Objectives: Acute liver failure is a rapidly progressive and life-threatening disease in children, whose clinical features differ from those of adults.

Materials and Methods: This is a review of a single center’s experience with pediatric acute liver failure in a region with insufficient deceased donor support. The study is a retrospective review and analysis of 22 pediatric patients with acute liver failure between January 2007 and May 2013.

Results: The cause of acute liver failure was indeterminate in 45.4% of cases. Listing for liver transplant was required in 72.7% of patients, whereas 27.3% developed spontaneous remission. In the patients placed on the liver transplant wait list, 75% underwent liver transplant and 25% died before undergoing liver transplant. The presence of ascites, high-grade encephalopathy, and laboratory findings including high lactate dehydrogenase and phos­phorous levels and international normalized ratio were significant parameters in selecting patients needing liver transplants. All liver transplants were from living donors. One- and 3-year patient survival rates after liver transplant were 75% and 75%. No serious donor complications occurred.

Conclusions: Living-donor liver transplant may be the only option to save the lives of pediatric patients with acute liver failure, especially in regions with insufficient deceased-donor support. Timely referral to a multidisciplinary transplant center, expedient evaluation of living donors, and appropriate timing of transplant are crucial for a successful outcome.

Key words : Living-donor liver transplant, Pediatric acute liver failure, Outcome, Pediatric liver transplan

Introduction

Acute liver failure (ALF) in children is a dramatic, dynamic, and rare clinical process characterized by rapid deterioration of liver function, leading to altered mentation and coagulopathy in previously healthy individuals without obvious underlying liver disease. Because of the lack of effective therapy to reverse hepatocyte injury or promote hepatic regeneration, supportive care is the only treatment option before proceeding to liver transplant. Hepatic encephalopathy (HE) may be subtle in pediatric ALF patients and may not appear until the terminal stage. The prognosis is determined by complications related to hepatic failure, including cerebral edema, overwhelming sepsis, and multiorgan failure. In contrast to adults, HE may not be essential to the diagnosis of ALF in children. Because children have causes different from adults, clinical outcomes of ALF also may differ. The cause of liver failure is indeterminate in 50% of pediatric patients with ALF.^1-6

Liver transplant has long been established as a lifesaving procedure that provides prolonged survival in select patients with ALF. After the evolution of new surgical techniques and establishment of successful immunosuppression regimens, the overall patient survival rate after liver transplant has increased to approximately 65% to 85%. To avoid complications, prognostic factors should be determined for appropriate patient selection for liver transplant before the development of high-grade HE. Clinical decisions regarding timing of liver transplant may be more difficult in children than in adults. In addition, the technical challenges of liver transplant and the risks of long-term immunosuppression make this decision even more complicated.^3-5,7

The heterogeneity of causes, the small number of cases, and the difficulty in predicting outcomes are challenges to the ability to draw satisfactory conclusions from clinical studies. In this retrospective review, we investigate the care of pediatric patients with AFL, analyzing the clinical and laboratory findings predictive of patient prognosis, the requirement for liver transplant, and timing of living donor evaluation and liver transplant in a region with insufficient deceased donor support.

Materials and Methods

Twenty-two pediatric patients with ALF were treated between January 1, 2007, and May 31, 2013. Demographic, clinical, and laboratory data were collected and retrospectively reviewed. Criteria for determination of ALF included (1) absence of known chronic liver disease, (2) biochemical findings appropriate for acute liver injury; (3) prothrombin time ≥ 15 seconds, and international normalized ratio (INR) ≥ 1.5 with encephalopathy resistant to vitamin K replacement or prothrombin time ≥ 20 seconds and INR ≥ 2.0 independent of HE. At time of admission, age, sex, duration of complaints, history of con­sanguinity, and findings on physical examination including ascites, jaundice, hepatomegaly, splen­omegaly, edema, and grade of HE were recorded. Patients were classified as hyperacute (7 d), acute (8-28 d), and subacute (29 d to 12 wk), according to time elapsed from overt jaundice to apparent enceph­alopathy, using the O’Grady classification. Although Child-Pugh and Pediatric End-Stage Liver Disease/Model for End-Stage Liver Disease scores have been used as predictors of mortality in children with chronic liver disease on wait lists for liver transplant, we noted these scores for all of our patients.

All patients in this study had been admitted to our intensive care unit. After initial medical examination and discussion with the family about prognosis and the possibility of liver transplant, a living-donor evaluation was undertaken immediately to determine whether a potential donor was available. Donor evaluation included medical screening and ethical investigations. The donor’s liver was evaluated in terms of quality, volume, and anatomy with radiologic work-up. Exclusion criteria included graft weight-to-body weight ratio of > 5% or < 1.0%. Laboratory values of potential donors were also recorded. After exclusion of frequently seen causes and acetaminophen intoxication, other possibilities of drug intoxication were evaluated in cases of close timing between drug exposure and symptom initiation. Hepatitis A, B, and C virus infections were screened by serologic tests, and other infections were diagnosed by immunoglobulin M positivity. Antinuclear antibody, antismooth muscle antibody, liver-kidney microsomal antibody, antids-DNA, and antimicrosomal antibody were all assessed. Suspected metabolic diseases were screened by blood and urine amino acid, urine reducing substance, and organic acid measurements with tandem mass spectrometer analyses. During follow-up, infection was diagnosed by positive blood, catheter, and urine cultures, pulmonary infiltration, and positive postmortem cultures. Patients who had gastrointestinal bleeding were also noted. Plasmapheresis was performed according to clinical findings and blood test results during follow-up. In cases of oliguria, hemofiltration was performed.

In most cases, King’s College Hospital criteria⁸ were the main determining factor for liver transplant. After transplant, recipient liver tissue was examined macroscopically and microscopically.

Surgical technique
All of the patients in our study group had been placed on wait lists, but deceased donor livers did not become available. Living donors were evaluated, and, when appropriate, living donor hepatectomy was performed. Belzer-University of Wisconsin solution was used as the preservation solution.

As described in detail in a recent publication,⁹ during the recipient’s surgical procedure, hepatic vein anastomosis was performed by using either a triangular or diagonal cavotomy. The graft hepatic artery was anastomosed to the proper right or left hepatic artery with a surgical microscope. Bile ducts were reconstructed by using an end-to-end biliary anastomosis in anatomically favorable cases and a Roux-en-Y hepaticojejunostomy or choledochojejunostomy technique in other cases according to graft type, indication for surgery, or number of bile ducts requiring anastomoses. A short transanastomotic silicone stent made from the tip of a 4.2-F or 6.6-F Broviac catheter (Bard Access Systems, Salk Lake City, UT, USA) were used in some living-donor liver transplant recipients during the Roux-en-Y hepaticojejunostomy procedure.

Medical treatment
As recently described by our group,⁹ liver transplant recipients were treated postoperatively with a double-drug immunosuppression regimen consisting of prednisone and calcineurin inhibitor (tacrolimus). Steroids were tapered and stopped by the end of 4 weeks. Ganciclovir (Cymevene, F Hoffmann-La Roche AG, Basel, Switzerland), 5 mg/kg twice per day for 2 weeks, was administered to high-risk patients for Cytomegalovirus infection, and valganciclovir (Valcyte, F Hoffmann-La Roche Inc., Nutley, NJ), 10 to 15 mg/kg twice per day, was continued for the next 22 weeks. In low-risk patients, valganciclovir (Valcyte), 10 to 15 mg/kg twice per day, was given for 24 weeks. In most cases, acetylsalicylic acid (Coraspin, Bayer Turk Kimya San Ltd. Sti. Istanbul, Turkey) was started the first day after liver transplant and continued for 6 months.

Follow-up
After discharge, recipients were followed weekly in the outpatient clinic for the first month, at 2-week intervals between 1 and 3 months, monthly between 3 and 6 months, and at 2- to 3-month intervals for the following 6 months. During follow-up visits, all participants underwent routine blood tests, including liver and kidney function tests, and serum immunosuppressive concentration, height, weight, and quality of life assessments.

Statistical analyses
For the purpose of our analyses, pediatric ALF patients were divided into 2 groups. Group 1 included 6 patients who did not require transplant during clinical follow-up after diagnosis of ALF, and group 2 included 16 patients who required liver transplant, 12 who received transplant and 4 who died before receiving a liver allograft. Statistical analyses were performed with SPSS software (SPSS: An IBM Company, version 15, IBM Corporation, Armonk, NY, USA). Results are presented as means ± standard deviation. A t test was used to compare groups, and correlation analysis was used to show the association between variables. Linear regression analysis was used to calculate adjusted associations. We used receiver operating characteristic curve analyses to assess the value of tests to predict abnormal cases. Survival analyses were conducted based on Kaplan-Meier method. P < .05 was considered to be statistically significant.

Results

Our analyses included 22 pediatric patients with ALF (10 female, 12 male) who were referred to a single hospital. Mean age was 49.1 months (range, 2-172 mo), mean height was 94.6 ± 26.4 cm (range, 56-150 cm), and mean weight was 17.6 ± 12.5 kg (range, 4.2-45 kg). No significant differences in demographic characteristics were reported (age, height, weight, sex, consanguinity) between the 2 groups (P > .05). In 10 patients (45.4%), the cause of ALF was indeterminate (Table 1). The mean time of illness before admission in this group was 4.8 days (range, 2-12 d; standard deviation of ± 2.7). Symptoms, including ascites (P = .033), splenomegaly (P = .029), and high-grade HE (P = .032), were significantly higher in group 2. Signs of jaundice and central nervous system findings (HE) were detected in all patients (Table 2).

Statistically significant differences in laboratory findings were detected between the 2 groups. Mean values of thrombocytes (platelet count), γ-glutamyltransferase, bilirubin, INR, prothrombin time, partial thromboplastin time, and ammonia, lactate dehydrogenase (LDH), and phosphorus levels were significantly higher in group 2 (Table 3). Mean Pediatric End-Stage Liver Disease/Model for End-Stage Liver Disease scores were significantly different between the groups and were higher in group 2 (35.6 vs 16.8; P = .008). In addition, the number of patients classified as Child-Pugh score C was statistically higher in group 2, whereas there were no patients classified as Child-Pugh score C in group 1 (14 vs 0; P = .006).

The mean intensive care unit stay was 2.5 days, and the mean hospital stay was 10.1 days for all groups. Four patients died before liver transplant when a suitable liver was not found in time, and 3 patients died after undergoing liver transplant. All patients in group 1 are alive (n = 6). No differences in hospital stay were observed between the 2 groups (P > .05).

Child-Pugh score (P = .002), Pediatric End-Stage Liver Disease/Model for End-Stage Liver Disease score (P = .008), prothrombin time (P = .001), partial thromboplastin time (P = .006), ammonia level (P = .006), lactate dehydrogenase level (P = .001), phosphorus level (P = .001), INR (P = .004), and grade of HE (P = .003) were noted to be statistically significant as predictive indicators for liver transplant (Figure 1).

In a multivariate regression analysis, Pediatric End-Stage Liver Disease/Model for End-Stage Liver Disease score (P < .001), Child-Pugh score (P < .001), phosphorus level (P = .037), γ-glutamyltransferase level (P = .024), and prothrombin time (P < .001) were significantly associated with the requirement for liver transplant (all variables of the correlation analysis were added to the model).

In 16 patients who required emergency liver transplant, a liver did not become available from the deceased donor pool after patients had been added to the wait list in the organ sharing system (group 2). A suitable living donor was found for 12 patients (8 male and 4 female patients). Of the 12 patients who underwent living-donor liver transplant, 9 received left lateral segment (segment 2 and 3), 2 received right lobes, and 1 received a left lobe. Despite full supportive therapy, the other 4 children died before undergoing transplant. Two of the recipients died within days after undergoing liver transplant, 1 with the diagnosis of brain death, and 1 due to primary nonfunction. In the remaining 10 patients, mean follow-up after transplant was 1030 days (range, 450-2408 days). Early postoperative medical complications included gastrointestinal bleeding (2 patients, 1 with Meckel diverticulum, and 1 with Roux-en-y), bile leak and abdominal abscess (2 patients), primary nonfunction (1 patient), brain death after transplant (1 patient), and pneumonia (1 patient). Infection, occurring in 40% of patients after transplant, was the primary complication. During the late postoperative period, aplastic anemia occurred in 2 patients (16%). One patient died 286 days after transplant, and 1 underwent bone marrow transplant 1 year after liver transplant. Both of these patients had been diagnosed with ALF of unknown cause before liver transplant. Cytomegalovirus infection occurred in 1 patient (8%). Four patients (33.3%) developed acute cellular rejection; all responded to treatment. A late complication of biliary stricture occurred in 1 patient and was treated surgically. The overall mortality rate in the liver transplant group was 25% (3 patients). On the basis of Kaplan-Meier analyses, 1- and 3-year patient survival rates after liver transplant are 75% and 75% in this series (Figure 2).

When donor complications were stratified using the Clavien-Dindo classification score,10 no serious lifethreatening complications were identified. In the 12 liver transplant donors, the total complication rate was 8.3% (1 patient), with the only complication being grade 1 wound infection.

Discussion

Liver transplant has become a safe and routine procedure for the treatment of acute and chronic liver disease. Starzl and associates were the first to perform a liver transplant in a 3-year-old pediatric patient from biliary atresia.¹¹ The first living-donor liver transplant procedures for pediatric ALF were in 3 patients, reported in 1994 by Tanaka and associates.¹² The group suggested that living-donor liver transplant was feasible clinically and ethically in patients with ALF. After this report, many centers reported their successful outcomes of living-donor liver transplant in pediatric ALF patients.^1,13-15

In Turkey, deceased donor donation rates are low. According to the Turkish Ministry of Health-National Organ and Tissue Transplantation System, the deceased donor donation rate was 3 to 4.8 donors per 1 million people between 2005 and 2014. Although patients with ALF have the highest priority on transplant wait lists, suitable livers for pediatric patients are rare even if split techniques are used, especially in regions with insufficient deceased donor support. Previous publications from pediatric liver transplant centers in Turkey also reported low transplant rates in pediatric ALF patients from deceased donors.^13,14 As shown in our report, in 16 pediatric AFL patients who required emergency transplant, a liver did not become available from the deceased donor pool after patients had been added to the wait list in the organ sharing system. A suitable living donor was found for 12 patients. Despite full supportive therapy, the other 4 children (25%) died before undergoing transplant. Twelve patients who had living-donor liver transplant probably would have had risk of dying if suitable living donors were not found. During the care of pediatric patients with ALF in a region with insufficient deceased donor support, 1 of the most important steps is the rapid evaluation to determine whether a living donor is available.

The morbidity and mortality risks for the donor should not be underestimated. Making decisions in a short time for donation brings about ethical, emotional, and psychologic dilemmas. Conversely, living-donor liver transplant has many advantages compared with other technical variant grafts. When a living donor is available, the timing of liver transplant can be easily organized according to recipient status, markedly minimizing wait time and postoperative mortality risk.^16,17 The posttransplant outcomes of pediatric recipients with ALF are generally considered to be poor compared with pediatric recipients with chronic liver disease and adult recipients with ALF.^18,19 We predict that correct timing for liver transplant is one of the most important parameters for survival. Other advantages include the quality of the liver and shorter cold ischemia times. However, it is imperative to carefully balance donor and recipient risks. The living-donor liver transplant presents a serious risk to the donor but allows the donor to actively participate in saving the life of a loved one.¹⁶

In patients with ALF, cerebral edema leads to HE, coma, brain herniation, and eventually death; however, in infants and children, symptoms of HE may be subtle. Hepatic encephalopathy may not appear until the terminal stage and may not be essential to the diagnosis of ALF in children. The Pediatric ALF Group defined ALF as having no evidence of chronic liver disease either at presentation or in the past (with the exception of Wilson disease) and vitamin K refractory coagulopathy (INR > 1.5 with HE or INR > 2 without HE). In addition, the Pediatric ALF Group reported that only 25% of patients with grade 3 or grade 4 HE recover spontaneously.^1,3 Hepatic encephalopathy staging is more difficult in children than in adults. All patients in our study had HE at the time of referral to the transplant/tertiary referral center (Table 2). In this review of our center’s experience, high-grade HE (grade 3 and 4) was an indication for liver transplant in most of the pediatric patients with ALF (88.9%). Our data revealed that grade of HE is closely associated with risk of mortality in pediatric patients with ALF.

Outcome after liver transplant varies by cause of ALF. Causes of ALF in pediatric patients differ from those in adults, with half being indeterminate.^1,3 In our patient population, the rate of ALF of indeterminate cause was similar to that reported in the literature (Table 1). Among all clinical and laboratory findings, HE grade and prothrombin activity have been postulated as the major prognostic factors for ALF. In most cases, mortality from ALF is associated with cerebral edema, overwhelming sepsis, or multiorgan failure.^7,20 Advanced HE and prolonged prothrombin time were found to be significant predictors of mortality or the requirement for liver transplant. Coagulopathy may determine hepatocellular failure in children with ALF and can be used to decide whether liver transplant is required.^16,21

Treating infections using wide-spectrum antibiotics is also important for successful outcomes, both before and after transplant. Plasmapheresis has been undertaken in an attempt to improve cerebral and systemic hemodynamics in ALF patients but was not found to significantly affect patient survival.^7,22,23 In all cases in this series, plasmapheresis was performed as a result of causative factors and clinical findings, and hemofiltration was performed in patients with oliguria.

In addition, although Child-Pugh and Pediatric End-Stage Liver Disease/Model for End-Stage Liver Disease scores have been used as predictors of mortality in chronic liver disease; a small number of studies have shown these to be useful in establishing the optimal timing for liver transplant evaluation and adding to wait list for pediatric patients with ALF.²⁴ The factors seen as predictors of poor outcome in this study included high-grade HE and abnormal laboratory studies, including prothrombin time, partial thromboplastin time, INR, ammonium, lactate dehydrogenase, phosphorous, and γ-glutamy­ltransferase levels, and platelet count. We need to be careful about closely following these factors before and after transplant.

Because some patients with ALF recover without transplant, it can be difficult to determine which patients are appropriate candidates for liver transplant. However, a higher mortality rate is seen in some diagnoses; in these patients, a rapid liver transplant is the only chance for survival. Because liver transplant is the only definitive treatment for ALF, several prognostic scoring systems have been introduced to identify which patients require early transplant and to predict mortality without transplant.

Noted contraindications to liver transplant include active uncontrollable sepsis, severe cardiopulmonary disease, multiorgan failure, extrahepatic malignancy, mitochondrial disease, active substance abuse, and HE grade 4 encephalopathy with severe neurologic impairment.^5,8,20,25,26 In our study, the King’s College Hospital criteria8 were the main determining factor for liver transplant.

Acute liver failure secondary to acetaminophen overdose, hepatitis A, and ischemia (approximately 60% spontaneous survival) was associated with better prognosis, whereas the prognosis was poor with drug-induced ALF, hepatitis B, and indeterminate causes (approximately 25% spontaneous survival).^1,3 Amanita phalloides (mushroom poisoning) and phosphorous intoxications were found to be associated with fatal hepatic failure and a high mortality rate both before and after transplant, especially in children.^6,27 Phosphorous intoxication was observed in 2 patients and mushroom intoxication was observed in 2 patients in this study, and all of these patients required liver transplant. Two of the patients died within days after transplant. Advanced HE and prolonged prothrombin time were found to be significant predictors of mortality. Infection is one of the most important factors affecting survival both before and after transplant.

In this series, 16 patients (68%) required liver transplant; however, only 12 patients (54%) could undergo the procedure. In some cases, late referral to the transplant center made it impossible to find a suitable donor within the critical time period. With this knowledge, early referral to a pediatric liver transplant center is the most important step in the care of patients with AFL. Hepatic encephalopathy should not be an important criterion for referral to a pediatric liver transplant center, as AFL could be in a late stage when HE appears. During that time, consideration of cause is also important. Early contact with a pediatric liver transplant center to make expedient living donor evaluation is important for appropriate timing of transplant. These are crucial for a successful outcome.

In conclusion, ALF is highly fatal in the absence of a living liver donor, especially in regions with insufficient deceased donor support. Our data in a limited number of patients suggest that some predictors may be used to determine the requirement for transplant before progression in HE grade and referral of patients to a liver transplant center. Timely referral to a transplant center, early evaluation of living liver donor candidates, supportive treatment according to cause of disease, and close follow-up are crucial in the care of pediatric patients with ALF.

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