title: Investigation of the effect of chlormethiazole on cerebral chemistry in neurosurgical patients: a combined study of microdialysis and a neuroprotective agent.
abstract: OBJECTIVE
  Promising pre-clinical results from laboratory studies of neuro-protective drugs for the treatment of patients with stroke and head injury have not been translated into benefit during clinical trials. The objective of the study was to assess the feasibility of administrating a potential neuro-protective drug (chlormethiazole) in conjunction with multimodality monitoring (including microdialysis) to patients with severe head injury in order to determine the effect of the agent on surrogate endpoints and penetration into the brain.
  
  
  METHODS
  Multimodality monitoring including cerebral and peripheral microdialysis was applied to five head-injured patients on the neuro-intensive care unit. Chlormethiazole (0.8%) was administered as a rapid (10 ml min(-1)) intravenous loading infusion for 5 min followed by a slow (1 ml min(-1)) continuous infusion for 60 min. The following parameters were monitored: heart rate, mean arterial blood pressure, intracranial pressure, cerebral perfusion pressure, peripheral oxygen saturation, continuous arterial oxygen partial pressure, arterial carbon dioxide partial pressure, arterial pH, arterial temperature, cerebral tissue oxygen pressure, cerebral tissue carbon dioxide pressure, cerebral pH, cerebral temperature, electroencephalograph (EEG), bi-spectral index, plasma glucose, plasma chlormethiazole, and cerebral and peripheral microdialysis assay for chlormethiazole, glucose, lactate, pyruvate and amino acids.
  
  
  RESULTS
  Despite achieving adequate plasma concentrations, chlormethiazole was not detected in the peripheral or cerebral microdialysis samples. The drug was well tolerated and did not induce hypotension, hyperglycaemia or withdrawal seizures. The drug did not change the values of the physiological or chemical parameters including levels of GABA, lactate/pyruvate ratio and glutamate. The drug did, however, induce EEG changes, including burst suppression in two patients.
  
  
  CONCLUSIONS
  Chlormethiazole can be safely given to ventilated patients with severe head injury. There was no evidence of hypotension or withdrawal seizures. Combining a pilot clinical study of a neuro-protective agent with multimodality monitoring is feasible and, despite the lack of effect on physiological and chemical parameters in this study, may be a useful adjunct to the development of neuro-protective drugs in the future. Further investigation of the capability of microdialysis in this setting is required. By investigating the effect of a drug on surrogate end-points, it may be possible to identify promising agents from small pilot clinical studies before embarking on large phase III clinical trials.
authors.affiliation: Department of Neurosurgery, Addenbrooke's Hospital, University of Cambridge, UK. p.hutch@which.net
authors.forename: P J
authors.initials: PJ
authors.lastname: Hutchinson
authors.forename: M T
authors.initials: MT
authors.lastname: O'Connell
authors.forename: J P
authors.initials: JP
authors.lastname: Coles
authors.forename: D A
authors.initials: DA
authors.lastname: Chatfield
authors.forename: M R
authors.initials: MR
authors.lastname: Coleman
authors.forename: P G
authors.initials: PG
authors.lastname: Al-Rawi
authors.forename: C R
authors.initials: CR
authors.lastname: Kett-White
authors.forename: A K
authors.initials: AK
authors.lastname: Gupta
authors.forename: D K
authors.initials: DK
authors.lastname: Menon
authors.forename: S J
authors.initials: SJ
authors.lastname: Boniface
authors.forename: M
authors.initials: M
authors.lastname: Heazell
authors.forename: P J
authors.initials: PJ
authors.lastname: Kirkpatrick
authors.forename: J D
authors.initials: JD
authors.lastname: Pickard
mesh_terms: D000328:Adult; D001923:Brain Chemistry / Q000187:drug effects*; D002719:Chlormethiazole / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use*; D003131:Combined Modality Therapy; D006259:Craniocerebral Trauma / Q000188:drug therapy / Q000503:physiopathology / Q000628:therapy*; D004569:Electroencephalography; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D007362:Intensive Care Units; D007427:Intracranial Pressure / Q000187:drug effects; D008297:Male; D017551:Microdialysis; D008875:Middle Aged; D008991:Monitoring, Physiologic; D018696:Neuroprotective Agents / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D018696:Neuroprotective Agents; D002719:Chlormethiazole