Planning a Multicenter Cooling Trial for Hyperammonemic Metabolic Crises

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DESCRIPTION (provided by applicant): The objective of this R34 proposal is to develop a protocol and manual of procedures for the conduct of a randomized clinical trial of therapeutic hypothermia as adjunct therapy in young children with hyperammonemia associated encephalopathy resulting from urea cycle disorders (UCDs) or organic acidemias (OAs). Consensus across sites will be critical for uniformity of treatment in these rare and very complex patients in the trial. During this one year grant we will work to build consensus across the 19 participating sites regarding the overall treatment protocol for these children that will have at is core adjunct hypothermia, metabolic and renal replacement therapy. We will then finalize the protocol and write the Manual of Procedures (MOP). We will also standardize the collection of advanced neuroimaging data across sites so that their utility as biomarkers for outcome can be tested during the trial. Newborns with hyperammonemia (HA) associated encephalopathy and UCDs or OAs are at great risk for neurological injury, developmental disability, and death. In the 1980s the mortality of neonates that presented with HA and in coma due to complete blocks in the urea cycle approached 50%, despite aggressive treatment with hemodialysis. Of the surviving children on therapy, 79% had one or more developmental disability. The degree of disability was significantly correlated to the duration of neonatal coma. Similarly, the mortality f neonatal OAs with HA associated encephalopathy was 33% and higher. The introduction of ammonia scavenger therapy for the chronic treatment of UCDs in 1987 improved outcome of long-term treatment for patients with urea cycle disorders. However, despite advances in intensive care and hemodialysis, over the subsequent decade mortality of children with severe UCDs or OAs still exceeded 50% for an initial hyperammonemic crisis at a major tertiary care medical center between 1991 and 2000 and more than 40% of survivors showed considerable intellectual disability. Thus, for neonates or young infants with the most severe forms of UCDs and OAs to truly benefit from the advances in long-term treatment and from liver transplant and to have a better quality of life, a novel, neuroprotective intervention is needed to improve the outcome of the initial crisis. Based on the results of small clinical studies, therapeutic hypothermia (TH) may constitute such a neuroprotective therapy. It is important to investigate its efficacy for HA associated encephalopathy definitively before it becomes common practice that is not evidence-based. Testing this in a well defined group of patients should allow to draw conclusions for other patients with HA associated encephalopathy. The purpose of the future randomized controlled trial will be to assess the efficacy and safety of whole body TH as adjunct neuroprotective therapy to standard of care treatment of neonates and young infants with HA associated encephalopathy.