Ravinder Anand

Development of a pediatric end-stage liver disease score to predict poor outcome in children awaiting liver transplantation

Background. A pediatric end-stage liver disease (PELD) score for children with chronic liver disease using easily obtainable, objective, verifiable parameters, would be useful to prioritize children awaiting liver transplantation. Methods. Data from the Studies of Pediatric Liver Transplantation (SPLIT), a consortium of 29 U.S. and Canadian centers, were used to develop the PELD score. Two pretransplantation endpoints were evaluated: (1) death, n=884; and (2) death or moving to the intensive care unit (ICU), n=779. The analyses were restricted to children with chronic liver disease who were listed for a first transplant. Preliminary analyses of 17 possible factors yielded 6 parameters of interest: age <1 year, total bilirubin, international normalized ratio (INR), albumin, growth failure (height or weight Z score <−2), and calculated glomerular filtration rate. In a univariate Cox regression analysis, age, bilirubin, INR, and albumin were significant (P <0.01) predictors of both endpoints; glomerular filtration rate was not significant for either endpoint; and growth failure was significant for death/ICU but not death alone. In the multivariate analyses, age, bilirubin, and INR were significant for the death endpoint; and bilirubin, INR, growth failure, and albumin were significant for the death/ICU endpoint. From these results, three PELD models were evaluated to predict both outcomes at 3 and 6 months: PELD 1 (age, bilirubin, INR); PELD 2 (bilirubin, INR, albumin, growth failure); and PELD 3 (bilirubin, INR, albumin, growth failure, and age). The area under the receiver operating characteristic curve (AUC ROC) was used to compare models. For PELD 3, the most inclusive model, the AUC ROC at 3 months was 0.92 for death and 0.82 for “death–moved to ICU.” A comparison of the AUC ROCs for the other models and for the model of end-stage liver disease ([MELD], the adult end-stage liver disease severity score model), none of which performed better than PELD 3, are presented. Conclusion. A model using five objective parameters can accurately predict death or death–moved to ICU in children awaiting liver transplantation.

Studies of Pediatric Liver Transplantation (SPLIT) : Year 2000 outcomes

Background. Initiated in 1995, the Studies of Pediatric Liver Transplantation (SPLIT) registry database is a cooperative research network of pediatric transplantation centers in the United States and Canada. The primary objectives are to characterize and follow trends in transplant indications, transplantation techniques, and outcomes (e.g., patient/graft survival, rejection, growth parameters, and immunosuppressive therapy.) Methods. As of June 15, 2000, 29 centers registered 1144 patients, 640 of whom received their first liver-only transplant while registered in SPLIT. Patients are followed every 6 months for 2 years and yearly thereafter. Data are submitted to a central coordinating center. Results. One/two-year patient survival and graft loss estimates are 0.85/0.82 and 0.77/0.72, respectively. Risk factors for death include: in ICU at transplant (relative risk (RR)=2.63, P <0.05) and height/weight deficits of two or more standard deviations (RR=1.67, P <0.05). Risk factors for graft loss include: in ICU at transplant (RR=1.77, P <0.05) and receiving a cadaveric split organ compared with a whole organ (RR=2.3, P <0.05). The percentage of patients diagnosed with hepatic a. and portal v. thrombosis were 9.7% and 7%, respectively; 15% had biliary complications within 30 days. At least one re-operation was required in 45%. One/two-year rejection probability estimates are 0.60/0.66. Tacrolimus, as primary therapy posttransplant, reduces first rejection risk (RR=0.70, P <0.05). Eighty-nine percent of school-aged children are in school full-time, 18 months posttransplant. Conclusions. This report provides one of the first descriptions of characteristics and clinical courses of a multicenter pediatric transplant population. Observations are subject to patient selection biases but are useful for generating hypothesis for future studies.

Studies of Pediatric Liver Transplantation 2002: Patient and graft survival and rejection in pediatric recipients of a first liver transplant in the United States and Canada

Abstract:  Studies of Pediatric Liver Transplantation (SPLIT) is a cooperative research network comprising 38 pediatric liver transplant centers in North America. Data from the 1092 patients who have received a first liver transplant since 1995 were analyzed for factors influencing patient survival, graft survival and acute rejection. The 3, 12, 24 and 36 month Kaplan–Meier estimates of patient/graft survival were 90.9/85.5, 86.3/80.2, 84.3/76.0, and 83.8/75.3% respectively. Univariate analysis identified initial diagnosis, type of graft (whole vs. living and cadaveric technical variant), growth failure and continuous hospitalization or ICU admission prior to transplantation as significantly influencing patient and graft survival. Subsequent multivariate analysis identified as risk factors for death: fulminant liver failure (RR = 3.05, p < 0.05), cadaveric technical variant grafts (RR = 1.95, p < 0.05), continuous hospitalization pre‐transplant (RR = 1.79, p < 0.05), height deficit >2 s.d. from mean (RR = 3.22, p < 0.05). Risk factors for graft loss included: fulminant liver failure (RR = 2.27, p < 0.05), cadaveric technical variant grafts, (RR = 1.97, p < 0.05). Eleven percent of the 1092 patients were re‐transplanted; vascular complications, particularly hepatic artery thrombosis (8.3% overall; 36.3% of graft failures), were responsible for the majority of re‐transplants. Infection was the single most important cause of death (40 of 141, 28.4%) and was a contributing cause in 55 (39%), particularly with bacterial or fungal organisms. The cumulative Kaplan–Meier estimates of first rejection at 3, 12, 24 and 36 months were 44.8, 52.9, 59.1, and 60.3%. Initial immunosuppression with tacrolimus reduced the probability of rejection (RR = 0.62, p < 0.05). Eleven percent of rejections were steroid‐resistant; chronic rejection led to 7 of 121 (5.8%) re‐transplants. The SPLIT registry, in compiling data from a large number of centers, reflects the current outcomes for pediatric liver transplants in North America.

Risk factors for rejection and infection in pediatric liver transplantation.

Rejection and infection are important adverse events after pediatric liver transplantation, not previously subject to concurrent risk analysis. Of 2291 children (<18 years), rejection occurred at least once in 46%, serious bacterial/fungal or viral infections in 52%. Infection caused more deaths than rejection (5.5% vs. 0.6% of patients, p < 0.001). Early rejection (<6 month) did not contribute to mortality or graft failure. Recurrent/chronic rejection was a risk in graft failure, but led to retransplant in only 1.6% of first grafts. Multivariate predictors of bacterial/fungal infection included recipient age (highest in infants), race, donor organ variants, bilirubin, anhepatic time, cyclosporin (vs. tacrolimus) and era of transplant (before 2002 vs. after 2002); serious viral infection predictors included donor organ variants, rejection, Epstein‐Barr Virus (EBV) naivety and era; for rejection, predictors included age (lowest in infants), primary diagnosis, donor‐recipient blood type mismatch, the use of cyclosporin (vs. tacrolimus), no induction and era. In pediatric liver transplantation, infection risk far exceeds that of rejection, which causes limited harm to the patient or graft, particularly in infants. Aggressive infection control, attention to modifiable factors such as pretransplant nutrition and donor organ options and rigorous age‐specific review of the risk/benefit of choice and intensity of immunosuppressive regimes is warranted.

Studies of Pediatric Liver Transplantation: 2002 update. An overview of demographics, indications, timing, and immunosuppressive practices in pediatric liver transplantation in the United States and Canada

Abstract:  Studies of Pediatric Liver Transplantation (SPLIT) was initiated in 1995 for the purpose of collecting comprehensive data from children undergoing liver transplantation. As of May 31, 2002, 1761 children were registered in SPLIT from 38 participating centers in the United States and Canada. This report focuses on the demographics, primary diagnoses, clinical indications for transplant, and probability of obtaining liver transplantation for the 1187 children receiving a liver transplant after registration in SPLIT. Demographic information is also provided for the 1092 children who received their first ever liver transplantation. For this cohort, we also describe immunosuppressive practices at the time of transplant, and how the use of different medications changes with time.

A multivariate analysis of pre-, peri-, and post-transplant factors affecting outcome after pediatric liver transplantation.

Objective:The purpose of this study was to identify significant, independent factors that predicted 6 month patient and graft survival after pediatric liver transplantation. Summary Background Data:The Studies of Pediatric Liver Transplantation (SPLIT) is a multicenter database established in 1995, of currently more than 4000 US and Canadian children undergoing liver transplantation. Previous published analyses from this data have examined specific factors influencing outcome. This study analyzes a comprehensive range of factors that may influence outcome from the time of listing through the peri- and postoperative period. Methods:A total of 42 pre-, peri- and posttransplant variables evaluated in 2982 pediatric recipients of a first liver transplant registered in SPLIT significant at the univariate level were included in multivariate models. Results:In the final model combining all baseline and posttransplant events, posttransplant complications had the highest relative risk of death or graft loss. Reoperation for any cause increased the risk for both patient and graft loss by 11 fold and reoperation exclusive of specific complications by 4 fold. Vascular thromboses, bowel perforation, septicemia, and retransplantation, each independently increased the risk of patient and graft loss by 3 to 4 fold. The only baseline factor with a similarly high relative risk for patient and graft loss was recipient in the intensive care unit (ICU) intubated at transplant. A significant center effect was also found but did not change the impact of the highly significant factors already identified. Conclusions:We conclude that the most significant factors predicting patient and graft loss at 6 months in children listed for transplant are posttransplant surgical complications.

Population pharmacokinetics of meropenem in plasma and cerebrospinal fluid of infants with suspected or complicated intra-abdominal infections

Background: Suspected or complicated intra-abdominal infections are common in young infants and lead to significant morbidity and mortality. Meropenem is a broad-spectrum antimicrobial agent with excellent activity against pathogens associated with intra-abdominal infections in this population. The purpose of this study was to determine the pharmacokinetics (PK) of meropenem in young infants as a basis for optimizing dosing and minimizing adverse events. Methods: Premature and term infants <91 days old hospitalized in 24 neonatal intensive care units were studied. Limited PK sampling was performed following single and multiple doses of meropenem 20 to 30 mg/kg of body weight every 8 to 12 hours based on postnatal and gestational age at birth. Population and individual patient (Bayesian) PK parameters were estimated using NONMEM. Results: In this study, 200 infants were enrolled and received the study drug. Of them, 188 infants with 780 plasma meropenem concentrations were analyzed. Their median (range) gestational age at birth and postnatal age at PK evaluation were 28 (23–40) weeks and 21 (1–92) days, respectively. In the final PK model, meropenem clearance was strongly associated with serum creatinine and postmenstrual age (clearance [L/h/kg] = 0.12*[(0.5/serum creatinine)**0.27]*[(postmenstrual age/32.7)**1.46]). Meropenem concentrations remained >4 &mgr;g/mL for 50% of the dose interval and >2 &mgr;g/mL for 75% of the dose interval in 96% and 92% of patients, respectively. The estimated penetration of meropenem into the cerebrospinal fluid was 70% (5–148). Conclusions: Meropenem dosing strategies based on postnatal and gestational age achieved therapeutic drug exposure in almost all infants.

Outcomes of liver transplantation for patients with alagille syndrome: The studies of pediatric liver transplantation experience

Alagille syndrome (ALGS) is a multisystem disorder that manifests as childhood cholestasis. Reports of liver transplantation (LT) for patients with ALGS have come largely from single centers, which have reported survival rates of 57% to 79%. The aim of this study was to determine LT outcomes for patients with ALGS. We performed a retrospective analysis of the Studies of Pediatric Liver Transplantation database, which contains information about 3153 pediatric LT recipients. Data were available for 91 patients with ALGS and for 236 age‐matched patients with biliary atresia (BA). The frequency of complex cardiac anomalies was lower in the LT group with ALGS versus published ALGS series (5% versus 13%). The pretransplant glomerular filtration rate (GFR) was <90 mL/minute/1.73 m2 in 18% of the LT patients with ALGS and in 5% of the LT patients with BA (P < 0.001). The height deficit at listing was worse for the ALGS patients (66%) versus the BA patients (22%). The 1‐year patient survival rates were 87% for the ALGS patients and 96% for the BA patients (P = 0.002). The deaths in the ALGS group mostly occurred within the first 30 days. No pretransplant factors associated with death were identified in the ALGS group. A survival analysis revealed that biliary (P = 0.02), vascular (P < 0.001), central nervous system (CNS; P < 0.001), and renal complications (P < 0.001) after LT were associated with death in the ALGS group. Renal insufficiency in the ALGS patients worsened after LT, and at 1 year, GFR was <90 mL/minute/1.73 m2 in 22% of the LT patients with ALGS but in only 8% of the patients with BA (P = 0.0014). More LT pediatric patients with ALGS either were currently receiving special education (50% versus 30% for BA patients, P = 0.02) or had received special education in the past (60% versus 36%, P = 0.01). Vascular, CNS, and renal complications were increased in the ALGS patients after LT, and this reflected multisystem involvement. Although the 1‐year survival rate was modestly lower for the ALGS patients versus the BA patients, the clustering of deaths within the first 30 days is notable and warrants increased vigilance and further investigation. Liver Transpl, 2012.

Post-transplant diabetes mellitus in pediatric liver transplantation

Abstract:  To determine the characteristics of pediatric liver transplant recipients who develop GI and/or PTDM, data on children undergoing their first liver transplant from the SPLIT database were analyzed (n = 1611). Recipient and donor characteristics that were evaluated included age at transplant, gender, race, primary disease, hospitalization status at transplant, BMI, recipient and donor CMV status, donor type, donor age, and primary immunosuppression. GI/PTDM was found in 214 individuals (13%) of whom 166 (78%) were diagnosed within 30 days of transplantation (early GI/PTDM). Multivariate analyses suggests that age >5 yr at transplant, hospitalization at transplant, a primary diagnosis other than BA, early steroid use, and tacrolimus use are associated with increased incidence of early GI. Routine monitoring for the development of GI and post‐transplant diabetes is indicated in the short‐ and long‐term care of children after liver transplantation.

Outcomes after liver transplantation in young infants

Background: Liver transplantation in infants younger than 90 days is increasingly common. These infants typically arrive for transplantation in fragile medical condition. It is commonly assumed that they may experience high complication rates, difficult postoperative courses, and poor graft and patient survival. Objectives: We sought to understand whether graft and patient survival rates in these young infants were lower than in older children, these patients experienced more complications than older children, and health care resource utilization was higher in this population. Patients and Methods: Data queried from the Study of Pediatric Liver Transplantation (SPLIT) database were limited to infants ages 0 to 90 days who had received their primary liver transplant between February 1996 and May 2004. Patients older than 90 days registered in the SPLIT database were used for comparison. Results: Thirty-eight patients, ages 0 to 90 days, were included in the analysis. Their severity of illness was reflected by a median calculated Pediatric Endstage Liver Disease score of 34.8 at transplant. A majority (89.5%) of infants received cadaveric liver grafts, of which 47% were reduced organs. The infants experienced prolonged hospitalizations, spending an average of 50.9 ± 7.6 days in the hospital after transplant. Long stays in the intensive care unit (average 22.1 ± 1.5 days) and need for mechanical ventilation (average 16.2 ± 2.7 days) also occurred. Length of hospitalization, intensive care, and mechanical ventilation were significantly higher than in older children (P < 0.0001). The reoperation rate (60.5%) was high and significantly greater than in older children (P = 0.007), with 10 patients (26.3%) needing 3 or more early reoperations. Reoperations occurred for bleeding, wound complications, biliary complications, and sepsis. There was no difference in vascular or biliary tract complications compared with older children. Bacterial infections were also common (52.6%) and were seen with greater frequency than in older children (P < 0.04). This infant cohort had an overall graft survival of 76.1% and overall patient survival of 87.8% at 1 year, with median follow-up of 12.5 months (range 0.6–84.0 months). Graft and patient survival in infants younger than 90 days was similar to that in older infants and children (P = NS). Conclusions: Young infants experience graft and patient survival similar to that in older cohorts of liver transplant recipients. Posttransplant complication rates, including the reoperation rate, were higher in this younger group, and the duration of hospitalization and intensive support were significantly longer. Future studies to better examine the factors, including age, that may contribute to the need for reoperation in children are warranted. Recognition and further analysis of the cost of care in this age group is also needed.