over benzodiazepines for sedation in mechanically ventilated patients following cardiovascular surgery. So now let's look at our general medical or surgical patients and see what specific recommendation they made with regards to that. So they looked at, should propofol as compared to benzodiazepine be used? They looked at, should dexamethasone as compared to benzodiazepine be used? And should dexamethasomidine as compared to propofol be used? So this is looking at propofol versus benzodiazepines. And as you can see, time to extubation was much more quick in patients that got propofol as compared to benzodiazepines. This is looking at propofol versus benzodiazepines. And time to light sedation was also happened much more quickly in patients that got propofol. Looking at dexamethasomidine versus benzodiazepine, there was no significant benefit for duration of mechanical ventilation, ICU length of stay, or the risk of delirium. And then looking at specifically at dexamethasomidine versus protocol or propofol, there was no significant difference in time to extubation. So the consensus statement that they came up with was to suggest either propofol or dexamethasomidine over benzodiazepines for sedation in critically ill mechanically ventilated adults. So evidence gaps. We need a lot more information with regards to long-term outcomes in this patient population. So our research group at Vanderbilt is getting ready to publish a study, Men's 2, which will hopefully help give some of this information that we are lacking. The cost considerations used to be a bigger issue than it is now. So at our institution specifically, Presidex and Propofol are roughly the same cost. And historically, Presidex is a lot more expensive. So it really should not be an issue at this point in most institutions with regards to choosing a sedative. And we do need more specific research in certain patient subgroups as well. So when we think about acute agitation, so if somebody is agitated secondary to pain, obviously you're going to give them an IV dose, so probably Fentanyl would be the best choice. If it's acute agitation in a patient that requires deep sedation, then continue the opiate and add potentially a Propofol or a dexamedetomidine infusion. If they cannot achieve the deep sedation with a dexamedetomidine, you're going to have to use the Propofol. And acute agitation in a non-intubated patient, this is where you're going to want to consider using a dexamedetomidine infusion. So this is all the authors of the different PADIS guidelines. I wanted to make sure that they got credit for all the information that I presented to you all today. So in conclusion, always remember pain, agitation, and delirium are related first. If you don't treat someone's pain, then they can become agitated and delirious. Not all mechanically ventilated patients need to be started on IV opiates and sedative infusions. Like Wes said earlier, there are many patients, if you walk around the ICU every day, that are not on continuous infusions. They may be receiving intermittent doses of analgesia, but he can show you pictures of patients that are texting while they're on the ventilator because they're so alert and oriented. Try to use IV boluses liberally before you put every patient on a continuous infusion. And to maximize strategies to avoid the use of continuous infusion, try to use IV opiates first. If you need lighter sedation, consider dexamedetomidine. If you need deeper sedation, consider Propofol. And always remember the value of using the whole interprofessional team with regards to making all these decisions. So that concludes my presentation. I'm happy to take any questions that anyone has at this time. Thank you.

analgesia

sedation

ICU

opiates

non-opiate analgesics

sedative agent