1165CHAPTER 97 Hepatic Transplantation death by neurologic criteria (brain death) or may have suffered extreme injury and qualify as donors after withdrawal of life sup port therapy (DCD; see Chapter[.]
CHAPTER 97 Hepatic Transplantation death by neurologic criteria (brain death) or may have suffered extreme injury and qualify as donors after withdrawal of life support therapy (DCD; see Chapter 20) Organ donation proceeds after declaration of circulatory death; these DCD organs experience a period of warm ischemia after withdrawal of support and before circulatory death Donors for pediatric LT tend to be young and free of preexisting disease This may allow for size-matched whole-organ transplant or enable the use of technical variant grafts, including segmental or lobar grafts A donor liver may be divided in situ (during the donor operation) or ex situ (on the backbench after recovery of whole liver) Liver reduction may produce a single, smaller-sized graft, or split, divided to result in two separate transplantable grafts The use of technical variant grafts has resulted in shorter waiting times and decreased wait list mortality for small children and infants in need of LT, though it has been associated with increased incidence of vascular and biliary complications when compared with whole-organ transplants but equivalent survival.8 Living donor transplantation has been an excellent option since first introduced in the 1980s The most common living donor graft for children is the left lateral segment graft, most often used in transplantation in infants Living donor LT allows better planning with elective, optimally earlier, timing for transplant While living donor transplant operations have increased operative and logistic complexity, recent reports demonstrate superior short- and long-term graft and patient survival following living donor LT compared with deceased donor transplantation.9 Determination of best donor option for a child awaiting LT requires complex, dynamic decision-making, largely dependent on the availability of donor offers or potential living donor and the patient’s clinical status In the stable child with a chronic liver condition, it may be appropriate to await a size-matched, ABOidentical donor liver offer with anticipated short ischemia time For children in the ICU, requiring advance support, or with acute liver failure, waiting for such a restricted donor offer would unduly increase the risk of dying before a suitable donor becomes available In such urgent situations, expanding donor options to include ABO-incompatible grafts and technical variant reduced grafts, such as monosegment grafts; using DCD or donors with increased risk for disease transmission; extending the geographic range; and accepting longer ischemia time can enable transplantation and can be lifesaving Liver Transplant Procedure The LT operation involves the removal of the native organ with preservation or creation of the inferior vena cava (IVC) outflow and hepatic arterial and portal vein inflow The donor graft is placed in the same position as the native liver Typically, three vascular anastomoses and one biliary anastomosis are required 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 The donor whole-liver suprahepatic IVC or segmental graft hepatic vein is anastomosed to the recipient IVC to establish venous outflow as the first step in implanting the liver graft The recipient retrohepatic vena cava may be preserved during the native hepatectomy, enabling a “piggyback” technique with venous anastomosis to the front of the IVC Portal vein anastomosis to establish inflow to the graft and restore mesenteric venous drainage 1165 from the small intestine and spleen is then performed Care is taken to identify and ligate preexisting portosystemic shunts that may compete with and compromise portal vein flow to the graft Reperfusion of the liver graft typically follows as the clamps are released, restoring portal inflow and hepatic venous outflow Hepatic artery inflow is then established after reperfusion, with anastomosis to the recipient hepatic or celiac artery If inadequate portal vein or hepatic artery flow is found, vascular grafts may be extended to the superior mesenteric vein or aorta to improve inflow This sequence of vascular anastomoses is possible because of the dual blood supply to the liver (portal vein and hepatic artery) and also enables shorter graft ischemia time Technical variations may include creation of a temporary portocaval shunt to maintain mesenteric venous outflow and minimize splanchnic congestion during the anhepatic phase Biliary drainage is accomplished by duct-to-duct anastomosis or donor bile duct to roux-en-Y anastomosis Primary liver disease, type of donor liver graft, and donor-recipient size mismatch are considered in determining best biliary drainage In children with biliary atresia, the roux-en-Y limb created for Kasai portoenterostomy typically serves for graft bile duct anastomosis Preexisting portal hypertension, adhesions related to previous abdominal surgery, and coagulopathy due to synthetic liver dysfunction contribute to risk for bleeding both intraoperatively and in the early postoperative period Ascites and prior episodes of cholangitis or intraperitoneal infection also contribute to this operative risk With significant donor-recipient size discrepancy or edema of graft, intestine or abdominal wall, primary abdominal closure may be delayed and a temporary patch closure employed to avoid impairment of liver graft blood flow or abdominal compartment syndrome Complications of Liver Transplantation 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 Technical complications encountered early in the posttransplant period include vascular and biliary complications, intraabdominal bleeding, and wound complications Organ dysfunction, infection, or rejection generally develop weeks after transplantation Immunosuppression toxicity may manifest at any time.10 Primary Graft Nonfunction Primary nonfunction (PNF) of the graft is a rare, but potentially devastating, complication characterized by severe hepatic dysfunction in the absence of vascular thrombosis The etiology of PNF is thought to be related to graft ischemia-reperfusion injury, poor graft preservation, or prolonged cold ischemia time Risk factors include steatosis, extremes of donor age, and DCD donor graft PNF may lead to early graft failure and require urgent retransplantation Vascular Complications Vascular complications following liver transplantation include stenosis or thrombosis of the hepatic artery portal vein or hepatic vein Routine bedside postoperative color Doppler US is indicated to assess vascular patency Vascular thrombosis is the leading 1166 S E C T I O N X Pediatric Critical Care: Gastroenterology and Nutrition cause of graft loss requiring retransplantation among patients in the Society of Pediatric Liver Transplantation (SPLIT) Registry, with hepatic artery thrombosis accounting for 52.3% and other vascular thromboses comprising 13.8% Stenosis may occur at the level of the anastomosis or relate to vascular dissection during organ recovery in the donor or from rotational malalignment of the donor and recipient vessels at time of anastomosis Typically, these complications occur early in the postoperative period and may present with laboratory or clinical signs of graft dysfunction or may be detected by Doppler US Intervention may include operative revision or repair, interventional radiology angioplasty, stent placement, or possibly retransplantation Hepatic artery thrombosis (HAT) is the most common vascular complication and an independent risk factor for graft loss and mortality.11 In the SPLIT Registry, 6.3% of patients developed HAT in the first 30 days Three distinct clinical presentations can arise: (1) acute necrosis resulting in hepatic infarction and primary graft failure; (2) ischemic cholangiopathy, presenting early as bile leak, biliary stricture, and abscess/bacteremia; and (3) asymptomatic without graft injury Risk factors include young age, low weight (incidence is greatest in patients ,10 kg),11 the use of vascular grafts, and hypercoagulable conditions.12 HAT can present with absent or diminished arterial flow or with abnormally low resistive indices on Doppler US When discovered in the immediate posttransplant period, HAT is an indication for emergent reexploration with thrombectomy or thrombolysis and revision Therapeutic anticoagulation should be initiated Even with restoration of good arterial flow, biliary stricture or hepatic necrosis may result Portal vein thrombosis (PVT) occurs in fewer than 5% of pediatric patients but can prove to be devastating to the graft if it occurs within the first few days after LT.13 The primary risk factors for PVT include pretransplant PVT or diminished portal venous flow due to established portosystemic varices that compete for mesenteric venous drainage Incidence of PVT also increases with technical variant grafts, including reduced and split segmental grafts Late presentation of PVT or portal vein stenosis is characterized by portal hypertension and ascites The onset of new or increasing ascites and portal hypertension in the weeks following liver transplantation should raise concern for hepatic venous outflow obstruction Hepatic vein stenosis may be seen in the early or delayed posttransplant period, often producing liver graft congestion, high abdominal drain output, and portal hypertension This complication most frequently occurs in association with technical variant grafts due to rotational or compression-related issues of the graft, resulting in venous outflow obstruction The resulting graft congestion can cause bleeding from a cut surface of segmental graft or further compromise graft inflow and cause portal hypertension Bleeding Since hepatic synthetic function includes both pro- and antithrombotic proteins, patients are vulnerable to both bleeding and thrombosis.14 Regardless, intraoperative blood loss requiring blood product transfusion often occurs Postoperative bleeding has been associated with worsening degrees of thrombocytopenia and hypofibrinogenemia.14 Blood component transfusion should be considered when patients experience hemorrhage However, hyperviscosity and aggressive correction of coagulopathy and thrombocytopenia should be avoided to limit the potential contribution to vascular thrombosis Biliary Complications Biliary complications are the most frequent surgical complication of LT, occurring in approximately 15% to 20% of cases.15 These complications may occur early or late after transplantation; thus, they should be considered in the evaluation of any posttransplant liver dysfunction The graft bile duct is sensitive to ischemic injury and particularly dependent on hepatic arterial inflow for perfusion Biliary complications may present as bile leak and can be complicated by abscess or biloma Biliary strictures that develop are a risk factor for biliary obstruction and cholangitis HAT-related biliary strictures classically involve large, centrally located ducts, though they may also be multifocal, typically involving duct branch points Ischemic cholangiopathy results in diffuse bile duct injury of large and small ducts and can be associated with severe ischemia-reperfusion injury or with DCD donor grafts that experience long ischemia time Initial management for biliary strictures includes percutaneous transhepatic catheter placement in interventional radiology with drainage of intraabdominal abscess or biloma However, surgical exploration, repair, and possible retransplantation may ultimately prove necessary Rejection Acute cellular rejection is the most common complication following LT and is defined as graft injury caused by recipient immune response infiltrating the graft Data from the SPLIT Registry suggest that acute cellular rejection occurs in nearly 35% of patients in the first year following transplantation with the highest incidence in the first months.13 Children with acute rejection often remain asymptomatic; diagnosis is suspected based on abnormal liver function studies The diagnosis of rejection is confirmed on liver biopsy (Fig 97.1) Episodes of acute rejection often respond completely to treatment with short courses of high-dose corticosteroid therapy and rarely lead to graft loss The treatment of acute rejection commonly includes high-dose corticosteroid bolus therapy, delivered over to days Additionally, maintenance immunosuppression may be increased to target higher levels of tacrolimus The intensity and duration of the treatment course are guided by the clinical response of the liver Persistent or steroid-resistant rejection may require treatment with antilymphocyte BD V • Fig 97.1 Histologic appearance of acute cellular rejection The triad of (1) portal area lymphocytic infiltrate, (2) endothelialitis—subendothelial lymphocyte infiltrate of portal vein (V), and (3) cholangitis—lymphocyte infiltrate of bile ducts (BD) CHAPTER 97 Hepatic Transplantation 1167 antibody therapy Additional agents, such as mycophenolate mofetil, may be added to maintenance immunosuppression to allow rejection to resolve While acute rejection is characteristically a cellmediated event, the development of antibody-mediated rejection has been increasingly recognized as an important factor in longterm graft survival and chronic rejection pressure monitoring and blood draws—one central venous catheter, usually in the internal jugular vein, and additional peripheral intravenous catheters as needed Large-bore nasogastric tubes permit gastric decompression and Foley catheters help quantify urine output Surgical abdominal drains are placed in the operating room to monitor for intraabdominal bleeding and bile leak Infection Fluid and Electrolytes Children who undergo LT have high risk of infectious complications owing to both the underlying conditions necessitating transplantation and the need for immunosuppression Sepsis remains an important cause of morbidity and mortality in these patients Early infections are typically bacterial or fungal in origin and can include wound infections, intraabdominal abscess or peritonitis, cholangitis, urinary tract infection, central line–associated infection, and bacteremia Infants appear to be at greater risk for severe bacterial infection than older children.16 Biliary or intestinal complications, need for early reoperation, or use of an open abdomen and staged abdominal closure are also associated with early infection posttransplant Any intraabdominal fluid collection secondary to bile leak, hematoma, or ascites may become infected Multidrug-resistant organisms have been identified as an increasing cause of severe sepsis in this population.17 Viral infections and other opportunistic infections may occur in the months following liver transplantation and are typically related to the overall degree of immunosuppression.16 CMV and EBV infection may develop after completion of antiviral prophylaxis Risk is most related to recipient CMV and EBV status at the time of transplant, though influenced by level of immunosuppression Donor-origin infection is rare and may not present until several months after transplantation, requiring a high index of suspicion for accurate diagnosis Careful fluid and electrolyte management helps minimize development of fluid overload, preserving graft perfusion and decreasing the risk of vascular thrombosis The postoperative period is often accompanied by capillary leak physiology; judicious fluid resuscitation may be necessary in the first 24 to 36 hours to maintain normotension and appropriate volume status Central venous pressure monitoring can aid in assessing fluid needs Hourly documentation of inputs and outputs is essential for assessment of fluid balance Drain output should be monitored and replaced with electrolyte-containing fluids Diuresis is often initiated in the second or third posttransplant day Posttransplant lymphoproliferative disorder (PTLD) is a unique and significant complication of EBV infection The major risk for its development of PTLD is primary EBV infection occurring in the first year posttransplant EBV-naïve recipients of EBV-positive donor grafts are at highest risk Current strategies for EBV management include active surveillance of EBV polymerase chain reaction in serum at frequent and regular intervals during the first year after transplantation Management includes decreasing or discontinuing immunosuppression, though chemotherapy may be indicated if the lymphoproliferative response demonstrates more malignant characteristics Posttransplant Management in the Intensive Care Unit Early postoperative intensive care unit (ICU) treatment after LT focuses on ensuring optimal graft function and vigilant monitoring for signs of complications Management entails careful titration of fluids and electrolytes, maintenance of appropriate cardiac output, judicious use of analgesia and sedation, and continuous evaluation of graft function and recovery Drains and Vascular Access Vascular access following liver transplantation characteristically consists of two arterial catheters to facilitate invasive blood Initial baseline and interval assessment of liver function is critical Early laboratory indicators of graft recovery include stabilization of serum glucose levels and serial improvement in serum lactate and bilirubin levels Coagulopathy will correct as hepatic function recovers The patient’s neurologic exam is another informative data point regarding graft recovery but can be obscured by the need for analgesia and sedation Elevation of hepatocellular enzymes alanine aminotransferase and aspartate aminotransferase is typically seen within the first 24 hours posttransplant, reflecting hepatocellular injury related to ischemia and reperfusion of the liver Higher peak enzyme levels may be seen with long ischemia times or with low or insufficient vascular flow With sustained optimal graft perfusion, transaminase levels should start to decline 24 to 36 hours posttransplant (Fig 97.2) Doppler US assesses vascular flow and direction in hepatic artery, portal vein, and hepatic veins Ultrasound may also detect bile duct dilation, intraabdominal fluid collections, or changes in renal perfusion 2000 International units/L Posttransplant Lymphoproliferative Disorder Graft Function AST (SGOT) ALT (SGPT) GGT 1500 1000 500 0 12 15 18 21 Days following liver transplantation • Fig 97.2 Liver and biliary enzymes posttransplantation This patient re- ceived a liver transplantation at time Hepatocellular enzymes alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are elevated early after liver transplant, reflecting ischemic injury and organ reperfusion g-Glutamyltransferase (GGT) rises gradually and peaks in to 10 days, reflecting bile duct recovery and proliferation SGOT, Serum glutamicoxaloacetic transaminase; SGPT, serum glutamic-pyruvic transaminase 1168 S E C T I O N X Pediatric Critical Care: Gastroenterology and Nutrition Anticoagulation Owing to the risk of vascular thrombosis, prophylactic anticoagulation and antiplatelet therapies are administered postoperatively according to center-specific protocols Thromboprophylaxis is effective in reducing thrombotic complications in adult liver transplant recipients, although there are no prospective or randomized studies in children.18 Protocols may include heparin infusion with goal anti-Xa levels depending on patient-specific risk factors or presence of known thrombus Centers also report adjunctive therapies, including targeted antithrombin (AT) and fresh-frozen plasma administration for repletion of AT and proteins C and S.14 Antiplatelet prophylaxis with aspirin is initiated with the attainment of full enteral feeds and typically continued for several months posttransplant.18 Respiratory Support Immediate postoperative extubation in the operating room is increasingly common and appears to be safe and well tolerated in the appropriate clinical context.19,20 Otherwise, prompt extubation in the ICU is desirable Prolonged ventilator support is associated with longer ICU and hospital length of stay Sedation As with all critically ill children, the goal is to ensure adequate analgesia and minimize sedation in patients following LT Lingering hepatic encephalopathy, the presence of ICU delirium, and rapid changes in medication clearance postoperatively are confounding factors in this population Infection Prophylaxis Perioperative antibiotics to cover biliary and enteric organisms, as well as provide surgical site infection prophylaxis, are typically continued for 24 to 48 hours postoperatively Chemoprophylaxis against viral and opportunistic infections is started in the days posttransplant CMV prophylaxis with ganciclovir is initiated either universally or on a targeted basis for discordant donor-recipient serologic status.21 Pneumocystis and fungal prophylaxis with trimethoprim-sulfamethoxazole and nystatin or fluconazole, respectively, are also routinely used Immunosuppression Immunosuppression after LT inhibits the cytotoxic T-lymphocyte-mediated immune response to the allograft to prevent graft rejection or immune-mediated injury while also preserving overall immunocompetence and minimizing the risk of infection, malignancy, and drug toxicities.22 Immunosuppression regimens are initiated intraoperatively and continued according to standard center-specific protocols Induction of immunosuppression with monoclonal or polyclonal antibodies is sometimes employed as a means of reducing steroid exposure or delaying initiation of calcineurin inhibitors (CNIs) Antibody induction immunosuppression was used in approximately one-third of all transplants in the SPLIT Registry between 2011 and 2018.13 Specific agents include antithymocyte globulin (ATG), a rabbit polyclonal antibody that causes depletion of host lymphocytes Reactions to ATG are common and can include anaphylaxis and symptoms of cytokine release Thus, antihistamine and steroid premedication is recommended More commonly used for induction therapy are monoclonal antibodies targeting the interleukin-2 (IL-2) receptor (basiliximab), which inhibit T-lymphocyte proliferation These medications not trigger cytokine release syndrome and are generally well tolerated.23 The CNI tacrolimus serves as the backbone of maintenance immunosuppression regimens in the vast majority of pediatric transplant recipients CNI inhibition of IL-2 results in decreased T-cell activation and proliferation Side effects of CNIs include nephrotoxicity, neurotoxicity, gastrointestinal disturbances, and hyperglycemia CNIs are metabolized by cytochrome P450 Therefore, clearance and serum levels can be dramatically impacted by other medications that interact with the P450 system, such as certain antifungals, antibiotics, and anticonvulsants Corticosteroids remain an important component of most immunosuppression regimens, but most centers attempt to decrease long-term exposure owing to side effects on growth and metabolism Corticosteroids act through suppression of antibody production and cytokine synthesis, decreasing proliferation of T cells, B cells, and neutrophils Postoperative hypertension is a frequent complication in the setting of CNI and corticosteroid combination therapy, which can be treated with calcium channel blockers Liver Transplant Outcomes Patient and Graft Survival Patient and graft survival rates continue to improve over time, with 1-year patient survival and graft survival rates reaching 96% and 91%, respectively.2 These improvements have occurred despite an increase in acuity at the time of transplantation, as evidenced by higher PELD/MELD scores and greater numbers of 1A and 1B listings at transplant.1 With advancements in posttransplant survival, increased attention has shifted to healthrelated quality of life (HRQL) following pediatric LT HRQL scores in LT patients, particularly in the domain of general health perception, have been lower compared with those of their healthy peers but similar to children with chronic disease or other solidorgan transplants.24 School functioning is an area of particular concern as well, with LT children being at high risk for cognitive deficits New validated disease-specific HRQL tools may provide further insight into treatment-related challenges and mental health concerns for this population.24 Retransplantation The need for liver retransplantation has historically been approximately 10% to 30% and associated with inferior outcomes at all time points compared with primary LT Early retransplantation, occurring within 30 days posttransplant, most commonly has been indicated for primary graft nonfunction or vascular complications Late retransplant indications have included chronic rejection, vascular complications, and biliary complications As a result of improved patient and primary transplant graft survival over the past 10 to 15 years, there has been a steady decrease in the need for retransplantation, which has fallen to less than 10% of transplant activity in the United States Patient and graft survival after liver retransplantation, however, remain approximately 10% lower that survival rates after primary transplantation CHAPTER 97 Hepatic Transplantation Key References Flynn E, Huang JY, Hardikar W, et al Antithrombotic management and thrombosis rates in children post-liver transplantation: a case series and literature review Pediatr Transplant 2019;23:e13420 Kwong A, Kim WR, Lake JR, et al OPTN/SRTR 2018 Annual Data Report: Liver Am J Transplant 2019;20(suppl 1):193-299 Meyers RL, Tiao G, de Ville de Goyet J, et al Hepatoblastoma state of the art: pre-treatment extent of disease, surgical resection guidelines and the role of liver transplantation Curr Opin Pediatr 2014; 26:29-36 Montenovo MI, Bambha K, Reyes J, et al Living liver donation improves patient and graft survival in the pediatric population Pediatr Transplant 2019;23:e13318 1169 Ng VL, Alonso EM, Bucuvalas JC, et al: Health status of children alive 10 years after pediatric liver transplantation performed in the US and Canada: report of the studies of pediatric liver transplantation experience J Pediatr 2012;160:820-826.e3 Perito ER, Roll G, Dodge JL, et al Split liver transplantation and pediatric waitlist mortality in the United States: Potential for improvement Transplantation 2019;103:552-557 Sundaram SS, Mack CL, Feldman AG, Sokol RJ Biliary atresia: indications and timing of liver transplantation and optimization of pre-transplant care Liver Transpl 2017;23:96-109 The full reference list for this chapter is available at ExpertConsult.com ... fewer than 5% of pediatric patients but can prove to be devastating to the graft if it occurs within the first few days after LT.13 The primary risk factors for PVT include pretransplant PVT or... period, often producing liver graft congestion, high abdominal drain output, and portal hypertension This complication most frequently occurs in association with technical variant grafts due to rotational... infected Multidrug-resistant organisms have been identified as an increasing cause of severe sepsis in this population.17 Viral infections and other opportunistic infections may occur in the months following