John (Iain) B. Glen

Former Anesthesiology Team Leader and Clinical Specialist in Anesthesia, AstraZeneca

Five research papers that inspired him.

The pharmacological properties in animals of CT1341—a new steroid anaesthetic agent

Child, K.J. et al. Br. J. Anaesth. 43, 2–13 (1971)

This paper, which describes the anaesthetic properties of a mixture of two steroids later to be known as alphaxalone and alphadolone, is unique in that it provides the first description of an anaesthetic expected to have significant advantages over thiopentone, the most widely used intravenous anaesthetic for more than 30 years at that time. In comparison with thiopentone, this steroid combination had a greater therapeutic index, could be given by repeated injection without the occurrence of cumulative effects and was devoid of vascular irritancy. The profile of this agent set the standard required for any new intravenous agent that could be used both to induce and maintain anaesthesia. This agent was marketed as Althesin (Glaxo) in Europe but was never introduced in the US. A number of anaphylactoid reactions were attributed to this agent and its surfactant vehicle, Cremophor EL, and it was withdrawn in 1984.

Intravenous anaesthesia by infusion. A technique using alphaxalone/alphadolone (Althesin)

Savege, T.M. et al. Anaesthesia 30, 757­–764 (1975)

Increasing concern at this time about pollution of the operating room atmosphere with anaesthetic gases is discussed in this paper. This study described, as one potential solution, an anaesthetic technique where anaesthesia was maintained with an infusion of alphaxalone/alphadolone. This is one of the first papers describing maintenance of anaesthesia with this drug combination supplemented with pethidine or fentanyl for analgesia. In 86% of patients, anaesthetic conditions were judged to be good or satisfactory. The technique was considered to be difficult to learn, but the infusion of 10% alphaxalone/alphadolone was delivered from a 100-ml burette and one can envisage that it would have been simplified if a suitable syringe pump had been available. A problem of spontaneous movements unrelated to depth of anaesthesia in some patients and recovery times that were not particularly rapid pointed to the opportunity for the development of a similar but improved agent.

A general method for calculating the dosage scheme in linear pharmacokinetics

Schwilden, H. Eur. J. Clin. Pharmacol. 20, 379–386 (1981)

Helmut Schwilden, an anaesthesiologist at the University of Bonn in Germany, was also a mathematician. In this paper, he builds on earlier work by Kruger-Thiemer to develop a method, using a linear pharmacokinetic model, to achieve a desired blood level or amount of drug in any other compartment. In order to achieve elaborate infusion schemes, an infusion pump is interfaced with a computer. With further development in Bonn, Leiden in Holland, Duke and Stanford in the US, Glasgow, Scotland, and Stellenbosch, South Africa, this approach led to the first commercial target-controlled infusion (TCI) system, the Diprifusor produced by AstraZeneca in 1995. The technique of TCI, which facilitates fine control of depth of anaesthesia, is now widely practiced in most countries of the world, but not in the US where it remains unapproved by the FDA.

Forum: attitudes to intravenous infusion anaesthesia

Wright P.J. & Dundee, J.W. Anesthesia 37, 1209–1213 (1982)

This paper reports the findings of a UK survey related to continuous infusion anaesthesia to ascertain how acceptable continuous infusion techniques would be to clinical anaesthetists. Only 15% of respondents had used continuous infusion anaesthesia, and the main reasons for not using the technique were lack of information on the technique, no previous experience, as this was not being taught, and lack of suitable equipment. When asked whether an alternative drug to those available at that time was found to be suitable for continuous infusion, 92% of respondents expressed an interest in using it. This was a reassuring finding, but the survey also highlighted the need for effective teaching of the technique, judging the depth of anaesthesia and an understanding of the pharmacokinetics of infusion anaesthesia.

Context-sensitive half-time in multicompartment pharmacokinetic models for intravenous anesthetic drugs

Hughes, M.A., Glass, P.S.A. & Jacobs, J.R. Anesthesiology 76, 334–341 (1992)

The simulations conducted in this study demonstrate that elimination half-life, the pharmacokinetic parameter most commonly used to describe duration of pharmacologic action, is of no value in characterizing disposition of intravenous anaesthetic drugs during dosing periods relevant to anaesthesia. This paper helped to explain my observation of rapid recovery from propofol anaesthesia in a range of animal species despite our pharmacokinetic group determining a prolonged elimination half-life and predicting that recovery following repeated administration or infusion would be prolonged. The short, context-sensitive half-time of propofol results from continuing distribution of the drug to peripheral compartments during an infusion in addition to hepatic clearance. For all intravenously infused anaesthetic and analgesic drugs, context-sensitive half-time based on the duration of infusion provides a much better prediction of the rate of decline in blood concentration at the end of administration.