Approximately 230,000-480,000 children are admitted to Pediatric Intensive Care Units (PICU) annually in the United States. Of these children, 16% present with neurocritical illness. Neurocritical conditions range from traumatic brain injury (TBI), stroke, seizures and status epilepticus, to hypoxic brain injury following cardiac arrest. While overall PICU mortality has declined significantly from 11% in the 1980s to 1.3%-5% in the contemporary era, mortality in children with neurocritical illness is as high as 12%, with highest mortality following cardiac arrest (24%). Brain injury and neurological system failure represent the proximal cause of death for 65% of all deaths in the PICU, with 14% of children acquiring brain injuries during their PICU stay. Among all PICU survivors, children with neurocritical illness also have higher rates of decline in neurofunctional status (7.3%) at the time of discharge vs baseline, compared to the general PICU population (4.8%). Thus, modern neurocritical care focuses on monitoring neurologic functional status and preventing secondary injuries that exacerbate the initial injury and worsen long-term outcomes (e.g., hypotension, hypoglycemia, hyperthermia, hypoxia, intracranial hypertension, or seizures). We currently lack valid tools for timely evaluation of the severity of the initial brain injury, for monitoring of secondary neurologic injury, and for risk stratification and outcome classification early in the PICU course of critically ill children. Inability to adequately classify and select study participants for targeted interventions is a well described problem in critical care studies. The overall goal of this proposal is to design a point-of-care plasma brain injury biomarker panel for pediatric neurocritical illness with a 30 minute time-to-results, using biomarkers that have been validated in adult populations. We hypothesize that point-of-care testing of brain injury biomarkers will allow for timely identification of patients who would benefit the most from neuroprotective interventions needing rapid initiation for optimal efficacy, and could then be used to monitor cerebral response to such interventions. As unique combinations of biomarkers are likely to be superior for each condition, we will use an already existing well phenotyped PICU cohort and plasma repository, and a comprehensive point-of-care panel of 14 brain injury biomarkers developed for adult TBI by Meso Scale Diagnostics (MSD, Rockville, MD). We will address our overall goal in the following specific aims: (1) Determine the sensitivity of a novel platform for detection of plasma brain injury biomarkers in children admitted to the PICU with clinical neurologic injury; and (2) Determine the extent to which circulating levels of brain injury biomarkers during PICU admission predict A) mortality before hospital discharge, B) neurologic disability at hospital discharge, and C) association with abnormalities on neuroimaging. If sensitivity of injury and predictive value for outcomes are confirmed, the point-of-care device developed for adult TBI will be tested prospectively in future pediatric bedside studies.
Neurocritical illness is a major cause of mortality and morbidity in the >230,000 children admitted to the Pediatric Intensive Care Unit (PICU) annually in the United States, and is the proximate cause for 65% of PICU deaths. We currently lack valid tools for timely evaluation of the severity of the initial brain injury, for monitoring of secondary neurologic injury, and for risk stratification and outcome classification early in the PICU course. This proposal seeks to advance the characterization of brain injury in pediatric critical care, by expanding the diversity of brain injury biomarkers and by reducing time-to-results, leveraging an effective point-of-care platform originally developed for adult traumatic brain injury biomarkers, and applying it in children.
