Posttransplant survival in pediatric fulminant hepatic failure: The SPLIT experience

Authors


Abstract

Pediatric patients with fulminant hepatic failure (FHF) tend to be the sickest and have the most urgent need for a liver transplant. The purpose of this analysis was to identify factors associated with posttransplant survival in this subset of patients. Data on all FHF patients registered in the Studies of Pediatric Liver Transplantation (SPLIT) registry from 1995 to 2002 were analyzed. Demographics such as age, gender, race, weight, and etiology of liver disease were recorded. Pretransplant degree of encephalopathy; intubation; dialysis; laboratory parameters such as serum bilirubin and international normalized ratio of coagulopathy (INR); and type of graft: cadaveric whole, cadaveric technical variant, or living donor were analyzed to determine effects on patient survival. Overall, FHF accounted for 12.9% (141 / 1,092) of primary transplants performed between 1995 and 2002. The etiology of liver disease was unknown in the vast majority of children (126 / 141; 89.4%). Mortality while on the waiting list for FHF children is significantly higher than for children with other liver disease (P < .0001). Six-month survival posttransplant for patients with FHF (74.5%) is significantly lower (P < .0001) than those with chronic liver disease (88.9%). A multivariate model demonstrates that the highest risk group includes those children with grade 4 encephalopathy (P < .0001), infants less than 1 year of age (P = .018), and children requiring dialysis prior to transplantation (P = .002). Pretransplant bilirubin and INR were not significant predictors of posttransplant survival after controlling for the other significant factors. Living donor and split / reduced grafts did not have a significantly increased risk of posttransplant death compared to whole grafts. In conclusion, despite advances in the surgical techniques and changes in organ allocation, pediatric patients with FHF continue to have a high pretransplant mortality and less successful posttransplant survival compared to children with chronic liver disease. (Liver Transpl 2004;10:1364–1371.)

Fulminant hepatic failure (FHF) is rare in infants and children. FHF is classically described as severe liver injury with the development of encephalopathy within 8 weeks of the initial symptoms, in a patient without a previous history of liver disease.1 Terms such as fulminant and subfulminant or hyperacute, acute and subacute have been used to further categorize FHF.2, 3 However, these terms are often not helpful in the pediatric patient since the majority of liver failure in children is acute in nature.4 Furthermore, in many pediatric patients evidence of prior liver disease and encephalopathy is difficult to diagnose, particularly in infants.4

Several authors have tried to address the transplant listing criteria for FHF patients who potentially have a reversible disease. Despite medical advances, there is a paucity of data in the pediatric population.4–6 In general, it is a devastating process that results in mortality rates close to 90%.3, 7 Furthermore, although there are a few reports of liver assist devices, liver transplantation is the only accepted modality of treatment.8 In pediatric patients with FHF, more so than any other group, waiting time is critical. At a national level, organ allocation has been modified to give this group of patients the highest priority (status 1). Several technical variants; such as reduced size, auxiliary, split, and living donor grafts have been introduced to shorten waiting times when whole livers from cadaveric donors are not available. The purpose of this evaluation is to assess posttransplant survival of pediatric patients with FHF and to identify what factors lead to poor outcomes in this group of patients.

Abbreviations:

FHF, fulminant hepatic failure; SPLIT, Studies of Pediatric Liver Transplantation; INR, international normalized ratio of coagulopathy; CI, confidence interval; RR, relative risk.

Patients and Methods

This study involved data collected by the Studies of Pediatric Liver Transplantation (SPLIT) Research Group on patients who had been registered and prospectively followed since 1995. As of May 31, 2002, 38 participating centers from the United States and Canada have registered 1,588 patients to receive their 1st liver transplant, 1,092 of whom have received at least 1 liver transplant. During this time 181 of the 1,586 patients registered in SPLIT were diagnosed with fulminant hepatic failure (FHF), and 141 (12.9%) of 1,092 of primary liver transplants were performed because of FHF. The definition of FHF as implemented in SPLIT is a clinical course including all 3 of the following major criteria:

  • A history of at least a few days of healthy existence prior to developing clinical liver disease.

  • No known chronic liver disease or identifiable inborn error of metabolism.

  • Inury severe enough to cause failure of the vital functions of the liver within 3 months of the onset of clinical liver disease. Failure of vital functions is defined as hepatic encephalopathy grade 2 and / or refractory hypoglycemia and / or factors 5 and 7 levels < 5% (prothrombin time > 30 seconds). An etiology need not be identified.

Demographics, including age, gender, race, weight, and etiology of liver disease, were recorded. Weight was transformed into standardized Z-scores calculated from age- and gender-specific normative data provided by the 2000 Centers for Disease Control (Atlanta, GA) growth charts. These charts provide normative values at monthly intervals for each gender until the age of 20 years. Pretransplant degree of encephalopathy, serum levels of bilirubin (mg/dL), and international normalized ratio of coagulopathy (INR) were included to determine severity of liver disease. The type of graft (either whole or a technical variant such as split or reduced graft, or living donor) and donor age was noted, as was initial immunosuppression. Patients with FHF frequently develop associated complications in other systems that can affect success after liver transplant. Hence, we analyzed the need for dialysis and intubation.

Kaplan-Meier estimates of the probability of survival pre- and posttransplant were calculated and distributions were compared using the log-rank test. The Cox proportional hazards model was used to test univariate and multivariate associations. Factors significant at the .20 univariate level were included in the multivariate model. Model reduction was performed using the backward elimination variable selection method. All statistical analyses were performed using the SAS System for Windows, version 8.02 (SAS Institute, Cary, NC).

Results

Overall, FHF accounted for 12.9% (141 / 1,092) of primary transplants performed and registered in SPLIT between 1995 and 2002. Figure 1 shows that children diagnosed with FHF are more likely to die while on the waiting list compared to children with other diagnoses (P < .0001). The estimated 3-month probability of survival for patients diagnosed with FHF is 58.8%, and it is 96.0% for other diagnoses. This disparity in survival is lessened posttransplant; however, Figure 2 demonstrates that posttransplant, children with FHF remain disadvantaged (P < .0001). The 6-month probability of survival posttransplant is estimated to be 75.9% for children with FHF and 90.8% for children with other diagnoses. The primary cause of death posttransplant in FHF children is multiorgan failure (n = 7), cerebral edema (n = 6), other central nervous system conditions (n = 2), infection (n = 7), cardiopulmonary factors (n = 4), liver failure (n = 3), and other (n = 7).

Figure 1.

Pretransplant patient survival by primary diagnosis.

Figure 2.

Posttransplant patient survival by primary diagnosis.

Tables 1 and 2 provide a summary of pretransplant demographic, clinical, and biochemical characteristics of the SPLIT FHF transplanted cohort and each group's estimated 6-month survival probability. A total of 23 recipients (16.3%) were younger than 1 year of age at the time of transplant, with an estimated 6-month survival probability of 67.1% compared with a 84.6% survival probability in children 13 years of age or older. Male gender comprised 55.3% of the population, 56.7% were Caucasian, 15.6% African American, and 18.4% Hispanic. The majority of organs were from donors older than 13 years of age. A total of 38.3% of recipients received cadaveric technical variant organs (split or reduced) and 43.3% received cadaveric whole organs. Living donors were used in 14.2% of recipients. Liver disease etiology was unknown in the vast majority of children (126 / 141).

Table 1. Characteristics of Pediatric Patients Receiving Liver Transplant for Fulminant Hepatic Failure
 N%# DeathEstimated 6-month survival %
Total141100.03675.9
Age at transplant    
 Missing1.70
 0–12 months2316.3967.1
 1–5 years4028.41078.0
 5–13 years4330.51271.2
 ≥13 years3424.1584.6
Gender    
 Male7855.31978.2
 Female6344.71772.8
Race    
 White8056.72572.3
 Black2215.6486.4
 Hispanic2618.4480.4
 Other139.2373.8
Organ type    
 Living2014.2570.7
 Cadaveric whole6143.31379.6
 Cadaveric technical variant5438.31871.1
 Cadaveric other (organ type not known)64.30
Donor age    
 Missing42.8250.0
 0–12 months72.1285.7
 1–5 years1712.1573.9
 5–13 years1913.5386.7
 ≥13 years9466.72474.9
Primary immunosuppression    
 Missing149.9564.3
 Cyclosporine4229.81173.0
 Tacrolimus7452.51781.5
 Other117.8372.7
Early mono/polyclonal antibodies    
 No12790.13475.2
 Yes149.9285.7
Etiology of liver disease    
 Acute hepatitis A1.70
 Subacute hepatitis B1.70
 Subacute hepatitis C1.70
 Fulminant liver failure unknown etiology12689.43375.8
 Subacute fulminant liver failure32.1166.7
 Wilson's disease32.10
 Drug toxicity32.1233.3
 Other fulminant liver failure32.10
Pretransplant dialysis    
 Missing1.70
 No12185.82679.8
 Yes1913.51049.6
Pretransplant intubation    
 Missing42.80
 No7251.11779.8
 Yes6546.11970.0
Patient status    
 ICU12387.23375.3
 Hospitalized, not in ICU149.9375.0
 Not hospitalized42.80
Encephalopathy stage    
 None3726.2784.5
 196.4288.9
 22316.3576.5
 34934.81178.8
 42316.31148.7
Table 2. Characteristics of Pediatric Patients Receiving Liver Transplant for Fulminant Hepatic Failure
 Patient statusAll Patients
AliveDead
NMedianMeanSENMedianMeanSENMedianMeanSE
  • *

    Standardized Z scores calculated from age- and gender-specific normative data provided by the 2000 CDC growth charts.

Weight at transplant (kilos; P = .01)10323.030.92.13520.022.12.813822.328.71.8
Standardized, weight Z score* at transplant (P = .02)102.3.2.135−.5−.5.3137.1.0.1
Bilirubin at transplant (mg/dL) (P = .15)10220.821.11.43514.717.02.713718.620.01.2
INR at transplant (P = .17)813.53.8.2242.63.3.41053.33.7.2

The mean weight of the children at the time of transplant was 28.7 ± 1.8 kg. Children who died posttransplant had a mean standardized weight score of −0.5 ± 0.3 compared to a mean standardized weight score of 0.2 ± 0.1 for children still living at last contact. Only 26.2% of recipients were without encephalopathy at transplant. A total of 51.1% of patients were in stage 3 or 4 encephalopathy, suggesting that the majority of this group of patients were critically ill at the time of transplantation. Intubation was required prior to transplant in 46.1% of patients and dialysis was required in 13.5% of patients. Most of the FHF recipients were in the intensive care unit at transplant (87.2%). Tacrolimus was used as the primary immunosuppression in over half of the patients (52.5%) and early mono / polyclonal induction was used in only 9.9% of participants. An analysis of liver function at the time of transplant confirms that these patients were critically ill with severe liver failure. The mean serum bilirubin of the entire group of transplanted patients was 20.0 ± 1.2 mg/dL and the mean INR was 3.7 ± 0.2.

A univariate analysis was used to identify potential prognostic factors for patient survival posttransplant from among these demographic, clinical, and biochemical parameters. Table 3 provides estimates of relative risk (RR) and 95% confidence intervals (CIs) for each individual factor. Patients with the most severe grade of encephalopathy (stage 4) had the highest posttransplant mortality (RR = 4.05; 95% CI: 1.56-10.51; P = .004). RRs for these patients remained high when compared to stage 3 (RR = 2.94; 95% CI: 1.26-6.87) and stage 2 (RR = 2.97; 95% CI: 1.03-8.59). Patients requiring dialysis pretransplant also were at higher risk for posttransplant mortality (RR = 3.96; 95% CI: 1.89-8.31; P = .0003). With each unit increase in standardized weight score, an approximate 21% risk reduction in mortality is expected (RR = 0.79; 95% CI: 0.66-0.95; P = .01). The univariate model found that infants less than 1 year of age had a nearly 2-fold increase in mortality compared to children 1 year of age or older (RR = 1.95; 95%CI: 0.92-4.14; P = .084).

Table 3. Univariate Analysis of Risk Factors for Death After Patient's First Transplant
FactorCategoryPatient Survival
ABRelative risk*P value95% CI
  • Abbreviations: CI, confidence intervals; Tx, transplant; Abs, antibodies; Cad/tech, cadaveric technical variant.

  • *

    Relative risk > 1 implies patients in category A have higher risk of outcome compared with category B.

Recipient's age0–11 months≥1 year1.95.084(.92, 4.14)
GenderFemaleMale1.19.60(.62, 2.29)
RaceBlack .52.22(.18, 1.48)
 HispanicWhite.61.36(.21, 1.77)
 Other .73.61(.22, 2.43)
Donor/organ typeLiveWhole1.22.71(.43, 3.41)
 Cad/tech 1.64.17(.81, 3.36)
Donor's age0–11 months 1.38.66(.32, 5.86)
 1–4 years≥13 years1.05.92(.40, 2.76)
 5–12 years .57.35(.17, 1.88)
Primary immunosuppressionCyclosporineTacrolimus1.01.96(.48, 2.18)
 Other 1.43.57(.42, 4.88)
Early use of mono/polyclonal AbsYesNo.64.54(.15, 2.67)
Pre-Tx dialysisYesNo3.96.0003(1.89, 8.31)
Pre-Tx intubationYesNo1.42.29(.74, 2.73)
Encephalopathy stage1 1.22.80(.25, 5.89)
 2 1.29.66(.41, 4.09)
 3None1.20.70(.47, 3.10)
 4 4.05.004(1.56, 10.51)
Standardized weight at TxContinuous predictor.79.01(.66, .95)
Bilirubin at TxContinuous predictor.98.18(.95, 1.01)
INR at TxContinuous predictor.79.11(.59, 1.05)

No significant differences in posttransplant survival were observed for gender, race, donor organ type, donor age, primary immunosuppression, and early mono / polyclonal antibody use. INR and bilirubin were suggestive in the univariate setting (RR = 0.79; 95% CI: 0.59-1.05; P = .11) and (RR = 0.98; 95% CI: 0.95-1.01; P = .18), respectively, as were cadaveric technical variant grafts compared to whole organs (RR = 1.64; 95% CI: 0.81-3.36; P = .17).

A multivariate model including age at transplant, organ type, dialysis prior to transplant, encephalopathy stage, standardized weight Z-score, pretransplant bilirubin, and INR was evaluated. These factors had a P value less than .20 in the univariate analysis. When considered simultaneously, only recipient's age at transplant, pretransplant dialysis, and encephalopathy stage remained as important predictors for posttransplant mortality. Table 4 provides the RR estimates for each of these factors in the final model. The highest risk group is patients with grade 4 encephalopathy (P = .005), infants less than 1 year of age (P = .018), and children requiring dialysis prior to transplantation (P = .002). Patients with grade 4 encephalopathy are at 4 to 5 times higher risk compared with patients without encephalopathy (RR = 4.51; 95% CI: 1.57-12.9; P = .005).

Table 4. Multivariate Analysis of Risk Factors for Death After Patient's First Transplant
FactorCategoryPatient Survival
ABRelative Risk*P Value95% CI
  • Abbreviation: CI, confidence intervals.

  • *

    Relative risk > 1 implies patients in category A have higher risk of outcome compared with category B.

Recipient's age0–11 months≥1 year2.81.018(1.19, 6.59)
Pretransplant dialysisYesNo3.41.002(1.58, 7.39)
Encephalopathy stage1 1.13.879(.23, 5.48)
 2None1.34.623(.42, 4.24)
 3 1.19.734(.44, 3.25)
 4 4.51.005(1.57, 12.9)

Discussion

FHF is a frequent cause of liver failure in children. The Centers for Disease Control estimates that there are approximately 2,000 deaths per year from acute viral hepatitis.7 It is difficult to extrapolate how many of these occur in the pediatric population. However, these numbers do not account for the children who present with acute liver failure but eventually recover. The SPLIT data base suggests that 12.9% of primary liver transplant recipients carried a diagnosis of FHF. In the vast majority of the patients the etiology of liver failure is unknown. These results are similar to those reported by Goss et al.9 in which 57 of 569 pediatric liver transplants were secondary to FHF. However, Jain et al.10 noted only a 5% to 7% incidence of acute liver failure in their 20-year experience of pediatric transplantation in Pittsburgh. The registry provides data from 38 centers across the continent. This multicenter experience can be different from single-center experiences.

Advances in surgical technique and improved immunosuppressive management have led to 1-year patient and graft survival rates of 80% to 90% in most centers performing pediatric liver transplants.9, 11 However, the mortality rate in children is worse in the presence of FHF, both pre- and posttransplant.12 The poor outcome in this group of patients is multifactorial. Patients may be referred late, or the decision to list may be delayed due to the lack of specific criteria for parameters that predict liver recovery. These delays are compounded by the wait for a suitable organ. Technical variants to whole grafts such as split and living donors have been introduced and, in addition, the organ allocation system has been modified to give this group of patients the highest priority.13–15 Despite these steps, the pretransplant mortality remains extremely high.

FHF frequently results in dysfunction of multiple organ systems, including increased intracranial pressure and cerebral edema, increased risk of infections, acute renal failure, cardiovascular abnormalities, and severe coagulopathy.15 This study sought to determine factors that lead to poor posttransplant survival.

In our study, children under the age of 1 year at the time of transplant had worse survival when compared to older children. In the largest published series of pediatric liver transplants, the survival rate for all the patients was dependent on 3 factors: the age of the patient (infants less than 1 year of age as the highest risk population), the era of the transplant (before or after 1993), and the number of transplants required.9 Another report from Durand et al.16 presented a mortality of 50% after liver transplant in infants < 1 year of age. These dismal results were dependent on organ availability, surgical procedures, optimum preoperative management, and patient selection.17

Cerebral edema and intracranial hypertension are commonly present in patients with FHF. Brainstem herniation is the leading cause of death, in 80% of cases.7 There is a direct correlation between the degree of encephalopathy and the intracranial pressure.18 Despite improvements in our understanding of the pathophysiology of high intracranial pressures and the ability to accurately monitor patients perioperatively, patients with grade 4 encephalopathy continue to maintain a high mortality.19–22 In both acute and chronic liver disease, comatose patients have been recognized as a high risk group. In our study, this subgroup of patients had twice the mortality compared to those who presented with grade 3 or grade 2 encephalopathy (RR = 2.94 and 2.97, respectively).

The degree of prolongation of prothrombin time or the level of hyperbilirubinemia have also been used as dynamic prognostic indicators for liver injury.21, 22 In our study, we did not find any association of these factors with posttransplant patient survival, after adjusting for other significant factors. Perhaps the rapid biochemical correction that occurs after a successful liver transplant negates the ability of these factors to predict posttransplant survival. Furthermore, this group of children was previously healthy prior to this acute catastrophic event, compared to children with chronic liver disease.

Renal dysfunction in FHF occurs as part of a multisystem disorder and is manifested by oliguria with sodium and water retention.15 It has been reported to occur in 40% to 84% of FHF cases, and is the result of either a functional disturbance (hepatorenal syndrome) or acute tubular necrosis, caused by intravascular volume depletion and / or toxic effects of drugs.23 Usually renal function returns to normal posttransplantation; however, temporary support may be required in the earlier stages.15, 23, 24 Renal failure has been described as a poor risk factor affecting patient survival after adult liver transplantation and has been incorporated into the new model for end-stage liver disease scoring system.25–27 In children, more so than adults, serum creatinine is a poor marker of renal function. In our study, lacking glomerular filtration measurements and with the imprecision of calculated glomerular filtration rates, only the need for dialysis was recorded as a surrogate for renal failure. Only a small number of recipients (19 / 141) required renal support, and the outcome in these children support the findings of several other studies that have shown lower patient survival in patients who required perioperative renal support.21, 28, 29

Cardiorespiratory dysfunction is another common accompaniment of the multiorgan disorder in FHF. Delivery of oxygen to the tissues is adequate or increased, but a decrease in tissue oxygen uptake occurs, resulting in tissue hypoxia and lactic acidosis.15 In combination with these alterations, deterioration of mental status frequently results in patients requiring mechanical ventilation support. In our study, 65 of 141 recipients required ventilator support prior to transplant. Unlike Goss et al.12 reported earlier, the survival in this subset of patients was not compromised after adjustment for other factors. It is frequently recommended that early intubation be required to protect the airway from aspiration and prevention of pneumonia23; however, longer durations of intubation compromise the lower airway and can lead to sepsis.7 The small subset of these patients does not allow firm conclusions to be drawn.

In FHF, more so than for chronic liver failure, time to transplant is critical to the outcome. Technical variants of whole grafts such as reduced size, splits, and living donors have been utilized to overcome the problems with size mismatch from adult donors.13, 30 There is concern whether these technical variants carry the same outcome as whole grafts and are capable of supporting an extremely sick recipient.13, 22 A total of 57% of recipients received partial grafts. After adjustment for other important covariates, the overall survival in this group was not statistically different from those receiving full organs, as reported by other large pediatric transplant series.31–33 The use of partial grafts did not compromise the outcome of the recipients. These grafts may allow earlier transplants in FHF when a whole organ from a cadaveric donor is not available and may also avoid the use of “marginal” donors or ABO blood group–incompatible donors under these trying circumstances.13, 22

Several centers have reported improved outcomes with a decreased incidence of rejection, steroid-resistant rejection, and chronic rejection in children treated with tacrolimus-based primary immunosuppression compared with their historic results using cyclosporine.34–36 Hence, it was important to assess the effect of immunosuppression on mortality outcomes. We did not observe any differences in mortality between the 2 calcineurin regimens or for patients who received antibody induction.

Conclusion

Despite surgical advances and modifications in the organ allocation system, FHF in children continues to carry an extremely high pretransplant mortality. The overall posttransplant survival is significantly worse than chronic liver disease recipients. Biochemical parameters such as pretransplant serum bilirubin or INR do not distinguish between those who will survive or die after a liver transplant after adjustment for other important variables. The highest risk group is patients with grade 4 encephalopathy, infants less than 1 year of age, and need for dialysis pretransplant. Technical variants such as living donor and split / reduced grafts had a similar outcome compared to whole grafts. Along with early referrals to a transplant center, these newer techniques may lower pretransplant mortality.

Ancillary