Acute liver failure and transplantation in children

Acute liver failure (ALF) was relatively easy to recognise in the days before liver transplantation became available as rescue therapy, because the diagnosis was based on end-stage disease manifestations such as profound coagulopathy, jaundice, encephalopathy and cerebral edema (in a patient with no history of chronic liver disease). These criteria no longer help us in an era when we struggle to define which patients are going to progress to this end-stage picture in the time necessary for evaluation and listing for life-saving transplantation. Ideally, identifying which patients will recover spontaneously or with appropriate treatment would relieve the justifiable concern that some patients receive a transplant when, given time, they would have recovered. Currently, the data to guide us in avoiding death without transplantation and unnecessary transplantation remain elusive.   This review will focus primarily on the aspects that surround the decision to undertake liver transplantation in a child with ALF. There are many excellent chapters and journal reviews which cover specific medical management of ALF and its complications; therefore this will not be addressed in this essay

Pediatric Transplantation in the United States, 1996–2005

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/73448/1/j.1600-6143.2007.01780.x.pd

Diverse and Complex Muscle Spindle Afferent Firing Properties Emerge from Multiscale Muscle Mechanics

Despite decades of research, we lack a mechanistic framework capable of predicting how movement-related signals are transformed into the diversity of muscle spindle afferent firing patterns observed experimentally, particularly in naturalistic behaviors. Here, a biophysical model demonstrates that well-known firing characteristics of mammalian muscle spindle Ia afferents – including movement history dependence, and nonlinear scaling with muscle stretch velocity – emerge from first principles of muscle contractile mechanics. Further, mechanical interactions of the muscle spindle with muscle-tendon dynamics reveal how motor commands to the muscle (alpha drive) versus muscle spindle (gamma drive) can cause highly variable and complex activity during active muscle contraction and muscle stretch that defy simple explanation. Depending on the neuromechanical conditions, the muscle spindle model output appears to ‘encode’ aspects of muscle force, yank, length, stiffness, velocity, and/or acceleration, providing an extendable, multiscale, biophysical framework for understanding and predicting proprioceptive sensory signals in health and disease

Pediatric Transplantation in the United States, 1995–2004

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/72899/1/j.1600-6143.2006.01271.x.pd

Society of pediatric liver transplantation: Current registry status 2011‐2018

BackgroundSPLIT was founded in 1995 in order to collect comprehensive prospective data on pediatric liver transplantation, including waiting list data, transplant, and early and late outcomes. Since 2011, data collection of the current registry has been refined to focus on prospective data and outcomes only after transplant to serve as a foundation for the future development of targeted clinical studies.ObjectiveTo report the outcomes of the SPLIT registry from 2011 to 2018.MethodsThis is a multicenter, cross‐sectional analysis characterizing patients transplanted and enrolled in the SPLIT registry between 2011 and 2018. All patients, <18 years of age, received a first liver‐only, a combined liver‐kidney, or a combined liver‐pancreas transplant during this study period.ResultsA total of 1911 recipients from 39 participating centers in North America were registered. Indications included biliary atresia (38.5%), metabolic disease (19.1%), tumors (11.7%), and fulminant liver failure (11.5%). Greater than 50% of recipients were transplanted as either Status 1A/1B or with a MELD/PELD exception score. Incompatible transplants were performed in 4.1%. Kaplan‐Meier estimates of 1‐year patient and graft survival were 97.3% and 96.6%. First 30 days of surgical complications included reoperation (31.7%), hepatic artery thrombosis (6.3%), and portal vein thrombosis (3.2%). In the first 90 days, biliary tract complications were reported in 13.6%. Acute cellular rejection during first year was 34.7%. At 1 and 2 years of follow‐up, 39.2% and 50.6% had normal liver tests on monotherapy (tacrolimus or sirolimus). Further surgical, survival, allograft function, and complications are detailed.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/153657/1/petr13605_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/153657/2/petr13605.pd

Intestine Transplantation in the United States, 1999–2008

Improving short-term results with intestine transplantation have allowed more patients to benefit with nearly 700 patients alive in the United States with a functioning allograft at the end of 2007. This success has led to an increase in demand. Time to transplant and waiting list mortality have significantly improved over the decade, but mortality remains high, especially for infants and adults with concomitant liver failure. The approximately 200 intestines recovered annually from deceased donors represent less than 3% of donors who have at least one organ recovered. Consent practice varies widely by OPTN region. Opportunities for improving intestine recovery and utilization include improving consent rates and standardizing donor selection criteria. One-year patient and intestine graft survival is 89% and 79% for intestine-only recipients and 72% and 69% for liver-intestine recipients, respectively. By 10 years, patient and intestine survival falls to 46% and 29% for intestine-only recipients, and 42% and 39% for liver-intestine, respectively. Immunosuppression practice employs peri-operative antibody induction therapy in 60% of cases; acute rejection is reported in 30%–40% of recipients at one year. Data on long-term nutritional outcomes and morbidities are limited, while the cause and therapy for late graft loss from chronic rejection are areas of ongoing investigation.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/79108/1/j.1600-6143.2010.03044.x.pd

Rebuttal from Raymond Reynolds, Callum Osler, Linda Tersteeg and Ian Loram.

This work was supported by BBSRC grant BB/I00579X/

Barriers to ideal outcomes after pediatric liver transplantation

Long‐term survival for children who undergo LT is now the rule rather than the exception. However, a focus on the outcome of patient or graft survival rates alone provides an incomplete and limited view of life for patients who undergo LT as an infant, child, or teen. The paradigm has now appropriately shifted to opportunities focused on our overarching goals of “surviving and thriving” with long‐term allograft health, freedom of complications from long‐term immunosuppression, self‐reported well‐being, and global functional health. Experts within the liver transplant community highlight clinical gaps and potential barriers at each of the pretransplant, intra‐operative, early‐, medium‐, and long‐term post‐transplant stages toward these broader mandates. Strategies including clinical research, innovation, and quality improvement targeting both traditional as well as PRO are outlined and, if successfully leveraged and conducted, would improve outcomes for recipients of pediatric LT.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/151257/1/petr13537.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/151257/2/petr13537_am.pd

Safety and Efficacy of Teduglutide in Pediatric Patients With Intestinal Failure due to Short Bowel Syndrome : A 24-Week, Phase III Study

Background This study evaluated the safety and efficacy of teduglutide in pediatric patients with short bowel syndrome-associated intestinal failure (SBS-IF). Methods A 24-week, phase III trial with 2 randomized, double-blind teduglutide dose groups and a nonblinded standard of care (SOC) arm was used; patients received 0.025 mg/kg or 0.05 mg/kg teduglutide once daily. Safety end points included treatment-emergent adverse events (TEAEs) and growth parameters. The primary efficacy/pharmacodynamic end point was the number of patients who achieved a >= 20% reduction in parenteral support (PS) from baseline at week 24. Results All 59 enrolled patients completed the study (0.025 mg/kg, n = 24; 0.05 mg/kg, n = 26; SOC, n = 9). Baseline demographics and disease characteristics were comparable among groups. TEAEs were reported by 98% and 100% of patients in the teduglutide and SOC groups, respectively. The most common TEAEs in the teduglutide-treated groups were pyrexia and vomiting. The primary end point was achieved by 13 (54.2%), 18 (69.2%), and 1 (11.1%) patients who received 0.025 mg/kg teduglutide, 0.05 mg/kg teduglutide, and SOC, respectively (P <0.05 vs SOC). Both 0.025-mg/kg and 0.05-mg/kg teduglutide groups showed clinically significant reductions in PS volume (P <0.05 vs SOC), PS calories, days per week and hours per day of PS infusions, and increases in enteral nutrition and plasma citrulline at week 24 compared with baseline. Two (8.3%, 0.025 mg/kg teduglutide) and 3 patients (11.5%, 0.05 mg/kg teduglutide) achieved enteral autonomy. Conclusion The safety profile of teduglutide was similar to that reported previously in children and adults. Treatment with teduglutide was associated with significant reductions in PS for pediatric patients with SBS-IF over 24 weeks.Peer reviewe

Complete Steroid Avoidance Is Effective and Safe in Children With Renal Transplants: A Multicenter Randomized Trial With Three‐Year Follow‐Up

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/93729/1/j.1600-6143.2012.04145.x.pd