Magnesium as a Neuroprotective Agent for Pediatric TBI

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DESCRIPTION (provided by applicant): The overall objective of this collaborative, multi-institutional project is to provide preliminary information required for subsequent, full-scale clinical trials of novel therapies for children with severe traumatic brain injury (TBI). This study will contribute both pediatric safety data for a specific pharmacotherapy (magnesium sulfate) and demonstrate the applicability in children of novel methods for assessing the effects of such therapy on the neuronal extracellular environment (cerebral microdialysis). Magnesium has a good safety profile and is being tested in pilot studies of adults with stroke and subarachnoid hemorrhage for its neuroprotective potential. There are, however, no data regarding its safety or efficacy in children with TBI. Cerebral microdialysis is being used both clinically and in research settings directed to adult TBI, but has not been used in children. The following Specific Aims address these gaps: 1. to examine the safety of magnesium for children with severe traumatic brain injury and therefore potentially compromised cerebral perfusion; 2) to examine the short-term efficacy of magnesium in modifying molecular markers of secondary brain injury 3) to examine the feasibility of measuring longer-term efficacy using clinical outcomes (functional, neuropsychological, and behavioral measures) as well as indicators of the severity of structural injury by MRI at three months post-injury. We will implement a randomized, placebo-controlled trial of magnesium in children with severe TBI who require intensive care and intracranial pressure monitoring. Based on subject availability with proposed inclusion/exclusion criteria, 24 subjects will be randomized. Clinically-required intracranial pressure monitoring will be accompanied by placement of a microdialysis catheter for research purposes. Following baseline measurements, study drug at (magnesium or placebo) will be administered as a bolus of 0.2 mmol/kg followed by 24-hour infusion. Using hemodynamic variables, cerebral perfusion pressure will be monitored. In addition, transcranial doppler velocities and brain interstitial lactate and pyruvate levels will be used to assess effects on cerebral perfusion. Microdialysis will be used to assess brain interstitial levels of ionized magnesium, ionized calcium, excitatory amino acids, and nitric oxide byproducts. In addition blood magnesium and calcium levels (both ionized and total) will be obtained. Multiple validated psychometric measures and MRI evaluation of CNS lesion numbers and location will address Specific Aim 3.