Thank you for the invitation to speak today. I really have no disclosures in relation to this presentation, and we're going to be talking about special considerations in sedation and analgesia in children with liver failure. The first thing I'm going to talk about, which I know is painful for most people, is pharmacokinetic changes that occur when you get liver failure. But I think they're very important because if you understand what occurs in the liver, you can understand whether certain drugs can be used in acute liver failure versus cirrhosis because the changes are different. The other thing to talk about briefly, which I'm just going to mention, for other drugs that other than sedation and analgesia, because most of these drugs don't have them, but a lot of the antibiotics we use and other drugs will have a child Pugh classification, A, B, or C. And in many of the references we use, pediatric lexicon will tell you, depending on your child Pugh score, how you should dose that medication in liver failure. But we're not going to talk about that specifically today. There is a MELD score, but most drugs are actually adjusted based on a child Pugh and not on a MELD. But you could, there are a few drugs that have MELD recommendations. So if you think about clearance through the liver, a lot of that is dependent on our hepatic blood flow. We do know that once we get cirrhosis and we start to get shunts, you can get decreased liver blood flow because of that intra- or hepatic shunting. Many of our drugs are bound to plasma proteins, and we know in acute liver, chronic liver failure, we get decreased amount of plasma proteins. And then we have intrinsic clearance, which is our cytochrome P450 system. We have drugs that fall into categories. They can either be high extraction, poor extraction, or intermediate extraction. And a good way I think of high extraction drugs, if I look at my PO dose and it's three times the IV dose, that's probably a drug that's high extracted, if you think big picture. Otherwise, you can find these numbers in the literature, but the drugs you are most concerned about in hepatic failure would be those ones that your IV and PO difference is significant. So those orally administered drugs normally pass through the portal vein and undergo that substantial metabolism prior to reaching the systemic circulation. So if we have shunts, now we're going to get a significant increase in the serum level of those medications, and those have to be considered. You're most likely to have shunts in cirrhosis. So if you just have acute liver failure, you actually may have no difference in the absorption of our oral medications, because we haven't had time for changes to occur yet. So you're going to be most concerned in those patients who go on to have cirrhosis. So that's, you just worry about bioavailability of those oral medications. We do have decreased production of drug-binding proteins, typo, sorry, I knew I'd miss one. Albumin, about 85 percent of our drugs bind to albumin, and about 15 percent bind to alpha-1-acetylglycoprotein, mostly our basic drugs, propranolol, lidocaine, those types of things. But both of those are reduced in liver failure. So if you think about our drugs that we give, it's the free drug that gives us our clinical efficacy and has the ability to go into our tissues. So if you have less binding proteins for that same dose of medication, more is going to get into your tissues in the receptor, and you may have an amplified effect of medications, because only those unbound drugs can enter and leave the tissue compartments. It also may lead to faster clearance of those drugs if they're renally eliminated, because that drug can get into the renal system, if we don't yet have hepatorenal syndrome that we've just learned about. With progression of liver disease, changes in body composition, such as ascites, so extracellular fluids and edema, drugs that are now free drug and hydrophilic, can go into those tissues. And then decreased muscle mass can alter your volume and distribution. So if we think of how drugs are metabolized through the liver, this is the very basic Farrington version. We have phase one and phase two reactions. Phase one reactions are usually making something smaller. So we have oxo-reductive processes. That's our cytochrome P450. That's more effective by liver disease. And if you think about all that shunting we get, then we get hypoxia in the liver, and that kind of dings off our cytochrome P450 system. Cytochrome 2C19 seems to go first. And if we have moderate to severe liver disease, you're going to get decreased activity of all. But that first one to go is 2C19. And with severe liver disease, you'll get decrease in all of the cytochrome systems. Phase two reactions are our conjugating enzymes. So we're adding something to a drug to make it bigger. Both of these have the same purpose, to make something more hydrophilic so it can be eliminated by the kidney. But you still maintain glucuronidation up until the very end. And you have up-regulation of what we call UGT activity in the hepatocytes. And that actually preserves that glucuronidation pathway. So in mild to moderate liver disease, you're probably not going to lose that ability. But when we get to severe or cirrhosis, we're going to lose both. So then we have to think about hepatorenal syndrome, because many of our drugs, even if they're not hepatically eliminated, may be renally eliminated. So then you're going to have to consider altering our intervals in drugs that have renal disease. But we also have to consider we have indirect methods of measuring carotene clearance. If we're using a serum carotene, we may not have as much muscle mass. And so our serum carotene is not going to rise as quickly. And so underproduction of carotene, when you lose that muscle mass, will make what we use to estimate carotene clearance inaccurate. And we will overestimate their renal function. So remember, the liver also produces creatine, which is our substrate for carotene production. So muscle mass and the liver both assist in producing creatine. And that's most likely to occur in cirrhotic patients. So chronic liver disease without significant fibrosis, drug pharmacokinetics are going to be somewhat unchanged and modified only to a small extent. So I'm kind of trying to display some of the myths that we talk about with hepatic failure. My attendings say, oh, we've got elevated liver function tests. I can't give the patient acetaminophen. Well, if you think about acetaminophen, remember, it's metabolized to glucuronide and sulfated. But then it's bound to that glutathione. So remember, that's the one enzyme we said is preserved in early hepatic failure. But patients who are known to have that low glutathione, alcoholics, they upregulate their alcohol dehydrogenase, which also increases that CYP2E1. So they're more likely to make more of that hepatic metabolite that's toxic just because that they have upregulated 2E1. Patients with chronic hepatitis C or non-alcoholic cirrhosis may also have less amount of glutathione. But what has been demonstrated with acetaminophen and liver disease? Most of these are adult studies, but I don't know how some of these got through IRBs. It's kind of interesting. The first one is 20 patients with chronic renal hepatic disease, and they gave them what we consider the maximum dose of Tylenol or acetaminophen, four grams per day versus placebo. They were on that for 13 days, the max dose for 13 days. This is why I'm like, really? You got this through IRB? And then they had crossover. So those who were on placebo were crossed over to drug, and there was no clinically significant changes in the clinical features of what we monitor, our bilirubin, our ALKFOS, bile acids, creatinine, albumin, or prothalbin time. A similar study was done in patients with hepatitis C, which was one of the categories we said might have less glutathione, but three grams per day, so slightly lower dose versus placebo for seven days. And again, no changes in any of our hepatic markers. When alcoholics were evaluated looking at that same max four grams per day for 48 hours, there was no change. But when they looked at them for out to 10 days, alcoholics, remember we said, are the most likely ones to see changes with acetaminophen. There was changes in their indices of liver function. So we do know that the elimination half-life of acetaminophen doubles, or it can increase by 50 to 100, slow by 50 to 100 percent. So if we think of our adult and pediatric patients with various forms of hepatic failure, we should use a normal dose because you have to give enough drug to get effect, but you may prolong that interval knowing that initially. So I might write Q12 initially if I'm having a patient with significant fever or pain, but if at 12 hours or eight hours they're still having issues, I can probably, knowing that Q6 for 13 days was fine, feel more comfortable using that medication. But due to the prolonged half-life, probably that initial order, if you've got an adult-sized patient, would be 650 PO or IV every eight. I'm trying to max at that two gram per day that we've talked about. And then pediatric patients, a normal 15 per kilo dose and maybe starting Q8 initially. But we would avoid it in our teenagers if you had them that were actually chronic alcoholics. I have seen, unfortunately, plenty of those, which is kind of sad. So you say, well, should I use acetaminophen or what about using an NSAID or a non-steroidal anti-inflammatory drug? Remember patients with severe liver disease, especially those with cirrhosis and ascites, have unstable renal hemodynamics. So even with a normal GFR and renal blood flow, renal blood flow is sensitive to any modest reduction in plasma volume. So if you think of how NSAIDs work, the impairment in renal function and any effect that we give effect on vasoconstrictive hormones is normally countermanded by the increased production of vasodilatory renal prostaglandins. But our NSAIDs decrease the ability of the kidney to produce vasodilatory renal prostaglandins. So therefore, they're going to decrease GFR and they're going to worsen our renal blood flow, which may actually worsen or enhance the development of acute renal failure. Those that are going to be most sensitive to the renal effects of NSAIDs are clearly those with ascites and sodium retention where we already have maybe some decreased delivery of fluid to the kidney. And there is evidence that when NSAIDs have been given, there is decreased diuresis after administration of furosemide. So you're giving a drug that's actually you think you're giving it because it's safer than Tylenol, but it's actually more risky to the patient with hepatic dysfunction. And then we have to remember that once we get hepatic dysfunction, we get coagulation disorders. So if you think of platelets, NSAIDs decrease the stickiness of the platelet by changing the production of thromboxane A2. So the NSAIDs actually decrease that. And so you're going to increase the risk of having bleeding. So in conclusion, when just comparing NSAIDs to acetaminophen, when administering PRN pain meds or something for fever control, acetaminophen is much safer than using an NSAID. Naproxen is the only NSAID that we know reduction in metabolism is significant. Ibuprofen, you can give a normal dose. You could probably use Catorlac, but overall, you should always use acetaminophen over an NSAID in a patient to try to preserve their renal function. Opioids, obviously, we try to avoid in renal failure if we're thinking about pain because they can worsen our hepatic encephalopathy. They're going to alter. Now you don't know if it's because I gave them an opioid, which now can actually cross the blood-brain barrier more quickly because, remember, less protein binding, more free drugs, so it gets across the blood-brain barrier more rapidly. And so that's always a concern. But if we choose to use an opioid or we need one because we've had a surgery, we've done a procedure, we need something with more strength, there's two drugs we should just never use in hepatic failure. We probably shouldn't be using them anyway. But remember, codeine is a prodrug. And so if we don't even know, both of these drugs are CYP2D6, which is the one enzyme that could have a low expression of the enzyme, a high expression of the enzyme or medium. And so some people who are completely healthy get no pain relief from codeine or tramadol because they're a low expressor of the enzyme that takes that prodrug to active drug. But when we have liver failure, you may have worse production of the enzyme and actually not even make these prodrugs into active drug and get pain relief. So you probably should just not think of them as an active agent. This is just a short version because we're going to go into sedation kind of infusions in a minute, which is a little bit more important, I think, in the interest of our time. But oxytocodone, you need to decrease the dose by half and extend the interval. Morphine IV, again, the same dose for a clinical effect, but extend interval. But remember, we said with that shunting, you're going to get decreased the ability of that first pass through the liver. So we know that you get a fourfold increase with both morphine and hydromorphone when given orally. So you have to consider that if you're giving an oral dose to cut the dose by a quarter. And then PO or IV morphine, again, where you're going to accumulate the M3 and the N6 metabolites. So a single dose, completely fine. We're giving it for a procedure. We're getting pain relief. But when we're trying to give chronic medications, remember, morphine has active metabolites that can accumulate, especially in hepatorenal syndrome. And the same thing would be true of hydromorphone that has an active hydromorphone 3-glucuronide. These are all really eliminated metabolites that have longer half-lives than morphine itself or hydromorphone. So these are just big picture concepts to remember when you're using these medications. But IV morphine, hydromorphone are going to be completely safe for a single procedure. They're just going to last longer than what you're used to based on metabolism difference. Now remember, fentanyl is about 85% bound to albumin. So we're going to have more free drug, and it's going to cross the blood-brain barrier more readily. So you might have a little bit more CNS effect. It's a high-extraction medication. So clearance is going to be affected by those changes in hepatic blood flow. But pharmacokinetics have been demonstrated to be unaltered in patients with just biopsy-confirmed cirrhosis after just a single dose. But nobody has really done good studies on this drug, looking at it when we give it with a continuous infusion. So when we're using it for regular intermittent dosing or a loading dose prior to initiating an infusion, you want to give the same regular dose that you would use to. But knowing that it's a high-extraction medication and we may not be clearing drug as fast, probably let's say if I normally would start my fentanyl infusion at a mic per kilo per hour, I'm probably going to start that patient at a half a mic per kilo per hour. The advantage of fentanyl, which is probably why it's the preferred opioid infusion for patients in hepatic failure, is it has no active metabolites. So versus morphine and hydromorphone that you have to worry about the accumulation of those active metabolites, that would not be a concern when we're using fentanyl. Rumi fentanyl, at most institutions, is restricted to the OR because of cost. But this is one time I have to say, okay, this may be our best agent. It's hydrolyzed by blood and tissue esterases. So it does not need the liver or the kidney to be eliminated. So no adjustments are needed for hepatic or renal dysfunction. So in a patient with significant hepatorenal syndrome, actually using Rumi fentanyl as a continuous infusion is probably our safest option. But if you're in a large hepatic liver center, that's something to discuss with your pharmacist or pharmacy and therapeutics because this is where cost might benefit your patient because if you stop another infusion and it takes a couple days for things to go away, that might leave them intubated longer and that's a cost benefit here. So although more expensive than fentanyl, it's more predictable clearance make it really the optimal choice for continuous infusion opioids. Benzodiazepines, as we all know, should be avoided for sedation because they have our highest association with delirium. But we do know that if we have to use a benzo for some reason, midazolam has active metabolites that are really eliminated. They actually can accumulate and they actually bind to the receptor differently and can make you hyper excitable. So then it makes you more difficult to sedate that patient. So midazolam should be, it's fine for a single dose for a procedure but should be avoided for long-term use. Lorazepam is diluted in propylene glycol that could accumulate in hepatic renal dysfunction, make the patient more acidotic, but it does have no active metabolites so if you needed to give something intermittently, probably more safe. And diazepam also has active metabolites and it does have some excipients in the product. So obviously any administered orally will have that increased bioavailability due to the decreased first pass. So if you were using, so if I had to give one of these, intranasal would be a preferred versus an oral sedation if I was doing something for a procedure because I'm not going to worry about that first pass. So if you need it for procedures, lorazepam has no active metabolites but probably any of the three for a once dose would be fine for a procedure. For status epilepticus, we would follow the drug of choice as lorazepam, followed by diazepam, and then we would give midazolam either intranasally or IM, but avoiding them for chronic sedation. Liver failure actually has been demonstrated in one, a couple papers not to be affected by liver failure. And there's one paper that looked at using continuous infusion and pripofol in patients with fulminant hepatic failure who had been deteriorating for cerebral edema. So they are at the very end stage of disease. And they did 10 mics per kilo per minute, an adult study here, and advanced until the dose was adequate to control ICP less than 15, and their medium dose was about 50 mics per kilo per minute, which is kind of what we think of as that higher adult dose, but a range of 31 to 89. No systemic complications, hypotension, acid-base abnormalities, or evidence of pripofol infusion syndrome. However, they do not tell us in this case series how many days patients receive pripofol. And remember, pripofol is in a lipid base, and triglycerides have to be eliminated through the liver. So if you choose to use pripofol, we need to make sure we're measuring triglycerides. But this really is a drug that needs probably more close research because it has an advantage there. Pripofol could be attractive also because if you're trying to assess your patient's neurostatus, you could actually stop it. It should have a fairly quick on and off, maybe not quite as quick as we're used to, but pretty close. In this one case report, they were waking patients up daily to check their ICPs. So in a pediatric patient where you might start a small baby at 100, you might start them at that 50 mic per kilo per minute, and advance is tolerated until you get the benefit that you need. And remember, adolescents, I might start them at that adult dose just because we don't know exactly what our target is going to be in this agent. But so far, appears to be safe and may be an attractive option for us. So in conclusion, we can say that acetaminophen is preferable. Oh, dexmedetomidine, I could not find any published data, but based on its metabolism, again, might be a very safe agent for us to use. Again, most of us do not load patients with dexmedetomidine. We wait for it to get to steady state. This might be one place where you might load the patient, infusing it over 10 to 20 minutes to make sure we don't get that bradycardia, only because there may be some slight decrease in its metabolism, which means it's going to take us longer to get to steady state. So you don't want somebody to keep bumping up the drip because we're not sedated. So a bolus dose might be appropriate here to make sure that we get our serum levels where we want them, and then start at our normal dose of 0.2 to 0.4, and titrate every six or so to make sure we're hitting target. If you need to give another loading dose if the sedation wears off, and over that same time period, that's probably safer. And that's just hypothetical me giving you my opinion without good published evidence. Acetaminophen is going to be preferred for mild to moderate pain in patients with hepatic failure. We want to avoid using NSAIDs because they can make our renal function worse. Fentanyl, rimi-fentanyl are preferred opioids for continuous infusion. Piperone may be preferred over morphine for PRN use due to the lack of active metabolites. Prepavol has predictable clearance in hepatic failure, but really seven cases is kind of small. So we just really need more evidence. And you really need to consider the phase of your patient. Are they acute hepatic failure? Are they in cirrhosis? Because in that acute phase, we probably haven't had a chance to see changes yet. Cirrhosis, we're going to see all the changes in first pass. Because you have to think cirrhosis versus non-cirrhosis. And I think I talked fast enough, and I have one minute to spare.

pediatric sedation

liver failure pharmacokinetics

Child-Pugh classification

acetaminophen vs NSAIDs

fentanyl for pain management

propofol and dexmedetomidine