**4. Transplant outcomes**

Unfortunately, medical contraindications may develop quickly over the course of illness, thereby preventing OLT. This was demonstrated in patients with APAP-induced ALF who fulfilled KCH criteria. Thirty percent were not listed due to the rapid development of preoperative contraindications to surgery and 35% of those who were listed were eventually delisted or not transplanted because of rapid clinical deterioration. The majority (90%) who met transplantation criteria but did not undergo OLT died (Bernal et al., 1998). In the largest US study, 29% of ALF patients underwent OLT but 25% of those listed (10% of the entire group) died prior to receiving an organ (Ostapowicz et al., 2002). In general, about 15-30% of patients die before OLT can be performed, usually due to brain death but other causes include sepsis, hemodynamic instability, multiple organ failure, and gastrointestinal bleeding (Bismuth et al., 1995; Castells et al., 1993).

#### **4.1 Survival with transplantation**

There are unique postoperative issues that afflict ALF patients. Despite OLT, elevated ICP and cerebral edema can persist for up to a day or more. In ALF patients who die post-OLT, as many as 13% succumbed to brain death (Barshes et al., 2006). Protective strategies, such as continued ICP monitoring, may be helpful through this period of risk. Although renal function often improves dramatically, patients may require renal replacement therapy for many weeks post-OLT, particularly in the setting of APAP-ALF. Immunosuppressive strategies that attempt to minimize nephrotoxic agents, such as calcineurin inhibitors, in this critical recovery period may be necessary. Nearly one third of post-OLT deaths in this setting are from bacterial or fungal infections (Barshes et al., 2006). The majority of these deaths occur within the first 2–3 months following the transplantation, usually due to neurologic complications or sepsis (Bismuth et al., 1995; DeVictor et al., 1992; Hoofnagle et al., 1995; W Lee, 2003; O'Grady et al., 1988; Russo et al., 2004; Wigg et al., 2005). In the largest Canadian study (60 patients transplanted between 1994-2007); the wait-list mortality rate was 6% with mean waiting time of 2.7 days. The perioperative mortality rate was 15%, and complications included neurological problems (13%), biliary problems (10%), and hepatic artery thrombosis (5%) (Chan et al., 2009). The Canadian data suggested that cerebral edema and extended criteria donor graft are associated with worse outcome.

The severity of multi-organ failure at the time of OLT is a good predictor of posttransplant survival (Devlin et al., 1995). Decreased renal function is also associated with worse spontaneous survival in non-APAP induced liver injury (Moore et al., 1991). In a multivariate analysis of UNOS data (1988-2003), four risk factors predicting post transplant survival were identified: history of life support, recipient age >50 years, recipient body mass index ≥30 kg/m2, and serum creatinine >2 mg/dL. If an individual had all of these risk factors, the 5-year post transplant survival was only 44-47%. Whereas, if none of these features were present, the 5-year post transplant survival was 82-83% (Barshes et al., 2006). The quality of the graft also impacts post-transplant outcome (Bismuth et al., 1995). Graft steatosis, reduced graft size, and ABO-incompatible grafts have all been shown in multivariate analyses to lead to decreased patient and graft survival (Bernal et al., 1998; Bismuth et al., 1995). On multivariate analysis of data from the United Kingdom, the strongest predictor of early mortality in seronegative ALF was higher donor body mass index (BMI), which may be a marker for donor graft steatosis (Wigg et al., 2005). This group found an odds ratio (OR) of 1.2 for every unit increase in donor BMI relative to a normal donor (BMI 25 kg/m2). For example, the OR for early death following OLT with a liver from an obese donor (BMI 35 kg/m2) is 1.2 to the power of 10 or 1.210 which is an OR of 6.2. The next most predictive variables were recipient age >50 years (OR 4.2) and non-Caucasian ethnicity (OR 4.9) Additional factors which have been reported to influence survival in ALF include recipient age >60 years, donor age >60 years, and mechanical ventilation at the time of transplant (O'Mahony et al., 2007; Mas et al., 2010). Unfortunately, graft quality needs to be weighed against the time factor, since patients may deteriorate while waiting for optimal grafts, sometimes to the point when they are no longer feasible candidates. Suboptimal grafts may fail; however, leading to the need for retransplantation.

Some advocate the use of venovenous bypass during the operation, but this is not uniformly practiced. Bypass is thought to minimize changes in cerebral perfusion pressure during the clamping of the inferior vena cava and portal vein as well as during reperfusion (Bismuth et al., 1996a; Jalan et al., 2003). Hepatectomy of the native liver with temporary portocaval anastamosis in certain patients may achieve temporary hemodynamic stabilization, with the expectation that a suitable graft will be available within the next 24-28 hours (Ejlersen et al., 1994; Ringe et al., 1993).

In infants with ALF transplanted between 1986 and 2000, only 24% had spontaneous recovery. Nearly half (47%) succumbed to sepsis or multiorgan failure, and 29% underwent

strategies that attempt to minimize nephrotoxic agents, such as calcineurin inhibitors, in this critical recovery period may be necessary. Nearly one third of post-OLT deaths in this setting are from bacterial or fungal infections (Barshes et al., 2006). The majority of these deaths occur within the first 2–3 months following the transplantation, usually due to neurologic complications or sepsis (Bismuth et al., 1995; DeVictor et al., 1992; Hoofnagle et al., 1995; W Lee, 2003; O'Grady et al., 1988; Russo et al., 2004; Wigg et al., 2005). In the largest Canadian study (60 patients transplanted between 1994-2007); the wait-list mortality rate was 6% with mean waiting time of 2.7 days. The perioperative mortality rate was 15%, and complications included neurological problems (13%), biliary problems (10%), and hepatic artery thrombosis (5%) (Chan et al., 2009). The Canadian data suggested that cerebral edema

The severity of multi-organ failure at the time of OLT is a good predictor of posttransplant survival (Devlin et al., 1995). Decreased renal function is also associated with worse spontaneous survival in non-APAP induced liver injury (Moore et al., 1991). In a multivariate analysis of UNOS data (1988-2003), four risk factors predicting post transplant survival were identified: history of life support, recipient age >50 years, recipient body mass index ≥30 kg/m2, and serum creatinine >2 mg/dL. If an individual had all of these risk factors, the 5-year post transplant survival was only 44-47%. Whereas, if none of these features were present, the 5-year post transplant survival was 82-83% (Barshes et al., 2006). The quality of the graft also impacts post-transplant outcome (Bismuth et al., 1995). Graft steatosis, reduced graft size, and ABO-incompatible grafts have all been shown in multivariate analyses to lead to decreased patient and graft survival (Bernal et al., 1998; Bismuth et al., 1995). On multivariate analysis of data from the United Kingdom, the strongest predictor of early mortality in seronegative ALF was higher donor body mass index (BMI), which may be a marker for donor graft steatosis (Wigg et al., 2005). This group found an odds ratio (OR) of 1.2 for every unit increase in donor BMI relative to a normal donor (BMI 25 kg/m2). For example, the OR for early death following OLT with a liver from an obese donor (BMI 35 kg/m2) is 1.2 to the power of 10 or 1.210 which is an OR of 6.2. The next most predictive variables were recipient age >50 years (OR 4.2) and non-Caucasian ethnicity (OR 4.9) Additional factors which have been reported to influence survival in ALF include recipient age >60 years, donor age >60 years, and mechanical ventilation at the time of transplant (O'Mahony et al., 2007; Mas et al., 2010). Unfortunately, graft quality needs to be weighed against the time factor, since patients may deteriorate while waiting for optimal grafts, sometimes to the point when they are no longer feasible candidates. Suboptimal grafts may fail; however, leading to the

Some advocate the use of venovenous bypass during the operation, but this is not uniformly practiced. Bypass is thought to minimize changes in cerebral perfusion pressure during the clamping of the inferior vena cava and portal vein as well as during reperfusion (Bismuth et al., 1996a; Jalan et al., 2003). Hepatectomy of the native liver with temporary portocaval anastamosis in certain patients may achieve temporary hemodynamic stabilization, with the expectation that a suitable graft will be available within the next 24-28 hours (Ejlersen et al.,

In infants with ALF transplanted between 1986 and 2000, only 24% had spontaneous recovery. Nearly half (47%) succumbed to sepsis or multiorgan failure, and 29% underwent

and extended criteria donor graft are associated with worse outcome.

need for retransplantation.

1994; Ringe et al., 1993).

OLT, of which half were still alive at a mean follow-up of 5 years. The authors concluded that infants had worse prognosis with ALF, since the etiology was more commonly an inborn error of metabolism. Extrahepatic disease sometimes excluded OLT as a means of treatment (Durand et al., 2001). The Studies of Pediatric Liver Transplantation (SPLIT) Research Group found that 13% of all primary transplants performed between 1995 and 2002 in children were done for ALF and that the majority of these cases were from unknown (indeterminate) causes (89%). The 3-month spontaneous survival was markedly diminished for children with ALF compared to those without (59% vs. 96%) and 6-month posttransplant survival was lower (76% vs. 91%, respectively). The majority of children with ALF (80%) die from brainstem herniation. On multivariate evaluation, risk factors for posttransplant mortality included grade 4 HE, age less than 1 year, and use of pre-transplant dialysis (Baliga et al., 2004).

Over the past thirty years, however, with advances in the field of liver transplantation and critical care management, the US 1-year survival rates following OLT for ALF have improved to 60-80% and 1-year post-transplant graft survival rates have improved from 63% to 75% (Bismuth et al., 1995; DeVictor et al., 1992; Hoofnagle et al., 1995; W Lee, 2003; O'Grady et al., 1988; Wigg et al., 2005). In Spain, Portugal, Belgium, and Italy, where the majority of ALF cases are induced by hepatitis B infection or cryptogenic causes, 1-year post-transplant survival is 61-79% (Areia et al., 2007; Detry et al., 2007; Escorsell et al., 2007; Montalti et al., 2005). These 1-year survival rates are less than the 1-year survival seen in patients who have been transplanted for chronic liver failure (80–90%) (Farmer et al., 2003; Freeman et al., 2008). However, by 1–4 years following transplantation this trend has reversed, and ALF patients have a better survival than those transplanted for chronic liver disease. Chan et al. reported the Canadian experience with 5- and 10-year patient survival rates of 76% and 69%, respectively, and graft survival rates of 65% and 59% (Chan et al., 2009). Poorer outcomes are seen in centers performing less than 25 liver transplants per year and less than 20 split-liver grafts per year for those doing living donor liver transplantation (Adam et al., 2000).

#### **4.2 Retransplantation**

Retransplantation occurs more frequently following emergent OLT (13%) compared to elective OLT (7%). The cause of graft failure is usually secondary to acute cellular rejection, primary graft nonfunction, or intrahepatic biliary strictures, all of which may be related to the quality of graft used or the use of an ABO incompatible graft (Adam et al., 1991; Farges et al., 1995; Gugenheim et al., 1990).
