1 Harvard Medical School Department of Anesthesia (Edwards 505) Massachusetts General Hospital Blossom Street Boston MA 02114, USA 2 Department of Physiology University College Rockefeller Building University Street London WC1E 6JJ, UK 3 Departments of Pharmacology & Therapeutics and Anesthesia Faculty of Medicine The University of Calgary 3330 Hospital Drive NW Calgary Alberta T2N 4N1, Canada 4 Klinik für Anästhesiologie und spezielle Intensivmedizin Universitätsklinikum Bonn Sigmund-Freud-Straße 25 D-53127 Bonn, Germany
This postgraduate issue of British Journal of Anaesthesia is based on the three-day Sixth International Conference on Molecular and Basic Mechanisms of Anesthesia (June 2830, 2001 in Bonn, Germany) organized by Keith W. Miller, Chris D. Richards, Sheldon H. Roth and Bernd W. Urban. This was the sixth in the series of International Conferences on Mechanisms of Anaesthesia that was started by Raymond Fink (1974 and 1979 in Seattle, and 1984, 1990 and 1997 in Calgary). It was the first in the series to be held in Europe, acknowledging the increasing contribution of European researchers to the field. Comprising leading clinical anaesthetists and basic scientists from all over the world this international and multidisciplinary group of clinical investigators and scientists discussed recent advances in mechanisms of anaesthesia, from the in vitro molecular to the in vivo CNS network level. Because of the increasing number of international participants, the next conference will take place in Nara, Japan, during the last week of February 2005.
The rate of increase in our understanding of the mechanisms of anaesthetics and anaesthesia is accelerating, justifying another postgraduate educational issue of the British Journal of Anaesthesia devoted to this topic; the last one,1 appearing in July 1993, focused on Receptors and transmembrane signalling: cellular and molecular aspects of anaesthesia. The current issue does, as the conference did, allocate substantially more space to levels of system integration beyond the molecular and cellular level in order to better bridge the gap between the basic and the clinical sciences.
Ascending the hierarchical order of the central nervous system from molecules to intact organisms, the materials in this issue have been arranged following the organization of the conference, dealing with the topics: Molecular Basis of Anaesthetic Interactions, Anaesthetic Interactions with Ion Channels and Other Receptors, Subcellular Mechanisms, Integration of Anaesthetic Actions, In-vivo Networks and, finally, Mechanisms of Anaesthetics and Anaesthesia. The reviews in this issue reflect the many aspects not only of the formal presentations but also of a great many formal and informal discussions that took place throughout the conference, lasting until well after midnight each day. In a parallel publication2 participants at the conference have been given the opportunity to present short papers on their communications.
Despite the lack of generally accepted hypotheses for anaesthesia mechanisms, general anaesthesia has become so safe since its introduction just over 150 years ago that the mortality associated with it has become almost immeasurably small. Some of this improvement has come from new agents with more rapid pharmacokinetics and much more from intensive training of staff and more intensive monitoring of patients. There has been no improvement in the pharmacological specificity of the agents employed. For example, most general anaesthetics cause respiratory and cardiac depression at clinical concentrations, a complication that assumes greater importance with infirm and elderly patients. Postoperative emesis is unpleasant for patients and results in longer hospital stays with their associated costs. However, current hypotheses that anaesthetics bind to specific sites on proteins rather than act non-specifically hold out hope that pharmacological selectivity may be achievable. Such binding sites should, and in fact do, discriminate between different agents. In fact, there is growing evidence that several physiological targets underlie general anaesthesia, and that different agents may act selectively on subsets of these targets.
It does matter to the practising clinician whether mechanisms of anaesthesia are understood: providing the right amount of anaesthetic, minimizing side effects, preventing awareness during surgery, comparing clinical outcome from different anaesthesia procedures all require monitoring of the anaesthetic state. Understanding different mechanisms of anaesthesia will help to identify which anaesthesia-related quantities anaesthesia monitors should measure.
The editorial of the postgraduate issue 9 years ago concluded that everybody was in agreement that the overall cellular effects were far more complicated than was thought 25 years previously.1 Today it can be safely stated that their actions on highly integrated systems within the central nervous system indicate a still higher level of complexity. This conclusion, based on observations in spinal cord, brain slices and the intact brain, is confirmed by genetic studies. As did the editors at that time, so may we now marvel that the more that is known about the multiplicity of underlying perturbations, the more surprising is the overall phenomenon. Yet this surprise may hold the clue to understanding general anaesthesia.
References
1 Halsey MJ, Prys-Roberts C, Strunin L. Editorial. Receptors and transmembrane signalling: cellular and molecular aspects of anaesthesia. Br J Anaesth 1993; 71: 1[ISI]
2 Urban BW, Barann M, eds. Molecular and Basic Mechanisms of Anesthesia, Lengerich, Berlin, Riga, Rome: Pabst Science Publishers, 2002 in press