From d-tubocurarine to sugammadex: the contributions of T. Cecil Gray to modern anaesthetic practice.

One hundred years after Morton's demonstration of the anaesthetic effects of ether, T. Cecil Gray revolutionized anaesthesia with his introduction of balanced general anaesthesia. Gray's technique involved i.v. induction, administration of a neuromuscular blocking agent (curare), tracheal intubation, controlled ventilation, maintenance of unconsciousness with a light inhaled anaesthetic (supplemented with opioids if necessary), and reversal of neuromuscular blocking agent at the conclusion of the anaesthetic. In the 65 yr since his seminal papers, our drugs have changed, and i.v. anaesthetics suitable for maintenance of anaesthesia have been introduced, but the basic principles of general anaesthesia today are those set forward by Gray 65 yr ago.

[Muscle relaxants]. / Muskelrelakserende midler.

BACKGROUND: Muscle relaxants were introduced into clinical anaesthesia for the first time in 1942. The purpose of this article is to provide an overview of the history of muscle relaxants, their mode of action and their role in current anaesthetic practice. MATERIAL AND METHOD: The review is based on clinical experience, own research and a non-systematic literature search using PubMed. RESULTS: A muscle relaxant is either suxamethonium (curacit) or one of many curare compounds. One of the curare drugs was brought to Europe from South America in the 1700 s and the active substance (called d-tubocurarine) was isolated in 1935. This type of drug paralyses striated muscles that are under voluntary control by interfering with the normal signalling system between nerve and muscle. Muscle relaxants provide optimal relaxation of skeletal muscles during surgical procedures, an effect that otherwise may require the use of high doses of anaesthetic drugs. However, muscle relaxants are not anaesthetic drugs, do not affect consciousness and have no pain relieving effect. A muscle relaxant that works optimally in all clinical settings has unfortunately not been developed so far. INTERPRETATION: Muscle relaxants are generally safe drugs when used appropriately, but especially suxamethonium may have serious side effects. A muscle relaxant is regularly used during induction of anaesthesia, but less during surgery, because modern anaesthetics possess some muscle relaxing effect.

Neuromuscular block.

Descriptions of the South American arrow poisons known as curares were reported by explorers in the 16th century, and their site of action in producing neuromuscular block was determined by Claude Bernard in the mid-19th century. Tubocurarine, the most important curare alkaloid, played a large part in experiments to determine the role of acetylcholine in neuromuscular transmission, but it was not until after 1943 that neuromuscular blocking drugs became established as muscle relaxants for use during surgical anaesthesia. Tubocurarine causes a number of unwanted effects, and there have been many attempts to replace it. The available drugs fall into two main categories: the depolarising blocking drugs and the nondepolarising blocking drugs. The former act by complex mixed actions and are now obsolete with the exception of suxamethonium, the rapid onset and brief duration of action of which remain useful for intubation at the start of surgical anaesthesia. The nondepolarising blocking drugs are reversible acetylcholine receptor antagonists. The main ones are the atracurium group, which possess a built-in self-destruct mechanism that makes them specially useful in kidney or liver failure, and the vecuronium group, which are specially free from unwanted side effects. Of this latter group, the compound rocuronium is of special interest because its rapid onset of action allows it to be used for intubation, and there is promise that its duration of action may be rapidly terminated by a novel antagonist, a particular cyclodextrin, that chelates the drug, thereby removing it from the acetylcholine receptors.

Status epilepticus treated with a muscle relaxant: the first success.

In 1958, an 11-year-old girl with status epilepticus was given the current treatments which failed to control the convulsions. In order to stop the fits, protect the airway, prevent hypoxia and hyperpyrexia, intermittent positive pressure ventilation (IPPV) and complete muscle paralysis with d-tubocurarine was used for a total of 6 h. The girl made a complete recovery, the first patient to do so using this plan of action.

[A new toy: upswing in curare use in Spanish anesthesia]. / A new toy: la irrupción del curare en la anestesia española (1946).

The introduction of curare for general anesthesia by Harold Griffith in 1942 was one of the most important moments in the development of anesthesiology. However, several years passed before curare came to be used in Spain. We review the early application of curare and the role played by Robert Macintosh, Professor of Anaesthesia at Oxford, in introducing the drug to Spain.

[Autopsy of a common error: the introduction of curare in Europe by W. Raleigh]. / Autopsie d'une erreur commune: l'introduction du curare en Europe par W. Raleigh.

One of the most erroneous and repeated assertion in the history of pharmacology for anaesthetists is to say that "the curare was introduced in Europe by Sir Walter Raleigh under the name of ourari". On the contrary, the names to be reminded are: Lawrence Keymis for the first citation of the word ourari, José Gumilla for the word curare and the description of its effects, Charles-Marie de La Condamine for the import of the first known samples. The mistake was initiated by Alexander von Humboldt and developed by the physiologist Münter, a student of Johannes Müller, quoted by Claude Bernard. The repetition of this error was facilitated by the world diffusion of Claude Bernard's work.

[Claude Bernard and his successors on curare: epistemological questions at stake]. / Claude Bernard et ses suiveurs sur la question du curare : enjeux épistémologiques.

Long lasting polemics about the mechanisms of the action of curare took place at the Société de Biologie over thirty years. After a period during which poisoning protocols were developed on various animal species, where Claude Bernard, Vulpian and their colleagues were involved, German electrophysiology combined its results with new histological data about motor end-plates, elaborating a theory in which young physiologists fought against Claude Bernard's views and finally managed to convince him. According to the new theory proposed by Vulpian, curare blocked transmission between end-plate and muscle. This first draft of the neurotransmission theory helps us to understand the rise of a novel physiology in the context of the school of Claude Bernard with a better integration of disciplines and a more prominent faith in reductionism and materialism.

[Curare and its successors. A 50-year's evolution]. / Curare und seine Nachfolger. 50 Jahre einer Entwicklung.

The introduction of curare into clinical anaesthesia by Griffith and Johnson in 1942 contributed to the termination of the era where anaesthesia was a reversible intoxication rather than the result of controlled drug action. Curare allowed general anaesthesia to be reduced to a lighter level, thereby conferring a significant safety factor to the patient. Both the shortage in supply of crude curare and its variable composition led the search for synthetic curare analogues conferring well defined pharmacodynamic and pharmacokinetic properties. Based on the chemical structure of tubocurarine which has been known since 1935 the efforts concentrated on bisquaternary ammonium compounds. Gallamine was the only synthetic curare analogue to contain three quaternary ammonium groups. This drug had significant undesired vagolytic effects. In 1951 succinylbischoline appeared to be the ideal muscle relaxant, particularly with respect to its fast onset and short duration of action. The disadvantages of its depolarising mechanism of action which were appreciated during the years to follow prevented the concept of depolarising neuromuscular blockade to be pursued further. With other muscle relaxants, including curare itself, histamine release, vagal blockade and ganglionic blockade were undesired effects to be eliminated in future compounds. Improved understanding of structure-activity relationships turned out to be an indispensable tool for future research. This in turn required more elaborate methods in chemical analysis, in electrophysiology of the motor endplate, and in ultrastructural research. As a result, alcuronium and pancuronium became available in the late sixties and early seventies. Both muscle relaxants had a non-depolarising mechanism of action with reduced side effects relative to curare. From now on better techniques for pharmacodynamic and pharmacokinetic research became available resulting in research activity with particular emphasis in this field. Researchers became aware that new muscle relaxants should be designed for larger volumes of distribution and more rapid biodegradation than those currently available. Concurrently, anaesthesia techniques had changed in a way to use intubation and mechanical ventilation as a routine procedure. The risk of intraoperative hypoventilation and hypoxemia was eliminated, yet, due to the lack of adequate monitoring techniques the slow recovery from curare, alcuronium or pancuronium neuromuscular blockade was hardly appreciated.(ABSTRACT TRUNCATED AT 400 WORDS)