Abstract
Background: We assessed the feasibility of administering a neuroprotective drug, vigabatrin (VGB; gamma-vinyl-gamma-aminobutyric acid) with multimodality monitoring, including cerebral microdialysis, in severe head injury patients, to measure surrogate endpoints and blood–brain barrier (BBB) penetration. Methods: Patients (n = 20) were randomised to VGB (0.5 g twice-daily, enteric) or control. ICP, ABP, CPP and cerebrovascular pressure reactivity index (PRx) were monitored. Microdialysate glucose, lactate, pyruvate, glutamate, glycerol, amino acids, VGB and GABA were analysed. Results: Preliminary evaluation of results (five VGB-treated patients) showed that VGB levels rose in brain microdialysates, followed by a modest increase in GABA. VGB and GABA increased more in abnormal brain than in sites further from lesions, and were higher after multiple VGB doses. Highest VGB and GABA microdialysate levels were 75 and 4 μmol/L respectively. Microdialysate glucose and glycerol sometimes decreased, and glutamate and tyrosine sometimes increased, following VBG administration; causation unproven. VGB did not overtly affect ICP, ABP, CPP, PRx, or microdialysate lactate, pyruvate and lactate/pyruvate ratio. Conclusion: Multimodality monitoring, including cerebral microdialysis, is feasible for studying surrogate endpoints following drug administration. VGB crosses the BBB, leading to modest increases in extracellular GABA. Further analyses are ongoing. Microdialysis may assist the development of neuroprotective agents by determining penetration into extracellular fluid of the brain.
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Acknowledgements
We gratefully acknowledge the following. Study support: the Medical Research Council (Grant Nos. G9439390 ID 65883 and G0600986 ID 79068) and the Academy of Medical Sciences/Health Foundation. Authors’ support: KLHC – the Medical Research Council (Acute Brain Injury programme grant) and the National Institute for Health Research Biomedical Research Centre, Cambridge; IT – Codman Inc grant, The Evelyn Trust grant, MRC RESCUEicp trial grant and BP-TNK Kapitza Scholarship; JN - British Journal of Anaesthesia/Royal College of Anaesthetists Fellowship; PJH – Academy of Medical Sciences/Health Foundation Senior Surgical Scientist Fellowship. We thank L Maskell for technical assistance with microdialysis and demography.
Conflict of interest: ICM+ software for brain monitoring (www.neurosurg.cam.ac.uk/icmplus) is licensed by the University of Cambridge (Cambridge Enterprise Ltd). Dr M Czosnyka has a financial interest in a part of the licensing fee. The other authors have no conflicts of interest concerning this study.
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Carpenter, K.L.H., Timofeev, I., Nortje, J., Czosnyka, M., Pickard, J.D., Hutchinson, P.J. (2012). A Microdialysis Study of Oral Vigabatrin Administration in Head Injury Patients: Preliminary Evaluation of Multimodality Monitoring. In: Schuhmann, M., Czosnyka, M. (eds) Intracranial Pressure and Brain Monitoring XIV. Acta Neurochirurgica Supplementum, vol 114. Springer, Vienna. https://doi.org/10.1007/978-3-7091-0956-4_53
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