[Ketamine racemate versus S-(+)-ketamine with or without antagonism with physostigmine. A quantitative EEG study on volunteers]

Abstract

The potency of S-(+)-ketamine is approximately double that of the racemic ketamine. This study was carried out to investigate the recovery of cerebral electrical function after a bolus of 1.3 mg/kg ketamine or 0.65 mg/kg S-(+)-ketamine and subsequent continuous application of 4 mg/kg h ketamine per h or 2 mg/kg S-(+)-ketamine, per h for 15 min. Furthermore, the centrally acting, cholinergic agonist physostigmine has been reported to antagonize ketamine and to shorten the recovery period. Therefore, after S-(+)-ketamine 0.012 mg/kg physostigmine was tested against saline placebo. METHODS. With their own informed consent and the approval of the ethics committee 12 healthy volunteers were enrolled in a double-blind cross-over study. All drugs were dissolved in identical volumes. On three dates with intervals of at least 1 week between, ketamine/NaCl, S-(+)-ketamine/physostigmine or S-(+)-ketamine/NaCl was administered (Table 1). The sequence was randomized. The EEG was recorded from 20 sites according to the 10/20 system and after Fast-Fourier transformation computed into amplitudes within the delta, theta, alpha, and beta bands and within the total spectrum. The median, the spectral edge frequency and the dominant frequency (dF) were also determined. Mean values of all electrodes before and at 10, 15, 30, 45 and 195 min after the bolus injection were compared using two-dimensional analysis of variance (ANOVA, significance level P < 0.05). RESULTS. The characteristic increase in theta-amplitude and decrease of alpha-amplitude were observed after ketamine and S-(+)-ketamine. Median and dF dropped from the alpha to the theta frequency range. Ketamine led to a greater increase in total, delta, theta and beta amplitude during anaesthesia. 3 hours after ketamine/S-(+)-ketamine anaesthesia a significant decrease in the median and dominant frequency and in total, delta, theta, alpha and beta amplitudes confirmed residual impairment of cerebral function after all study drugs. No differences were found between physostigmine and placebo. DISCUSSION. The EEG changes during ketamine/S-(+)-ketamine administration suggest a slightly deeper anaesthetic level after ketamine. The course of recovery was not different after ketamine and after S-(+)-ketamine. The spectral edge frequency did not differ between measurement points, and is therefore not suitable for assessment of the depth of anaesthesia reached with ketamine/S-(+)-ketamine. The dose of physostigmine tested was probably too low to produce antagonism of S-(+)-ketamine. An increased dosage of physostigmine has yet to be studied, but is likely to cause a higher rate of side effects, such as nausea, vomiting and bradycardia, and possibly even tonic-clonic seizures.