Der Anaesthesist
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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). ⋯ 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)
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As the mechanism of action of ketamine, particularly its non-competitive antagonism at the N-methyl-D-aspartate receptor (NMDA), has become better understood, the use of the drug as a neuroprotective agent has received increasing interest. Although the potential prometabolic effects of ketamine might be counterproductive to neuroprotection, the increase in intracranial pressure it has repeatedly been reported to produce does not appear to be relevant clinically under certain conditions, e.g. in patients with normocapnia and a stable blood pressure. Also, the drug has been shown to be anticonvulsant in clinically applied doses rather than epileptogenic, as was previously assumed. ⋯ But as both in vitro and in vivo studies are inconclusive, the benefits of the drug are still controversial. In addition, the potential neurotoxicity attributed to extremely high ketamine doses is poorly understood. Consequently, well controlled animal experiments and studies in humans would be necessary to establish the role of ketamine and its more potent enantiomer S-(+)-ketamine in combination with other neuroprotective measures and to shed light on its true neuroprotective potential and its possible neuroregenerative effects.
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Among anaesthetic drugs, ketamine occupies a special position. biochemically, ketamine is a racemate consisting of equal shares of two optical enantiomers. Pharmacological investigations show differences between those enantiomers in both qualitative and quantitative properties. ⋯ The main problems associated with the ketamine racemate in clinical use are desirable psychological dysfunction and a prolonged period of arousal. There are grounds for the assumption that the use of S-(+)-ketamine will minimise those problems without reducing anaesthetic potency or restricting the advantages of ketamine anaesthesia.
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ANAESTHETICS, ENDOCRINE SYSTEM, AND STRESS: The effects of anaesthetics on the nervous system are invariably associated with endocrine reactions, which are of great importance for the general characterization of anaesthetics or anaesthetic regimens. In this context, the endocrine stress response is mainly represented by adrenaline (A), noradrenaline (NA), antidiuretic hormone/vasopressin (ADH), adrenocorticotropic hormone (ACTH), and cortisol. PHARMACOLOGICAL PROFILE AND ANAESTHETIC ACTION OF KETAMINE: The pharmacological profile of ketamine is characterized by the term "dissociative anaesthesia." At the present time, the anaesthetic action of ketamine cannot be explained by a single mechanism. ⋯ The combination of S-(+)-ketamine and midazolam has weaker sympathomimetic and general endocrine-stimulating properties, and can be used for analgosedation in patients with cardiovascular instability and exogenous catecholamine requirements. In combination with propofol, the sympathomimetic and general endocrine-stimulating effects of S-(+)-ketamine are less pronounced because of contrasting properties of both drugs. This combination might be useful in patients with endocrine deficits and for analgosedation, when rapid recovery is necessary and negative circulatory effects should be avoided.
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This review focuses on the significance of S-(+)-ketamine as a neuroprotective agent. Evidence in the literature supporting or contradicting a neuroprotective or even therapeutic role of ketamine in global cerebral ischaemia is critically reviewed, and data from an ongoing study in a rat global cerebral ischaemia model (15 min ischaemia with S(+)-ketamine administered 15 min after reperfusion) are reported. ⋯ Only at higher ketamine dosages was protection found reliably, especially in models of complete forebrain ischaemia lasting over 10 min. In our own study, only after 90 mg/kg S(+)-ketamine was there significantly better preservation of cortical neurons than without treatment; 30 and 60 mg/kg did not produce this effect.