History of anaesthesia: The ketamine story – past, present and future

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The history of ketamine begins in the 1950s at Parke-Davis and Company's laboratories in Detroit, Michigan, USA. At that time, Parke-Davis were searching among cyclohexylamines for an ‘ideal’ anaesthetic agent with analgesic properties.
Maddox, a chemist, discovered a process which led to the synthesis of phencyclidine or PCP [N-(1-phenyl-cyclohexyl)-piperidine] on 26 March 1956.1,2 Parke-Davis pharmacologist, Dr Chen, received the compound CI-395 (Fig. 1) from Maddox on 11 September 1958. Chen and, in the same period, Dr Domino,1 began to study the experimental effects of the drug on animals. Phencyclidine created potent analgesia in animals: laparotomies were performed in monkeys without pain, but the animals were in a cataleptic state with their eyes open, and muscle relaxation was of poor quality. Chen3 defined catalepsy as a ‘characteristic akinetic state with a loss of orthostatic reflexes but without impairment of consciousness, in which the extremities appear to be paralysed by motor and sensory failure’.
Parke-Davis then investigated the potential of phencyclidine as a human anaesthetic under the trade name of Sernyl (Parkes-Davis). In 1958, the first human trials of PCP (Sernyl) were published by Dr Greifenstein (1915 to 1997), professor of anaesthesiology at the Wayne State University, Detroit. PCP caused increases in blood pressure, respiratory rate and minute volume, with conservation of corneal and laryngeal reflexes. The presence of nystagmus and increased salivation were noted. These studies revealed genuine narcosis, with a cataleptic state, potent amnesia and analgesia produced by ketamine anaesthesia.4 Greifenstein and John Stirling Meyer, head of neurology at Wayne State University, concluded that phencyclidine produced a ‘centrally mediated’ sensory deprivation syndrome.1
Surgical incision, and in 30 patients of Greifenstein's series, the complete operation, could be performed under Sernyl alone. But Sernyl was unsatisfactory for surgery in 13 patients, five of whom suffered severe excitation. Ten of the 64 patients were unmanageable in the postoperative period, and some had a very prolonged postoperative recovery (3 to 18 h). It was immediately observed that in no instances did the electroencephalographic (EEG) trace resemble that obtained following the administration of a barbiturate, nor did it resemble the pattern of sleep.4
Johnstone and Evans published their clinical experience in the British Journal of Anaesthesia in 1959.5 They stated that ‘Sernyl was undoubtedly the most potent general analgesic agent which had been used in clinical medicine’. It had the unique advantage over other sedatives and analgesics that it did not cause depression of cardiovascular and respiratory function, nor depression of pharyngeal and laryngeal reflexes, and could be used safely in elderly patients. However, the usefulness of the drug was limited by the excitation which sometimes persisted for more than 12 h after a single dose. The authors spoke of psychotic reactions.5
With growing clinical knowledge, it became clear that phencyclidine was not suitable for human anaesthesia. Eticyclidine, CI-400 or PCE (N-ethyl-1-phenyl-cyclo-hexylamine; Fig. 2), was developed by Parke-Davis in the late 1950s,6 but, because of frequent hallucinations and the concomitant discovery of ketamine, it was not used extensively in clinical practice. The molecule induced a state of catatonia with generalised rigidity and had, like PCP, neither respiratory nor circulatory depressant effects. In 1960, Collins et al. analysed the provided state of consciousness as a kind of trance resulting in a ‘dissociation’ from the environment. On the EEG, delta waves appeared to be related to the analgesic effect. They supposed that the mechanism could possibly be a direct cortical dissociation, or a block of the thalamus or thalamocortical paths.7 PCE was placed into the Schedule I list of illegal drugs in the 1970s.
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