Hello, and welcome to the Pediatric Multiprofessional Critical Care Review course. The topic that was allocated to me is Hepatic Failure and Organ Transplantation. I'll start by thanking Dr. Ravithi Agarajan and SCCM staff partners for the invitation. As always, I begin these talks by taking you through the content that is expected. This content outlined for subspecialty exams can be found at abp.org. So what they expect you to know is pathophysiology of hepatic encephalopathy to recognize the cardiopulmonary interactions with the liver, association of hepatic and renal failure. We'll discuss this briefly. Common causes of chronic hepatic failure, recognize hypoglycemia and coagulopathy as a complication of hepatic failure. And the clinical and laboratory manifestations of hepatic failure, physical findings of acute and chronic hepatic dysfunction, and lastly, laboratory findings associated with hepatic dysfunction and the hepatic manifestations of metabolic disorders. Continuing on, they expect you to know the clinical course of fulminant hepatic failure, the clinical course of chronic liver failure, understanding the clinical course after liver transplantation, the clinical manifestations of hepatic encephalopathy, principles and treatment of fulminant hepatic failure, and the treatment of a patient with ischemia-induced hepatic insufficiency. I won't be able to cover that. And planned treatment for patients with ascites. I also won't be able to cover this part. And in the end, recognize the indications for liver transplantation, understand the role of liver support devices, recognize common non-infectious complications of liver transplantation So if you were to talk about acute liver failure, it's an uncommon condition. And the average incidence is about 5.5 to 6.2 cases per million population per year in the developed world. So that translates approximately 2,000 cases per year in the United States alone. Now the frequency in children is unknown. But if you were to look at the liver transplant data, what it does tell you is that pediatric acute liver failure is about 10% to 15% of US pediatric liver transplants annually. One of the largest studies that was done on pediatric acute liver failure is a prospective multicenter case study, which collected demographic, clinical laboratory, and short-term outcome data on children from birth to 18 years. And the criteria that they used to diagnose pediatric acute liver failure meant that children had to have no evidence of chronic liver disease. There's biochemical evidence that is present for acute liver injury. And then there's hepatic-based coagulopathy targets. For example, PT more than 15 seconds or INR more than 1.5, which is not corrected by vitamin K in the presence of hepatic encephalopathy, or PT more than 20 and INR more than 2, regardless of the presence or absence of clinical hepatic encephalopathy. In addition to nonspecific symptoms that was present in children with acute liver failure, 53% of the patients had encephalopathy on admission. An additional 15% of patients developed encephalopathy within the next seven days. 13% had a grade 3 or 4. And encephalopathy was less common in younger children, specifically less than three years of age. Blisters were present in 7%. Ascites, due to the portal hypertension, which leads to vasodilatation, decreased effective arterial blood volume, was present in about 22% patients. Hyperglycemia, largely due to their inability to synthesize and store glycogen. Failure of glucose synthesis, hyperinsulinemia, increased glucose utilization was also noted in this study. Other complications included bleeding and sepsis. So in this study, what they noticed is that the etiologies of acute liver failure in children differ from those that are seen in adults, with children having more indeterminate cases and fewer estaminophen-induced liver failure. Because as you can see in the slide, that indeterminate cases were almost half of all infants and children. There was an association between etiology and gender with the percentage of females significantly higher in the acetaminophen group as compared with the other non-acetaminophen groups in general. Children under the age of three years of age accounted for almost 40% of patients in the indeterminate group. This slide shows the data slightly differently. As you can see, it's sort of a U-shaped curve when you plot frequency with age, with higher number of cases being seen in the less than three years old age group. And then you see an uptick more so in the teenage years. What was also interesting about this was the authors compared the acute liver failure that is caused by acetaminophen and those of the indeterminate cause. And what they see is that it appears to occur more commonly during the cooler months. But this was not statistically significant. I had reached out to Dr. Squires, who was the lead author on the study that we have just discussed. And now they are in, when you combine the phase one and phase two, they are up to almost 1,000 patients. This slide gives you an idea about the 986 patients that have been enrolled. This is until about a year ago. And as you can see, in less than three months of age, the top three are indeterminate, metabolic and viral hepatitis. There is some GALT that is also present. When you look at three months to three years of age, then the top two are indeterminate and metabolic, which is present. Then when you look at older children, you start seeing that indeterminate still holds its ground. But then you start seeing acetaminophen ingestion, autoimmune, and some metabolic, which is also present. The workup of a patient with PALF is listed here. What tests need to be done, including an acetaminophen levels, HSV, HLH workup, ANASMA, Wilson's disease serum, seroloplasmin, the glucose-lactate pyruvate, ammonia, and creatine kinase to screen for mitochondrial hepatopathies. One thing we did want to mention is that lactic acidosis and an elevated molar ratio of lactate to pyruvate, that is more than 25, are common in all causes of PALF. So these tests tend to be not specific for a mitochondrial etiology, but may point you in that direction. And finally, liver biopsy and tests for GALD. So this is what we had talked about, the lactate-pyruvate ratio in the diagnosis and outcomes of pediatric acute liver failure. So the hypothesis here is that an elevated serum lactate more than 2.5 in combination with an elevated lactate-pyruvate molar ratio more than 25 would identify patients with primary mitochondrial causes of PALF. This study was only 110 patients, and as you can see, this graph looks at the lactate-pyruvate molar ratio and compares it to the final diagnosis. In this case, if you look at the mitochondrial column, you see only 25% of the patients had more than 25 ratio. But of course, there were only eight participants in this group. But when you look at the other diagnosis and the indeterminate, you see almost 40% to 50% of patients had an elevated LP molar ratio. The authors next examined the LP molar ratio as a function of serum lactate or pyruvate. And what they noticed is that lactate and the LP molar ratio were correlated in all three diagnostic groups, with the strongest correlation being in the mitochondrial group, the p-value of 0.015 followed by other diagnosis. Based on this, you could make the argument that maybe some of these indeterminate patients do have mitochondrial dysfunction, but rather than that, I think it's more likely that there is some secondary mitochondrial dysfunction that is present in large numbers in patients with pediatric acute liver failure, which seems to be driving this process. In acute liver failure, almost all the organs of the body get affected. For example, the brain, which we will discuss in the next few slides, can develop cerebral edema, cerebral inflammation, impaired cognition. The kidneys, on the other hand, can demonstrate decreased GFR, increased plasma renin activity, increased urinary sodium retention, along with hypertension and decrease in systemic vascular resistance. The liver can have decreased bile acid production, which we will discuss in the cartoon right next to it here. There is increased ammonia production, glutamine, methionine, increased cytokine load. Along with this, there's bacterial overgrowth, which decreases small bowel motility and increases mucosal permeability. Bile acids play a role here also. So normally, we never thought that the GI microenvironment plays such a huge role in the pathogenesis of vatican cephalopathy, and in healthy individuals, you have the normal level of bile salts that are metabolized from this cholesterol metabolism. And then the 7-alpha-dehydroxylating bacteria, they thrive from the energy that is derived from the normal levels of primary bile acids, leading to a normal ratio between the primary and the secondary bile acids. But in contrast, what happens is when you have cirrhosis, the inflammation tends to shift the cholesterol metabolism to the acidic pathway, as it is called, and you have more of these secondary bile acids that are produced, thereby altering the ratio between the primary and the secondary bile acids. And what that does is leads to mucosal permeability, leading to a whole new set of complications that occur in acute liver failure. This cartoon illustrates all the factors that play a role in the pathogenesis of hepatic encephalopathy. This is from a GUT paper. And as you can see, it starts off with the protein excess that is sometimes given, infections that are present, sedatives, diuretics, hyponatremia, acidosis, GI bleeding, and trauma. And the ones that tend to are sort of more relevant for the hepatic encephalopathy are ammonia, benzodiazepines, low sodium, and inflammatory cytokines, leading to an astrocyte swelling, oxidative stress, and hepatic encephalopathy. Although we have listed some of the precipitating factors that play a role or contribute to hepatic encephalopathy, the precise mechanisms for how hepatic encephalopathy develops are still not completely understood. What we do know is that there is mild cognitive impairment, there's attention deficits, there's psychomotor slowing and impaired visual motor and bimanual coordination. And how do you assess the hepatic encephalopathy in young children? These grades are listed here. Grade one and two is just inconsolable crying, sleep reversal, along with unreliable or normal reflexes that may be present. And the neurological signs are generally untestable in the early grade. In the mid, you can have some stupor, somnolence, while in the late or grade four encephalopathy in younger children, they might be comatose with arousal only to painful stimulus. Reflexes generally tend to be absent, and some neurological signs that you might see in this group are the decerebrate or the decorticate posture that is present. Another grading system that is often followed for encephalopathy is the West Haven criteria in which grade zero is no abnormality detected. And as the patients tend to get worse, they increase on the scale. And as a result, this translates into higher mortality. So if you see overactivity, unrest, delusions, repetitive picking motions, movements, and disorientation with respect to place, they generally become evident in grade three. That's where you'll find most of these patients. Impairment of consciousness characterizes progression of grade three to grade four, which results in coma. And patients are generally incapable of three features of the memory, registration, retention, and recall, which is markedly reduced in these patients. In grade four, the patients often lose the usual chemical control of breathing, leading to respiratory alkalosis, extensor posturing, suggesting structural brain injury. And this generally happens in grade four, maybe completely reversible if the ammonia levels are corrected. Let's briefly discuss the role of ammonia. Colonic bacteria and mucosal enzymes, they break down the digestive protein, releasing ammonia from the gut. Ammonia then enters the portal circulation of the liver and is converted into urea through the urea cycle defect. In cases of hepatic failure, what happens is this ammonia accumulates and is shunted into the systemic circulation. In the previous slide, we had talked about the role of ammonia as it enters the systemic circulation. And at high levels, this ammonia can cross the blood-brain barrier, where the astrocytic glutamine synthetase then converts the ammonia and the glutamate into glutamine, which in turn acts as an osmolite and increases the cerebral volume, resulting in brain edema and edematous neurons, which are present. That's sort of the conventional role of ammonia. There are other factors that are thought to play a role in the pathogenesis of hepatic encephalopathy, for example, GABA type A receptors, which causes inhibition through a chloride channel opening. So there are efforts on to see if we can antagonize the GABA A receptors. Another one that seems to be showing up on MRI, especially on T2 weighting images, is manganese toxicity. The pictures tend to be similar, so there's some interest in that also. If we look at the astrocyte in detail, we previously talked about how high levels of ammonia lead to astrocyte swelling and dysfunction. And it has also become clear that increased exposure of ammonia for a prolonged period of time can lead to alteration in the NMDA receptor. There is also altered GABA excitation that happens because of these high ammonia levels. There is collapse of the chloride gradient, which also contributes. And this ammonia also interferes with mitochondrial function, which gives rise to excessive production of free radicals and induction, leading to more astrocyte dysfunction, energy failure, oxidative stress, all of it contributing to hepatic encephalopathy. Acute liver failure will affect different parts of the brain in different ways. In early stages of acute liver failure, there is no effect on the blood-brain barrier permeability or edema, for example, in the frontal cortex. But if you look at the cerebellum, you will see evidence of vasogenic edema and blood-brain barrier permeability. Blood flow and lactate are not affected in the early stages of acute liver failure. But later stages, the cerebellum shows increased lactate and reduced blood flow. In contrast, the frontal cortex shows edema and increased blood flow. Now let us look at the treatment of hepatic encephalopathy. These are basic principles that we as intensivists are well familiar with. Seismovilemia, that is important to alleviate the high-pressure portal venous system that is present. Treat the hypokalemia, if any, as it impairs the ammonia detoxification and differential across the blood-brain barrier. We have to prevent hypoglycemia. You maintain the glucose homeostasis, avoid the interruptions, give protein 1 to 2 gram per kilo per day. We should also use fat-soluble vitamins to anticipate fat malabsorption and associate deficiencies that are present. Rifaximin, we'll talk a little bit more in detail in the next slide. Lactulose, also we'll discuss in the next few slides. Antibiotics also play an important role. The other thing I want to talk about is hemostasis for GI bleed prevention, H2 receptor antagonists, protein pump inhibitors, and sucrofate. Platelets transfuse at 20,000, or if you're bleeding, DDAVP, there is little value that has been shown. If there's an active bleeding, plasma exchange has been used. Cryoprecipitate if fibrinogen is low. And factor VII for rapid correction or if ICP monitoring is required, although the trend seems to have gone away from it. And to decrease the portal pressure and splenic blood flow, octretide and vasopressin. Because of the laxative effect, lactulose tends to be one of the first-line treatments for hepatic encephalopathy. In essence, it reduces the colonic pH and interferes with the mucosal uptake of glutamine in the gut. By reducing the pH, it makes it unfavorable for the urease-producing bacteria that split the urea and make ammonia. In contrast, it promotes the growth of lactose-forming bacteria in the intestine. The adverse effects associated with lactulose administration include abdominal bloating, sweet taste in the mouth, severe dehydration, and hyponatremia. There are several antibiotics that can be used as empirical treatment for hepatic encephalopathy, but neomycin was one of the first antibiotics to be investigated. What it does is it inhibits the mucosal glutaminase, which reduces the ammonia production in the gut. It also reduces the ammonia-forming coliform bacteria that produce urease, as we've talked about, and they're prevalent in the gut. Its side effects are ototoxic and nephrotoxic effects. Rifaximine, on the other hand, is minimally absorbed with few adverse effects, and there is minimal drug-to-drug interaction. The use of rifaximine really increased after a large multicenter study in 2010 that demonstrated that remission of hepatic encephalopathy was prolonged in patients that were treated with rifaximine as compared to patients who did not receive the medication. There is more evidence to support that in addition to the antibiotic effect, rifaximine actually works in many other ways, and this cartoon sort of explains some of the benefits. We talked briefly about the reduction in ammonia producing flora. It reduces the endotoxin ammonia and the pro-inflammatory mediators that are present. There is also reduction in hepatic inflammation that happens as a result that has improved renal function and improved cognition and neuromuscular coordination. Finally, in terms of adjunct therapy, we should monitor these patients for seizures, we should avoid sedation, flamazenil, or hypothermia. As far as ICP monitoring goes, there's really no consensus regarding impact on outcome. It really is a balance, balancing the risk versus benefit that it may provide. Nutritional interventions are an important piece in the management of patients with acute liver failure. Skeletal muscles compensate in these patients by metabolizing ammonia. And when there is loss of lean body mass, it increases the ammonia load to the brain, which leads to worsening of hepatic encephalopathy. Therefore, it is important to supplement protein, one to two grams per kilo protein daily, and the source of the protein is also important, preferably should be a vegetable protein. When you talk about extracorporeal support for treatment of hepatic encephalopathy and acute liver failure, there are two things that seem to come up a lot more are MARS or molecular adsorbent recirculating system and plasma exchange. Now, this study sort of did a head-to-head comparison, and there were these 10 children who underwent 22 MARS sessions, and they've listed the pretreatment and post-treatment along with the percent change in bilirubin, unconjugated bilirubin, ammonia, and INR. And the MARS was alternated with a combined plasma exchange and hemodialysis treatments in eight children, and they've looked at the percent change on the same parameters. So as you can see that the standard MARS treatment only slightly decreased the total bilirubin, ammonia, 20% change, and the INR, which actually increased with MARS. when you look at plasma exchange, it reduced the serum bilirubin by 36%, unconjugated bilirubin also 34%, INR actually came down, which is what you would expect, by 35%, and ammonia was reduced by about 48% in both. So this study seems to suggest that there is superior efficacy of a combined plasma exchange hemodialysis treatment as compared to the intermittent MARS therapy, which the adults seem to use more than the pediatric side. We at our center, we tend to use more plasma exchange and CRT as a treatment for these patients. This was another retrospective data from a single center, which looked at six children who underwent 17 MARS sessions. Two adolescents were treated with the adult filter, while four children were treated with the mini-MARS filter. The mean serum ammonia levels decreased significantly following treatment with MARS from an initial of 89 down to 58, but no other significant changes were observed, as you can see in the bilirubin graph. The outcome in these patients, three patients died and two were successfully transplanted. So there is some data to support the use of MARS, more so maybe in older children. However, for younger children, maybe plasma exchange might be a better way. This is a study from 2015, which had looked at 20 patients who had the highest degree of hepatic encephalopathy and who were treated with MARS, as is, since this was a national center for pediatric liver transplantation in this country. And they noted that the hepatic encephalopathy improved in 30% of the treated patients, but progression to grade four occurred in 45% of the patients despite the treatment. But what the eventual conclusion was that 80%, as you can see here, of the MARS-treated patients survived to undergo liver transplantation, but their survival was equivalent to that of the non-MARS-treated patients with severe liver failure. So this seems to suggest that although MARS is safe and it can probably get you, might serve as a bridge to the liver transplantation. So this is another study that looked at all children who were admitted to the PICU with liver failure for 10 years, and they were managed as per the standard protocol. Of the 165 children who were admitted with pediatric acute liver failure, 136 met the criteria, and 45 of them received CRT. And as you can see, those who received CRT, overall survival was better. 58% survived, 19 were successfully bridged to liver transplantation, and seven spontaneously recovered. They also demonstrated in the study that if you're unable to reduce ammonia by 48 hours, it generally confers a poor prognosis. They actually say that for every 10% decrease in ammonia from baseline at 48 hours, the likelihood of survival increases by 50%. And the prognosis was slightly better in patients who were older than one year of age. This is a prospective observational cohort study from the PALF study group. And as you can see, this slide is a little busy and confusing, so I'll walk you through it. Group 1 here is the patients that never developed hepatic encephalopathy. Group 2 did not have it on admission, but developed it subsequently. And group 3 has hepatic encephalopathy at study enrollment. And we'll talk about 3M and 3S in a second. So the group 1 is the one, as you can see, has the most spontaneous recovery. Overall, the mortality in the whole cohort was 11%. Group 3 is the one which is of most interest to us in the sense that these are the patients that demonstrate grade 3 to 4 hepatic encephalopathy in almost 55% of the patients. Or there is progression of hepatic encephalopathy. And then you can further break this group into two parts based on the INR. So 3S is the one that has a higher INR of more than 2 or has higher coagulation issues. Now, the mortality in this group was 46%. But when you look at patients in group 3 whose INR was less than 2 or had a milder version of the hepatic-based coagulopathy, then mortality in that group was only 17%. So that sort of indicates to you that how the group 3 sort of numbers fall in place based on their coagulation defects. And group 2 sort of falls in the middle where spontaneous recovery is not as much, but a lot of patients got liver transplantation. But this group in general has less numbers compared to the other two. This is the data from the same group. And this slide is also confusing. I'm sorry for that. But this is, again, that same group 3 participants where P stands for progression, R stands for regression, L stands for low hepatic encephalopathy, and H stands for high hepatic encephalopathy or grade 3 and 4. So the group that interests us more is this 3H, which has a very high mortality, which is what I wanted to show you. And it's lowest in the group in which there was regression of the hepatic encephalopathy, which is this line here. And this slide also shows here that patients in whom there was progression of hepatic encephalopathy ended up with a liver transplant, and where it regressed, as you can see in this blue line, they did not need it. Switching gears, we'll move on to the hepato-renal syndrome, which partly results from increased renal vasoconstriction that is present that has reduced GFR. We talked about that a little bit. There's rise in creatinine and impaired sodium and water excretion. Overall, it's more a diagnosis exclusion and is classified as type 1 and 2. Type 1 tends to be more serious between the two with a twofold increase in creatinine and decrease in urine output. Overall, occurs over a two-week period with other organ insults and can be precipitated by an acute event or insult. A bad GI hemorrhage, a surgical procedure, a bad infection, all those can result in hepato-renal syndrome. So let's look at the diagnostic criteria that have been proposed for hepato-renal syndrome. You have to have cirrhosis of the sides. We talked about an increase in serum creatinine, more than 1.5. No improvement in serum creatinine after two days with diuretic withdrawal and volume expansion. There's absence of shock, no acute insult, and absence of kidney disease. So that's why it's where we kind of talked about how it's a diagnosis exclusion. I had alluded to some of the precipitating factors in the previous slide, a bad infection, a bad hemorrhage, which can result in a decreased circulatory volume. There is a splenic arterial vasodilatation. There's nitric oxide production that also plays a role in it. And once the body senses this decreased circulatory volume, there is increased sympathetic nervous system. There's vasopressin that kicks in. There's increased cardiac output that tries to compensate for it. The angiotensin system also increases, resulting in renal vasoconstriction, decreased GFR, elevated creatinine, sodium retention, ascites. There's no proteinuria and no histological structural changes that are noted. The treatment for hepatorenal syndrome essentially is vasopressin and norepinephrine. You might have to do renal replacement therapy if the kidney is failing. Since you have to address the liver also, MARS has been tried where albumin-bound toxins are eliminated. TIPS results in a decreased renin plasma aldosterone in noradrenalin levels. That has also been tried. There are a few controlled studies that show TIPS to be a definitive treatment for hepatorenal syndrome. But there are some positive results that have been seen. So it's often been used as a bridging modality to transplant. But it remains controversial if liver kidney transplantation is better for this group of patients than an isolated liver transplantation. It all depends upon how the kidney is progressing and the increased mortality that is associated. The American Society of Transplantation had come out with these guidelines as to when to refer patients for liver transplantation. And I thought I'll just briefly touch on it. So if you have a child with an acute liver failure or acute decompensation of an established liver, you should immediately refer to a pediatric liver transplant center. Grading is 1A. Child with a chronic lung disease and evidence of deterioration is 1B. Then the other ones I thought that were interesting were liver-based metabolic crises, which is medical or other surgical therapy where it doesn't work, 1B. Undersectable hepatoblastoma, for example, 1B. Biliary atresia, if the total bilirubin is more than six milligrams beyond three months post-procedure, it's 1B. Then first year of life with severe uricycle defects to prevent or minimize irreversible neurological damage. Crigler and Ajar, similarly. And we've talked about undersectable hepatoblastoma, 1B. And patients with autoimmune conditions, autoimmune hepatitis, or they have bile salt, excretory pump disease, those get a grading of 2B. This is Dr. Starzl, who was a pioneer in the field of liver transplantation. He had about 1,700 total publications, out of which 500 were based on liver transplant. This little girl sitting on the knee was one of the first survivors of liver transplant in the 60s, and her name was Julie Rodriguez. If you look at the OPTN data, you will see that majority of the liver transplants are for biliary atresia, about 32%. Next is 22% for metabolic and genetic conditions, while acute liver failure is only about 11%. And the rest is a combination of a tumor cirrhosis or immune disorder, which is anywhere from 4% to 9%. In this graphic, we illustrate the various anastomosis that are present in a pediatric liver transplant. As you can see, the hepatic artery, which is, if you follow the red arrow, you see the anastomosis there. If you follow the purple arrow, you'll see the anastomosis for the portal vein. And if you see the blue arrow, you'll see the bile duct. And then you have the outflow anastomosis, that is, the hepatic vein onto the cava on top here. This cartoon just illustrates how the hepatic artery and the portal vein anastomosis are generally performed in an end-to-end fashion. The biliary anastomosis, too, is performed usually in an end-to-end fashion from the donor. But sometimes if there's a discrepancy in size, then a coli-doco jejunostomy is preferred. This picture shows you that sometimes how a venous jump graft may have to be used, especially if the donor portal vein is thrombosed. Then they use this jump graft, which, as you can see in this dark blue in the graphic, which can be from the superior mesenteric vein or the splenic vein. In a living donor liver transplant, a left lateral liver graft, that is, segment 2 and 3, is transplanted into a small child. And the right liver graft is transplanted into a large child or a small adult, which is segments 1 and 5 to 8. The portal vein is generally anastomosed in an end-to-end fashion, either to the recipient's portal vein trunk or by using a vascular graft, as is shown here. The hepatic veins are generally anastomosed using the piggyback technique. The preferred biliary reconstruction procedure is generally a Roux-en-Y hepatic jejunostomy due to the small bile duct size or underlying liver disease, which is biliary atresia in most cases. This picture on the left shows an aortic graft that is sometimes used from aorta to hepatic artery, especially if there's hepatic artery thrombosis. The most often conduit is the iliac artery of the donor, which is often anastomosed to the recipient's infrarenal aorta. Looking at some of the complications of liver transplantation, the first one that comes to mind is hepatic artery thrombosis, which is often associated with a graft loss. The incidence is about 3% to 10%. You can also have portal vein thrombosis, which is about 4%, a biliary structure leak, and bowel perforation in about 5% of cases. Out of these, the most important one is hepatic artery thrombosis, which is nonspecific and late and can include fulminant hepatic necrosis, bile leakage, and bacteremia. And it is often to address the thrombosis that you often find these patients on some combination of a dextran, heparin, or prostaglandin, and then you switch over to aspirin or inoxaparin in a few days' time. The other issues with liver transplantation are splenic artery steel syndrome or hepatic artery pseudoaneurysm. Now, in the steel syndrome, what happens is the blood flows preferentially from the celiac axis into the splenic artery, and the hepatic artery becomes relatively hypoperfused, and the risk factors for developing this are not clearly understood. The venous complications are less common, occur in about 1% to 2% of transplant recipients. They can cause portal vein stenosis and thrombosis, or you can have portal pseudoaneurysms that are often present. They are generally associated more with technical problems, such as vessel misalignment, differences in the caliber of the anastomosis, previous surgeries that might have happened there, decreased portal venous inflow, hypercoagulable states, and increased downstream resistance, which may be present. Biliary complications usually occur in the first three months, and they're generally associated with biliary structures, leaks, or stones. Most commonly, the issues behind the biliary complications are technical problems or ischemia. These pictures illustrate the complications that we've talked about. It would have been easy for me to point it out if we were in person, but most of them are very clear. If you can just look at the biliary structure, the arterial stenosis, which is seen at the bottom part of the screen, the hepatic stenosis is very, very clear, and then the portal stenosis on the left side. Continuing about the complications, sometimes it's all about the size that matters. If you have a liver that is bigger than the abdominal cavity, then sometimes you end up in situations like this, where the abdominal cavity is open for a brief period until there is enough growth, and you're able to decrease the edema so that the structures can approximate each other, and you can actually close the abdominal wall. Issues that have been done are temporary mesh closures have been performed. There's healing by secondary intention that has to happen, and often back dressings are also used. This will give you an idea how things progressed over time for this child. It started off on the left upper corner of the slide, and as you can see, gradually progressed until he healed completely in the end. Steroids, as you know, is the cornerstone of immunosuppression in transplant, and when you give cortisol, then it binds to the glucocorticoid receptor, which then translocates to the nucleus where it influences gene transcription. It impairs the neutrophil macrophage function, and there are other non-genomic mechanisms that also exist. Other therapies that have been used are calcineurin inhibitors, cyclosporine, and tacrolimus. Calcineurin inhibitors, they activate the N-fat, or the cytoplasmic N-fat by dephosphorylating it, which then translocates into the nucleus and up-regulates the expression of IL-2, thereby stimulating the growth and differentiation of the T-cell response. The adverse events of calcineurin inhibitors include hirsutism, diabetogenesis, neurotoxicity, which has been underappreciated, but now we're getting more and more data, headache, tremor, is worse with low magnesium, therefore it's always very important that we keep the magnesium levels close to 2, nephrotoxicity due to severe vasoconstriction of the afferent arteriole, and reversible with discontinuation of calcineurin inhibitors. A very serious and potentially fatal complication of transplantation is PTLD. PTLD are lymphoid and or plasmacytic proliferations that occur in the setting of solid organ or allogeneic hematopoietic cell transplantation as a result of immunosuppression. It is related to EBV, but EBV-negative disease does occur. This graph shows how the incidence of PTLD increases over time after transplant to about anywhere from 2% to 4% five years out. PTLD has been classified as early lesions, polymorphic PTLD, or monomorphic. Early lesions are an infectious mononucleosis-type acute illness where you have the B-cell proliferation, but there is no evidence to suggest that there is any malignant transformation that is happening. In polymorphic, you have these lymphoid infiltrates that demonstrate evidence of malignant transformation, but do not meet all the criteria for one of the B-cell or lymphomas that are usually seen. Monomorphic lymphoid proliferations meet the criteria for lymphomas that are recognized in immunocompetent patients. That's why it's called monomorphic. The risk factors are the degree of immunosuppression, EBV serostatus, pre-transplant malignancy, fewer HLA matches, and younger age, especially if there is a radiological evidence of a mass or elevated serum markers such as high LDH levels. They generally suggest PTLD. In general, for treatment of PTLD, EBV monitoring is very important, and that is something that happens very routinely in most ICUs and on the floors. But the main options for reduction are reduction of immunosuppression, immunotherapy with a CD20 monoclonal antibody like rituximab, chemotherapy-radiation combinations have been tried, and in general, adoptive immunotherapy with EBV-specific cytotoxic cells. They are generally reserved for persistent severe disease. The main goals of therapy are eradication of the PTLD and preservation of graft function. This graph illustrates when the timeline of these infections, although some of them are changing, as you can see that a lot of the bacterial, viral, and fungal are sort of happening early on in the sense bacterial is the first one to come within the first few weeks. The fungal is also happening at the same time, and the viral infections seem to come on later after transplantation. This paradigm is shifting a little bit. We have recently shown that MDROs in liver transplant patients do happen somewhere around seven to eight weeks later. So I think this paradigm is moving. Fungal infection only occurs in about 10 to 20%, and generally it's candida aspergillus. And when you look at the viral infections, then there's CMV, EBV, we've talked about, HSV, adenovirus, and parvovirus. And for the viral prophylaxis, if the donor and recipient are both negative, then there's no treatment. But if the donor's positive and or the recipient's positive, then generally we start them on GAN cycle with 10 mg per kilo per day for 14 days for prophylaxis. In the interest of time, I won't go over the slide, but this lists the complications that are generally present in the first week, after the first week, and late. Which of the following factors are best characterized in the pathogenesis of hepatic encephalopathy? The role of ammonia as a neurotoxin and its interference of brain function at several sites. B, changes in the uptake of neurotransmitters. C, inhibitory GABA in the development of hepatic encephalopathy. D, deposition of manganese in the basal ganglia. The answer is A. Next, which of the following donor and recipient characteristics is not associated with early hepatic artery thrombosis? Prolonged cold ischemia time. Prolonged hepatic artery anastomosis time. Small vascular structures. And D, low hematocrit. The answer is D.

Pediatric Multiprofessional Critical Care Review

Hepatic Failure

Organ Transplantation

Hepatic Encephalopathy

Hepato-Renal Syndrome

Acute Liver Failure

Diagnostic Criteria

Treatment Options