The
phencyclidine derivative
ketamine is a non-competitive
N-methyl-D-aspartate (
NMDA) receptor antagonist with the thalamo-neocortical projection system as the primary site of action. Racemic
ketamine consists of the enantiomers
S(+)-ketamine and R(-)-
ketamine. Racemic
ketamine has never been considered an adequate anaesthetic agent in neurosurgical patients since it produces regionally specific stimulation of cerebral metabolism (CMRO2) and increases cerebral blood flow (CBF) and intracranial pressure (ICP). However, recent experiments suggest that both tracemic
ketamine and
S(+)-ketamine may reduce
infarct size in animal models of incomplete cerebral ischaemia and
brain injury. This experimental protective effect appears to be related to decreases in Ca++ influx and maintenance of brain tissue
magnesium levels due to
NMDA and
quisqualate receptor blockade by
ketamine. Studies in dogs have shown that racemic
ketamine (2.0 mg/kg) increases CBF in the presence of the cerebral
vasodilator N2O. In contrast, studies in rats without background anaesthesia showed increases in CBF after racemic
ketamine (100 mg/kg i.p.). This suggests that the cerebrovascular effects of racemic
ketamine are related to the pre-existing cerebrovascular tone induced by background anaesthetics. Cerebrovascular CO2 reactivity was maintained regardless of the baseline cerebrovascular resistance. There are several mechanisms by which racemic
ketamine may increase CBF. It induces dose-dependent
respiratory depression with consequent mild
hypercapnia in spontaneously ventilating subjects. This produces vasodilation due to the intact cerebrovascular CO2 reactivity. Racemic
ketamine also induces regional neuroexcitation, which leads to stimulation of cerebral
glucose consumption in the limbic, extrapyramidal, auditory, and sensory-motor systems. This regional neuroexcitation with increased CMRO2 produces increases in CBF that can be blocked by infusion of
barbiturates or
benzodiazepines. However, increases in CBF with racemic
ketamine (1 mg/kg) may also occur during normocapnia and without changes in CMRO2. This effect is related to some additional direct cerebral vasodilating potency of racemic
ketamine based on a mechanism involving blockade of Ca++ channels. The effects of racemic
ketamine on CBF autoregulation have not been investigated systematically. However, studies in rats have shown that CBF autoregulation was maintained with low- and high-dose
S(+)-ketamine. Infusion of racemic
ketamine alters intracranial volume and ICP. Studies in spontaneously ventilating pigs with and without
intracranial hypertension have shown that racemic
ketamine (0.5-5.0 mg/kg) produces increases in PaCO2 and ICP. In contrast, identical experiments with
mechanical ventilation and controlled PaCO2 showed no changes in ICP following racemic
ketamine infusion. This implies that increases in ICP are related to inadequate ventilation with consecutive
hypercapnia and increases in intracranial blood volume. However,
mechanical ventilation may not be sufficient to control ICP following racemic
ketamine. Experiments in mechanically ventilated dogs indicate that racemic
ketamine (2 mg/kg) increases cerebral blood volume and ICP even in the presence of normoventilation, a response that is reversible by
hyperventilation or the administration of
diazepam. Studies in patients have shown that racemic
ketamine (2.0 mg/kg) reduces CBF in the presence of cerebral
vasodilators like
halothane or N2O. In contrast, studies in unanaesthetised humans showed increases in CBF after racemic
ketamine (2-3 mg/kg). This observation is consistent with animal studies and suggests that the cerebrovascular effects of racemic
ketamine are related to the pre-existing cerebrovascular tone induced by background anaesthetics. Studies in humans with and without intracranial pathology confirm the data from animal experiments. (ABSTRACT TRUNCATED)