A microdialysis study of oral vigabatrin administration in head injury patients: preliminary evaluation of multimodality monitoring.
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.


CONCLUSIONS
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.
Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK. klc1000@wbic.cam.ac.uk
Keri L H
KL
Carpenter
Ivan
I
Timofeev
Jürgens
J
Nortje
Marek
M
Czosnyka
John D
JD
Pickard
Peter J
PJ
Hutchinson
D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000368:Aged; D000596:Amino Acids / Q000378:metabolism; D000927:Anticonvulsants / Q000008:administration & dosage*; D001794:Blood Pressure / Q000187:drug effects; D001923:Brain Chemistry; D001930:Brain Injuries / Q000188:drug therapy* / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D005260:Female; D005947:Glucose / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism; D006801:Humans; D007427:Intracranial Pressure / Q000187:drug effects / Q000502:physiology; D019344:Lactic Acid / Q000378:metabolism; D008297:Male; D017551:Microdialysis; D008875:Middle Aged; D008991:Monitoring, Physiologic; D013997:Time Factors; D020888:Vigabatrin / Q000008:administration & dosage* / Q000378:metabolism; D055815:Young Adult; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D000596:Amino Acids; D000927:Anticonvulsants; D019344:Lactic Acid; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D020888:Vigabatrin; D005947:Glucose