Abstract
Management in the early postoperative period requires the coordinated efforts of the transplant team and the pediatric intensive care staff, and other key ancillary services, such as interventional radiology, nephrology and infectious diseases that are frequently involved in the management of these children. Patients with end-stage liver disease undergoing liver transplantation require meticulous medical care in the immediate postoperative period to assure adequate perfusion of the graft and avoid exacerbation of injury to other organ systems. Care should be guided by attention to the pretransplant physiologic state, which might include advanced portal hypertension and compromise to other organ systems, such as seen in hepatorenal or hepatopulmonary syndrome. Specifics of the transplant procedure including information regarding blood loss, challenging vascular anastomosis, and graft function following reperfusion are also essential considerations in the management plan.
Introduction
Management in the early postoperative period requires the coordinated efforts of the transplant team and the pediatric intensive care staff, and other key ancillary services, such as interventional radiology, nephrology and infectious diseases that are frequently involved in the management of these children. Patients with end-stage liver disease undergoing liver transplantation require meticulous medical care in the immediate postoperative period to assure adequate perfusion of the graft and avoid exacerbation of injury to other organ systems. Care should be guided by attention to the pretransplant physiologic state, which might include advanced portal hypertension and compromise to other organ systems, such as seen in hepatorenal or hepatopulmonary syndrome. Specifics of the transplant procedure including information regarding blood loss, challenging vascular anastomosis, and graft function following reperfusion are also essential considerations in the management plan.
General Principles of Early Postoperative Management
General aspects of the surgical procedure and common intraoperative complications are reviewed in Chapter 43. It is not uncommon for recipients to experience blood loss and replacement that exceeds their estimated blood volume and which can result in third-space fluid losses and pulmonary edema, transfusion-associated acute lung injury and acute renal insufficiency. Likewise, placement of a graft that exceeds the mass of the explanted liver can increase intra-abdominal pressure and impede ventilation. Management of fluid and cardiovascular support to maintain graft perfusion but limit pulmonary complications can be challenging. Monitoring of changes in arterial blood pressure and central venous pressure can detect acute intra-abdominal hemorrhage or vasodilatation caused by cytokine release related to allograft necrosis or systemic infection. The overwhelming majority of children remain intubated during the first 12 to 24 hours following the procedure even when they have not had evidence of pre-existing lung disease. Likewise, many receive ionotropic support during the anhepatic and postperfusion phases of the procedure, which is gradually tapered off following abdominal closure. Cardiac function may be depressed during the procedure because of the circulation of cytokines and of lactic acid released from the graft at reperfusion and it may not be restored to normal until the metabolic function of the liver is re-established.
The classic hallmarks of primary non-function of the graft is cardiovascular instability, coagulopathy that is difficult to correct with fresh frozen plasma and persistent lactic acidosis. Although many patients are relatively fluid overloaded at the conclusion of the procedure, efforts are not made to encourage diuresis until at least 24 to 36 hours following the procedure because of concerns regarding hypoperfusion of the graft resulting from a sudden drop in intravascular volume and blood pressure. Some degree of diuresis occurs spontaneously on the second and third postoperative day provided the patient does not have intrinsic renal injury or advanced pretransplant hepatorenal syndrome.
Patients typically receive prophylactic antibiotics for 24–72 hours to prevent common postoperative bacterial infections including wound infections. In fact, the rate of wound infections following liver transplantation in children is low, typically <5%, whereas blood stream infections are seen in up to one-third of patients even with perioperative prophylaxis [1–3]. In situations where there is increased risk for postoperative intra-abdominal abscess, such as inadvertent enterotomies during surgical dissection or hepatic abscess in the explant, antibiotics should be extended and tailored to suspected organisms. Patients that are naive to cytomegalovirus (CMV) and Epstein–Barr virus (EBV) are at risk to contract these infections via passenger lymphocytes in the transplanted graft. Recipients who have had prior infection with these latent viruses are at risk to develop reactivation of the infection, resulting in clinical illness when exposed to immuno-suppressive agents. To prevent symptomatic cytomegalovirus infection in the immediate postoperative period, most centers use antiviral prophylaxis with either ganciclovir or vangancyclovir. The method (intravenous vs. oral) and the duration for therapy varies, but a common approach is to administer 14 days of intravenous therapy followed by 10–12 weeks of oral therapy [4]. Antiviral therapy is intensified or restarted if patients develop clinically relevant cytomegalovirus disease. However, the threshold value of CMV DNA in the blood that should prompt pre-emptive therapy in asymptomatic patients is not well established.
Vascular complications are not uncommon after liver transplants in children and can cause serious graft dysfunction and even loss of the graft and the need to re-transplant. For this reason, it is common practice to implement an anticoagulant strategy that is either a continuation of one started during the transplant or is started de novo in the postoperative period. Heparin as a continuous infusion is started once the bleeding of the transplant is under control and the post-transplant coagulopathy that often is seen immediately after the transplant improves. Heparin at a dose of 10–20 units/kg/hour is started to achieve activated partial thromboplastin times ranging between two and two and half times normal. More recently heparin level (anti-factor Xa) monitoring has become the method of choice in regulating heparin therapy and infusion rates. Evidence suggests that anti Xa monitoring is better at achieving therapeutic levels and reduces the number of dose adjustments. There is no evidence that measuring anti Xa levels leads to fewer complications, either thrombotic or hemorrhagic.
Anti-platelet therapy with aspirin or clopidogrel is started once the child has started enteral nutrition and the acute dangers of thrombosis or bleeding have resolved.
Anticoagulation therapy with either unfractionated continuous intravenous heparin or, alternately, with low molecular weight heparin may be continued for longer in the face of thrombotic complications or when, in the opinion of the liver transplant service, sufficient thrombotic risk exists, either because of complex vascular reconstructions or a thrombotic predisposition on the part of the recipient. Anticoagulation therapy may be lengthened to six months or longer.
Returns to the operating room (OR) are not uncommon, particularly in children who have had prior complex surgery such as a Kasai procedure, or children who have received a split or reduced size transplant. The most common reason for returning to the OR in the first 48 to 72 hours after the transplant operation is bleeding. Bleeding is typically slow but continuous and may require adjustments in anticoagulation strategy. Typically, the first few postoperative days are a balance between anticoagulation and a certain permissive bleeding in the interests of not suffering from thrombotic complications. Returns to the OR are generally indicated when:
1. The abdominal distension interferes with ventilation;
2. Urine output is suffering from raised intra-abdominal pressure; or
3. Additional conservative therapy of watchful observation is deemed not to be in the best interests of the child.
Less common than bleeding in the first week after the transplant, suspected intra-abdominal infections may precipitate a return to the OR. And lastly, vascular problems such as thromboses or graft compression from a tight abdominal closure may precipitate a return to the OR.
Patients generally receive some initial immunosuppression in the OR, usually steroids, and chronic immunosuppressive treatment is started 12–24 hours after surgery. A detailed discussion of immunosuppression protocols and agents is included below. In patients with significant alterations in renal function prior to transplant, renal-sparing protocols that rely on biological therapy during the first few postoperative days and delayed calcineurin inhibitor (CNI) exposure until later in the first week may be effective in preserving long-term renal function.
Early graft function as judged by coagulation parameters and clearance of bilirubin should improve steadily following reperfusion of the graft. When this improvement is not observed, graft injury resulting from ischemia–reperfusion injury or vessel thrombosis should be suspected. Doppler ultrasound interrogation of the graft is ordered routinely on postoperative day 1 or even earlier if the operation ends in the early morning. Early ultrasound may identify either arterial or portal venous thrombosis prior to graft injury, allowing for expedient thrombectomy and the prevention of graft injury or loss.
Ischemia–reperfusion injury is more common in extended criteria grafts and when there has been prolonged cold or warm ischemia time. Patients receiving technical variant grafts may display rising serum aminotransferases in the first 24 hours, likely released from hepatocyte injury near the cut surface as a result of marginal blood supply in that area. This elevation does not reflect global injury to the graft and is not usually associated with prolonged coagulopathy. Bilirubin levels that stall or begin to rise during the first five days after surgery are more likely to be an indication of a biliary leak, either “cut-edge” or anastomotic, than of acute rejection. Changes in the color of effluent from abdominal drains may herald this complication. Screening ultrasound to detect biliary leaks during this early period is rarely helpful since residual hematomas and ascites collections following the surgical procedure obscure the field; CT examination may be more revealing.
Small-for-size graft syndrome may occur when the size of the graft to body weight ratio (GBWR) of the recipient is less than 1–1.25% of the body weight of the recipient. In general, most infants receive grafts that are generous and may exceed 3% or even 4% of their body weight even when reduced in size. Small-for-size syndrome is characterized by a prolonged INR, ascites, and poor clearance of jaundice. Other causes of graft dysfunction must be carefully excluded since small-for-size syndrome is mostly a diagnosis of exclusion.
Immunosuppression
The introduction of CNIs as immunosuppressive agents in the 1980s was pivotal to successful liver transplantation in both adults and children. Most pediatric liver transplant centers use an immunosuppressive protocol that couples a CNI (usually tacrolimus) with steroids and a cell cycle inhibitor, such as azathioprine or mycophenolic acid. The mechanism of action of these agents, side effects, and drug interactions are detailed in a recent review [5]. Although the addition of an antimetabolite may not be essential in the first few weeks to months, its use may facilitate steroid withdrawal or avoidance. Table 44.1 summarizes a representative immunosuppression protocol including a timeline for target CNI levels during the first post-transplant year. Induction with monoclonal antibody therapy, although popular in the 1990s, is now used sparingly since the risk of graft loss to rejection in liver transplantation frequently does not outweigh the risk of opportunistic infection and malignancy posed by these agents. Although acute rejection is common following liver transplantation, with an incidence of approximately 40% in children in the first year following transplant (Figure 44.1), a single episode of acute rejection does not appear to increase the risk of graft loss [6]. Therefore, most protocols in pediatric liver transplantation are aimed at achieving a low rate of immunosuppression-related complications while accepting some episodes of early acute rejection [7]. Discontinuation of steroids during the first 6 to 12 months is now routine in many programs (Figure 44.2). Approaches that individualize immunosuppression regimens to reduce toxicity based on individual patient risk factors are becoming more popular, for example the use of induction therapy with delayed CNI exposure in patients with pre-transplant renal insufficiency/failure. Strategies of immunosuppression in pediatric solid organ transplantation have been the focus of several excellent reviews that highlight the mechanism of action and side effect profiles of commonly used agents [5, 8].
Pediatric liver transplant immunosuppression management
Table 44.1 Immunosuppression after liver transplantation. (a) Target tacrolimus levels post liver transplant including recommended levels after late rejection (b) Suggested schedule for steroid withdrawal post liver transplant (a) Tacrolimus (calcineurin inhibitor)
| Time post-transplant | Goal tacrolimus levels (ng/mL) |
|---|---|
| Post-transplant | |
| Months 1–3 | 10–12 |
| Months 3–8 | 8–10 |
| Months 8–18 | 5–8 |
| Beyond 18 months | 3–5 |
| After late rejection | |
| Months 1–3 | 10–12 |
| Months 3–4 | 8–12 |
| Months 4–8 | 8–10 |
| Months 8–18 | 5–8 |
| Beyond 18 months | 3–5 |
(b) Suggested steroid withdrawal schedulea
| Time post- transplant | Daily steroid dosage (mg/kg) |
|---|---|
| Months 1–3 | 0.3 |
| Months 3–4 | 0.2 |
| Months 4–5 | 0.1 |
| Months 5–6 | 0.05 |
| Months 6 | 0.05 every other day for 2 weeks then STOP |
(c) Cyclosporine serum goals post-transplant
| Time post- transplant | Goal trough level (ng/mL) | Goal 2-hour peak level (ng/mL) |
|---|---|---|
| Months 1–3 | 250–300 | 800–1200 |
| Months 3–8 | 200–250 | 600–1000 |
| Months 8–18 | 150–200 | 400–800 |
| Beyond 18 months | 50–150 | 200–600 |
a With normal laboratory tests; excludes patients with recent or ongoing rejection and/or patients with diagnosis of autoimmune liver disease.
Figure 44.1 Incidence of first rejection for patients in the Studies of Pediatric Liver Transplantation Registry depicted by era of transplant. Total sample 5774 patients.
Figure 44.2 Post-transplant steroid use in the Studies of Pediatric Liver Transplantation Registry by year of transplant. Note the percentage of patients that remain on steroids in long-term follow-up has decreased over time. Patients who had a retransplant after 1 month are excluded.
Diagnosis and Treatment of Rejection
Acute rejection most commonly occurs during the first two to six weeks following transplantation or during periods of diminished immunosuppression exposure as a result of non-adherence or malabsorption. The histologic pattern of rejection includes several key elements (Figure 44.3), and grading of the severity of rejection is based upon histologic injury and liver functional impairment. First-line therapy generally includes steroid boluses, but episodes related to diminished immunosuppression exposure may respond to increasing levels of CNI. In early acute rejection, over 60% of patients will respond to bolus intravenous solumedrol (10–20 mg/kg over three to five successive days), as judged by improvement in serum liver enzymes and direct bilirubin levels [9]. It is important to confirm suspected episodes of rejection histologically since multiple other causes of graft injury including CMV and EBV infection may mimic the clinical signs of rejection. However, histologic evaluation of response to augmented immunosuppression therapy is usually reserved for patients with suboptimal clinical response. In the setting of severe acute rejection, a Rejection Activity Index score of 7, or steroid-resistant rejection associated with significant graft dysfunction, therapy with an anti-lymphocyte preparation may be necessary.
Figure 44.3 Post-transplant rejection. (a) Acute cellular rejection. Portal tract containing a dense lymphocytic infiltrate. The infiltrate fills the entire portal tract, with spillover of lymphocytes into the periportal (zone 1) hepatic parenchyma, in a pattern of interface hepatitis. The bile duct (BD) shows infiltration of the epithelium by several lymphocytes. The portal vein shows endothelial infiltration (E), also by lymphocytes. (b) Development of de novo autoimmune hepatitis. The portal tract also contains a dense lymphocytic infiltrate, with prominent interface hepatitis (upper left). However, the bile duct and the endothelium of the portal vein are spared by the infiltrate (right side of the image). (Hematoxylin & eosin stain, original resolution of both images ×200.)
Long-Term Maintenance of Immunosuppression and Tolerance
Follow-up studies of long-term survivors of liver transplantation reveal that patients require less immunosuppression as time elapses from transplant and that many display acceptable graft function while on monotherapy with a CNI: approximately 65% at both five years and ten years [10, 11]. Minimization of CNI exposure with reduction to once daily dosing may also be well tolerated by those without evidence of chronic inflammation on biopsy [12, 13]. A smaller fraction, up to 20–40%, may even have operational tolerance as defined by normal or nearly normal graft histology after complete withdrawal of immunosuppression. Some of this experience has been reported in small groups of patients that were withdrawn from immunosuppression because of life-threatening complications such as post-transplant lymphoproliferative disorder or progressive renal insufficiency. However, two multicenter trials to withdraw immunosuppression in pediatric patients have demonstrated that a third or more of carefully selected patients can fulfil the definition of operational tolerance by maintaining normal graft function while off immunosuppression therapy for at least one year [14]. Patients most likely to tolerate immunosuppression withdrawal include those with normal liver enzymes and graft histology at baseline. However, in the subset of patients that develop mild acute rejection during withdrawal, the process appears easily reversible with enhanced immunosuppression. Experimental protocols to develop immune-based screening tools to optimize selection of patients for immunosuppression withdrawal are underway.
Infectious Complications
The success of liver transplantation depends not only upon maintaining graft function but also upon the effective prevention and treatment of infectious complications. Since the early 1980s, infectious complications have been one of the most prominent causes of post-transplant mortality, demonstrated in an early SPLIT publication in which infection was the most common cause of death even in long-term follow-up [3].
Early Infections
Approximately one-third of patients develop a bacterial infection within the first 30 days after liver transplantation [3]. Antibacterial prophylaxis is generally made up of ampicillin and a cephalosporin. More directed antimicrobial prophylaxis may be initiated because of known pathogens in certain children based on individual infectious histories.
Early postoperative intra-abdominal infections are predominantly caused by aerobic enteric gram-negative organisms. Enterococci and staphylococci are also commonly isolated. The spectrum of bacterial isolates depends both upon the institution and patient colonization, but infection by anaerobic bacteria is uncommon. An important exception is in the setting of ischemic necrosis of the graft, and in this situation empiric antibiotic regimens should include anaerobic coverage. Fungal infections are far less common, documented in approximately 10% of patients within this same time frame. Intra-abdominal fungal infections are more common in the setting of bowel perforation, large volume transfusion or prolonged exposure to steroids in the pre-transplant period [15, 16]. Factors associated with an increased risk of early bacterial or fungal infection include age <12 months and receiving a technical variant graft. Increased risk in the setting of segmental grafts is likely related to surgical complications, particularly those involving the biliary tree.
Serious viral infections, including CMV, EBV, and adenovirus, typically present at a later time point in postoperative recovery. CMV disease occurs in 10% and is typically delayed until CMV prophylaxis therapy has been completed [17]. The manifestations of CMV infection depend upon whether the infection is primary or a reactivation. Patients who have positive serologies supporting a previous infection prior to transplant can develop reactivation within the first few postoperative weeks if antiviral prophylaxis is not given. Symptoms tend to be milder in reactivation, but multisystem disease can occur. Manifestations of CMV disease, either reactivation or primary infection, commonly include fever, diarrhea, and elevation of liver enzymes. Less commonly, patients can develop a bilateral pneumonia. A high index of suspicion must be maintained because patients can develop severe disease quickly. Early treatment with ganciclovir can circumvent multisystem injury.
Most EBV disease also occurs after 30 days post-transplant. Patients who are seronegative for EBV at transplant and acquire a primary infection while on T-cell immunosuppression are at increased risk to develop post-transplant lymphoproliferative disease. Increasing experience with immunosuppression protocols has helped to reduce the incidence of this disorder, which is now reported to be <3% during the first 15 months post-transplant [18]. The disease can present at any interval after transplant but is most common when levels of immunosuppression are relatively high. Post-transplant lymphoproliferative disease in the liver transplant recipient frequently presents as bulky adenopathy in the head and neck region and in the intra-abdominal or retroperitoneal area. Discrete lung lesions and ulceration in the small and/or large colon are also commonly observed. Presentation of gastrointestinal lesions typically includes chronic diarrhea and low serum albumin secondary to mild protein-losing enteropathy. Treatment strategies include reduction or elimination of CNIs when possible and rituximab, a monoclonal anti-CD20 antibody.
Pneumocystis jiroveci infection is also of concern during the first postoperative year. Prophylactic regimens of oral trimethoprim–sulfamethoxazole are fairly standard for the first 12 months. This and other opportunistic infections are rarely seen outside of setting of intense immunosuppression, such as antibody therapy for resistant rejection. The immunomodulatory impact of recent viral infection with CMV may also increase infection risk.
Infections in Long-Term Follow-Up
Bacterial infections presenting after the recovery from the transplant procedure are more commonly community acquired and can include bacterial pneumonia, urinary tract infection, and invasive pneumococcal disease [19]. Recipients of solid organ transplants appear to be at higher risk for invasive pneumococcal disease than the general pediatric population and should be immunized appropriately [20]. Isolation of enteric bacteria from blood culture should raise the strong suspicion of biliary tract obstruction, as described below. Common viral pathogens such as respiratory syncytial virus and rotavirus can cause exaggerated infections in transplant recipients particularly when acquired during periods of intensified immunosuppression. Community exposure to varicella with subsequent infection can also result in a more severe course. Patients with evidence of acute varicella should be treated with intravenous acyclovir to prevent disseminated disease.
Evaluation of the Febrile Patient
The approach to a febrile episode in a liver transplant recipient varies by the interval from transplant and the level of immunosuppression. Patients who are within the first few postoperative weeks require a comprehensive search for blood-borne pathogens and intra-abdominal sources. This evaluation should include assessment of EBV and CMV viral load, even in patients who have been receiving prophylaxis. Evaluation for respiratory infection can be guided by the presence of respiratory symptoms. Gastroenteritis, either hospital- or community-acquired, is also likely to be associated with typical symptoms. Patients with central access are managed with empiric antibiotics while awaiting blood culture results, even if a plausible source other than the line is identified. Central catheter infections are relatively uncommon, and isolation of enteric organisms from central line cultures should prompt evaluation for an intra-abdominal or biliary source. Acute rejection rarely causes significant fever (38.5°C (101.5°F)) but it can be associated with persistent low-grade fever over several days. Patients who are receiving intensified immunosuppression for treatment of acute rejection are at higher risk for reactivation of both EBV and CMV and it should be recognized that tissue infections may not always result in recovery of virus from the blood.
In intermediate and long-term follow-up, the differential also includes community-acquired infections. It is not uncommon for transplant recipients to have exaggerated and prolonged viral infections, even years after transplantation when immunosuppressive levels are relatively low. Late biliary strictures are also an important cause of unexplained fever and can result in positive blood cultures for enteric organism even when liver enzymes are normal. The more common presentation of biliary strictures however is a patient who has had intermittent elevation of cholestatic markers, with or without a history of acholic stools, who presents with high fever and a septic appearance. When fever occurs immediately after a percutaneous liver biopsy, chronic biliary obstruction with subclinical cholangitis is almost always the cause.
Selection of empiric antibiotic coverage should be designed to cover enteric organisms and skin flora if the patient has central access. Attention to a history of isolation of resistant organisms such as vancomycin-resistant enterococci or extended-spectrum beta-lactamase-producing species should also guide choices. Short-term empiric CMV therapy may also be warranted in patients with the appropriate clinical symptoms while confirmatory tissue samples are obtained. Isolated fever has been associated with CMV viremia, even in long-term follow-up, and therapy with intravenous ganciclovir is appropriate in these patients, even without evidence of tissue invasion.
Evaluation of Graft Dysfunction
The differential diagnosis of graft dysfunction varies with interval from transplant. Primary non-function of the allograft is a devastating problem that occurs in approximately 1–3% of patients and which is usually suspected even prior to abdominal closure. Grafts that are ultimately classified as having primary non-function typically do not exhibit appropriate reperfusion, despite patent vessels, and do not produce bile during the later operative phase. These grafts develop progressive ischemic necrosis, and liver synthetic function is severely compromised. Expedient retransplantation is necessary for patient survival. Causes of less severe early graft injury include ischemia reperfusion injury (one to five days) and postsurgical complications such as vascular thrombosis and biliary tract obstruction. Ischemia reperfusion injury and hepatic arterial thrombosis (HAT) can both cause a similar pattern of moderate to severe early graft injury, which includes high aminotransferases and rising bilirubin. Timely diagnosis of HAT can allow thrombectomy before significant graft injury occurs [21]. Acute rejection can present as early as five days after transplantation but most frequently presents between one to six weeks. For this reason, immunosuppression protocols are aimed at achieving the highest levels of suppression within this timeframe. Small-for-size syndrome is also an important cause of graft dysfunction within the first few weeks. Transplantation of an organ that is less than 0.8% of the patient’s weight may result in a constellation of problems, including prolonged coagulopathy, increasing cholestasis, and signs of ongoing portal hypertension. Portal vessels in the smaller organ are unable to accommodate the rate of portal blood flow, which is proportional to patient size. Conversely, grafts that are significantly larger than the explant have been associated with an increased risk of ischemic congestion secondary to hepatic outflow obstruction. In this situation closure of the abdominal wall can lead to increased intra-abdominal pressure and compression of the hepatic outflow track.
For grafts that have a GBWR of greater that 4%, delayed abdominal wall closure improves graft perfusion by reducing intra-abdominal pressure thus avoiding an intra-abdominal compartment syndrome. With the latter situation not only graft perfusion may be compromised, but kidney compression can lead to either oliguria or anuria, diaphragmatic excursion is limited leading to hypoxia or hypercarbia which can exacerbate poor graft perfusion and may lead to poor perfusion of the lower extremities. Patients can generally tolerate either skin closure alone or temporary closure with either GORETEX or silastic sheeting for only a few days to more than two weeks to allow the liver to accommodate in size until primary closure can be achieved safely.
Bowel wall edema can also cause a delay in abdominal wall closure. This situation may occur in patients who have no pre-existing portal hypertension and porto-systemic shunting, and in whom portal clamping may cause intestinal edema and intramural hematomas. In this situation, delaying the bile duct anastomosis for a few days until the bowel edema improves may reduce bile duct complications such as leaking from the anastomosis rather than rushing to complete all aspects of the operation at the same time.
In long-term follow-up, the etiology of graft injury is more diverse. Acute rejection, vascular thrombosis and biliary obstruction are still observed, but chronic inflammatory injury independent of these problems is also observed. Routine surveillance of graft histology in long-term follow-up has not been universally adopted, but programs that have implemented such screening suggest that chronic hepatitis is common in long-term survivors, even in those with normal liver enzymes. A recent analysis of biopsy samples from recipients being screened for inclusion in an immunosuppression withdrawal trial identified a sub-set of patients with significant portal inflammation, many with interface activity. Gene expression profiles of liver tissue from these patients were enriched in genes that regulate T-cell mediated rejection, suggesting that these sub-clinical inflammatory responses may be a manifestation for late rejection [22].
Screening Strategies
Although there is little consensus on the optimal interval, routine screening of serum liver enzymes and bilirubin levels is universal across all liver transplantation programs. In addition, several studies have observed that graft histology may be significantly abnormal even in the face of normal liver enzymes, leading to biopsy screening protocols at some centers. Screening protocols for graft imaging are even less standardized.
Serum liver enzymes, bilirubin, and coagulation are usually monitored daily in the first seven to ten days following transplantation. The pattern of alteration guides further evaluation of complications that might warrant surgical intervention. As the likelihood of vascular thrombosis and bile leak diminish during the second post-transplant week, monitoring is shifted to a twice or three times per week schedule to allow early diagnosis of acute rejection. As patients complete their first post-transplant month, rejection becomes less likely and monitoring is gradually tapered from a weekly to a once monthly schedule at 8 to 12 weeks. Some programs continue to monitor at monthly intervals even after the first post-transplant year, while others shift to a quarterly schedule. A survey of centers included in the SPLIT Registry conducted in 2009 revealed that the majority of centers monitor no less than every three months, even in stable patients. Such monitoring allows not only assessment of serum liver enzymes, which may reflect subclinical liver injury, but also assessment of the relationship between liver enzymes and CNI levels. Some manipulation of CNI dosing to achieve normalized liver enzyme levels is acceptable, particularly in patients with a history of rejection. However, significant enzyme elevation (>3–4× baseline) and any rise in serum direct bilirubin should prompt graft biopsy since the pattern of enzyme elevation can be identical across a wide differential for graft injury.
Annual graft Doppler ultrasound assessments of the hepatic artery and portal vein are performed at some centers. Graft imaging is an obvious requirement when assessing new-onset graft dysfunction since biliary obstruction and vascular thrombosis can occur at any interval. It is helpful to exclude bile duct dilatation prior to percutaneous liver biopsy, since the risk of bile leak may be increased in the setting of biliary obstruction and it is essential to confirm hepatic arterial patency before planning percutaneous intervention for biliary obstruction. An increase in spleen size associated with a fall in platelet count may be an important sign of hepatic outflow obstruction or portal vein stenosis, which can be successfully treated with balloon angioplasty if diagnosed early. When laboratory tests are normal, the merits of screening ultrasound are less clear. Progressive fibrosis of the biliary jejunal anastomosis causing partial obstruction and bile duct dilatation can be diagnosed on ultrasound, allowing effective use of percutaneous interventions before the obstruction causes graft injury or leads to cholangitis. Late hepatic arterial loss with resulting ischemic cholangiopathy is less amenable to therapy, but earlier diagnosis may help to set expectation for impending problems.
Graft Injury and Common Complications
Hepatic Arterial Thrombosis
The incidence of HAT varies from 2% to 15% and the frequency of occurrence is related to the size of the recipient and donor vessels, the age of the recipient, and the quality of the donor organ [23, 24]. Occult or obvious procurement injures to the arteries of the graft may also manifest themselves in the early postoperative period as thrombotic complications. The loss of the hepatic arterial flow to the newly transplanted organ can present in a variety of ways. In stable recipients who have received good-quality organs, the thrombosis may be asymptomatic initially and present with liver enzyme elevations of a minor to moderate degree a few days after the actual thrombotic event. In other patients, HAT may present with massive necrosis of hepatocytes, impressive serum aminotransferase elevation of >5,000 IU/L, and signs of liver failure such as acidosis, uncorrectable and severe coagulopathy, and hemodynamic instability requiring vasopressors to support arterial blood pressure. Presentation may also be with early biliary complications such as bile leaks and bile duct necrosis. Since the bile ducts derive their blood supply exclusively from the hepatic artery, early bile leaks from the extrahepatic ducts and development of intrahepatic bile collections (bilomas) may be the chief symptoms even if the damage to hepatocytes is minor and liver synthetic function is not affected.
Ultrasound monitoring of the newly transplanted graft on postoperative day 1 is done chiefly to ensure the integrity of the arterial and venous flow to the liver. Early revascularization of the hepatic artery may be attempted when the thrombosis occurs on postoperative day 1 and is not accompanied by signs of graft damage. Revascularization is often successful in preventing subsequent graft damage [21]. However, even with successful restitution of arterial flow, chronic bile duct damage may present weeks or months after the transplant, with biliary sepsis secondary to stricture formation in the biliary tree. Strictures may occur at the anastomosis and be amenable to dilatation or surgical correction, or they may be multiple and located throughout the liver and require retransplantation [25].
Early postoperative HAT that is not successfully corrected usually requires early retransplantation in all patients. It may also occur later after transplantation and may present with signs of biliary sepsis or bile duct strictures with elevation of cholestatic enzymes. In patients with late presentation of HAT, therapeutic decisions are based chiefly on the severity of the damage to the graft and whether correction of the damaged ducts can be accomplished to the extent that long-term good-quality survival can be sustained. Revascularization in the late-onset HAT is not usually possible surgically nor can it reverse the damage that has already been well established in the graft.
Since HAT may have such devastating consequences, measures are taken to prevent this from happening. Meticulous technique must be used in the anastomosis of the two arterial segments from the donor and recipient. In vessels that are <3 mm in diameter, interrupted 8–0 prolene is used. In larger vessels in infant liver transplants, running or interrupted 7–0 prolene is used. Vessels are prepared for anastomosis by insuring that the intima is not damaged in any way, either in the preparation of the vessels or in the performance of the anastomosis. Operating microscopes have been used in the past, but in general, these are not necessary if 4.5× surgical loupes are used. For infants with metabolic diseases who have no signs of portal hypertension and have very small hepatic arteries, celiac axis conduits to the infrarenal aorta may be used as there is a very low incidence of thrombosis with this type of arterial reconstruction.
After the anastomosis, flow probes are used to determine the blood volume flow through the anastomosis. As mentioned above, low-dose anticoagulation with heparin is commonly used and antiplatelet agents such as aspirin are started when the child resumes oral intake. Full therapeutic anti-coagulation is used postoperatively only when the recipient is believed to be at increased risk for HAT. Ultrasound monitoring on the first postoperative day is always done for a baseline evaluation of flow and resistive index, and it is then ordered on an as-needed basis for the duration of the hospital stay of the recipient.
Recipients of live donor livers have a very low incidence of HAT. The excellent quality of the graft and the short preservation time results in a low resistance to blood flow through the graft and is thought to reduce the risk of HAT. The risk of HAT is increased in small graft weight to recipient weight ratios (≤1%), organs from small (<5 kg) donors, organs with complex donor arterial anatomy such as replaced right hepatic arteries that require more complicated reconstructions than usual, and in grafts from marginal donors. Approaches to prevent HAT vary widely across programs, but most centers include some form of anti-coagulation therapy in the immediate post-transplant period and long-term therapy with an anti-platelet agent. Frequently the approach is tailored to the specific surgical conditions and events [26].
Portal Vein Thrombosis/Stenosis
The portal vein supplies the liver with 80% of its blood supply and 50% of the oxygen supply. Despite this, portal vein thrombosis (PVT) after transplantation is usually asymptomatic and is most frequently diagnosed on routine postoperative ultrasound monitoring. PVT is the most frequent vascular complication after liver transplantation in children, and is most frequently observed in infants with biliary atresia, those with hypoplastic veins, babies with technical variant grafts such as split and living donor grafts, and those with robust arterial inflow [27, 28].
Unlike HAT, where technical factors may not play a dominant role in the etiology of the thrombosis, acute post-transplant PVT is often technical in origin and can be corrected with revision of the anastomosis and improvement of mechanical factors that may be contributing to impaired flow [29]. Intra-operative monitoring of the portal vein flow and intra-operative Doppler examination of the graft is essential to ensure that there is adequate portal venous flow at the conclusion of the operation prior to closure.
Patients with pre-existing large collateral varices or with surgically created portosystemic shunts may have to have the collaterals ligated at the time of the surgery or in the early postoperative period if the portal vein flow is insufficient to prevent thrombosis. Anti-coagulation prophylaxis is very much dictated by local practice and no single regimen has been proven to be superior [30].
Postoperative ultrasound is very sensitive and accurate in the determination of PVT. Clinical signs may be very subtle and not helpful in detecting portal vein flow problems. Liver enzyme elevation is not a feature of PVT. There may be a slight base deficit with a low serum bicarbonate, which is in contrast to the metabolic alkalosis that is often seen in the immediate post-transplant period. More commonly, PVT is seen in the technical variant transplants such as split-liver and live donor transplants. It is also more common when the recipient portal vein is hypoplastic or atretic and requires reconstruction with an interposition vein graft. In these situations, the portal vein ends up being longer than with whole liver transplants and takes a more meandering course as it lies horizontally across the inferior vena cava before coursing upward to a subphrenic location where it is anastomosed usually to a very short segment of donor vein. Care must be taken during the transplant to orient the vein properly in order to avoid twisting. Careful attention should also be directed to the anastomosis between the recipient vein, which may be quite small in diameter (<5 mm), and a donor vessel that is normal adult diameter.
If portal vein flow is not easily detected by ultrasound on the first postoperative day, the patient should be immediately re-explored. In re-exploration for PVT, it is usually not enough to simply remove the clot. The anastomosis must usually be undone, and the graft flushed with heparin and tissue plasminogen activator to clear microthrombi from the portal circulation. The recipient vein is usually also cleared both mechanically and with heparin, and the anastomosis is redone in an attempt to correct what may have been a technical issue contributing to poor flow after the first anastomosis. If the recipient portal vein is unusable, a jump graft formed from a deceased donor vein may be required from the superior mesenteric vein of the recipient to the donor portal vein. Infants with biliary atresia often develop hypoplasia and atresia of their extrahepatic portal veins, which may render them inadequate to revascularize the new liver with mesenteric blood. These babies often require replacement of their entire portal vein with donor vein, or a jump graft from the superior mesenteric vein.
Early PVT, if left uncorrected, will usually result in the symptoms of portal hypertension over the course of the ensuing months and years, including the development of esophageal and gastric varices and hypersplenism [27]. Chronic portal hypertension may also result from the gradual stenosis and ultimate occlusion of the extrahepatic portal vein. This is more common in technical variant transplants than with whole liver transplants. Frequent and regular monitoring of the transplanted liver’s vasculature along with careful physical examination looking for splenic enlargement accompanied by thrombocytopenia may allow for successful radiological intervention to correct a stenosis. Percutaneous balloon dilatation of a venous stricture, anastomotic or otherwise, may restore mesenteric venous pressures to near normal [31]. In older children with larger veins, endovascular stenting may allow for permanent correction of a recurrent venous stricture. Stenting in smaller children is contraindicated because of the fixed nature of the stent, which will not expand to allow for the increasing venous flow that accompanies the growth of the child.
The meso-Rex bypass was first used in the setting of PVT after transplant of whole livers. This operation accesses the intrahepatic left portal vein within the recessus of Rex where the vein is still patent [32]. A vein graft is brought from the superior mesenteric vein to the intrahepatic portal vein and can successfully re-establish mesenteric flow to the liver. Unfortunately, when this technique is applied to PVT in technical variant grafts, it may be difficult or impossible to work with the remnant of the donor left portal vein. This is because the left portal vein stump may be located within the hepatic parenchyma, the Roux-en-Y loop to the bile duct lies over whatever remains of the donor left portal vein, and the distance between the superior mesenteric vein and the donor left portal vein is longer than what it may be in a whole liver. The Roux loop usually develops into a source of mesenteric venous blood for the graft through the development of spontaneous venous collaterals between the bowel and the bile duct. These collaterals, if taken down, may exacerbate the symptoms of portal hypertension. If the meso-Rex bypass cannot be attempted, a distal splenorenal shunt can be successfully used to palliate the symptoms of portal hypertension. Unfortunately, children with chronic portal vein stenosis or thrombosis after transplantation may ultimately require re-transplantation to completely reverse their symptoms of intractable bleeding from intestinal varices.
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