Hello. This presentation is on sedation and analgesia. My name is Todd Dorman, and I presently work at Johns Hopkins University School of Medicine in Baltimore. The key points for this presentation on sedation and analgesia are that, number one, you need to measure using a validated scale for anxiety, agitation, and pain. And then, number two, you need to establish goals of therapy. And number three, you need to monitor not only the process of care, the root drug and dose, but the outcome compared to goal. So on rounds, as an example, you'd want to be able to say what their score was, by which methodology you're using a validated scale. We're going to cover those during the talk. And then you'd want to say what that you actually were achieving compared to goal. So their pain score is three, with a goal being four, and using X scale, so that everybody is aware of all of these, that you're using validated scales, that you're establishing goals of therapy, and then you're looking at that goal and what you're actually achieving. The basis for reviewing this material today is under the triad of agitation, where agitation sits in the center. And three fairly common things within the ICU are connected to that agitation, or potentially connected, pain, anxiety, and delirium. I'm going to cover today agitation, pain, and anxiety. Delirium is covered elsewhere in this course. So let's start with the goals of agitation therapy. Agitation defined as motor restlessness resulting from any type of internal discomfort, such as pain, delirium, and anxiety, the triad previously presented. And our goal is to treat the underlying internal discomfort while maintaining an awake patient who is able to follow commands. So we want to try to avoid just treating the symptoms and forgetting that we need to get at the underlying discomfort. It's important to note that agitation is associated with increased complications and length of stay. In this work published by J.C. Woods, you can see just that effect, that on these medical ICU patients, the length of stay was prolonged with those who were agitated, and days on a ventilator were also negatively impacted. What scale should you use to measure agitation? Well, there are several, and they're all been validated, and you can choose which one that you're most comfortable with in your institution. I'll share with you what is the most commonly used one. So here's one called the Ramsey sedation scale. You can see that it goes from one to six, and that at this end of one is awake, anxious, agitated, restless, or both. You get here in the middle where the patient is responding to commands only, and they're getting deeper asleep, all the way down to does not respond to a light glabel or tap. Another option would be the Riker sedation agitation scale called the SAS scale, and here you can see it sort of goes one for unarousable, common cooperative is in the middle at four, and then dangerously agitated is up here as a seven. This third option, the Richmond agitation sedation scale, or the RAS, is the most commonly used one, and you can see this is on two slides. Zero now is the pivot point in the middle of common alert, and as you go more positive, then you're getting more and more agitated, so you're starting restless, agitated, all the way up to combative. And when zero is the pivot point, the negative direction of deflection is drowsy, light sedation, and sort of deeper all the way to unarousable. This side slide, I'm sorry, groups the three different scales together so you can see the comparison more easily. So which of the following must be a major focus of the sedation and analgesia plan for the ICU patient? Attaining a pain score zero, monitoring only the route of drug administration, formal iterative evaluation using validated scales, monitoring only the drug and the dose or titration to avoid delirium. I'll pause a moment just for you to reflect. If you'll reflect on the key goals, we said you needed to be using validated scales that you're going to use iteratively. You do want to monitor the drug and the dose, but we said you want to do more than that, the actual score compared to the goal. And so three is the best answer, although not complete for all of the goals. So what would be the optimal level that you would shoot for? Well, you're looking for a patient who is calm, comfortable, and easily arousable, and that corresponds to the following scores on the three different scales. And you can see zero, two, and four, depending upon the scale that you've chosen to use as your validated scale. Again, with the last one, RASS, being the most common, so your target would be somewhere in the zero range, so minus one to one, since that's the pivot point zero. And to help cement that, there's the question, when using the RAF scale, which of the following is the most common goal? And you can see that choice three is plus one to minus one, and so that would be the most common goal. Now that you've chosen the validated scale and you've created a goal for what you want to achieve in the particular patient, what are the sedation strategies you could use? So we're going to cover sedation protocols with daily sedation interruptions or maintenance of light levels of sedation. The concept here is that very different than it was 20-30 years ago. It is now less is more. And bedside protocols are very useful to help us titrate sedation in analgesia, and then for reminders that we do all the steps, daily checklists have also been shown to be useful. So for the next six slides, I'm going to cover some of the data. Here's one of the studies that has looked at protocolizing sedation during mechanical ventilation, and you can see that there are significant benefits for the duration of mechanical ventilation and the duration of sedation infusions when you protocolize care around sedation. Let's take the next step. Besides just protocolizing the care, what happens if you, on a daily basis, interrupt the sedation and the vast majority of your critically ill patients realizing that there will be a small subset that it may not be safe to do daily interruption, but for the vast majority you could. And here's a trial by Cress et al. looking at about 128 MICU patients. They did a daily interruption, and you can see the control group was an interruption just at the discretion of the clinicians. And you can see for all of the variables monitored, duration of mechanical ventilation was reduced, ICU length of stay was significantly reduced, hospital length of stay was significantly reduced, and the percentage of days awake was significantly better when you did daily interruptions. So let's carry that one step forward. Besides waking the patient up, what if we did a breathing control trial during that time period? And you can see here that ventilator-free days and time to discharge from the ICU and the hospital, as well as one-year mortality, all benefited from awakening trials that were combined with breathing trials. This slide is demonstrating that if you're going to wake the patient up and it's appropriate, can you do early physical and occupational therapy in the patient? And would that be beneficial? And would that be another benefit on top of not only waking them up? And so here you can see that there was benefit in ICU delirium. Fewer days when you did both awakenings with early physical therapy. The time in the ICU with delirium was better. The hospital days of delirium were different. Ventilator free days were greater. Duration mechanical ventilation was almost half, and the ICU length of stay was borderline, but trending towards improvement as well. So Gerard further looked at the spontaneous awakening trial and spontaneous breathing trial and ended up showing just what you would expect from the data I've presented so far, which is that the ventilator free days were less. The time to discharge was less from ICU and from the hospital, and one-year mortality was less as well. So many people like to use continuous IV sedation methodologies in order to sedate the patient. This study is trying to show you that if you can go to intermittent, you would be better off because you can see here that the continuous IV sedation was not beneficial. In fact, somewhat detrimental to the patients with length of ICU and hospital stays that were longer in duration mechanical ventilation that was longer. So a question to help guide us is being intubated mechanically ventilated, does that cause such anxiety that patients require sedation and sometimes neuromuscular blockade? Does it cause such pain that patients require aggressive analgesic regimen? Does it require significant doses of sedatives and analgesics? Does it obligate the care team to ensure that they can awaken most patients daily? And does sedation and mechanical ventilation always lead to complications? Let me pause a moment to let you reflect and choose an answer. The correct answer is number four, that it obligates the care team to ensure that they can awaken most patients. It's been demonstrated that many patients can be managed without any anti-anxiety or any anti-pain medicines if they don't have a source of pain in the ICU and so that they don't need sedatives to tolerate mechanical ventilation. Clearly, recently we've learned that the COVID population, in order to get adequate mechanical ventilation, does require sedatives and analgesics commonly. In fact, may require quite high doses of both. So let's now discuss sedatives. Sedatives are substances that depress the central nervous system, resulting in calmness, relaxation, reduction of anxiety, and sleepiness in most patients. Sedatives can also cause slowed breathing, slurred speech, staggered gait, poor judgment, and slowed reflexes. So you have to think carefully about using them and then monitoring the patients that are receiving them. Sedative effects that we do like in the ICU tend to be anxiolysis and then some would argue that we like the amnestic effect that some of these agents have. Others would argue that they're not beneficial to be amnestic and that that can lead to some of the delirium. Sedatives that we are going to discuss do not have any analgesic properties, except dexmedetomidine and ketamine, both of which do have some analgesia and analgesic or opioid sparing possibilities. Opioids themselves do not have anxiolysis or amnestic properties. We should always consider pain as a driver of the agitation and if we believe the patient has pain, we should start by treating the pain prior to providing sedatives. The sedative or anesthetic agents used to create sedation in the ICU include benzodiazepines, propofol, dexmedetomidine, ketamine, etomidate, and the butyrophenones. It's worth reminding everyone that prior to picking a drug, we should think about non-pharmacologic interventions, such as the psychological support with frequent orientation, day-night cycling, and reassurance of the patient, physical interventions such as touch and PTOT, ambulation, mobility where possible, and compassion. So now you have a variety of sedatives to choose from. How do you decide which ones to choose? Well, you're going to think about the pain first, as I mentioned. You're going to wonder whether the patient has procedures today and that can impact your choice of sedative, right? Do they have to transport the patient and do you want them sedate for that transport or awake and maintaining their airway? What's the expected duration of the need of the sedation? Are you just thinking it's for the procedure or do they need sedation in a longer term for, let's say, an open abdomen or something? What's their organ function because of the metabolism of these agents? And then, do the agents induce drug withdrawal or is the patient suffering from drug withdrawal? And so picking an agent that they might be used to taking may very well be beneficial. And finally, you have to think about what's on your formulary. This slide is just trying to show you that there is great variability by country and just if you just look at midazolam and propofol as an example. So let's walk our way through these agents and try to hit the high points. Benzodiazepines are sedative, hypnotic, amnestic, anxiolytic, and anticonvulsant, so have great variety and beneficial effects. They do not have any analgesia associated with them. Many are lipid soluble and those are that are metabolized in the liver and then excreted in the urine. They have synergistic respiratory depression with opiates, so thus you're going to have to monitor carefully pulse oximetry and consider whether entitled CO2 is beneficial in some patients as well. You can have active metabolites and including midazolam, which has an active metabolite that's about 50% as active. So if you get enough of that metabolite buildup, then the midazolam can actually act as a long-acting drug as opposed to a short-acting drug. You can develop tolerance to these agents and the benzos are associated with a higher rate of delirium, so it's an agent class you're going to want to try to minimize where possible in your ICU. The three most commonly used benzodiazepines are diazepam, which is valium, lorazepam, which is ativan, or midazolam, and here you can see some simple comparison of them with midazolam being the short duration fact acting and lorazepam probably being the second most commonly used. I mentioned that the benzodiazepines themselves are associated with delirium. Here's one of the original studies looking at ativan from the group at Vanderbilt, and you can see the probability of transitioning to delirium was great even at fairly low doses of ativan. So since benzos work but have the complication of delirium, then what other agents might you consider? Well, how about propofol? Well, it's a sedative. It's an anesthetic, an amnestic, and an anticonvulsant. It also does not have any analgesic activity. It is a respiratory and can be a cardiovascular depressant. It's very rapid onset and short duration, and you can see this is in minutes, and its clearance has little change relative to liver or kidney disease. Propofol, like all the drugs that we use, have side effects. I already mentioned respiratory depression and the hypotension secondary potentially to the cardiovascular depression, but it comes in a fat soluble solution, so it can increase your triglycerides, and those should be monitored. And then there is something called the infusion syndrome, where patients will demonstrate all of these five, or at least several of these five, such as metabolic acidosis, hyperkalemia, cardiomyopathy, myopathy, and hepatic changes as well. Growing in utilization in the ICU secondary to the study showing significant benefit has been dexmedetomidine. It's an alpha-2 agonist that's highly protein bound. Its side effects are slowing the heart rate, something that at least in adult ICU is frequently desired. It can lower the blood pressure by decreasing both your vascular resistance or peripheral dilatation and your cardiac output. It's been approved only for sedation for less than 24 hours, although it is frequently used for in prolonged fashion. And patients tend to appear asleep, but if you walk up and touch them, call their name loudly, etc., they open their eyes and they tend to be quite responsive until you get to higher doses of dexmedetomidine. The group at Vanderbilt has also shown that dexmedetomidine increases the days alive without delirium or coma, and you can see that work done here in comparison to the benzodiazepine atavandlorazepam. Detamine can be used in the ICU as well. Keep in mind that it is a PCP derivative. It's highly lipid soluble, so it crosses the blood-brain barrier. It's a non-competitive antagonist of NMDA receptors. It can be a bronchial smooth muscle relaxant, so it can have some benefit in those with asthma. Here's the dosing paradigm listed, but it has also been associated with nightmares. Its dose used in pain management tends not to be associated with nightmares, and so it has grown as a pain management strategy in the ICU, but it is not generally used for continuous sedation unless it's combined with other agents. Etomidate can be used. It's not really used much anymore for continuous sedation or ongoing sedation. It's associated with adrenal suppression even in single dose, and importantly, it's associated with myoclonus. That could be important in a subset of patients. Let's say they have some sort of hormonal secreting tumor. Myoclonus could cause increased secretion of that hormonal agent. And then finally, for this quick review of the agents, the butyrophenones, halodels, or haloperidol is the most commonly thought of one. These are antipsychotic tranquilizers. Most of these tend to be slow in onset. Some only come in oral versions. There tends to be less respiratory depression with these or hypotension compared to other agents. These drugs can be useful in the agitated delirious and the psychotic patient. You do have to remember that they prolong QT, and this can be very problematic in some patients, right? We have some patients that may be on multiple agents that impact QT prolongation, putting them at risk of TORSAD. You might wonder if the routine use of brain function monitoring is recommended, and it is not recommended, as you can see there in the very first bullet on this slide. In a patient that you are using neuromuscular blockade and deeper sedation, some people advocate brain function monitoring in that population. An example of one of the tools is something called BIS, or the bispectral index, and it uses a modified EEG to produce a numerical indication of the patient's level of consciousness. As a reminder to a point I made earlier, the goal is to address pain and discomfort first, and then think about adding the sedative anesthetic or hypnotic agents as necessary. So you do analgesia first prior to sedation, or analgesia first sedation, or some people call this analgo-sedation. Since you're supposed to treat pain first if the patient has it, let's cover that. So pain is an unpleasant sensory or emotional experience associated with actual or potential tissue damage, and can be described in those terms. It can be very subjective, and the data from the literature shows that it's under-recognized and under-treated in most ICU patients. So pain is common in the unit. Here's a study looking at surgical and medical patients, again using a standardized scale for pain and for agitation. The incidence of pain was 51 percent. You can see that more than a third of the surgical patients and about two-thirds of the medical patients received no preventative analgesics, and the medical patients tended to have higher scores than the surgical patients. They also tend to receive less pain medicine, slightly less pain medicine. So besides its association with agitation, why are we worried about pain? Well, it can augment the stress response and lead to prolonged catabolism and ileus. ADH release is part of, again, a stress response that is associated with the stress response with immune dysregulation. It can be associated with a hypercoagulable state, and all of these can contribute to myocardial work as well. So let's review a question that'll help guide our discussion. Important components of pain assessment include, your options are one, relying on changes in vital signs. Two, increasing dosing strategies only when the patient appears to be in pain. Number three, having a clear understanding of how much each type of procedure should hurt. Number four, minimizing analgesics in patients who are asleep. And number five, using a validated scale, establishing a goal and measuring against that goal. I don't think this one's that difficult, given we discussed this at the beginning. We've already discussed it as part of another answer to a previous question. And again, number five, validated scales with a goal and measuring against that goal. It's important to break old myths. Pain assessment is not just relying on changes in vital signs. The patient's saying they have a pain score of nine out of ten, but their blood pressure and heart rate are not showing it. It's interesting their blood pressure and heart rate may not be elevated, but that's not a marker of their pain. Deciding a patient does not look in pain is not appropriate anymore. Knowing how much a procedure or disease should hurt is decent as a general guide, but again, it's a subjective issue, so there's huge variability at play. You cannot assume that sleeping patients do not have pain, and especially if you've given them any sedatives, you may be making them appear asleep. And assuming that all patients will tell you that they have pain is also not correct. So there's also a variety of standard scales that you can think of using. Many places use the simple descriptive pain intensity, some like the numerical score, with the worst being down here at ten. Some use a visual analog scale, where on patients who can do, they can hold the marker and put an X on the distance from no pain towards severe pain. But most commonly in today's world, people are using behavioral pain scales, so looking at facial expressions, upper limb movement, and mechanical ventilation issues, because patients tend to be sicker in the ICU and tend to be ventilated more frequently than historically. So you've determined that you're going to use a standardized scale, and you determine that the patient is having pain that is outside of your goal, and so you're going to think about using analgesics, which are designed to blunt or create the absence of pain or the blunt, the response to noxious stimuli. So you're going to think about these as whether the patient needs any adjuvants. You're going to think about whether there's a regional technique that might be useful, and then the stall worth of pain management outside of regional anesthetics is opioids. And these adjuvants are important in today's world because of the utilization of multimodality pain management, where you're using opioids plus other agents, potentially including nonsteroidals, ketamine, and other anti-pain medications. So in the multimodal world, starting early is beneficial for these adjuvants. You want to avoid the needed dosing and go to regular dosing where possible. You know, this is a common mistake with something like Tylenol, where it works better when given as a routine med around the clock compared to a PRN, but there are topical options. There are other nonsteroidals. There are some of the anticonvulsants, again, some of the antidepressants, and then the possibility of blocks and long-acting local anesthetics. Since opioids are the mainstay, it's important to remember that they're metabolized by the liver and excreted in the urine, and here are some of the facts that compare the different potential opioids. Morphine was most commonly used. It looks like fentanyl is probably the most commonly used agent in today's ICU. It's 100 times more potent than morphine. Meparidine or Demerol is not very good and is essentially not used anymore. Hydromorphone or Dilaudid is very common, and somewhere between it and fentanyl is the most commonly used agent in many ICUs. It's very potent. It has a euphoria associated with it, which is beneficial, and then in a subset that need long-acting, methadone can be considered, but you have to have a lot of experience of titrating methadone before you would just want to start using it. Here's a table to help you compare them for their mechanism of action, their onset times, their elimination times, their metabolic pathways, if they have an active metabolite, and what's their equi-analgesic dose, so you can think about how to compare these when you're administering them. So, like all meds, they have side effects. The opioids, in this case, respiratory depression is the one that we probably fear the most. They can produce hypotension from sympatholysis, but also some with histamine release. They can contribute to an ileus and have a decreased GI motility, and many patients will develop pruritus associated with them. And depending upon the patient, a regional or neuraxial approach may be very useful as a primary strategy or as an injunctive strategy. These could include spinals, epidurals, regional blocks, today's world more commonly nerve catheters as well. The concerns are that you can get venodilatation and hypotension principally from the spinal and epidural. You have to know about local anesthetic toxicity and the space you're putting the local anesthetic. And then catheter removal is important, and you have to think about the timing of taking it out compared to any concomitant anticoagulation that the patient might be receiving. These last couple of slides attempt to show you how the SCCM practice guidelines for the management of pain, agitation, and delirium try to take all of this and combine it together so that there's preventative issues including early mobilization and trying to avoid agents. There's treatment with DEX as a better agent than the benzodiazepines. If you're going to use any of the antipsychotics, you have to worry about TORSAD and be paying attention to those related issues. Always think about other strategies and multimodality pain management. You want to try to get to normal day-night cycling as well. And so keep in mind that the key points of the talk are you want to measure these anxiety, agitation, and pain. You want to measure them using a validated scale. You want to establish a goal of therapy that's individualized for the patient and potentially individualized for the day that that your patient is experiencing their hospitalization. And then you want to monitor not only the processes of care such as drug and dose and route, but the outcome compared to goal. So I hope this was very useful to you in understanding these topics and can help improve your care for your patients in your ICU. Thank you.

sedation

analgesia

agitation

pain

validated scale

ICU