Hi, everyone. My name is Sapnika Chadkar, I'm the Vice Chair for Pediatric Anesthesiology and Critical Care Medicine and the Anesthesiologist-in-Chief at the Johns Hopkins Children's Center. And I'm thrilled to present to you today the board review for analgesia, sedation, and neuromuscular blockade. Very important topics, a lot to unpack. Just a few notes, as we go through this talk, you'll see a couple symbols that look like a key, and those are key points. So as we go through the ABP content specifications for the exam, I'm going to highlight some specific points that are most likely going to come up on the exam, based on my own experience, but also based on the specifics of the ABP content. All right, so let's go ahead and get started. I have no disclosures. First we're going to start off with a question that represents many of the different topics that we are going to cover. And this one here is a six-year-old boy who's recovering for acute respiratory distress syndrome, which required high-frequency oscillatory ventilation and neuromuscular blockade for more than 72 hours. Following his recovery, he's difficult to wean from mechanical ventilation and demonstrates weakness in all four extremities. All of the following are true regarding the likely cause of his weakness, except number one, CSF exam will reveal a normal cell count, protein, and glucose, two, deep tendon reflexes will be decreased, three, sensation will be normal, four, this problem occurs only with amino steroid NMBAs, and five, elevation of CPK may be seen early in the course of the disease. So I'll give you a moment to pick out the answer to that question in your mind, and then we will get started and cover the answer very soon. So if we're gonna talk about neuromuscular blockade, obviously it's really important to understand the mechanisms of neuromuscular transmission. I'm not gonna belabor that here, you have a really nice pictorial and we'll go through this several times over the course of this, but essentially everything that leads to muscle contraction is really important to understand how these medications work. So you all know the uses of neuromuscular blocking drugs in our specialty to facilitate tracheal intubation, surgical muscle relaxation, and facilitating improved oxygenation and ventilation often in our situation of during mechanical ventilation in the pediatric intensive care unit. So the acetylcholine receptor is a ligand-gated receptor that has five subunits, and it's important to remember that the adult receptor is at the synaptic cleft, but the fetal receptors are actually on the membrane, it forms a pore, and then acetylcholine binds to the alpha subunits and leads to a conformational change, and then the ions flow and leads to the muscle contraction. So this is a very key topic, and you'll see, if you see a little key on the slide with key points, that means it's something that was on the ABP content or I had it as a question on my board. So those are the primary criteria for this, and if it's in red, it's also a big take-home point. So neuromuscular blocking drugs, you all know there's the depolarizing agents, which are acetylcholine receptor agonists, and succinylcholine is our depolarizing agent that we use, binds to the alpha subunit of the nicotinic acetylcholine receptor. You'll see this term a lot as well. The non-depolarizers are competitive antagonists. They bind to the alpha subunit also of the nicotinic acetylcholine receptor, but they block acetylcholine, thus the receptor remains closed. And reversal of those agents depends on their metabolism, their excretion, or whether we actually are able to give a reversal drug. So again, just some very important points about depolarizing agents, activating the receptor. They cause a decrease in twitch height, and I'll show you what that means momentarily. There's no fade when you use a twitch monitor or post-titanic facilitation. They are potentiated by cholinesterase inhibitors, so if you actually give neostigmine to a patient who receives succinylcholine, they may actually have a prolonged block. And if you give them too much, the reason we can't just re-dose sucs five minutes later, you can actually cause what we call a phase two block, so they can have actually prolonged neuromuscular blockade as a result. The non-depolarizers, on the other hand, are competitive antagonists. They do cause post-titanic facilitation, and you can reverse them, obviously, with cholinesterase inhibitors. So what does fade look like? So hopefully all of you in the room, if we were to put a twitch monitor on you, would have what looks like A. You'd have very four strong twitches that were equivalent across the way. But then with post-titanic facilitation, or what we see with non-depolarizing neuromuscular blockade, you might see what you see in B for a patient who is very weak or still has a lot of medication on board, or C, where every twitch progressively becomes lower in amplitude. So let's talk a little bit about succinylcholine. It's a depolarizing neuromuscular blocking agent. The great thing about Sucs is it's wonderful in emergencies. It can be administered IV, IO, or IM. It's the most rapid neuromuscular blocker that we have. If you want to facilitate tracheal intubation, the quickest Sucs, hands down, is what we have. Metabolism is via pseudocholinesterase. And the adverse effects, so these are gonna come up a few times, probably, on the boards. Increased ICP, intraocular pressure, and intragastric pressure. Arthriticardia is a significant side effect, and malignant hyperthermia, as I've mentioned the other things on that list. Masseter spasm. How many of you have seen masseter spasm before? All right, so a few people in the room. So masseter spasm is what it is. It's contraction of the masseter muscles. It means you can't open the patient's mouth, and it can cause a difficult intubation. Obviously, that's when you don't want it to happen. Masseter spasm used to be seen a lot more often when we were using halothane in the operating rooms, at about a 1% incidence, so pretty high. The etiology is often either an inadequate dose of succinylcholine, you haven't given enough neuromuscular blocker, or it's a prelude to malignant hyperthermia. So an important note here, if you have masseter spasm, it doesn't mean you're necessarily going to develop malignant hyperthermia. But about 50% of patients with masseter spasm will develop malignant hyperthermia, potentially. So MH, how many of you have seen MH in the room? Okay, so a significant number of you. So it's a familial disorder of muscle metabolism. It's autosomal dominant with variable penetrance, and it's a mutation of the ryanodine receptor. So triggering agents, most likely on the boards, it's going to be succinylcholine or an inhalational anesthetic. But the important thing to remember is that nitrous oxide is the one inhalational anesthetic that is not a malignant hyperthermia trigger. The at-risk population, I apologize, there's a typo here, King-Denborough is a core myopathy that is a very high risk for MH, but Duchenne's muscular dystrophy is also a risk for malignant hyperthermia. Clinical signs, tachycardia will almost always be the first sign of MH, followed by hyperthermia, potentially hyperkalemia, rhabdomyolysis, hyperkerbia, and acidosis. So how do you treat it? You avoid triggering agents, obviously. Dantrolene is a medication that likely will come up as well. It blocks the release of calcium from the sarcoplasmic reticulum. It can cause muscle weakness, so if you administer dantrolene to a patient with MH, be ready for that potential. And then treating symptoms, cooling for hyperthermia, bicarb for acidosis, glucose and insulin for hyperkalemia, and diuresis and hydration for rhabdo. How do you diagnose it? It's a muscle biopsy with a halothane caffeine contracture test and genetic analysis for abnormal genes. So you should know this table. This is a key point. So even though many of you may not have seen the full constellation of all of these different syndromes, the boards do love to make sure that you are able to identify the difference between all of these different things. So you can see it can get confusing because serotonin syndrome, anticholinergic toxidrome, NMS and MH all have a lot of similarities. So the vital signs, they're almost all hypertensive and tachycardic. The degree of hyperthermia is one area that differentiates many of these syndromes. The pupils, so medriasis is only seen in serotonin syndrome and anticholinergic syndrome. You don't see it in NMS or MH. Sialeria, so you're dry with anticholinergic syndrome, but you're salivating with serotonin syndrome. So you should know this table well. And so I'm going to briefly, intermittently be presenting you with some key points that I pulled directly from the ABP content specifications. So they want you to know that the clinical signs of acidosis, cyanosis and increased CO2 production may antedate defined muscle spasm in MH. And you can read through the other things that I've listed here. But differentiate post-op fever from MH. They want you to know how to treat MH. The triggering agents, as we just mentioned. Non-anesthetic stress can also trigger MH, but it's lower likelihood that they'll bring that up. And the safe agents. So it's important to know if they give you a question stem that says that they only got non-depolarizing relaxants, narcotics, nitrous, barbs and propofol or any combination of those, it's not going to be MH most likely. Pseudocolonesterase deficiency, another thing that is important to keep in mind. Long blockade following succinylcholine. The diagnosis is either whether it's a qualitative defect or a quantitative defect. And so a qualitative defect is defined by the dibucane number. So basically that means whether dibucane can actually antagonize the acetylcholinesterase. So a normal number is 80. So a lower dibucane number means that you have a qualitative defect. Quantitative defects are by measuring the enzyme levels and we'll go through some of the etiologies for that. And again, the treatment for pseudocolonesterase deficiency is essentially give a patient sucks. They won't move or wake up for a while. They might be awake under there. So it's really important to keep that in mind and give them an amnestic. Airway control, mechanical ventilation, FFP if you want to replace their pseudocolonesterase and time. Time is a tincture of time. Most people are heterozygous. There are some homozygous patients out there, but it's very rare. Quantitative pseudocolonesterase deficiency can be seen in pregnancy, liver disease, plasmapheresis, and a significant number of medications that you see there. Again, this is a little lower yield, but it's important just to keep in mind for your clinical practice. Succinylcholine contraindications. You know, all of you know this is a key point. So know all of these contraindications. Remember that mild hyperkalemia isn't necessarily an absolute contraindication to succinylcholine. You can give a patient with chronic renal failure succinylcholine, and it will increase their K, but remember they're used to having a high potassium at baseline, so it's all in context. But some of these are basically black and white as far as the boards go in terms of the succ contraindications. And remember that the reason for things like denervation injury or burn injury that succinylcholine can have this significant impact of hyperkalemia, for example, is that the extrajunctional acetylcholine receptors are upregulated. So they have more receptors out there to cause that reaction. So the bottom line, when we look at the package insert for succs, basically they say it's for emergency securing of the airway, anticipated difficult airway, and when you don't have IV access. In young children and infants, you should always give it with atropine, because bradycardic arrest is real with succinylcholine administration, especially in young patients. And think about the problems that we just talked about. So the non-depolarizers that you know and love. So we are going to focus mostly on the aminosteroids with one benzyl isoquinolinium, ROK, VEK. I bring up PANK, even though many of you probably haven't used PANK or haven't seen it for a while. It still shows up on the board specifications, so it's important to know the side effects of PANKuronium. And then cis-atricurium is obviously what we primarily use in our clinical practice, but it is important to know about atricurium as well. So the differences between all of the different neuromuscular blockers are based on their chemical structure, onset, duration, whether or not they have hemodynamic effects, metabolism, and their potency. So atricurium, again the big red key point here to take home is atricurium can cause histamine release. So if they do give you a patient that got atricurium, that is a potential thing that they're looking for. It's not as important to know the doses because most of us aren't using atricurium, but you should know that it is metabolized by plasma esterases, Hoffman degradation, which can lead to laudanazine, which we'll talk about shortly. Cis-atricurium, which you all have probably used, has no cardiovascular effects. So there is no histamine release associated with cis-atricurium. Its onset is intermediate, so when you use it for intubation, you have to be ready to wait for a significant proportion of time before you can intubate the patient with neuromuscular blockade on board. It's great in renal failure because of the Hoffman degradation, and you guys know the doses. So pancuronium, they do still love to talk about it. So the big red thing to remember about PANK is it causes tachycardia. So the reason we use pancuronium often in neonates in the NICU who are getting surgery or having bedside procedures is because we like the tachycardia in the babies, right? We didn't have to give them atropine, they become tachycardic, and it was long-acting, which we used to love, but now we're learning more and more that potentially long-acting neuromuscular blockade isn't the best thing, and it is primarily renal excretion. Rockuronium, perhaps our most commonly used neuromuscular blockade, can cause some mild tachycardia. Anecdotally, you probably haven't seen this that much. It's rapid onset of action, as you know. You do need to know that the speed of onset and duration of action of rockuronium is completely dose-dependent. So if you give a low dose of rockuronium, if you give half per kilo, you will get there. The patient will eventually be muscle relaxed. It'll just take a significant component of time. So that's why in RSIs, rapid sequence inductions, we give a higher dose so that we can reach that level faster. The problem with that, though, is the rockuronium, even though we think of rock as quick on, quick off, if you give a big dose, it hangs around still for a long time. Infants are more sensitive, so we tend to use a lower dose with infants. Renal failure can have an impact because of the metabolism, and it can be painful on injection, so hopefully you're not giving rock to a patient who's completely awake and can sense that. So vecuronium. So vecuronium, as you know, is also non-depolarizer, no cardiovascular effects. Its onset is intermediate, and we use it more in the operating room when we know that there's a patient who is a relatively easy airway, and we're going to be using that drug throughout the case. Its metabolism and excretion is hepatic. So that's an important point because if you have a patient with liver failure or a patient with post-liver transplant who just came back from the OR and they got vecuronium, there's a chance that it's still on board and it's going to be there for a while. And these are just a schematic of the deacetylation metabolism of vecuronium. So what are the issues with using neuromuscular blockade in the ICU? Prolonged paralysis, we're going to talk about that, increased or decreased sensitivity, which they love to bring up on the boards, tachyphylaxis, metabolic products, and monitoring. So what are the clinical findings? So this goes back to our initial question, which most of you answered correctly. So with prolonged paralysis and neuromuscular blockade, you have flaccid paralysis, decreased DTRs, respiratory insufficiency, normal CSF findings, sensory is intact, and decreased motor nerve conduction. The etiology is often excessive dosing, you just gave too much, or accumulation of the parent compound or metabolites. We see this in critical illness, polyneuropathy, disuse, denervation atrophy, and then associated conditions. Remember that aminoglycosides are often implicated in prolonged paralysis in association with neuromuscular blockade and weakness in the ICU. So how do you prevent it? Obviously limit use of neuromuscular blockers, monitor the train of four. We may not always do this at the bedside as much as we should, but we should have all patients who are on neuromuscular blockade on a twitch monitor. Adequate nutrition, correcting electrolytes, following CK levels, and looking at our high risk populations. Again, if they're on aminoglycosides, they're on corticosteroids, female, or asthma. So this is a key point, if you take home anything from that whole last 10 minutes, is recognize that a patient may have no residual muscle blockade, but can become paralyzed again if they're hypokalemic, hypomagnesemic, cold, or poorly perfused. They love to talk about the cold patient in the postoperative period being weak, and it's always gonna be because they're cold, okay? So that's another key take home point. So what are things that can increase your sensitivity to neuromuscular blockade? Number one is neuromuscular disease. So myasthenia gravis makes sense, muscular dystrophy. If you're weak at baseline, you're gonna be highly sensitive to these drugs. Electrolyte disturbances, hypokalemia, hypocalcemia, hypomagnesemia, so correct those electrolytes. Respiratory acidosis, metabolic alkalosis, hypothermia, as I already mentioned, and medications. Here's a long list of medications that are implicated in increased sensitivity to neuromuscular blockers. Keep that aside, look at it, study it, know that list. Again, remember the drugs that we already talked about. So what about decreased sensitivity? So we talked about prolonged neuromuscular blockade. Which patients actually need more drug? So there are patients who get tachyphylaxis over time with increase in their receptors as a result. There are actually these four medication classes that cause decreased sensitivity, aminophilin, phenytoin, carbamazepine, and BARBs. Thermal injuries, they often, you know, your burn patients may often need more in order to achieve the same effect. And upper motor, lower motor, and demyelinating diseases as well. This is just a list of all the metabolic products that I just mentioned. Again, it's important to remember that Vecuronium, Pancuronium, and Atrocurium do have metabolites. Which brings us to Laudanazine, which is the metabolite produced by Hoffman degradation. It's epileptogenic. Remember, it's not removed by dialysis or hemofiltration, so that can be an issue. We don't know what the toxic level in humans is, but there have been rare reports of seizures with patients who got Atrocurium. We don't see this as often, but just something to put to the side. Trana4 monitoring. So what is Trana4? As you know, it's the repetitive stimulation of the neuromuscular junction. Two hertz for two seconds, looking at four twitches. So you have to have some receptors open in order for this to work. So you can't attempt to do twitch monitor testing on patients who are fully blocked. It's not going to give you any information. You're not going to get any twitches, obviously. But the goal is to start to see spontaneous recovery and to see your twitch heights start to become more equivalent over time. You all know that you can only reverse non-depolarizing agents, and you do need residual muscular function, as we said. There are two types that we're going to focus on in terms of reversal. There's inhibition of acetylcholinesterase, which you all have probably used. And then binding of endogenous steroid. This is a big new hot topic. I'm not sure it'll come up on the boards, but it's important to know this drug for your future practice. And that's Sigamdex. So first let's talk about the one that you're more familiar with, anticholinesterases. They inhibit acetylcholinesterase and increase acetylcholine at the neuromuscular junction. So Neostigmine is the one that we primarily use. Some of these others we use in myasthenia gravis. Side effects are, remember these side effects, bradycardia, salivation, the whole B sludge mnemonic is important to remember as it relates to anticholinesterases. And we always pair this drug with anticholinergic, either atropine or glycopyrrolate. And in the OR we always give it, and in the PICU also you should do this, always give it before the Neostigmine. Don't give it after, because you need that to work first. We've had patients arrest because someone didn't give an anticholinesterase before Neostigmine. Sigamdex, how many of you have used Sigamdex? Okay, I see a smattering of hands, that's great. So this is the new drug on the market. It was FDA approved December of 2015. It's a modified cyclodextrin which encapsulates lipophilic molecules and binds, it loves rocuronium, and I'll show you a couple of examples here in a second, and it also binds endogenous steroids at baseline as its mechanism. So this is a nice schematic showing how the rocuronium molecule gets docked inside the lipophilic core of Sigamdex, and the negatively charged carboxyethyl groups hold the rocuronium really tightly. So this has really kind of changed a lot of our practice in the operating room and has started to change our practice in intensive care units to have this medication available. This is an x-ray diffraction image in case you weren't convinced how much it loves rocuronium. It really kind of gets in there and hugs rock and takes, so Sigamdex can be great, especially since we do use a lot more rocuronium than succinylcholine in the pediatric ICU environment. We now have an immediate reversal agent that can take the rock away in that unanticipated difficult airway scenario where you need the patient to breathe again. So overall, is it better than anticholinesterase? So this is a really great Cochrane review that was recently done on the efficacy and safety of Sigamdex compared to neostigmine in adults. They looked at 41 randomized controlled trials with 4,000 patients, so a very large cohort, and they found, hands down, with all doses, Sigamdex versus neostigmine was significantly faster. And again, Sigamdex can be given when all of your receptors are completely occupied and you have zero twitches, and so that's another major advantage of that. And there was no difference in serious adverse events. So again, Sigamdex loves rocuronium, so it has the highest affinity for rock and the speed of the reaction is much faster than for, for example, pancuramide atrofurium. Remember though, it doesn't do squat for succinylcholine, okay? So it sucks, you just have to wait. So Sigamdex dosing is 16 milligrams per kilogram if you just gave your big dose of rock and you need it to go away, you need to give a big dose of Sigamdex. But otherwise, if you do have some twitches and you're at the, for example, for me, at the end of an OR case, or you have a patient who just came back to the PICU, you can usually give two to four milligrams per kilogram to reverse. What's the issue with Sigamdex? It's expensive. So that's why many hospitals are still not completely on board with us replacing neostigmine use with Sigamdex. It's cleared renally, so you do have to consider that in patients with low creatinine clearance. There is an anaphylaxis risk, although it's about .3%, and one thing we always have to remember for our adult patients is that, or older adolescents, is that if they're on contraceptives and they get Sigamdex, you have to tell them they have to use some non-hormonal contraceptive immediately after that, because it's not gonna work for about seven days. All right, moving on to sedation and analgesia. So obviously there's a lot of different agents that we can talk about for sedation and analgesia. I'm gonna focus on the ones that are highest yield, but also throw in a little bit of information for your reading pleasure later on about some of the other drugs. Inhalational anesthetics agents, as you all know, are used both in the operating room and for us in the PICU, especially in cases of status asthmaticus that are refractory to our traditional therapies. Here are all the structures for your viewing pleasure. So what are the advantages? Easy to titrate, inhalational administration obviously, rapid on and off for many of our inhalational agents. Inhalationals are one of the only things that we use that causes all of the good things, so amnesia, sedation, and analgesia, that trifecta, and it can have beneficial physiologic effects, anticonvulsant, bronchodilator, cerebral protection. So what are the disadvantages? Equipment, you need to have a delivery monitoring and scavenging system, cost of the agent and equipment, the physiologic effects. As you all know, inhalational agents do cause cardiovascular depression. They can cause cerebral vasodilatation. They are MH-triggering agents except for nitrous oxide. Can cause some hepatotoxicity, that's lower yield, and alters the metabolism of some other drugs. So just a brief note about nitrous oxide. Remember, nitrous oxide is N2O, it's not NO or NO2. It's easy to administer, it's non-invasive, that's why they use it in the dentist's office all the time. It's rapid on and off, it's inexpensive, and it's administration is relatively straightforward and easy. The problems with nitrous oxide though, and the reason we don't use it on every single patient, is environmental pollution. There is a concern that healthcare worker exposure, that workers might be impacted with infertility, spontaneous abortion. The problem with nitrous is also its low potency. You can't use it by itself to create a state of general anesthesia. It has to be combined with other agents. You can use it for minimal sedation cases by itself. The physiologic effects are relatively mild and simple, and that's why we like it in the OR. You rarely have myocardial depression, but you can see that obviously in your patients who do have some myocardial depression at baseline. It can increase your PVR, depending on who you're attending is, or you as faculty who are out there, whether you think that it increases the risk for pulmonary hypertension, there's a lot of controversy about that topic, so we'll just leave that there. Vitamin B12 effects, megaloblastic anemia, bone marrow suppression, and myelopathy. Benzos. So, benzos were the most commonly used agent for ICU sedation across the board, and in some units it still is the first-line agent that we go to, but its use is significantly decreasing over time, but it's a drug that we need to know and know well, because we still use it for a variety of indications. As you know, it binds to the GABA receptor, it increases chloride conductance, and leads to hyperpolarization. Benzos are amnestics, they can cause anxiolytics, but they do not cause analgesia. So, important point there. You know the three that we primarily use, and then, of course, flumazenil is a reversal agent. So, what are the benefits of midazolam? Well, it's rapid on and off. Midaz is probably what we are all most familiar with. With limited cardiovascular effects, except in patients, of course, who have some cardiovascular depression. Those of you who work in a cardiac ICU probably have seen that many don't want to use benzodiazepines in the immediate post-operative period in those patients. It doesn't cause pain with IV administration. So, that's one of the big advantages, and why we tend to go to it as first line. It is FDA approved for ICU sedation, and we do have a large clinical experience. People are comfortable with it in infants and children. So, what are the disadvantages? Delirium is the big hot topic now that's come up with benzodiazepines. We'll talk about that a little bit more. There is a variable effect after prolonged administration, and it's metabolized by the P450 system. So, obviously, for the rest of the boards, you have to know all those drugs that impact the P450 system, and so midazolam is impacted by that as well. Lorazepam, really briefly, is inexpensive. It does have a longer half-life. It doesn't have any active metabolites. The issues with it, though, is the diluent, is propylene glycol, so that can be a little challenging from a pharmacy perspective. And infants have deficient glucuronoyl transferase, so that can also impact their metabolism. So, what data do we have on benzos and delirium? Well, this is the big adult men's study that was done back in 2010 that really kind of caught a lot of traction that showed comparing dexmedetomidine, which we'll talk about shortly, compared to lorazepam in adult ICU patients that, hands down, over time, lorazepam was associated with an increased risk for delirium in these ICU patients compared to dex. We have our own pediatric data that's emerging. Connie Traub's recent study was an international point prevalence study with a large number of patients, 835, that showed that the odds ratio with benzos of delirium prevalence was 2.2. And then Heidi Smith, who has the PCAM ICU that some of you use, showed that benzodiazepines were associated with a decreased risk of ICU discharge, most likely due to delirium. So we're starting to show in pediatrics that benzos are associated with delirium, which is why a lot of units have started to move away from that. This is just a brief slide showing the context-sensitive half-life of some of the most commonly used sedatives. Again, you can see that diazepam, if once you give it, it's going to have a very long half-life, so keep that in mind. Just a brief note about flamazenil. It's a GABA antagonist used as a reversal agent for benzos. The duration is about 30 to 60 minutes, so obviously you have to be very careful about giving flamazenil to a patient who's been on benzos for a very long time. You want to reverse the effects of acute benzo administration. It can cause seizures and ventricular arrhythmias, so that's an important take-home point as well. Propofol, you all know Propofol, know it, love it. It's an IV anesthetic agent that's an alkyl phenol. It's a lipid emulsion, so important to remember, it's soybean oil, glycerol, and egg phosphatides, and that'll come up in a question later. It's highly lipophilic, so that's why it has very rapid CNS penetration, so that's why it's pretty much instantaneous. Important note with Propofol is that it's an amnestic. It can cause anxiolysis, but it has limited analgesia, so that's why it's important if you do have a painful procedure that Propofol by itself will likely not be sufficient. It does have rapid redistribution following a single bolus dose, which makes it a nice drug in kind of an acute situation where cardiovascular compromise isn't an issue. It is metabolized hepatically, so it does have prolonged elimination in neonates and infants, and it does have an increased volume of distribution in children versus adults, so we have to use larger induction doses in children. It's not unusual for a 60 kilo 50-year-old to only require 200 milligrams of Propofol to go to sleep for general anesthesia in the operating room, but for a healthy 14-year-old teenager to require 350 to 400 to get them to the same point, so another important point to remember. What are the CNS effects? I think you all know this. It can reduce IOP, cerebral blood flow, CMRO2, and ICP, which may or may not be a good or bad thing depending on what you're trying to achieve at the time. Depression of MAP may decrease the cerebral perfusion pressure, and it is not uncommon to see excitatory movements during bolus administration, so it doesn't necessarily mean they're having a seizure. Those of you who've given Propofol to an adolescent might have seen myoclonus, which is relatively common in healthy adolescents, and it can have very excellent anti-emetic effects as well. 10 to 20% reduction in MAP related to decreased SVR primarily. It can slow the heart rate significantly, and it can prolong the QT interval. Some additional notes. There is no effect from Propofol on T-cell function or adrenal function that may come up. Bacterial contamination is an issue, so that's why you can't let Propofol sit around after it's been drawn up for more than four hours is our JACO rule. It does cause pain with injection, so you can give some lidocaine locally through the IV. Remember not to give a big dose, so 2% lidocaine, generally one milligram per kilogram to help with that. It can cause skin sloughing with extravasation, so if you have a Propofol extravasation, that's a problem. Anaphylactoid, if you have an egg allergy, it's recommended to avoid, although there is some new data coming out, but for the purposes of the boards, if they have a bona fide egg allergy, stay away from Propofol. Hyperlipidemia and Propofol infusion syndrome. So red point, no Propofol infusion syndrome. So what are the clinical symptoms of Propofol infusion syndrome? Can cause Brady dysrhythmias, hypotension and cardiac failure, and metabolic acidosis. So if you have a patient with potential PRIS on the boards, they will have metabolic acidosis and hypotension, plus minus the rhabdomyolysis. The risk factors, again, these data are emerging and now they're starting to show that PRIS is not just a problem in kids, they're seeing it in adults as well. Mostly in kids less than eight years of age, but as I mentioned, older patients. Infusion rates, higher, more high risk, duration, which is why often we have a time limit in many ICUs for how long you administer Propofol. Hemodialysis may be beneficial, but again, that data is limited. And here's an example of what you might see an EKG look like after administration in Propofol-related infusion syndrome. So why do we get PRIS? So it's primarily related to mitochondrial function, but again, this research is still ongoing. There's an initial case report in Lancet that talked about a two-year-old boy that had increased plasma concentrations of malonylcarnitine and C5-acylcarnitine. Fatty acid oxidation is disrupted, and oxygen utilization is disrupted as well. So recognize the association between Propofol infusion and acidosis, hypotension, and death in children. That's taken straight from the ABP. BARBs, again, I don't wanna fixate too much on BARBs because you use them for a very specific indication in the PICU, primarily for seizure disorder or status epilepticus, but they do bring it up on the content specifications. Remember, BARBs do cause sedation and amnesia, but no analgesia, and they act through the GABA system. Thiopental is what we used to commonly use for induction. We no longer use thiopental in the operating room setting. There's the chemical structure. It has longer side chains, which increases its potency and also increases its half-life. Cardiovascular effects, as you all know, with barbiturates are an issue. They are negative inotropics. They cause respiratory depression, and the CNS effects obviously can decrease all of those things listed there. Etomidate, so we will talk a little bit more about etomidate since it's one of the trifecta of propofol, ketamine, etomidate that we often use in intubation scenarios, especially in the trauma bay or urgent intubation scenarios. It was introduced in 1972, and it's the ester of a carboxylated imidazole, so the imidazole ring is really the key to a lot of what you hear about the similarities between etomidate and some other drugs, and also why we see problems with steroids afterwards. So it's the only R enantiomer that's hypnotically active. It acts through the GABA system as well. It does cause pain on injection as well, but often when we're giving etomidate, it's in a trauma scenario, et cetera, where that isn't the primary issue involved. It can maintain cerebral perfusion pressure, which is why often in neurotrauma cases, it might be the preferred drug of choice. As I mentioned, there is pain on injection, and you all know that etomidate, and again, this is the red key point, is associated with adrenal suppression even with a single dose, and that's because it inhibits the 11-beta-hydroxylase, which leads to cortisol, corticosterone, and aldosterone. Ketamine. All of you know ketamine well. Also, it's a phenacyclidine derivative. It's a dissociative anesthetic, and it causes unresponsiveness, as you've seen, with the eyes potentially open. It is excellent amnestic and analgesic. The nice thing about ketamine, when you're trying to maintain spontaneous ventilation, it maintains your airway reflexes at certain doses and by itself. So anything, when I say that these drugs maintain airway reflexes, for example, that's only when it's used on its own, right? As soon as you start committing polypharmacy, all bets are off, and things start to change. It's water-soluble, and its mechanism of action, it's important to know, is via the NMDA receptor antagonist and reduction of glutamate release. And it is metabolized hepatically, and it does have an active metabolite, which is noreketamine. The hemodynamic effects. It releases endogenous catecholamines, which is often why you do see an increase in heart rate and blood pressure in patients who are not catecholamine depleted. It can cause hemodynamic and respiratory instability in those patients, but most of the time it is very stable from a hemodynamic and respiratory perspective. And again, has controversial effects on PVR, and may be related to changes in PaCO2. So bronchodilator, so if you have an asthmatic who needs to be intubated on the boards, think about ketamine as a potential, make sure there are no other contraindications to that. Limited respiratory depression, as I mentioned. Again, when it's used by itself. It does cause a rightward shift of the ventilatory response to CO2. And it maintains airway reflexes, but remember it also increases salivation. So if you are trying to maintain airway reflexes in an intubation scenario, be ready with your suction or give something like glycopyrrolate to help with that. CNS effects, as I mentioned, NMDA antagonism. It increases cerebral blood flow and CMRO2. So some people do choose not to use it in a neurotrauma type situation, but there are others that have used it. I would say for the purposes of the boards that ketamine probably isn't going to be your first choice in a neurotrauma scenario with concern for increased ICP. And then obviously emergence phenomenon, hallucinations are a concern. This may be the one time that a benzodiazepine may be beneficial in this scenario to help with the delirium that may result as a result of the ketamine. But there are also some other adjuncts that you might have used, including dexmedetomidine that may help with that. It can cause increased nausea and vomiting, so we try to avoid it in the OR, especially in patients who have a history of post-op nausea and vomiting. It does have abuse potential. Opioids, finally in the list of all the sedation. Analgesia topics. As you know, opioids cause analgesia, but they do not cause amnesia unless the patient is actually apneic, and of course then they will be amnestic. There are differences in chemical structure, half-life, potency, cardiovascular effects, and metabolic products. As you know, the mechanism of action, it's important to remember this mechanism of action is that they're all G-protein coupled receptors and inhibit adenylate cyclase, and they're also involved in post-synaptic hyperpolarization and reducing presynaptic calcium influx. So another key point taken straight from the specifications, know that narcotics cause the least depression of myocardial function of all anesthetics, which is often why a pure narcotic induction might be used in cardiacs who are going to the operating room, because again, it maintains the most cardiovascular stability, including heart rate and blood pressure when used by itself. So key points, another thing that the board loves to kind of tackle here is the differences between tolerance versus dependence versus addiction. So know these definitions and know them well. There will be a case study of someone who has one of these things, and you need to be able to delineate which they are. So remember, tolerance is a greater amount of drug is needed to maintain the therapeutic effect. Dependence is that they'll get a withdrawal syndrome if the drug's discontinued, reduced, or you give an antagonist. And addiction is an actual psychiatric disorder with compulsive use of the substance despite harm. Morphine, it's cheap, it's a mu-agnest. It has a relatively nice half-life if you're trying to achieve analgesia for a significant period of time. It can cause venodilation, and as you know, with morphine, there's also this concern of histamine release. Anecdotally, that may happen. There are some studies to show that morphine causes an increased risk of histamine release, but generally in the PICU setting, we don't see that from a clinical impact perspective. Demerol, again, not likely going to be a major thing that they're gonna focus on, but it is on this content specification, so know about Demerol. Know that Demerol does cause tachycardia, potentially, and that's a side effect, and it does interact with MAO inhibitors and may increase the risk of seizures and dysphoria. Dilaudid, we all use Dilaudid commonly. Again, the longest half-life of the opioids that we use most commonly. It does not have any metabolites, which is nice, and minimal cardiovascular effects when used alone, and there's a slight risk of histamine release, but not as significant as morphine. Methadone, an MDA receptor antagonist that blocks the reuptake of serotonin. Very long half-life, so remember that if you get a stem with a patient that got methadone, that it hangs around for a long time, and it also takes a long time for any weans of methadone to actually impact your withdrawal score, so that's another important counterpoint. This is one of the drugs you need to know potentiates or is potential for QT prolongation, so remember that. You may need to do serial EKGs to follow patients who are on methadone for long periods of time, and it has great oral bioavailability, so that's another nice advantage. A little note about the synthetic opioids, fentanyl, which we all use very commonly, but also sufentanyl, alfentanyl, and remifentanyl. The half-life of most of these drugs is minutes as a continuous infusion with the exception of fentanyl, but the other drugs are very short half-lives. They can cause a decrease in heart rate, but generally also no histamine release and CV stability. So here's an example. Obviously, as you all know, Remy's on, it's on, it's off, it's off. It's the quickest on and off that we have in terms of opioid. However, fentanyl, on the other hand, we give fentanyl the shake as this really great short-acting drug, right? But as soon as you put a patient on a fentanyl infusion and they've been on it for a long time, we've all seen the fentanyl hang around for a long time, so that context-sensitive half-life is really important to remember. Remember that the synthetic opioids can cause chest wall rigidity if you give a bolus of the drug. So if you have a stem that the patient has chest wall rigidity immediately after a bolus of fentanyl, that's a possibility. And the treatment is obviously to paralyze them. That's one option. Give an antagonist or an alpha to adrenergic agonist. You can develop tolerance very rapidly, especially to Remy fentanyl, especially in kids. And metabolism of Remy is via plasma esterases. A quick note about phenothiazines and butyrophenones, because haloperidol is also another drug that will likely come up at some point during the boards in some capacity. Important to know that these drugs do lower the seizure threshold. They can cause dystonic reactions, cardiac dysrhythmias. Here's another QT prolongation that Dr. Cutco was talking about earlier. Dexmedetomidine, I think those of us who get to use this often know and love it. So it's a drug that will probably show up in more frequency on the boards now. It's an alpha to adrenergic agonist that's increased its use of the first line agent for sedation. The important thing to remember about dexmedetomidine compared to clonidine, its sister drug, is that its alpha two to alpha one ratio is much higher. So it's 1,600 to one versus clonidine, which is so it's seven times greater. It has a shorter elimination half-life than clonidine, two hours versus eight hours. A more rapid distribution half-life, five minutes versus 10 minutes. And we can give it IV. However, there's a couple papers coming out in Pete's Critical Care Medicine soon about IV clonidine infusion use. There's a couple papers that have already come out and also IV bolus use of clonidine. So that's kind of new on the frontier. Dexmedetomidine is also preferred when you want to maintain airway reflexes and provide patients with some comfort simultaneously. So it's important to know the mechanism of action of dexmedetomidine, which is primarily through the locus coeruleus. And you can see here, and then I have some other pictorials here that you can view to see how it works in the negative feedback loop that alpha two adrenose receptors cause. And this is a nice schematic showing all of the different side effects of dexmedetomidine that may be preferred. It does cause bradycardia, as you all know. So that is something that might need to be dealt with. May or may not be clinically relevant. And then does cause some vasoconstriction as well. So in the last few minutes, this is actually kind of a newish topic that I added to this talk because as I was looking through the content specifications, they do talk about local anesthetics a significant amount. And I actually had several questions that were directly related to local anesthetics and local anesthetic toxicity. How many of you have seen local anesthetic toxicity in the PICU environment? Okay, so several of you raised your hands and it's something to be cognizant of. So hopefully this will be helpful from a clinical practice perspective but also for the boards. So as you know, local anesthetics are used in a multitude of different settings. We use it for multimodal pain management on the anesthesia side, local infiltration when you're putting in lines, for example, central anoraxial anesthesia and analgesia via epidurals or spinal anesthetics, and then peripheral nerve blocks. So the incidence of peripheral nerve blocks for post-op care is increasing as well. So the mechanism of local anesthetics is they block the voltage-gated sodium channels along the nerve fiber in both the CNS and the PNS. The nerves contain both afferent sensory and efferent motor nerves and they have to diffuse through the tissue, obviously, to block the nerve. So these are a couple key points that the degree of the block depends on the concentration and the volume. Again, not as relevant to you, this is more of an anesthesia-specific thing, but important for you to know from a clinical perspective if you have a patient who's complaining of numbness or tingling and has a regional nerve block. The minimum concentration needed for the nerve block is a reflection of how strong the local anesthetic is and whether the properties and size of the nerve fiber being blocked relevant to that potency. These are the, this is important for you to know. So the classes of local anesthetics are amino esters and amino amides. So the ones that primarily, you know, the ivocanes, the rapivacane, mapivacane, lidocane, and bupivacane are the ones you primarily see in the PICU setting, but chloroprocaine is something you might also come across that might be used in epidurals. Remember that the ones that were commonly used or were used to are metabolized in the liver, so that can be an issue moving forward. For those of you who take care of bladder exstrophy repairs, our patients who come back, burn patients who might have epidurals, et cetera, that's an important point. So the key point for all of you from a peds critical care perspective is synthetic absorption of local anesthetics. It's dependent on where you put it, the dose, and whether epinephrine was added. So they want you to recognize that many local anesthetics are mixed with epi and that catecholamines can produce systemic alterations. So why do we actually add epi? We add epi in order to cause local vasoconstriction to decrease the risk of systemic absorption, and also to be able to sense whether there was systemic absorption, because then you'll start to see tachycardia and hypertension. So the greatest risk of systemic absorption comes with intracostal nerve blocks. So if you think about it, if you're about to put in a chest tube and you're using local anesthetic there, it's possible that you could get systemic absorption simply from where you're trying to insert the chest tube. Caudals and epidurals, followed by brachial plexus blocks, and finally the femoral sciatic nerve block. Obviously there's a lot of vasculature there. Toxicity. CNS, sometimes the first sign is gonna be a seizure. So keep that in mind. Myocardial depression is often kind of the next thing that comes along. Obviously direct injection of a nerve is a bad thing. We don't want that. In the CNS, you have toxicity if you have high blood levels, if you directly inject it into an artery or a vein, or into the CNS, obviously. It's dose dependent. If you have low doses, that can produce depression, but if you have high doses, that's when you start seizing. And seizures are, again, the big take home. So often when we put an epidural in, we ask if someone's having numbness or tingling because we want to know if they have systemic toxicity, and then go from there. Respiratory arrest, and hopefully you'll never see cardiovascular collapse as a result of local anesthetic toxicity. They do want you to know that higher doses are needed to produce cardiovascular toxicity, and that I want everybody to know the maximum cumulative doses of lidocaine that you can give a patient. You will always be thankful that you remember those, and remember they're cumulative. So if a patient has six different places you're putting local, you need to add up all of that to come up with the total dose that you can give the patient. So lidocaine with epi is seven milligrams per kilogram, and remember 1% and 2% are different concentrations, so you have to do that calculation. And without epi is three milligrams per kilogram. It can cause vasodilatation through vascular smooth muscle, and always remember that cardiac arrest from bupivacaine is the worst. So you probably have all seen a lot of bupivacaine use. Bupivacaine hangs onto the heart and does not let go. So that is the worst local anesthetic from a cardiovascular toxicity perspective compared to lidocaine. How do you treat it? Supportive care, vasoconstrictors, epinephrine, CPR PALS. Always remember if you're concerned about local anesthetic toxicity, you might get called to the ORs, the PICU team to put a patient on ECMO, and that's because that's usually the only thing that will help that patient in that time. 20% intralipid is a potential antidote for bupivacaine toxicity specifically. Propofol doesn't cut it, it has to be 20% intralipid. Here's a nice schematic showing the management of local anesthetic toxicity. And then I also wanted to kind of finish up to bring up the sedation continuum. This is also, and this will come up in one of the questions we're gonna go over. It's important to know the ASA classifications for the sedation continuum, which can get a little gray, right? So as you pass between moderate to deep to general, people say they're doing moderate sedation or analgesia, i.e. conscious sedation, but usually it's not really conscious sedation when you get those patients that come to you in the PACU that maybe got a little bit more than they were supposed to. So remember that even with deep sedation and analgesia, based on the ASA classifications, they're still having a purposeful response following repeated or painful stimulation. So that's still a pretty light state of sedation in the grand scheme of things. It takes very little to push a patient over into general anesthesia. All right, so in the last few minutes, let's do some questions. So an eight-year-old is playing with lighter fluid near a campfire and sustains second and third degree burns to 45% of his body surface area. He's intubated and admitted to the ICU. He's developed AKI. His allergies include eggs, soy, and shellfish. You're asked to provide sedation and neuromuscular blockade for burn debridement and dressing change on the second hospital day. Of the following drug combinations, which is the most appropriate to use? Fentanyl and cisatricurium, ketamine and succinylcholine, midazolam and PANK, morphine and rocuronium, or propofol and becuronium. Okay, so the majority of you selected the right answer, but there was some heterogeneity, so let's go through. So fentanyl and sesatracuram was the first one that was chosen by most of you, that is the correct answer. But let's, so number four, morphine and rocuronium got a reasonable number of answers. So according to the board specifications, the reason that morphine and rocuronium would not be the right answer is there's this potential histaminergic release that's associated with the rocuronium. He also does have some acute kidney injuries, so that may be associated with the morphine metabolism, so it may not be ideal. But that would have been my second choice as well, so this one is a little bit confusing. So number two, ketamine and succinylcholine. So that ketamine is obviously something we use often for burn patients, it can be a great drug from an analgesia and sedation perspective, but they don't want you to give succinylcholine because it's a very short-acting drug, obviously. It's a burn dressing change, right, so you're not going to be able to maintain that for a significant period of time. The succs is just gonna go away as soon as you give it. So that's more of a rapid sequence induction situation. And then the others, propofol and vecuronium, again, he may have some hemodynamic instability and you don't need necessarily a long-acting drug. And then midazolam doesn't have any analgesic properties, so that's why it can't be included. So the fentanyl and cis is ideal because the fentanyl will provide him with analgesia and the cisatricurium is ideal given his acute kidney injury, okay? All right, we'll go to the next question. A teenager who had an outpatient surgical procedure two days ago comes to the ER. He has mild hypertension, agitation, and diarrhea. You see his physical exam, temperature of 104, heart rate of 115, blood pressure of 135 over 85, respiratory rate of 14. Moist skin, agitated and confused, tremors in her hands and feet. Her pupils are six millimeters. The DTRs are hyperactive and she has ankle clonus. Her cardiac exam reveals only sinus tach and her breathing is unlabored. She has active bowel sounds. Of the following, these symptoms are most indicative of exposure to, one, diphenhydramine or Benadryl, two, risperidone, three, sertraline, four, succinylcholine, and five, theophylline. Okay, so again, some heterogeneity on this one as well. So most of you chose the right answer. So the answer is sertraline, so 45% of you. So let's go through some of the others that were somewhat popular. So let's start with number one, diphenhydramine. So diphenhydramine does have a lot of the similarities here but what we've noticed is that, with diphenhydramine, they're hot and dry. So having diarrhea is going to be unlikely with a patient that got a benadryl toxicity. Okay, and let's see. So succinylcholine, a significant proportion of you chose that. So I think many of you are thinking malignant hyperthermia. The issue is here that, in malignant hyperthermia, you don't necessarily see pupil dilatation. Okay, so dilated pupils are classic with sertraline and serotonin syndrome. So that's primarily what you need to be thinking about. But otherwise, the autonomic hyperreactivity, mental status changes, and the neuromuscular abnormalities are the key components of why it would be consistent with sertraline toxicity. Okay, all right, next question. A 16-year-old girl who weighs 50 kilos is brought to the PICU immediately following an anterior spinal fusion for congenital scoliosis. Her past medical history reveals no prior respiratory or cardiac problems. It was a five-hour surgery with an estimated blood loss of 550 mLs. Physical exam on arrival, respiratory rate of 10 to 12, heart rate of 110, blood pressure of 88 over 50, temperature of 91. Pulse ox is 95% on an FiO2 of 50%. She can lift her head on deep stimulation for three seconds and squeeze the hand weakly. According to her anesthesia record, she received midaz, fentanyl, propofol, and VEC by a continuous infusion and inhaled isoflurane. All were discontinued approximately one hour prior to extubation and arrival in the PICU. So this girl's shallow breathing is most likely due to the effect of fentanyl, isoflurane, midazolam, propofol, or VEC urine. Okay, so the majority of you chose Vecuronium and that's almost always going to be the right answer. So again, they want you to remember that neuromuscular blockade, regardless of when it was stopped, can always present itself later on down the road. Now what do you notice about this patient's vital signs? She's cold, right? So being cold in combination with the VEC drip just coming off, remember they didn't tell you that they reversed the neuromuscular blockade, did they? So that means that they just kind of assumed that the neuromuscular blockade was going to go on its merry way and they'd bring her to the PICU and all would be well. So she's cold and has residual neuromuscular blockade on board. The fentanyl would be unlikely, especially if it was turned off an hour ago. This wasn't a long PICU course, it was just an OR course. So it was a short administration. So that's why Vecuronium is the right answer here. All right, last but not least. You're asked to provide conscious sedation in the ONC clinic to a 12-year-old boy who's undergoing bone marrow aspiration with intrathecal chemo. The patient has a history of AML and is in the maintenance phase of chemo. You meet with the patient and his mother to conduct a pre-procedural eval. The boy's four feet, eight inches tall and weighs 180 pounds. Physical exam reveals a heart rate of 90 beats per minute, respiratory rate of 18, and a blood pressure of 130 over 80. His pulse ox is 98% in room air. Of the following, the finding that is most likely to make the boy a poor candidate for moderate or conscious sedation is, according to mom, in the past at another facility, he required, quote-unquote, lots of midazolam to achieve adequate sedation for the bone marrow aspiration. Two, his body mass index is 40 kilograms per meter squared. Three, anthracycline drugs were part of his chemo, although recent echo demonstrated a shortening fraction of 40%. Four, he also has asthma that's controlled with steroids and occasional use of beta-2 agonists. And five, he consumed a small amount of clear liquids four hours ago. Okay, so number two was the most popular answer, and that's the correct answer. His body mass index is 40 kilograms per meter squared. So this child is morbidly obese, which puts him at very high risk for a multitude of complications associated with moderate or conscious sedation. Even though that might be what they ought to do in an operating room setting, you would want him to have the potential for more invasive monitoring and intubation if necessary. Number one, again, this would require getting a little bit more history. It wouldn't automatically make him not a candidate because mom said they couldn't do it before with midazolam. You have other agents at your disposal. Three, he has a normal shortening fraction, and the anthracycline history doesn't seem to be significant. Asthma, you can deal with asthma and moderate conscious sedation, not a big issue there unless it's very severe. And as you know, less than two hours is reasonable for a clear liquid, so four hours ago isn't going to be a contraindication. So.

analgesia

sedation

neuromuscular blockade

mechanisms of neuromuscular transmission

depolarizing agents

non-depolarizing agents

succinylcholine

rocuronium

benzos

propofol