During the first 5 days after an intracranial haemorrhage, the red blood cells slowly haemolyse. Most of the oxyhaemoglobin, released in the cerebrospinal fluid, is transformed into bilirubin by an enzyme-dependent process. After 5 days, the haemolysis increases without a corresponding enhancement in the formation of bilirubin. Consequently, the oxyhaemoglobin concentration also increases. A spontaneous oxidation of the haem groups follows and after about 10 days the proportions of oxy- and methaemoglobin are about the same. This process occurs independently of the cause of the haemorrhage.
SUMMARY A spectrophotometric method for semi-quantitative determination of oxyhaemoglobin, methaemoglobin and bilirubin in the cerebrospinal fluid is described and evaluated.
The oxyhaemoglobin, methaemoglobin and bilirubin concentrations were determined in subdural haematomas and cerebrospinal fluid from 18 patients. The total haem derivative concentration ranged from 55 mumol/l to 13.9 mmol/l in the haematomas and from 0.1 mumol/l to 8.2 mumol/l in the cerebrospinal fluid. Bilirubin was the dominating fraction in haematomas with haem derivative concentrations lower than 1 mmol/l. For haematomas exceeding this value, the bilirubin transforming capacity seemed to have reached a maximum. More of the oxyhaemoglobin was oxidized to methaemoglobin in these cases, a reaction known to release superoxide radicals. The possible pathophysiological significance hereof, e.g. in cerebral vasospasm, is discussed.
P195
Clomethiazole (CMZ; ‘Zendra’) is a neuroprotective drug that enhances GABA-A receptor activity. Two clinical trials in stroke patients (pts) were performed: 92CM01 (n=17) and CLASS (CLomethiazole Acute Stroke Study; n=678 on CMZ). In CLASS, a post-hoc analysis showed that CMZ appeared to improve outcome in pts with clinical signs suggestive of a large stroke. Dosing for the pivotal trial, CLASS-I, was based on information from these previous studies. In 92CM01, a loading dose of 6 mg/kg given over 15 min followed by a maintenance dose of 69 mg/kg to 24 h was the maximum CMZ dose that could be given without excessive sedation. In this study, plasma sampling from each pt allowed for individual kinetic modelling. In CLASS, the same dose regimen was used. One sample for drug analysis was taken from each pt at the end of the 24-h infusion. In total, 619 CLASS pts were eligible for a population kinetic evaluation. The clearance estimates in both studies were in the same range. Therefore, the pharmacokinetic parameter estimates from study 92CM01 could be used to simulate the plasma concentrations according to a 2-compartment model for different dosing regimens. According to the protocols, CMZ infusion should be temporarily interrupted if pts become excessively sedated. In CLASS, there were 218 infusion interruptions in 158 pts. CMZ kinetics did not differ between pts who had interruptions and those who did not. There was a delay in the occurrence of excessive sedation, with the majority of interruptions seen between 10 and 24 h. Pts with clinical signs suggesting a large stroke were particularly susceptible to sedation in CLASS, a new dose regimen was needed to reduce excessive sedation in these pts. For CLASS-I the adjusted dosage regimen was calculated as a total CMZ dose of 68 mg/kg, given as a 15 min loading dose, followed by two maintenance doses over 7.75 and 16 h respectively. This should avoid high plasma concentrations during the second half of the infusion period. Taking into account treatment interruptions, CLASS-I pts are predicted to receive an average dose of 63 mg/kg, the same as was actually received by such pts in CLASS.
‘Zendra’ is a trademark, the property of the AstraZeneca group of companies
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