e2 49 Munoz SJ, Stravitz RT, Gabriel DA Coagulopathy of acute liver failure Clin Liver Dis 2009;13 95 107 50 Wang SC, Shieh JF, Chang KY, et al Thromboelastography guided transfusion decreases intraop[.]
e2 49 Munoz SJ, Stravitz RT, Gabriel DA Coagulopathy of acute liver failure Clin Liver Dis 2009;13:95-107 50 Wang SC, Shieh JF, Chang KY, et al Thromboelastography-guided transfusion decreases intraoperative blood transfusion during orthotopic liver transplantation: randomized clinical trial Transplant Proc 2010;42(7):2590- 2593 51 Brown JB, Emerick KM, Brown DL, Whitington PF, Alonso EM Recombinant factor VIIa improves coagulopathy caused by liver failure J Pediatr Gastroenterol Nutr 2003;37:268-272 52 Rolando N, Harvey F, Brahm J, et al Prospective study of bacterial infection in acute liver failure: an analysis of fifty patients Hepatology 1990;11:49-53 53 Antoniades CG, Berry PA, Wendon JA, Vergani D The importance of immune dysfunction in determining outcome in acute liver failure J Hepatol 2008;49:845-861 53a Abouna GM Extracorporeal liver perfusion for hepatic coma Lancet 1971;1:1185 54 Eiseman B, Liem DS, Raffucci F Heterologous liver perfusion in treatment of hepatic failure Ann Surg 1965;162:329-345 55 Parbhoo SP, Chalstrey LJ, Adjukiewicz AB, James IM, Hillenbrand P, Kennedy J Extracorporeal perfusion of pig liver in the treatment of acute liver failure Br J Surg 1971;58:746-748 56 Sen PK, Bhalerao RA, Parulkar GP, Samsi AB, Shah BK, Kinare SG Use of isolated perfused cadaveric liver in the management of hepatic failure Surgery 1966;59:774-781 57 Demetriou AA, Brown Jr RS, Busuttil RW, et al Prospective, randomized, multicenter, controlled trial of a bioartificial liver in treating acute liver failure Ann Surg 2004;239:660-667; discussion 667-670 58 Ellis AJ, Hughes RD, Wendon JA, et al Pilot-controlled trial of the extracorporeal liver assist device in acute liver failure Hepatology 1996;24:1446-1451 59 Squires RH Living donor liver transplant in pediatric acute liver failure: an important option, but when we use it? J Pediatr Gastroenterol Nutr 2014;58(1):1-2 60 Deep A, Stewart CE, Dhawan A, Douiri A Effect of continuous renal replacement therapy on outcome in pediatric acute liver failure Crit Care Med 2016;44:1910-1919 61 Li R, Belle SH, Horslen S, et al Clinical course among cases of acute liver failure of indeterminate diagnosis J Pediatr 2016;171: 163-170 62 Squires JE, Rudnick DA, Hardison RM, et al Liver transplant listing in pediatric acute liver failure: practices and participant characteristics Hepatology 2018;68(6):2338-2347 63 Organ Procurement and Transplantation Network Policies 2020 Available at: https://optn.transplant.hrsa.gov/governance/policies e3 Abstract: Pediatric acute liver failure is a life-threatening condition in which previously healthy children lose hepatic function rapidly, requiring immediate medical attention It is a rare entity in pediatric intensive care unit settings, but expertise is crucial to achieving optimal outcomes Management consists of supportive measures, with a focus on anticipation, prevention, and treatment of complications along with early consideration for liver transplantation Timely intervention to treat the metabolic derangements associated with acute liver failure is pivotal and can help mitigate the morbidity associated with this condition This chapter focuses on acute liver injury and does not detail the management of endstage and life-threatening complications of chronic liver disease Key words: Pediatric acute liver failure, liver injury, hepatic encephalopathy 97 Hepatic Transplantation PATRICK J HEALEY, BRITT JULIA SANDLER, ABIGAIL APPLE, THOMAS V BROGAN, AND JORGE D REYES • Liver transplantation (LT) is now widely accepted as the standard of care for the management and treatment of acute liver failure and end-stage liver disease in children Since the first liver transplant in a child performed by Thomas Starzl in 1963, remarkable progress has been made; children undergoing liver transplantation today should realize 5-year survival exceeding 80%.1 The improvement in outcomes has resulted from continuous progress across the spectrum of care of children in need of LT Advances in diagnosis and management of liver disease, development of improved intensive care support and therapies, and refinement of transplant surgical technique and perioperative care have contributed to improved overall patient and graft survival The recognition of the importance of nutritional support, prompt diagnosis and treatment of infection, and advances in management of the multisystem complications of both chronic liver disease and acute liver failure have contributed to improved pretransplant survival of these children and improved condition at time of transplantation Expansion of donor liver graft options beyond the wholeorgan deceased donor graft to now include segmental or isolated lobe grafts, split liver grafts, living donor, and deceased after circulatory death (DCD) grafts have greatly expanded the transplant possibilities for children on the waiting list.2 Changes in donor organ allocation policies and improved organ preservation allowing broader geographic distribution have also increased potential access for children to donor liver grafts Posttransplant management has also improved, including immunosuppression, earlier recognition of rejection and infection, and earlier recognition of vascular and biliary complications, all of which have contributed 1162 • • Liver transplantation (LT) has become the standard of care for children with end-stage or metabolic liver disease, acute liver failure, and unresectable liver tumors, with most common indication being biliary atresia A child’s ability to tolerate the transplant-specific physiologic demands and recover following LT are related more to pretransplant functional status and physiologic reserve than the magnitude of the transplant procedure itself Donor liver grafts now include segmental or isolated lobe grafts, split liver grafts, living donor, and deceased after circulatory death grafts • • • PEARLS The overarching principle guiding specific intraoperative technical decision-making is to optimize liver graft perfusion (inflow) and avoid outflow obstruction and resultant graft congestion and edema Complications following LT occur commonly and may derive from pretransplant recipient condition, graft-specific factors (including preservation and ischemia-reperfusion injury), technical or intraoperative complications, the immunologic response to the graft, or infection Transplant outcomes now exceed 90% patient survival at year and 80% at years to improved outcomes While the primary indication and role of LT is to increase survival in patients with life-limiting acute or chronic liver conditions, the overall excellent survival outcomes realized today have allowed for expanded consideration of LT in certain clinical situations to improve quality of life of children suffering debilitating complications or side effects related to their liver disease Current State of Pediatric Liver Transplantation In 2018, approximately 525 children were registered on the United Network for Organ Sharing (UNOS) national liver transplant wait list, more than half of whom were aged years or younger.1 During the year, 700 children were added to the wait list and 563 LTs were performed; 62 were living donor transplants A trend toward increased medical urgency, evidenced by an increased proportion of Status 1A and 1B listings, has continued over the past several years The increasing acuity at transplantation is reflected in higher utilization of split liver transplants, which comprised 19.2% of pediatric liver transplants performed, as compared with 14.4% in 2008 This contrasts to the static 1% proportion of split liver grafts performed in adults over the same period The utilization of living donor LT also continues to expand, representing 11% of transplantations performed in 2018 Together, the increased use of split liver and living donor transplant and high acuity at operation reflect overall limited access to suitable donor organs for children on the wait list.3 Despite these efforts to increase transplant opportunity for children, CHAPTER 97 Hepatic Transplantation approximately 4.3% of children died on the wait list, and another 2.7% were removed from the list because they had become too sick to benefit from operation The wait list mortality was highest in children younger than year who had a death rate of 17.1 deaths per 100 wait list–years This pretransplant mortality risk is highest of all age groups awaiting a lifesaving LT.1 Indications for Liver Transplant Liver transplantation is indicated for irreversible liver failure, lifethreatening complications of underlying liver disease, or secondary organ complications resulting from the liver disease Primary liver disease or condition-specific indications fall into four broad categories: chronic liver disease, acute liver failure, metabolic liver disease, and unresectable liver tumors (Box 97.1) Other disorders, many of which are newer indications, include cystic fibrosis liver disease, nonfatal metabolic liver disease, and portosystemic shunts The most common indication for LT in children is biliary atresia, followed by metabolic and inborn disorders, autoimmune and familial cholestatic disorders, and acute hepatic necrosis Unresectable malignancy accounts for approximately 5%, and retransplantation now comprises slightly less than 10% of pediatric LT performed annually Biliary atresia is a progressive fibro-obliterative disease of early infancy that results in biliary obstruction and fibrosis and can progress to biliary cirrhosis despite performance of a Kasai • BOX 97.1 Indications for Liver Transplantation in Children End-Stage Liver Disease Liver Tumor Cholestatic liver disease Biliary atresia Alagille syndrome Progressive familial intrahepatic cholestasis Primary sclerosing cholangitis Disorders of bile acid synthesis Unresectable malignancy Hepatoblastoma Hepatocellular carcinoma Benign liver tumor Hemangioendothelioma Chronic Hepatitis Viral hepatitis Autoimmune hepatitis Cryptogenic cirrhosis Metabolic Liver Disease a1 Antitrypsin deficiency Urea cycle defects Tyrosinemia Glycogen storage disease Wilson disease Cholesterol ester storage disease Crigler-Najjar type Organic acidemias Primary oxalosis Acute Liver Failure Fulminant viral hepatitis Autoimmune hepatitis Acetaminophen-induced hepatic necrosis Toxin-induced hepatic necrosis Wilson disease Retransplantation Hepatic artery thrombosis Primary graft nonfunction Ischemic cholangiopathy Chronic rejection Miscellaneous Cystic fibrosis Neonatal iron storage disease Drug toxicity Polycystic liver disease Hepatopulmonary syndrome Parenteral nutrition–associated liver disease Caroli disease Liver insufficiency postresection or injury 1163 portoenterostomy Despite a high rate of progression of liver disease, approximately two-thirds of infants will clear their jaundice following the Kasai portoenterostomy, delaying the need for early LT and permitting time for growth Children with biliary atresia represent approximately 45% of pediatric LT, with the majority requiring a transplant before age years These infants typically present with jaundice, coagulopathy, or poor growth They may also develop episodes of cholangitis, or bacterial peritonitis Hepatic cirrhosis is often associated with portal hypertension, hepatosplenomegaly, and ascites Nutritional failure and hypersplenism contribute to increased risk for bleeding and infection.4 In addition to the liver disease, approximately 15% of infants with biliary atresia have associated congenital malformations that may include polysplenia or asplenia, interrupted inferior vena cava, preduodenal portal vein, and situs inversus (biliary atresia splenic malformation) These anatomic malformations may specifically impact technical aspects and decisions of the liver transplant procedure, limiting options for suitable donor liver grafts in this select group of biliary atresia patients Metabolic liver diseases include a spectrum of clinical presentations and urgency and result from a single hepatic enzyme deficiency that leads to alteration in synthesis, transport, function, or breakdown of carbohydrate, fat, or protein Some metabolic disorders may be associated with progressive liver disease and cirrhosis (e.g., a1-antitrypsin deficiency, Wilson disease, progressive familial intrahepatic cholestasis), or malignancy (e.g., tyrosinemia) Other inborn errors of metabolism are characterized by absence of hepatocellular injury but result in extrahepatic organ injury or dysfunction due to failure of normal hepatic enzyme function Urea cycle defects cause abnormal protein breakdown, resulting in hyperammonemia, which can cause significant neurologic injury and impair development Hyperoxaluria type manifests with renal complications, and hypercholesterolemia or disorders of iron metabolism can cause serious cardiac complications Clinical presentation of metabolic liver disease may range from the newborn period (extreme hyperammonemia due to urea cycle defect) to adolescence and into adulthood (e.g., CriglerNijjar, Wilson disease) The urgency of LT is related to risk of severe or life-altering complications of the specific metabolic defect, and the effectiveness of alternative supportive therapies Although many children recover from acute liver failure with supportive intensive care management, renal replacement therapy, and liver-specific support in nutrition and coagulation, those with overwhelming hepatocyte necrosis may develop extreme hypoglycemia, progressive encephalopathy, and coagulopathy refractory to supportive measures Life-threatening extrahepatic complications—including cerebral edema with intracranial hypertension and coma, renal failure due to hepatorenal syndrome, and pulmonary hypertension—may develop and are associated with high mortality without urgent LT Of the primary liver tumors of childhood, hepatoblastoma is the most common, often presenting with a large primary liver mass during infancy Greater than one-third are unresectable at presentation, and many have pulmonary metastases at presentation.5 Despite good response to neoadjuvant chemotherapy, approximately 10% of these large tumors will remain unresectable The achievement of a satisfactory oncologic resection—including complete removal of the tumor with negative histologic margins while providing sufficient remnant liver volume for adequate liver function—may not be possible in cases of large tumors Total hepatectomy and liver transplant is indicated in those cases Hepatocellular carcinoma (HCC), the second most common liver 1164 S E C T I O N X Pediatric Critical Care: Gastroenterology and Nutrition malignancy, typically occurs in older children and adolescents In contradistinction from its association with chronic viral hepatitis in adults, HCC in children typically arises in an otherwise normal liver and presents as a large unresectable tumor Despite the advanced clinical status at presentation, long-term survival outcomes following liver transplant now exceed 80%, approaching those of nonmalignant diagnoses.6 Combined liver-intestine transplantation is indicated in the context of irreversible parenteral nutrition–associated liver disease in children with intestinal failure and short-bowel syndrome Liver-kidney transplantation in children is primarily indicated in metabolic liver disease resulting in renal failure, such as hyperoxaluria or methylmalonic academia Unlike in adults, combined liver-kidney transplantation for hepatorenal syndrome in children is rarely performed, and renal recovery often follows liver transplantation alone With improvements in overall survival outcomes plus greater awareness and management of transplant complications contributing to lower early morbidity, LT is now appropriately indicated to improve quality of life in children with liver disease–associated complications such as intractable pruritus or poor growth and development Contraindications to LT include uncontrolled systemic infection, presence of uncontrolled extrahepatic malignancy, or progressive life-limiting extrahepatic disease or condition Liver Transplant Evaluation The goals of transplant evaluation are to identify anatomic and functional data necessary to perform the LT procedure safely while also identifying other medical, social, or infection history that must be managed in order to achieve a successful outcome Liver transplant evaluation typically includes laboratory tests to determine ABO blood type, complete blood count, electrolytes, and renal and hepatic synthetic function studies Virology studies to identify past infection or vaccination for hepatitis A, B, and C or human immunodeficiency virus in addition to serologies for cytomegalovirus (CMV) or Epstein-Barr virus (EBV) aid in managing immunosuppression and infection prophylaxis posttransplant Doppler ultrasound (US) of the liver and computed tomography of the abdomen provide information regarding vascular anatomy and patency or thrombosis of portal venous inflow and allow assessment of size and space considerations for potential donor grafts Echocardiography is obtained to assess cardiac anatomy and function, especially to identify preexisting pulmonary hypertension or atrial or ventricular enlargement or dysfunction Social work and/or a psychological evaluation aid in assessing patient and family support challenges to adherence with recommended care and psychosocial issues that may require specific support, including financial or housing assistance in anticipation of hospitalization related to the transplant Patient and family education regarding pre-, peri-, and postoperative stages of the transplant process is a key component of LT evaluation General information regarding the transplant system in the United States specifically in the geographic region of the transplant center and the process of prioritization and allocation of donor organs to patients on the wait list must be discussed Donor options (including whole-organ, live donor, and deceased donor grafts) and technical variant grafts (including reduced lobar or segmental liver grafts) are reviewed along with specific complications that may be associated with each different donor graft type A thorough discussion of risk of posttransplant infection specifically relating to immunosuppression and risk for viral infections—particularly EBV and CMV—should be included Additionally, education should address potential donor-transmitted infections plus procedures and protocols to monitor and manage them if they occur Alternatives to transplant should also be discussed to ensure that LT is the most appropriate course Pretransplant Considerations The ideal management of a child awaiting LT should focus on optimizing overall health The child’s ability to tolerate the transplant-specific physiologic demands and recover following LT are related more to pretransplant functional status and physiologic reserve than to the magnitude of the transplant procedure itself Therefore, it is critical to actively monitor and promptly manage complications of advancing liver disease, portal hypertension, variceal bleeding, and any intercurrent illnesses Children with advancing liver disease often require nutritional support or treatment of infection Supplemental enteral feedings or parenteral nutrition may be used to provide optimal calorie and protein intake Diuretic management and fat-soluble vitamin repletion are commonly required, indicating progressing portal hypertension and liver dysfunction Decreased muscle mass, fatigue, and abdominal distension due to hepatosplenomegaly or ascites may contribute to restrictive pulmonary physiology or increased work of breathing, further demonstrating the importance of adequate caloric intake Another essential goal of the preoperative period is to optimize the child’s transplant priority on the wait list itself, which is determined by clinical urgency of the recipient and the severity of liver disease Systems to prioritize candidates waiting for LT differ in various countries In the United States, UNOS administers the Organ Procurement and Transplantation Network, which matches donors with recipients Children with acute liver failure qualify for most urgent listing, Status 1A Children with chronic liver disease or malignancy who experience life-threatening complications may qualify for Status 1B Children under 12 years of age on the wait list are prioritized according to a calculated Pediatric End-Stage Liver Disease (PELD) score, which incorporates values for bilirubin, albumin, and international normalized ratio (INR) In young infants, growth failure and age less than year also contribute to the PELD calculation The PELD score will ideally stratify children according to their 3-month liver disease–related mortality risk, with higher scores indicating greater risk of dying without transplant.7 Adolescents and adults are prioritized according to a calculated Model for End-Stage Liver Disease (MELD) score, which incorporates bilirubin, INR, and creatinine In specific cases in which the calculated PELD score does not accurately represent the severity of liver disease and associated mortality risk, centers may request a higher PELD exception score, which is reviewed by a national review board Active management of children on the wait list and frequent reassessment of listing priority are strategies shown to be associated with higher transplant rates and lower wait list mortality Transplant Considerations Donor Considerations Evaluation of potential donors for LT includes assessment of liver function; screening for donor medical history for disease, malignancy, and infection; ABO blood typing; and general size-matching with the intended recipient Deceased donors may meet criteria for ... with acute liver failure is pivotal and can help mitigate the morbidity associated with this condition This chapter focuses on acute liver injury and does not detail the management of endstage... which comprised 19.2% of pediatric liver transplants performed, as compared with 14.4% in 2008 This contrasts to the static 1% proportion of split liver grafts performed in adults over the same... highest in children younger than year who had a death rate of 17.1 deaths per 100 wait list–years This pretransplant mortality risk is highest of all age groups awaiting a lifesaving LT.1 Indications