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Anaesthesia research is important

Bevan, D. R.

European Journal of Anaesthesiology: November 2001 - Volume 18 - Issue - p 16-20
Original Papers
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Summary The purpose of this paper is to describe the impact of anaesthesia research on clinical practice. The evolution of neuromuscular blocking drugs from the laboratory to the operating room is used as an example. Particular emphasis is given to the pioneers whose vision made this possible: H. R. Griffith and G. E. Johnson; D. Savage, J. B. Stenlake and W. C. Bowman and J. Viby-Mogensen. Our challenge is to ensure the supply of clinical scientists for the future.

Department of Anesthesia, Toronto General Hospital, Room 460, Eaton North, Elizabeth Street, Toronto, Ontario, Canada

Correspondence: D. R. Bevan (E-mail: david.bevan@uhn.on.ca).

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Introduction

Anaesthesia research has radically modified clinical practice, addressed important clinical problems and has enormous scientific potential.

Those of us who have been anaesthetists for more than 30 years have modified almost every component of our practice (Table 1). Patients are now usually admitted on the day of surgery, receive no premedication, are connected to a new generation of monitors and anaesthesia is induced and maintained with very different general and local anaesthetics, muscle relaxants and analgesics — only oxygen and nitrous oxide have withstood time. The changes have occurred either because technology has offered devices that were always coveted, such as pulse oximeters and capnographs, or because our use of drugs has followed evidence-based practice. The evolution of muscle relaxant drugs is a model of successive improvement.

Table 1

Table 1

This introduction will trace the scientific foundations of neuromuscular pharmacology, recognizing those individuals and studies that have shifted our perspective and changed the way in which we interpret data and apply it in our clinical practice.

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The development of modern muscle relaxants

Pioneers: Griffith and Johnson

The first controlled study of the use of neuromuscular blocking drugs in anaesthesia was performed in the small Homeopathic Hospital, Montréal, by Griffith and Johnson (Figure 1) [1]. The first of 25 subjects was anaesthetized on 23 January, 1942 (Figure 2) and the results were published only 6 months later. The study demonstrated that surgical conditions for abdominal surgery were improved by administering small doses of d-tubocurarine, although spontaneous ventilation was maintained and the trachea was not intubated.

Figure 1.

Figure 1.

Figure 2.

Figure 2.

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From laboratory to operating room: Savage, Stenlake, Bowman

After the successful introduction of curare, succinylcholine was utilized as a rapid-onset, short-duration neuromuscular blocking agent. However, the serious and irritating side-effects, such as hyperkalaemia, malignant hyperthermia, prolonged duration from plasma cholinesterase abnormalities, myalgias and fasciculation were rapidly identified. Consequently, several pharmaceutical companies and medicinal chemists began to search for new compounds that possessed some of the properties of d-tubocurarine and succinylcholine, but without their side-effects.

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Pancuronium and aminosteroids

In 1967, the first synthetic relaxant, pancuronium, was introduced [2]. David Savage and colleagues attached two quaternary nitrogen atoms to the rigid steroid nucleus and demonstrated that the new compound possessed neuromuscular blocking properties similar to those of d-tubocurarine (Figure 3) [2,3]. This led to the aminosteroid series of vecuronium [4], rocuronium [5], and rapacuronium [6] in attempts to produce a quick-onset, rapid-recovery relaxant devoid of cardiovascular side effects.

Figure 3.

Figure 3.

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Atracurium and benzylisoquinolines

Atracurium was developed by Stenlake in an attempt to produce an ultra-short-acting muscle relaxant that was independent of the liver and kidney for termination of its action (Figure 4) [7]. Chemical degradation of atracurium occurred by a process known as Hofmann elimination. Atracurium was a mixture of 10 isomers, some of which caused histamine release. One of the isomers, cisatracurium, was introduced later because it did not release histamine and, thus, causes erythaema, hypotension and occasional bronchospasm [8]. Other benzylisoquinolines did not undergo Hofmann elimination, doxacurium [9], or were metabolized by plasma cholinesterase, mivacurium [10].

Figure 4.

Figure 4.

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Relation between potency and onset

Investigators at Strathclyde University, Glasgow, recognized that potent drugs have a slower onset of action than less potent agents (Figure 5) [11]. This is because spare receptors must be occupied before blockade can be observed. Blockade of these spare receptors will occur faster, and onset will be more rapid, if more drug molecules are available, i.e. if potency is low.

Figure 5.

Figure 5.

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Clinical observations

It is more than 20 years since Viby-Mogensen and his colleagues showed that residual neuromuscular blockade (train-of-four ratio <0.7) was common in patients left in the recovery room after surgery involving neuromuscular blocking drugs. The frequency is more common after long-acting relaxants, such as pancuronium [12], than after intermediate-acting agents, such as atracurium, vecuronium or rocuronium [13]. However, it is only in the last 4 years that the same Copenhagen group was able to demonstrate that residual block after pancuronium was associated with poor outcome. In a well-conducted prospective, randomized trial the incidence of postoperative complications was increased threefold in patients undergoing abdominal surgery who had a train-of-four ratio <0.7 in the recovery room after receiving pancuronium [14].

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Linkages

This brief summary of some of the important investigations and investigators that influenced the direction in the development of neuromuscular blocking drugs demonstrates the advantages when clinicians, pharmacologists and industrial medicinal chemists co-operate to develop effective new drugs. Although similar interactions can be observed in the development of other drugs used during anaesthesia practice, few have been as co-operative as for muscle relaxants. However, such relations can be threatened.

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Cost–benefit of pharmaceutical research

In the developed world, there has never been so much money invested in ‘medical’ research. Governments spend freely in national research programmes, specialist societies feel responsible for the support of academic institutions and industry invests heavily in the anticipation of greater profits. Some projects have been spectacular in the new knowledge generated from massive investments, e.g. the Human Genome Project. Yet, despite the obvious success, clinical scientists have been more critical. ‘All our arguments about cloning and ethics will pale before the fact that we will be judged by not worrying about places … that cannot afford the treatments we discover’ [15].

Others have suggested that: ‘Breakthroughs in the treatment of humanity’s horrible disorders are not going to come from genetic discoveries alone but from a partnership of medical scientists doing basic and clinical research.' (Patricia Baird, geneticist).

It would be unfortunate if medical research funding were restricted to fashionable mega-projects to the exclusion of support for developments that may have considerable benefit for our patients. For example, the relief of postoperative pain is important and warrants generous support.

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Industrial relations: conflict

There are several examples of conflicts between clinical scientists and the pharmaceutical industry that supports them. John Le Carré in The Constant Gardener may have exaggerated the consequences of such conflict, although he states that he drew on ‘several cases where highly qualified medical researchers have dared to disagree with their pharmaceutical paymasters and suffered vilification and persecution for their pains’ [16]. The major problem concerns the publication of results that are unfavourable to the sponsor. Investigators should not be coerced into signing contracts that prevent them from making such findings public after allowing a brief period, no more than 3–6 months, for industry to confirm the findings.

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Recruitment of clinician scientists

The success of anaesthesia pharmacological research has depended upon linkages of which the vital key is the ‘translational scientist’, who is capable of transferring the huge growth of fundamental research to the clinic. There is some concern that the supply of such clinician scientists is not keeping pace with demand. In addition, the difficulty in recruiting academic anaesthetists both in Europe and North America may eventually affect our ability to sustain scientific development of our specialty.

For the future, leaders in our specialty should recognize our shortfall, actively recruit appropriate candidates and support them until they establish their independence. I believe that the opportunities for clinical scientists in anaesthesia have never been greater, the opportunities for development have never been so broad and the potential support for well-qualified candidates has never been better.

Anaesthesia research in the last 50 years can boast of its success in improving our ability to provide safe clinical care. Although there are many threats, they can and must be overcome. We should remember Griffith, Savage and Stenlake. Anaesthesia research is very important.

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References

1 Griffith HR, Johnson GE. The use of curare in general anesthesia. Anesthesiology 1942; 3: 418–420.
2 Baird WLM, Reid AM. The neuromuscular blocking properties of a new steroid compound, pancuronium bromide. Br J Anaesth 1967; 39: 775–780.
3 Buckett WR, Marjoribanks EB, Marwick FA et al. The pharmacology of pancuronium bromide (ORG NA97), a new potent steroidal neuromuscular blocking agent. Br J Pharmacol 1968; 32: 671–682.
4 Fahey MR, Morris RB, Miller RD et al. Clinical pharmacology of ORG NC 45 (Norcuron). Anesthesiology 1981; 55: 6–11.
5 Wierda JMKH, de Wit APM, Kuizenga K, Agoston S. Clinical observations on the neuromuscular blocking action of ORG 9426, a new steroidal non-depolarizing agent. Br J Anaesth 1990; 64: 521.
6 Wierda JMKH, van den Broek L, Proost JH, Verbaan BW, Hennis PJ. Time course of action and endotracheal intubating conditions of Org 9487, a new short-acting steroidal muscle relaxant; a comparison with succinylcholine. Anesth Analg 1993; 77: 579–584.
7 Stenlake JB, Waigh RB, Urwin J et al. Atracurium: Conception and inception. Br J Anaesth 1983; 55: 3S.
8 Lien CA, Schmith VD, Belmont MR, Abalos A, Kisor DF, Savarese JJ. Pharmacokinetics of cisatracurium in patients receiving nitrous oxide/opioid/barbiturate anesthesia. Anesthesiology 1996; 84: 300–308.
9 Dressner DL, Basta SJ, Ali HH et al. Pharmacokinetics and pharmacodynamics of doxacurium in young and elderly patients during isoflurane anesthesia. Anesth Analg 1990; 71: 498–502.
10 Savarese JJ, Ali HH, Basta SJ et al. The clinical neuromuscular pharmacology of mivacurium chloride (BW 1090U): a short acting nondepolarizing ester neuromuscular blocking drug. Anesthesiology 1988; 68: 723–732.
11 Bowman WC, Rodger IW, Houston J et al. Structure: action relationships among some desacetoxy analogues of pancuronium and vecuronium in the anesthetized cat. Anesthesiology 1988; 69: 57.
12 Viby-Mogensen J, Jorgensen BC, Ording H. Residual curarization in the recovery room. Anesthesiology 1979; 50: 539–541.
13 Bevan DR, Smith CE, Donati F. Postoperative neuromuscular blockade: a comparison between atracurium, vecuronium, and pancuronium. Anesthesiology 1988; 69: 272–276.
14 Berg H, Viby-Mogensen J, Roed J et al. Residual neuromuscular block is a risk factor for postoperative pulmonary complications. Acta Anaesthesiol Scand 1997; 41: 1095–1103.
15 Folkman, J. Globe & Mail, January 2001
16 Le Carré, J. The Constant Gardener. New York: Schriber, 2001
Keywords:

ANAESTHESIA; SCIENCE; research

© 2001 European Society of Anaesthesiology