It's a pleasure to introduce Sapna, Dr. Sapna Kuchakar. Sapna is a professor of pediatrics and vice chair of anesthesia and critical care at Johns Hopkins University and my neighbor. Welcome. Good morning, everyone. Good morning. It's awesome to be here. So, a couple disclaimers. I am not going to get a bottle of water today because I am not going to probably stay on time. And that is because, no offense to Dr. Basu, he has 60 minutes this morning to cover, what did you say, 10 questions? Sedation and analgesia cover at least 6% of the entire ABP critical care board exam. So, that's number one. And you can imagine that sedation and analgesia and the related topics all kind of bleed into various components of this, right? Neuromuscular disease, for example. Obviously, pharmacology, which you'll hear from Tom all about. So, it's really, really important to pay attention to this. I can tell you it's probably one of the biggest challenges of my entire career to take my 122-slide slide deck and cut it down to 25 minutes, okay? So, my plug for you, not because I want you to go home and listen to my voice, although it's beautiful. Watch the recording. Watch the entire recording of the entire one-hour-long talk that I've given previously. I will point out a couple tiny edits of new literature that's come out, things you guys should be aware of. But overall, that talk is pretty evergreen. So, I'm just going to try to focus on pearls here. So, that's my disclaimer, which probably took five minutes of my time. Okay. So, let's get started. And also, I'm an anesthesiologist as well as an intensivist, so I'll bring a lot of that perspective in, which I've learned over the years in training PICU fellows, et cetera. It comes in really handy for the boards, especially. My disclaimers are just a couple NIH grants, and I am the senior associate editor of PCCM. All right. So, interestingly, sedation and analgesia is its own content domain. I think there's 10 content domains. It's its own. You'll notice when you look at the content specs, though, that every single domain has a very long list of bullet points for each thing and things that you should be paying attention to. Then you get to domain three, and it's literally A, B, and C. It's the most general content domain possible, and that's because there's so much minutia that they could focus on. But luckily, we've done this before. We know what topics are going to be focused on for the most part. So, these are my, like, big, big, big-picture takeaways, and then we'll dive in further. You need to know the pros and cons of every drug class of sedation and analgesia that you use in the ICU and specific drugs. Number two is extremely important. They love this topic. You have to know the difference between malignant hyperthermia, serotonin syndrome, anticholinergic toxidrome, and neuroleptic malignant syndrome. There will be a tiny subtlety in each one of those questions that will clue you into what the answer is. One of the new things, which I'm thrilled to see, is that on the boards, they're actually sharing that benzodiazepines are an independent risk factor for delirium based on the literature that we have in kids. So, that's something that is not in my previous talks other than my waxing poetic about it, but now it's actually based in the literature. And then sedation is a continuum, and that's really important to remember. So, the questions are, and I'm not going to ask you guys to raise your hands, but they'll, again, be pretty straightforward in the sense that if you read it carefully and you look at the context clues, it'll make sense, right? So, here's a six-year-old recovering from acute respiratory distress syndrome, required oscillation, neuromuscular blockade for more than 72 hours, and during his recovery, he's having trouble weaning, demonstrates weakness in all four extremities. All of the following are true except, right, is his CSF going to show anything funky? Probably not, right? Will his deep tendon reflexes be decreased if he's weak? Right. Will his sensation likely be normal? Right. Does this problem only occur with aminosteroid NMBAs? I see a lot of blank stares. Okay, and then elevation of CPK may be seen early in the course of this disease. All right, so this is classic ICU-acquired weakness, and the goal that they're trying to share with you here is that it can happen with any neuromuscular blockade that you might be using as an infusion, not just aminosteroids, but also the other class, the benzoisoquinoliniums. So, it's a mouthful. All right, so let's get into uses of neuromuscular blocking drugs. Despite what anyone may tell you, in terms of the boards and in clinical practice, the three main reasons that we use neuromuscular blockade are, obviously, to facilitate tracheal intubation, for surgical muscle relaxation, and in the OR, it might help us to use less anesthetic and have potentially less hypotension as long as they're amnestic, and then, obviously, to facilitate improved oxygenation ventilation during mechanical ventilation in certain situations. So, I think you guys all are pretty clear on that, but this is where they get into the details, right? So, you have to know the difference between depolarizing NMBs and non-depolarizing. We only have one in the depolarizing category, succinylcholine, so you have to remember that succinylcholine binds to the alpha subunit and activates the receptor, right? So, it brings an overflow of acetylcholine and results in sustained depolarization, and that's why you see fasciculations, right? So, you can see the fasciculations. They may not ask you this, they probably won't, but you can have myalgias after someone receives succinylcholine because of the very profound fasciculations that the patient experiences. Non-depolarizers, which you all are very familiar with, remember, they function as competitive antagonists. They also bind to the same nicotinic acetylcholine receptor, but it's a competitive antagonism. And then, remember that, as opposed to succinylcholine, which, unless you have pseudocholinesterase deficiency, will just go away, and you'll be back to having full muscle strength within usually a few minutes. With non-depolarizers, the reversal and the actual going away of the drug depends on the redistribution, gradual metabolism, excretion, or, of course, if you give specific reversal agents. So, again, watch the recording. There's lots of things to remember about succinylcholine. You can give it many different ways. It's an amazing drug in the right circumstances. I gave it three times on an OR call for children having level-one traumas. It's IV, IO, or IM administration makes it a great medication from that perspective. Wrap it on and wrap it off. It is metabolized by pseudocholinesterase. So, I don't have a slide on this in the short version, but if you have pseudocholinesterase deficiency, you will have residual paralysis or block. And also, patients who are functionally pseudocholinesterase deficient, i.e. pregnant women with an increased volume of distribution, for example, they are likely to have potentially prolonged block. The adverse effects, increased ICP, increased IOP, and increased gastric pressure. So, actually, when you're giving it for a full stomach, you have to be thoughtful that IGP might actually increase your risk of vomiting, but, again, it's the quickest way to get someone paralyzed for tracheal intubation. Infants are highly susceptible to bradycardia and potentially asystole, so that's why we tend not to use succinylcholine in small infants and neonates. Malignant hyperthermia is probably what they're going to fixate on. Other than inhalational agents, succinylcholine is the only medication that is a risk factor for MH for the most part. And then in terms of specific contraindications, I just want you guys to remember that, you know, for example, a fresh burn, a fresh trauma, not an absolute contraindication to use succinylcholine. However, if you have been weak for a long time, we'll get into that in a second, that's a reason you may not. So in a trauma that literally just came into the operating room, the chances of having, for example, life-threatening hyperkalemia are low. And why is that? Well, when you have denervated muscle, for example, a patient with cerebral palsy or a long-term muscle disease, they upregulate their acetylcholine receptors, and that's when you give succinylcholine that can lead to a flood, including increase in potassium. So that's why you get hyperkalemia in those circumstances. Okay, so I know this table looks like it's from the 70s, but I put it up here because it's still the classic table. And I just want you guys all to memorize this table and know what the differences are between these four different syndromes, the medications that cause them. Now, there is some crossover in the medications, but for the most part, for example, for anticholinergic toxidrome, diphenhydramine is a common culprit, and that's often what will come up on the boards. For MH, remember, if they had an inhalational anesthetic in the operating room or got succinylcholine, that's a potential. Neuroleptic malignant syndrome, obviously antipsychotics are high-risk for that, and the same thing for serotonin syndrome with SSRIs. So the key points here, know when to differentiate a post-op fever that's low-grade from MH. They're never going to tell you that they have a fever and that's it, and then they have MH. They're going to have a constellation of other symptoms. Recognize malignant hyperthermia in the patient not exposed to anesthetic drugs. So there are a small number of drugs that can cause MH, so if they give you the constellation of symptoms and it makes sense and there's nothing else that sounds better, MH is probably the answer. Know that acidosis, cyanosis, and increased CO2 production may antedate defined muscle spasm. So often people think if you don't have muscle spasm, it's not MH. That's not necessarily true. You can have these other symptoms. And know the safe agents. So it's never going to be malignant hyperthermia if the only thing they got was, for example, non-depolarizing relaxants, narcotics, nitrous oxide, barbiturates, or propofol. Those things do not cause MH on the boards or in real life. All right. So remember we talked about the classes of drugs. So aminosteroids, the two that we use most commonly are rocuronium and vecuronium. There is a black box warning on pancuronium, so we aren't using it here in the United States. And the only thing to remember if there's a residual question on the boards about it is that it causes tachycardia. That is the classic kind of side effect, which is why we used to love it. And neonates, right? Because tachycardia is not a bad thing in those patients. We don't want them to become bradycardic. And then in terms of the benzyl isoquinolinium derivatives, cesetracurium is the only one that we use in the intensive care unit. And I'll talk a little bit about that in a second. So what do you need to know about the different classes? Well, remember ROC, that speed of onset and duration of action is dose dependent. So that's why you guys are giving 1.2 to 1.6 milligrams per kilogram of rocuronium in an intubation scenario when you want it to work quickly. If you give a smaller dose, you'll eventually have a blockade, but it'll take a lot longer. Cesetracurium, it goes away because of Hoffman degradation. So remember that there is a metabolite that may be created, laudanazine. May or may not come up on the boards, but there's more on the full slide set. And it's typically ideal in renal failure. So if they give you a patient that's in renal failure, they ask you which drug. Now, your ICU may tell you they don't want you to use it because it's extremely expensive. But for the boards, cesetracurium is the right answer. And then finally, vecuronium, remember, is hepatic metabolism. I can remember multiple times a board question where a patient is status post-liver transplant, history of liver failure, comes out and is just not waking up. And often it's because of vecuronium that was given in the operating room. So keep an eye out for that. So my final kind of point on that is that recognizing that a patient with no residual, a patient may have no residual muscle blockade but can become paralyzed again if they're hypokalemic, hypomagnesemic, cold, or poorly perfused. That's another favorite of theirs. Like, why are they still weak? Their paralysis is all gone. The neuromuscular blockade's all gone. Well, remember, all of those things can cause muscle weakness in and of themselves. All right, as I mentioned, electrolyte disturbances, most often they're cold. So look at the temperature. All right, just quickly on monitoring, just remember that fade and the twitch monitor only occurs with non-depolarizing neuromuscular blockers. So that's important to remember. And remember that if you only have one twitch, it doesn't mean that only that 75% of your receptors are blocked. That's not how it works. It's not proportional. But it's important to remember that you need four strong twitches. And even then, you may still have about 25% of your receptors blocked. So reversal is really important. So how do we reverse? Well, back in the day, neostigmine was the way to reverse non-depolarizing neuromuscular blockade. But now many of us are using Sugamidex routinely. The things to remember with neostigmine, it's a cholinergic drug. So remember the B sludge mnemonic. So if someone receives neostigmine, that might be something they ask about. You always need to pair neostigmine with atropine or glycopyrrolate because of the severe risk of bradycardia. We've had patients in the operating room that got the neo first before the atropine, and then they arrest, because you haven't given the stuff beforehand. Now, Sugamidex is an exciting drug, but not without its downsides. It loves rocuronium. And in the full slide, you have like four slides of just rocuronium being danced around by Sugamidex, because it just binds up all the rocuronium, OK? Vecuronium is not really significantly impacted by Sugamidex. Remember, Sugamidex, rocuronium. It's renally cleared, so you have to be very thoughtful about that. There is an anaphylactic risk, and it makes contraception ineffective for seven days. So it's really important to remember that, both clinically and for the boards, because you do need to tell women of childbearing age that they need to use other methods for seven days, at least. OK, so that's neuromuscular blockade. Exciting stuff. Let's move on to sedation and analgesia. So just a quick word on inhalational anesthetic agents. The four that you need to know are isoflurane, sevoflurane, and desflurane. And then, of course, nitrous oxide. Remember, nitrous oxide is N2O. It's not NO or NO2. The nice thing about inhalational agents, they're easy to titrate. Obviously, you need some special machines to make that happen. Isoflurane is what we most commonly use, for those of you who use it in the ICU for status asthmaticus. Really, there's not going to be much on inhalational, but I just brought it up to be complete. It's important to know, as far as sedation and analgesia goes, what the context-sensitive half-life of the medications that we use are. There's going to be a lot of underlying themes surrounding that. This is the big new thing, right? So, with regards to ICU sedation, they have some up-to-date literature on benzodiazepines and delirium. So, back in 2013, when I did an initial survey, benzos were the most commonly used for ICU sedation. It was first-line. Luckily, we're seeing a change from that. Remember that benzos do not have any analgesic properties. They do have amnesia in the right doses, anxiolysis. The options you have are midaz, lorazepam, and diazepam, and, obviously, the reversal agent is flumazenil. Propofol. Things to remember about Propofol is it's highly lipophilic, so it has very rapid CNS penetration. It acts through the GABA system. It rapidly redistributes after a single bolus dose. It is hepatically metabolized. And remember, with Propofol, a little can go a long way depending on the disease state, right? So, obviously, we try to stay away from Propofol, and, you know, septic patients, patients who are hemodynamically unstable. However, if it's the only medication you have around, if you give a tiny dose, it will go a long way. And there is an increased volume of distribution in children versus adults. So, to induce a healthy 15-year-old in the operating room with just Propofol, it takes about five per kilo, if that tracks. So, it's very important to remember who you're dealing with when you get these patients and you're giving Propofol. This is a big — I'm sorry that this key-point thing is in the middle of the slide, but Propofol infusion syndrome is also a favorite. Hopefully, you'll never see it in your entire career, but that's why the boards like to test it. So, remember, the clinical symptoms are Brady dysrhythmias, hypotension and cardiac failure, metabolic acidosis. That will almost always be one of the, like, clues. You can have hepatomegaly, rhabdomyolysis. The risk factors are mostly young children. We are starting to see more of it in adults, but mostly young children, higher infusion rates and higher or longer duration, obviously. And hemodialysis may be beneficial, but sometimes by the time you see PRIS, things have already gone too far. So, recognize that the association between Propofol infusion and acidosis, hypotension and death in children. Quick word about Etomidate. It's a non-barbiturate anesthetic agent. It has limited cardiovascular effects, which makes it a beautiful drug in acute trauma, for example. It does decrease CMRO2 and ICP. You'll hear people say Etomidate's the best drug for neurotrauma, and it may be in the circumstance, but you still need to pay attention to blood pressure while maintaining CPP. And then issues are it's painful on injection and adrenal, again, going back to the religious order that Jerry mentioned, it can cause adrenal suppression with a single dose, and that is something that tends to be harped on on the boards. Ketamine, my favorite and yours. It's a dissociative anesthetic. It does, it's beautiful because it has amnestic qualities. It has analgesic qualities. It maintains airway reflexes, and it's a bronchodilator. So, if you have or have an asthmatic, and they're asking you what type of sedative intubated asthmatic should be on, ketamine is probably your first choice. It's an NMDA receptor antagonist. It is hepatically metabolized. It can cause, we all know the catecholamine depletion piece of it, which there is the potential for decreased blood pressure in patients who are catecholamine deplete. As far as the boards are concerned, and the faculty can chime in if they know differently, it is not considered to be a risk factor for increased ICP, so don't stay away from ketamine in a circumstance with ICP. In fact, they may ask you if ketamine's okay. And of course, it does have anticonvulsant effects as well. Opioids and apicuanalgocedation. Remember, opioids cause analgesia, but they're not amnestic. So, you know, back in the day, it used to be, oh, fentanyl's the best thing to intubate patients with. And again, you give enough fentanyl, yeah, everybody's gonna be amnestic, right? But it's a great analgesic, which is why you always have to use a sedative or an anesthetic along with it when you intubate patients. And of course, also, if you're trying to achieve sedation. There's differences in all of the opioids. You need to know the ones that are in bold on the slide because all of them are fair game to be tested on. The most important thing is context-sensitive half-life. The only medication that we have that will go away instantaneously when you turn off the infusion is remifentanyl. But remember that even a fentanyl infusion, despite being a short-acting opioid, can last a very long time, depending on how long the patient's been on it and the pharmacokinetics of and their actual metabolism. So, what to know about opioids. Know that narcotics do cause the least depression of myocardial function of all of the anesthetics. So, for example, if you have, like, in the adult anesthesia world, if you have a 90-year-old woman who came in with a hip fracture, actually, they might do an opioid-only induction if they don't know what their cardiac function is like, for example. These three topics are really important to understand the difference between. They will test on this. What is the difference between tolerance versus dependence versus addiction? So, remember that tolerance is the kids we have on long-term mechanical ventilation who just need more and more drugs to achieve the same effect. Remember dependence is when we start adding the medications because they can't come off the dexmedetomidine or the opioid that we started them on. And then addiction is a psychiatric disorder with compulsive use of substance despite harm. It seems really easy to, like, you know, figure out which one's which here on this slide, but it's pretty subtle the way they present it on the boards. Just quick word about haloperidol. It will almost always be on there as a risk factor for many things. As we mentioned, go back to that table with all of the different syndromes. One thing to remember, that haloperidol can cause cardiac dysrhythmias and QT prolongation. Again, another favorite, dexmedetomidine. You guys are all getting really good at using this. A big take-home point with dexmedetomidine is that its alpha-2 to alpha-1 receptor selectivity is very high and much higher than clonidine, which is why children have such dependence on dexmedetomidine after being on infusions for a period of time, right? So that alpha-2 receptor is playing a huge role. It maintains airway reflexes. Obviously, it has a risk for bradycardia in the populations that are at risk for that. And it has a more rapid distribution half-life than clonidine, five minutes versus 10 minutes. So just a point to remember about dexmedetomidine. I won't get into the mechanism, but the locus coeruleus is what to remember with regards to dexmedetomidine, and that's why it can have a positive impact on shivering. It can be potentially positive for sleep. There are theoretical effects on other organ systems, but those are the two to remember. All right, and then finally, to finish up, let's talk a little bit about local anesthetics. Again, I hope none of you ever see local anesthetic toxicity in your careers, but it's something to remember and know how to treat. So remember that local anesthetics can be given topically, centrally, or peripherally, and we have many different agents. The classes are amino esters, which are hydrolyzed by plasma esterases, and chlorpropane is probably gonna be the most common that you'll come across if patients come with epidurals, et cetera. And then aminoamides are metabolized in the liver, and that's primarily what we see the most of, bupivacaine, lidocaine, mipivacaine, and ropivacaine. So remember the kind of the order of events with toxicity of local anesthetics. When people are putting epidurals in laboring women, for example, we ask them if they have like a funny taste in their mouth. Those are examples of CNS effects, right? So that's the CNS effect before you get to potentially seizures, hopefully you don't get there. Cardiovascular effects are myocardial depression, and then, of course, if you have direct injection into a nerve, that can be toxic as well. So the toxicity and the systemic absorption of local anesthetics depends on the site of injection, the dose, and whether epinephrine was added. So one key component that the boards mentions they want you to know is recognize that many local anesthetics are mixed with epi, and that catecholamines can produce systemic alterations. So the reason that we put epi in may also be to help prolong the block, but also for us to recognize if there's systemic absorption, right? Because then you'll see tachycardia and hypertension. So remember that, and this actually was a board question for me, that systemic absorption risk is highest with intracostal nerve blocks. The intracostal nerves are close to a lot of vasculature, right, so it's very easy potentially as you're inserting the needle to potentially have some vascular injection along the way, as opposed to other areas. And then caudals and epidurals, brachial plexus blocks, and the femoral sciatic nerve block is probably the least because, again, big vessels, easier to avoid that vasculature. Management of local anesthetic toxicity. So recognizing it, A, calling for help immediately, and then controlling seizures, obviously, and then remember that lipid emulsion is the first-line therapy after you've done all of the supportive care and called for help. So lipid emulsion doesn't mean giving propofol. All of the carts should have an emergency bag of 20% lipid to administer. And what does that do? That essentially binds up the local anesthetic. The most powerful local anesthetic in terms of cardiac toxicity is bupivacaine. Bupivacaine hangs onto the heart like nobody's business and does not want to let go. So if you have an accidental IV injection of bupivacaine, that's generally game over. You start CPR, obviously, and then prepare for ECMO. So ECMO is really the next step. If you've, while you're getting the lipid, make sure you're activating all the things. And so all of those might be tested on. And then my last slide is the sedation continuum. So remember that it's very easy to go from a state of minimal sedation to moderate sedation and moderate sedation to deep sedation and general anesthesia. And whether any of us want to admit it or not, my former fellows here have offered this many times, we are probably providing general anesthesia to a large cohort of our patients in the intensive care unit. Whether you want to call it that or not, that's what it is. So keep in mind what the differences are. So notice that deep sedation analgesia has purposeful response following a repeated or painful stimulation. So it's a very subtle change to get to general anesthesia. So it's important to also memorize this table as one of them. Happy to answer more questions. Watch the recording. Thank you, guys.

sedation

analgesia

malignant hyperthermia

serotonin syndrome

neuromuscular blockers

local anesthetics