Volume 100: basic sciences in the British Journal of Anaesthesia
Basic sciences in anaesthesia, and more specifically basic science papers published in the British Journal of Anaesthesia (BJA), provoke widely differing responses. To begin by being provocative, and honest, we have all heard our colleagues (and maybe yourself) question the place of this type of material in the official journal of your medical Royal College. However, most of you would not question the use of the Mapleson breathing circuits,1 the subject of an editorial to mark 50 years since publication,2 or the use of dantrolene in malignant hyperpyrexia.3 These are just two examples of basic sciences applied to the practice of anaesthesia and both were published in BJA. The basic sciences cover a wide range of topics that include: (i) the design and bench evaluation of new apparatus, (ii) in vivo (animal), ex vivo (animal/human), and in vitro (animal/human) physiology, pharmacology, chemistry, and biochemistry, (iii) application of genomic, proteomic, and metabolomic strategies, and (iv) modelling.The first laboratory investigation, at least a section of the paper, in the BJA was in 1924 [volume 1(3)] by Gwathmey.4 The author states that ‘the laboratory work for this paper was done in the Pharmacological Department of the University and Bellevue Medical College under the supervision of Dr George Barclay Wallace, using white mice and dogs’. In 2008, the details of this paper are largely unimportant but illustrate the commitment of the BJA to publish challenging scientific information from its inception. Unfortunately, this work on ethylene and other hydrocarbons was not from the UK but from the USA.
From a history of science perspective, developments in modern science have been mirrored by what the BJA has published. In the 1920s and 1930s, and as far as the early post-war era, the emphasis was on cutting edge physiology performed in a species that, in 2008, is difficult to use—man! The ensuing 20-yr period saw the widespread use of dogs and there were some notable papers including the work by Dundee5 measuring thiopentone narcosis and of Steffey and Eger6 showing that volatile anaesthetic potency or MAC was, in part, determined by brain noradrenaline. The use of dogs continues to this day and a simple PubMed search for ‘British Journal of Anaesthesia and dog’ yields 536 hits. In 1957, a distinction between original and clinical manuscripts was made with original largely (but not exclusively) apparatus/technique based. In June 1957, two sections entitled physiology and pharmacology appeared, and the first ‘hard-core’ science ‘special issue’ was reproduced in 1962 [34(4)] namely ‘Symposium on chemical structure in relation to function with special reference to anaesthesia’ which was followed in 1969 [41(3)] by ‘Biochemistry and the anaesthetist’. August 1975 [47(8)] saw the first ‘Experimental section’ although this did cover a range of topics including experiments in man and then in January 1986 [58(1)] ‘Laboratory Investigations’ section made its first appearance only to be removed a year later then back again in January 1994. At that time, one gets a sense of the BJA (and anaesthesia in general) wanting to embrace the basic sciences but not really being sure of the best way to go about it. The current BJA places basic science and clinical work on similar themes, for example cardiovascular, together and I am of the opinion that this is most appropriate presentation format. Indeed complementary basic, clinical and perhaps modelling papers published together enhance the reading experience.
Most of our clinical readership will use propofol, but without the perseverance of Glen and colleagues;7 8 this may have disappeared from the market before it formally arrived. The saga of propofol was played out on the pages of BJA. ICI 35 868 or 2,6-diisopropylphenol was described in 1980 in two papers. The anaesthetic was dissolved in Cremaphor EL and, as we know, this causes histamine release and is associated with adverse reactions. Rather than consigning the compound to a life as a research reagent, Glen and Hunter9 reformulated this anaesthetic into soya bean oil, egg phosphatidate and glycerol (intralipid), and propofol as we know it was born. The rest is, of course, history and undoubtedly led to the discovery of a number of fascinating additional properties for this simple molecule including antioxidant activity.10 Other notable papers on new agents include early description of the neuromuscular blockers 1,1'azobis[3-methyl-2-phenyl-1H- imidazo(l,2-a)pyridinium] dibromide, AH 8165 or fazadinium in 197311 and Org NC 45 or vecuronium.12 To continue with the neuromuscular blocker theme, BJA recently published several papers on the latest addition to ‘reversal’, sugammadex (Org 25969).13 14 Sugammadex offers a novel mode of reversal for rocuronium block that does not involve inhibition of cholinesterase. The compound is a synthetic 
-cyclodextrin which selectively binds to rocuronium and effectively removes it from the effect site. The safely encapsulated rocuronium is then excreted in the urine.
Thirty-five years ago, Halevy and Frumin15 described experiments in mice that were barbiturate sensitive and barbiturate resistant, indicating a genetic basis for anaesthetic action. More recently, Lucchinetti and colleagues16 made use of cutting edge gene chip technology (Affymetrix Rat Genome U34A array) to describe regulation of a small number of genes/gene clusters in the heart after anaesthetic pre-conditioning.16 The authors are candid in their comments regarding the changes in mRNA not necessarily ending in changes in expressed protein and this is echoed in an accompanying editorial.17 Takemori and colleagues18 used quantitative polymerase chain reaction to show that endothelin-1, nitric oxide synthase-3, and adrenomedullin mRNA are upregulated in rats after sevoflurane anaesthesia. The authors suggest that interplay between the expression of these vasopressors (if mRNA equals protein) may explain the vasodilatory and hypotensive effects of sevoflurane. At the other end of the genetic spectrum, BJA has published works on knockout (KO) animals. These are animals that have been genetically engineered to lack a particular protein of interest, typically a receptor. From an anaesthetic perspective, studies with µ-opioid (MOP) and N-methyl-D-aspartate (NMDA) receptor KO19 20 animals are important. In the case of MOP–KO mice, the antinociceptive and respiratory depressant effects of morphine and morphine-6-glucuronide were formally ascribed to MOP further confirming that a distinction between ‘µ1 and µ2’ is incorrect: there is simply MOP.
Basic science is an integral part of anaesthetic research and as history has shown us several major anaesthetic developments have reached your practice via this route. Indeed, the recent Royal College of Anaesthetists strategy report (2005: www.rcoa.ac.uk/publications) recommends: ‘Generic research in the basic sciences relevant to anaesthesia; research which is also widely applicable to other disciplines. The key message is that anaesthetists should be scientists with an intellectual interest which extends beyond the walls of the operating room, the intensive care unit or the pain clinic’. I would end as I began, with a provocative thought: a speciality without a research base and for anaesthesia this should include the basic sciences sits on the precipice of de-skilling and an almost inevitable plummet to into the service only abyss.
Professor of Anaesthetic Pharmacology
Department of Cardiovascular Sciences (Pharmacology and Therapeutics Group)
Division of Anaesthesia, Critical Care and Pain Management
University of Leicester
Leicester Royal Infirmary
Leicester LE1 5WW
UK
E-mail: DGL3{at}le.ac.uk
References
1 Mapleson WW. The elimination of rebreathing in various semi-closed anaesthetic systems. Br J Anaesth (1954) 26:323–32.
2 Mapleson WW. Editorial I: fifty years after—reflections on ‘The elimination of rebreathing in various semi-closed anaesthetic systems. Br J Anaesth (2004) 93:319–21.
3 Harrison GG. Control of the malignant hyperpyrexic syndrome in MHS swine by dantrolene sodium. Br J Anaesth (1975) 47:62–5.
4 Gwathmey JT. Laboratory and clinical experiments with ethylene and other hydrocarbon gases. Br J Anaesth (1924) 1:108–12.
5 Dundee JW. A method for determining the duration of thiopentone narcosis in the dog. Br J Anaesth (1953) 25:291–6.
6 Steffey EP, Eger EI. The effect of seven vasopressors of halothane MAC in dogs. Br J Anaesth (1975) 47:435–8.
7 Glen JB. Animal studies of the anaesthetic activity of ICI 35 868. Br J Anaesth (1980) 52:731–42.
8 Adam HK, Glen JB, Hoyle PA. Pharmacokinetics in laboratory animals of ICI 35 868, a new i.v. anaesthetic agent. Br J Anaesth (1980) 52:743–6.
9 Glen JB, Hunter SC. Pharmacology of an emulsion formulation of ICI 35 868. Br J Anaesth (1984) 56:617–26.
10 Murphy PG, Myers DS, Davies MJ, Webster NR, Jones JG. The antioxidant potential of propofol (2,6-diisopropylphenol). Br J Anaesth (1992) 68:613–8.
11 Brittain RT, Tyers MB. The pharmacology of AH8165: a rapid-acting, short-lasting, competitive neuromuscular blocking drug. Br J Anaesth (1973) 45:837–43.
12 Baird WL, Bowman WC, Kerr WJ. Some actions of Org NC 45 and of edrophonium in the anaesthetized cat and in man. Br J Anaesth (1982) 54:375–85.
13 de Boer HD, van Egmond J, van de Pol F, Bom A, Booij LH. Sugammadex, a new reversal agent for neuromuscular block induced by rocuronium in the anaesthetized Rhesus monkey. Br J Anaesth (2006) 96:473–9.
14 Hunter JM, Flockton EA. The doughnut and the hole: a new pharmacological concept for anaesthetists. Br J Anaesth (2006) 97:123–6.
15 Halevy S, Frumin MJ. Genetic control of barbiturate depression: strain and sex variation. Br J Anaesth (1973) 45:999–1004.
16 Lucchinetti E, da Silva R, Pasch T, Schaub MC, Zaugg M. Anaesthetic preconditioning but not postconditioning prevents early activation of the deleterious cardiac remodelling programme: evidence of opposing genomic responses in cardioprotection by pre- and postconditioning. Br J Anaesth (2005) 95:140–52.
17 Schwinn DA, Podgoreanu M. The new age of medical genomics. Br J Anaesth (2005) 95:119–21.
18 Takemori K, Kobayashi K, Sakamoto A. Expression of pulmonary vasoactive factors after sevoflurane anaesthesia in rats: a quantitative real-time polymerase chain reaction study. Br J Anaesth (2008) 100:190–4.
19 Romberg R, Sarton E, Teppema L, Matthes HW, Kieffer BL, Dahan A. Comparison of morphine-6-glucuronide and morphine on respiratory depressant and antinociceptive responses in wild type and mu-opioid receptor deficient mice. Br J Anaesth (2003) 91:862–70.
20 Sato Y, Kobayashi E, Hakamata Y, Kobahashi M, Wainai T, Murayama T, et al. Chronopharmacological studies of ketamine in normal and NMDA epsilon1 receptor knockout mice. Br J Anaesth (2004) 92:859–64.
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