Effects of S(+)-, R(-)- and racemic ketamine on the brain

Abstract: Racemic ketamine, introduced in the mid-sixties, contains equal proportions of the enantiomers S(+)- and R(–)-ketamine. Early clinical reports indicated unfavourable effects on intracranial pressure (ICP) and on the cerebral circulation. Current literature on this topic is however sparse, and available reports are divergent. The aim of this doctoral dissertation project was to study cerebral and systemic haemodynamic effects of S(+)-, R(–)-, and racemic ketamine in pigs at normal and increased ICP, and of S(+)- and racemic ketamine in humans. In study I, static cerebral autoregulation (AR) was investigated during constant intravenous (iv) infusion of racemic ketamine, 15 mg/kg/h, in mechanically ventilated pigs. The arterial blood pressure in upper body parts (including the brain) was non-pharmacologically reduced or raised (by decreasing right ventricular preload or increasing left ventricular afterload, respectively, using balloon catheters positioned in the inferior caval vein and descending aorta) by approximately 20 and 40 % from the baseline level. Cortical cerebral blood fl ow (CBF) was determined by external scintillation detection of intra-arterially injected 133Xe. Seven pigs had cerebral AR, and one pig had a pressure-dependent CBF. We conclude that cerebral AR is not abolished during ketamine infusion. Study II consists of two parts. In part IIa, we investigated whether repeated iv bolus injections of racemic ketamine induce acute tolerance, i.e. tachyphylaxis, with respect to the CBF response. No signifi cant differences were found between responses to three consecutive injections. In part IIb, equipotent iv bolus doses of all three ketamine compounds were administered in randomized order, and systemic and cerebral effects were evaluated. S(+)-ketamine was found to be associated with less cerebral and systemic haemodynamic depression, possibly indicating a clinical advantage over racemic or R(–)-ketamine. In study III, the part IIb study design was applied in pigs subjected to intracranial hypertension (ICP ~ 23 mmHg) induced by titrated expansions of bilateral epidurally positioned balloon catheters. None of the study drugs was found to further increase ICP. Instead racemic ketamine reduced ICP by up to 11 %. We conclude that racemic, S(+)-, and R(–)-ketamine are all safe in established intracranial hypertension, and that racemic ketamine might offer some advantage with respect to ICP. In study IV, fourteen healthy adult volunteers were given, in a double-blinded randomized sequence, subanaesthetic equipotent iv bolus injections over 60 seconds of S(+)- (0.3 mg/kg) or racemic ketamine (0.6 mg/kg) on two occasions, at least seven days apart. Global and regional values of CBF were determined by arterial spin labelling magnetic resonance imaging (ASL-MRI), offering high temporal and spatial resolutions despite no injection of contrast dye or exposure to radiation. Dynamic cerebral and systemic haemodynamic responses to each study drug were assessed over 50 min. There were no differences between S(+)- and racemic ketamine with respect to effects on global and regional CBF (rCBF) or on MAP. Both drugs increased rCBF in the frontal cortex, anterior cingulate, insula and thalamus (by 4.7-11 %), and decreased rCBF in the temporal and parietal cortex, caudate nucleus and putamen (by 3.3-19 %). We conclude that S(+)- and racemic ketamine have similar effects on global and regional CBF, and on MAP, and that ASL-MRI is suitable for pharmacodynamic studies of perfusion-altering drugs.