Thank you for the opportunity to speak with this amazing group of colleagues. I have no conflicts of interest. I will be discussing medications for which we're using them for a non-FDA approved indication, so I need to just say that up front. We're going to talk about the diagnosis of hepatic encephalopathy, kind of understand the different levels of encephalopathy and what scoring systems we might be using, the controversies about each of the treatments, and then talk about nutrition support as part of that whole pattern. So this is the types of liver failure we're going to see, which each of our previous speakers have alluded to. You can have hyperacute liver failure, and this is the one that's most likely to give us cerebral edema and hepatic encephalopathy. So you can see, depending on which stage of liver failure you're in, acute or subacute, our risk of having hepatic encephalopathy will vary, and so this scoring system is out there, and it's kind of important to know where you are in your armamentarium. This is just a different pictorial of what our previous speakers have spoken about, but you can see, if you take all comers with acute liver failure, in about 50% of the time, we don't know what the cause of the liver failure is. About 12% overall is acetaminophen and 10% metabolic, but you can see there's a long list there, as each of our other speakers have spoken of. This is critically important of trying to identify the cause, because the underlying treatment of hepatic encephalopathy is treating the underlying liver disease and what caused it. So if you can identify the cause and treat that cause, that also will treat your hepatic encephalopathy. You can see in the first 90 days, about 35% are unknown, 20% are the viral hepatitis, about 15% are drug-induced but non-acetaminophen. When we get to 91 to three years of age, a higher percent are unknown, and this is where our inborn errors of metabolism are pertinent. And then after age four, we're more likely to have about 40% unknown and a higher percent of those being acetaminophen overdose or misadventures, depending. Fluid management is really key when we're talking about treatment of hepatic encephalopathy, because we know that over-hydration can actually lead to pulmonary or peripheral edema, under-hydration can lead to renal dysfunction, and making our hepatorenal syndrome actually worse. And that's going to actually contribute to our encephalopathy and possible hypotension. So having a total fluid order on your patient is critically important, such that as we add things and subtract things, the nurses are keeping that total fluid slightly below 90% of maintenance. Nutrition is important because as all of our previous speakers have alluded to, these patients can get very, they're really sick, and so if we don't give them nutrition support, so a lot of people have said, you know, we don't want to give them nutrition because that gives them more ammonia as they break down nutrition, but that's the worst thing we can do. So we need to maintain adequate nutrition to avoid that catabolic state. There's really little evidence to support enteral formulas designed for hepatic disease. Those that are enriched with branched-chain amino acids, I mean, logically, we think the liver could break them down more readily, but there's no well-designed clinical trials in pediatric hepatic liver failure that shows that they make a difference, and they're quite expensive. Obviously, if the gut works, we want to use that, but if enteral intake is not possible, obviously, TPN would be initiated, starting with about a gram per kilo of protein, and then we're going to titrate based on what our ammonia is and how we're doing, and don't forget that all of our trace elements are eliminated through the biliary tree, and so those have to be adjusted in acute liver failure, and that's just, this is just the recommendations from Aspen for how to dose with liver failure. Once we've decided that we're worried about hepatic encephalopathy, we have to stage that patient, and you can see here that there's, it goes anywhere from stage 0 to 5, or sorry, 0 to 4, and there's one scoring system for children less than 3 that we can see here on the slide, and then this is the one for children 3 to 18, and this is important to kind of, each time you have your patient, kind of going through that and knowing whether you're at stage 0 to 2 or 3 or 4, because how aggressive our treatment is going to be depends on what level of encephalopathy that they have. So just some other general measures, we're going to treat these patients almost like we do our head trauma patients, because we're worried about, once they have hepatic encephalopathy, we're worried about increased ICP. You want to minimize the stimulation in the room, you want it to be as quiet as possible, so those parents who like to listen to the TV as loud as possible while you want them to sleep, you need to send them out to the lounge, so really minimizing stimulation as much as possible has been shown to be beneficial, elevating the head of the bed 30 degrees, so not forgetting these basic 101 things, and then critically looking for other things that could explain our altered mental status that might be making you think you've got hepatic encephalopathy. Treat suspected sepsis, looking for any abnormal electrolyte disturbances, treating hypoglycemia, and then remove or reduce sedative medications if possible, because you want to make sure that what you're seeing is not the fact that your sedatives are not being dosed appropriately before a hepatic failure, and you're starting to see accumulation of active metabolites that's just leading to a worsening in your clinical neurologic picture. So really the treatment of choice that has been a standby forever, obviously it's hyperammonemia, which is our cause of our encephalopathy, is lactulose, and this is where knowing what stage you are is important, because obviously we're going to start at about a half a mil per kilo per dose, dropping at about 30 initially, and if you have levels one through two, you might just start at two to three times a day, and looking for two to three loose stools per day, but if I'm stage three or four, you're probably going to initiate a dose every two hours to get a more rapid evacuation of stool, and then back off once you get your ammonia to come down. So again, the treatment dose is the same, but how aggressive we are will vary based on the level of encephalopathy that we're looking at. Obviously if you have an inadequate response to lactulose, there is some data for bowel decontamination with rifaximin. Now remember, rifaximin should not be ever used up front as your first treatment of choice, because it may take two to three days before you really see an effect on the ammonia. Lactulose is going to give us the quickest bang for our buck, so that's why we always use it first. So the adult, there's a lot more adult data for rifaximin for hepatic encephalopathy, and the dose they use is the same as the FDA-approved dose for C. diff. So if you're looking to use rifaximin in children, there's no well-designed clinical trials. You would look up and you could say, well, the dose for C. diff is 15 to 30 per kilo per day, because there's indications for rifaximin that you dose as low as 10. You wouldn't want to just pick a dose. You want to say, OK, the C. diff dose worked in adults. We're going to use that same dose in children. So 15 to 30 per kilo per day, stopping at 400 three times a day. But you need to also recognize that there is some data in adults that 400 three times a day is equivalent to 550 twice daily. And many hospitals only carry one size. At my hospital, we therapeutic interchange. Anybody who comes in on 400 TID gets changed to 550 BID, because we only carry the 550 size. So knowing what goes on at your institution can be kind of helpful. There is a liquid that can be compounded. There's some stability data for about 60-day stability, but it's really dilute. It's really made for neonates to decontaminate the gut and short bowel syndrome. And so it's 20 milligrams per mil. So if you've got a teenage kid, probably just crushing that tablet at the bedside, putting in about 10 cc's of water is going to be the best thing to do, because that's not going to give them a lot of volume down the NG tube. But in a small child, we can compound that liquid and dose appropriately there. There is a nice adult study that looked at once we control that hepatic encephalopathy, how can we prevent it from coming back? And they actually looked at nitrous oxide compared to rifaximin and preventing the recurrence of hepatic encephalopathy. And this was a prospective, randomized, double-blind controlled study. They had 60 patients. And as you can remember, I said 400 TID was equal to 550 BID. So that's the dose they used in this study was 550 BID of rifaximin versus nitrous oxide 500 POBID. And they did this trial for 24 weeks. So the patient had already been treated for their hepatic encephalopathy with lactulose. It had gone away. They're still on their baseline lactulose. And these medications were added to see if we could prevent recurrence of hepatic encephalopathy. And the dose here, so using my same analogy as before, this is the dose they used and what was its indication. And the nitrous oxide dose was the same as what you would give an adult for a cryptosporidiasis or Giardia. So if you're going to go back and look at our pediatric dose, we need to look for those same indications to pick the dose that we're going to use. And in this study, though, you can see that we saw that nitrous oxide showed a statistically significant improvement in the test score and mental status in the adult patients in this trial. And remember, the trial was 24 weeks. So the nitrous oxide provided 136 days, or 80% of that 24 weeks, they were without hepatic encephalopathy versus 40% with rifaximin. So it looks like a little bit more efficacious if you're having a patient who keeps getting recurrences on lactulose, that it might be a reasonable thing to add to prevent the hepatic encephalopathy from coming back. You can see nitrous oxide also showed a statistically significant decrease in the biomarkers that our previous colleagues have talked about, ammonia, tonic necrosis factor alpha, and octafane. So again, lactulose still is our backbone. If we need to bring down the ammonia quicker, or if they're failing lactulose, we can add some rifaximin in that acute stage. But then perhaps nitrous oxide might be more efficacious chronically in patients who keep recurring on lactulose to prevent them from having a recurrence. Because at 80% of the 24 weeks, we did not have a recurrence. So just going back and saying, was the Giardia dose of nitrous oxide, you can see it's dose based on the age of the patient. And there is a commercially available suspension, and there are tablets that can be crushed. So applying the adult data to children can be helpful. We've all heard about continuous renal replacement therapy, but this can be critically important to children who are failing lactulose therapy alone. Removal of ammonia is efficient with CVVH, and it has been shown to manage our fluid balance as well as reduce our ammonia. And in one large pediatric trial looking at CVVH alone, reduction of ammonia within 48 hours of renal replacement therapy initiation was associated with a significant improvement in survival. So we would say that your inability to reduce your ammonia by 48 hours really confers poor prognosis and acute liver failure. So CRRT should be considered at an early stage to prevent further deterioration in our patients. And on average, in that one large clinical pediatric trial, for every 10% decrease in ammonia from baseline at 48 hours, the likelihood of survival increased by 50%. So start early with CVVH in patients who have an elevated ammonia with that level three or four, or if you're having difficulty bringing down ammonia with our standard medical therapy. I mean, personally, I would start CVVH before I would start Rifaximin, because it's going to be much more efficient and effective in reducing our ammonia. We do also need to, even though we're talking about hepatic encephalopathy, and we want to treat that and bring the ammonia down, you also have to acknowledge that the development of hepatic encephalopathy is correlated with the development of cerebral edema. It occurs in up to 80% of those with advanced stages three or four. So luckily we all know how to treat head trauma, so treatment of hepatic encephalopathy is going to be similar. So detection of that cerebral injury in the early stages is difficult, because non-invasive monitoring with clinical assessment or radiologic studies really lacks sensitivity, as our previous speakers have told us. And so you really have to think about it in those patients with worsening mental status, severe headache and vomiting, coma, hypertension with bradycardia or tachycardia or papilledema, those same things we look at in head trauma patients with. As alluded to earlier, like how do we monitor, and it was discussed so nicely before, I'm just giving this one caveat because it's already been reviewed, but putting in an ICP monitor remains controversial because of the complications of the procedure. And there's really a lack of evidence that actually putting in that monitor improves survival, but the risk of bleeding is high with the placement of an ICP monitor due to existing coagulopathy that hasn't been nicely reviewed for us, and the actually risk of bleeding can be as high as 10 to 20% placing a monitor in a patient with hepatic encephalopathy. So using our clinical signs and symptoms are probably better than putting in a BOLT or a Ventric as we've already discussed. There are no well-designed clinical trials comparing mannitol to hypertonic saline for the treatment of signs and symptoms of cerebral edema and hepatic encephalopathy, but we're going to consider either of those in patients with stage 3 or 4 coma, those who require mechanical ventilation, EEG with slowing, or increased ammonia, or if we do have a CAT scan that shows features of edema. And we're going to use the same dose that we would use in head trauma, half to a gram per kilo. Remember that may give you a brisk diuresis, therefore you really have to monitor our hydration kind of closely. So hypertonic saline may be preferred here because we know the patients do have hyponatremia with hepatic failure, and you could either use a continuous infusion to try to maintain serum sodium between 145 to 155, or you can use either 3% or 23.5% boluses if they have signs and symptoms of herniation, just as you would in a head trauma patient. So our treatment of cerebral edema and hepatic failure is no different. There are some treatments with conflicting data or very small pilot trials in pediatric patients, whereas we just reviewed plasmapheresis and plasma exchange can be very beneficial in improving our coagulation profile. It doesn't improve neurologic outcomes, so all those nice things that we just learned that it does is awesome, but if you have hepatic encephalopathy it has not been shown to really alter that level of hepatic encephalopathy. So it's useful for all. There are other types of liver failure, and it's not that we wouldn't use it, but you wouldn't initiate it solely because you had hepatic encephalopathy. There is the molecular absorbent recirculating system, or MARS, and it will improve your biochemical profile, such as ammonia, bilirubin, carotene, but as we also learned, most places don't have access to MARS, but it is one other thing that can bring down ammonia. The use of branched-chain amino acid-enriched nutritional formulas as mostly adult data, again, have not been shown to improve hepatic encephalopathy, and they are expensive. So again, people think you should use them, but there's no clinical evidence that they improve your encephalopathy. And then there are metabolic ammonia scavengers. There's Lola. It has been studied in adults, but there is not a pediatric clinical trial on using Lola that has been shown to be beneficial. If you think about, we're trying to decontaminate the bowel to prevent the production of ammonia, so prebiotics and probiotics, but there's so many different ones on the market that no one clinical trial has shown that one product is beneficial in decreasing the production of ammonia by altering our gut flora. And we know that rifaximin, nidazoxide, and lactulose work, but neomycin has failed in clinical trials, even though we use it in short gut syndrome to kind of decontaminate the bowel. It's not been shown to be helpful in hepatic encephalopathy, nor has metronidazole, and the concern with chronic metronidazole use is the adverse effects and the neuropathy. So again, not efficacious. Flumazenil has been demonstrated, and if you give a dose of flumazenil to alter the hepatic encephalopathy, the patients become more alert, but it's not something that you could use chronically. So if you're trying to discern, is this a sedative effect? Is something else going on with my patient? Maybe a dose of flumazenil to see if you get a change in their mental status, but again, no clinical trial has shown that we should be using that on a regular basis. We talked about lactulose. Can you say, well, what other laxatives? Why can't I use any of them? Most other laxatives that have been studied have failed to be efficacious for hepatic encephalopathy. There are some ongoing clinical trials now with adding MiraLax to the lactulose, which have showed additive benefit. So if you're thinking about that patient that you've gotten their ammonia down and you're having difficulty having them take the lactulose, I don't know if you've ever tasted it. It really is not very palatable. If their ammonia is already down, initiating an aggressive regimen with MiraLax might be reasonable to see if you could also maintain that ammonia level down, but I would only recommend that in a patient that we really couldn't get them to take their lactulose because now that they're alert and oriented, they're spitting it out. So that might be a reasonable approach since there are some ongoing adult trials looking at the additive effect of MiraLax on to lactulose. And then albumin could be helpful, as we already learned, but not something that we would use routinely or chronically. So in conclusion, if a treatable cause of hepatic failure is identified, initiate treatment. That is going to be the best thing we can do to prevent or treat hepatic encephalopathy. Clinical fluid orders to prevent fluid overload are critical. Renal replacement therapy for stage three and four, and start early. Lactulose to reduce ammonia and maintaining adequate nutrition. And CVBH also allows us to give that patient adequate nutrition, so if they do qualify for a transplant, they're in much better clinical condition to survive that transplant. And then standard treatments for clinical evidence of increased ICP, no different than what we would do for those patients who have had trauma. Thank you.

hepatic encephalopathy

diagnosis

treatment

liver failure

ammonia levels