Okay, I'm sure you guys are super excited to talk about hepatic failure and organ transplantation. So my three talks this morning, I would say on the boards, there are probably somewhere under 10 questions total on the three. However, these are super fundamental to what we do. So as always, focus on what's important, which is your patients. These boards will pass. This too shall get past you. It's fine. Don't worry about that. We will highlight in these slides some of the things that I mean, universally, I think all the faculty would say, this is what you're going to get asked, or in some way how they're going to ask you. Just a couple disclosures, minor ones, the key points to take away. So on the ABP specs, the things that they really want you to know, you need to be able to interpret the pathophysiologic parameters of liver failure. Most of us were trained to do this as house staff residents and things. In the context of what we have, the stems of the question make it tricky. And that's what you have to recognize that they're asking you. Because Scott's not here anymore, but Scott Weiss has a benefit that every question is about sepsis. Is it really? That's what you have to figure out. Recognize the distal organ association of liver failure. There's one that's really important that will get asked about. And then identify the most important aspects of peritransplant management. And again, there's one that you really will get asked about. So the first thing to start with is the epidemiology of pediatric acute liver failure. And this is not really any surprise to all of you. What I'm showing you is a very simplistic table here about the causes of pediatric liver failure, and then the age of the patient. Birth to three months, three months to three years, and then up to teenage years. As everyone probably understands, there's a bimodal distribution of liver failure. This has really not changed in as long as we've studied acute liver failure. In the newborn period, most of it is indeterminate or metabolic disease or gestational alloimmune liver disease from the mom. And then there's a lull in the kind of toddler age group. And you probably will not get asked this about the etiology of liver failure unless it's one of those distal organ associations. And then as you get into school age years and teenage years, it's almost always going to be Tylenol poisoning that's the issue. But just as you know, as you're dealing with it at the bedside, there's a bimodal distribution. And the graphs to the right just show the kind of age relation of this. And so the take home is that incidents and cause vary by age. But most of the time, PALF is an indeterminate or the cause of PALF is indeterminate. The three-week outcome, and this is important too because in these questions, what will be drawn out is the time course of disease. How soon after the kid presented are they showing up with signs of liver dysfunction? How soon or how far along the course? So more than half have spontaneous recovery. About one in 10 die without liver transplant and about a third require liver transplant. So the presentation and recognition is going to be your key when you're reading these stems. The nonspecific but most important sign is hepatic encephalopathy. This will get asked in different ways. So in the newborn period, pay attention to buzzwords like irritability, lethargy, difficulty feeding. Of course, they will mix in things that will make you think of sepsis. Of course, they will mix in things that make you think of cardiac failure. But you have to be keyed into the fact that this irritability or lethargy in a newborn could be liver failure. And so hypoglycemia is the other tag on to this because that is kind of a hallmark presentation that can be tested on pretty easily. The laboratory findings in the setting of above, as everyone kind of knows, your INR is going to be high. Your PT is going to be high, but not corrected by vitamin K, but with hepatic encephalopathy. So just pay attention to that downstream signal. The nonspecific abnormalities that you should be recognizing are the elevation in transaminases. Bilirubin elevation is almost thrown in there all the time as a red herring. So try not to be too focused on that. And then hyperammonemia. A workup other than the basic hepatology labs and metabolic panels would include liver ultrasound and potentially biopsy. But very rarely would that be your choice of an answer, the next best step. Additional workup includes acetaminophen levels, viral titers and things, and your inborn errors of metabolism. And of course, a previously healthy eight-year-old is not going to be the answer, right? So your take-home complex presentation, which can be confounded by the presence or absence of other illnesses. And this is where it'll get you, sepsis or liver failure. It looks the same, but most of the time, these questions for the septic patient aren't going to involve a predominant focus on irritability or predominant focus on lethargy. They're going to focus on the hemodynamic instability of that patient. In the synthetic function, abnormality of the duration matters. So outside of that first two days, that persistent dysfunction, that failure to kind of slow down in the dysfunction will be a key for you to say, this is some primary liver disease versus just shock liver. So the extrahepatic associations of acute liver failure, there are many. The main one, as we talked about and get into a little bit more, is hepatoencephalopathy. But there are hepatorenal effects that we'll talk about also. And I think one of the things that we know clinically, and this is where it's important to just pay attention more and more, as yesterday's lectures kind of keyed into some of the things that you will see in reality, are the associations with bacterial infection and endotoxin, how they affect your gut motility, and other things. So vital organ function energetics can be affected in isolation or together in liver failure. And as Dr. Zimmerman pointed out, mitochondrial function and bioenergetics are dramatically affected in liver failure. We spend a lot of time in these perioperative patients or these transplant patients thinking about, well, what's happening in the pulmonary axis? What's happening with pulmonary vascular resistance? Is this portosystemic hypertension? Is this hepato-pulmonary syndrome? Those are not really going to be tested on. But those are the things that happen in reality that you have to be thinking about, right? So in this situation, just be thinking primarily about the brain and the kidney as they're related to liver failure. So hepatic encephalopathy is worth a little bit of a dive in this brief segment. So alterations in cerebral function that result from liver failure, really not well understood. Most of the time outside of the newborn period where you would have a kid who is lethargic or irritable, mild cognition deficits, psychomotor slowing, impaired visual spatial skills. So one of the best things you can do as a proper intensivist is a real neuro exam on everyone. Those classes that all of us hated to take in medical school, like histology and dermatology, they're so important now. So if you can teach yourself how to do a proper neurologic exam, hepatic encephalopathy is something that's a really great thing to track along the way of your clinical exam. But these stages of encephalopathy, birth to toddler year, these are things that you really should be aware of. And of course, no one's going to miss the comatose kid, hopefully. But it is the early stage that is really important to pay attention to. So why does this happen? You can find a bunch of different papers on the pathophysiology of hepatic encephalopathy, New England Journal papers, Blue Journal papers, all the other things. But as I talk about on rounds with the trainees and other people, when we ask about hyperammonemia and why that's a bad thing, people will say astrocyte swelling, neuronal degradation, you know, brain mitochondrial problems. But the truth is, if you clean your toilet with it, it should not be on your brain, right? So hyperammonemia is bad for you. And until we have a real isolated mechanism, no one's going to ask you these questions. The truth is, though, it's that rate of rise that we have to pay attention to. Hepatorenal syndrome, near and dear to my heart. We actually don't have great medicines in the US to deal with this. But if you need to look up a great resource for understanding hepatorenal syndrome, our good friend Akash Deep, who's at King's College in London, has a bunch of different papers on this. And it's really worth reading about. So what happens is you have renal vasoconstriction that leads to decreased GFR, functional injury by elevated creatinine, and then it's really an aberrancy of sodium and water loss. So you have concurrent liver failure and AKI, but one leads to the other. So type 1 or type 2, this is kind of in the weeds. For you to understand is really understand the time course of what came first, chicken or egg. And in this era of really imprecise diagnostics for both liver failure and kidney injury, it's really sometimes difficult to tell. But just know that this is one of those things that we talk about all the time. So what are you going to do? As many people know, our management of acute liver failure is early recognition. So that stage 1, stage 2 encephalopathy, that metabolically abnormal kid is prophylactic and supportive. You want to maintain normal bulimia, treat your metabolic. So impair ammonia detoxification, promote that idea of waste removal agents. Your nutritional interventions is to augment your protein, prevent hypoglycemia, and then we'll talk about the other things, rifaximin and lactulose. Octreotide and vasopressin are also used. So lactulose is a first-line laxative effect. It reduces your colonic pH and interferes with how the gut will take up glutamine and promotes lactose-forming bacteria in the intestine and you essentially get rid of your ammonia that way. And acetylcysteine if you have tylenol toxicity. Neomycin also inhibits glutamine uptake and reduces ammonia production in the gut. So other than waste, it actually reduces formation. Rifaximin, I don't know how many people have used rifaximin in this room, but it is minimally absorbed, very few side effects. It is not universally available. So even in Chicago where we have seven high-level PICUs, it's not available in all the PICUs in the city of Chicago. So these are one of those things. On call, when you're in your shop, you want to know where the closest burn center is. You want to know where the closest hyperbaric chamber is. You want to know, do we have botulinum toxin in the house? You want to know, do we have rifaximin in the house? Those are the things that help your survival as an early career attending. So you want to monitor for seizures. Really be careful with the use of benzodiazepines, hypothermia. ICP monitoring. A lot of data, and if you go through PCCM, there seems to be an article on ICP monitoring and hepatic encephalopathy. This should never be one of those that you're getting into an arm wrestling match with your neurosurgeon. It feels like that at the bedside at times, but it shouldn't be that. It should be one of those, does it help your management? Current state, the data actually doesn't really show that there's a consensus impacting outcome. You have to balance the risk and the benefit of it. One of the things that, again, is so beneficial for working in the pediatric ICU, we're partnered with very smart people, and those smart people include pharmacists and nutritionists. So pay attention to the nutritionists when they're talking to you about protein and nutrition in these patients. This could be something that is testable, because you could do math on it, but you want to make sure you supplement your protein daily. The rise of our extracorporeal liver support therapies, so MARS is not universally available. However, it is working to be that way. It's inline albumin-based dialysis after CRT. Prometheus is another system, and then there's single-pass albumin dialysis, which if you have a good nephrology partnership, you can pull it off, or if you know how to do it, you can pull it off. This works. Metabolic control is paramount. Most interventions are about supporting and detoxification, the work of the liver. So peritransplant management. I think one of these, these are not, the indications for transplant and what are the grades of liver failure associated with being on the PELD list and the referrals are not testable materials, but again, this gets back to understanding what your resources are. If you're at a transplant place, you hardly ever think about it. If you're not, one of the biggest things you do as a clinician is understand, what are my limits? I don't want to go up against the limit and have to transfer a kid. You need to be able to think about it ahead of time. So immediate contact with the liver transplant center for anybody, any child who's got liver failure is worth it. Children with chronic liver disease or episodes of spontaneous bacterial peritonitis, uncorrecting coagulopathy, so this could be also something that shows up. You have a kid who has chronic liver disease who has a full abdomen and a fever, be wary of spontaneous bacterial peritonitis being something that's testable. And then metabolic crises, and then we have our kids who have biliary atresia, post-hepatoportoenterostomy. And these are the level of bilirubin post-procedure that is just kind of a literature grade tiering so these transplant centers can look at it. In the peritransplant scenario, the situation that you are going to get asked about is not the one that we navigate the most frequently. It's two in the morning, can I use fluid, should I give diuretic, should I call the transplant team? That is not the issue. What shows up is HAT, or hepatic arterial thrombus. So just be thinking about that in the perioperative phase, specifically in the first day or two of graft failure, and you have a kid who doesn't look that great, and you're thinking they're going to throw in a bunch of random stuff about sepsis, and then what they're really wanting you to identify is hepatic arterial thrombus. Not, oh, can I use diuretics, oh, the vascular anastomosis is real tight, I don't want you to do that. Independent thought, not independent action. That's not the answer. But just be thoughtful about the peritransplant management is hepatic arterial thrombus. So prophylaxis and the other things to be paying attention to are hepatic necrosis, biliary leak, which would be obvious at the bedside. Medicine management, the anticoagulation agent and alternatives, these are the things that are going to help you in your everyday. Post-transplant management, I think some of the speakers yesterday did talk really nicely about the immune axis and what's really testable material and what you have to know. Steroids, as much as we kind of make dermatology ICU jokes, are a mainstay of what are done in acute issues with post-transplant management. So it's good to know the mechanism. Rogers and Dr. Zimmerman's book and other books have great pictures. Spend the time looking at the pictures to understand, okay, the mechanism of steroids and how you translocate the glucocorticoid receptor to the nucleus. You influence gene transcription. You impair neutrophil and macrophage function. Calcineurin inhibitors, I think there was a question yesterday about adjusting, you know, one of your calcineurin or the calcineurin inhibitor. So again, mechanistics are hard to understand when you read them, but if you spend time looking at the figures and understand what triggers what, this will really help you, okay? And that's worth doing. Those are easy things to test and easy things to answer correctly. And again, so the early problems, peritransplant, they'll make it look like sepsis, but the earliest trouble is going to be thrombus, arterial thrombus. And then the later management include biliary tree problems, strictures, and sepsis, okay? So pay attention to your stem, it'll get you through. So the pearls for this carry a high index of suspicion. Adjust medications for liver metabolism, hepatic encephalopathy slash hyperammonemia are going to be your triggers. Normal metabolic parameters as a bedside clinician are going to be the things that you target because ultimately we don't have liver A's yet. You have to do what you can do, which is difficult in a lot of situations to control the metabolics and control the temperature. But supportive care for secondary and organ dysfunction to be thinking about, are there places if we can't do it who can use extracorporeal support, kidney support therapies to help this patient, okay? And I will be back soon, thanks.

hepatic failure

organ transplantation

hepatic encephalopathy

Tylenol poisoning

extracorporeal liver support