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.

Harold Griffith Memorial Lecture. The Griffith legacy.

1992 was the anniversary of Crawford Long's use of ether in 1842, and Griffith and Johnson's introduction of Intocostrin into anaesthetic practice in 1942. Harold Randall Griffith was born in Montreal in 1894 and died in 1985. He interrupted his medical studies to serve in the first world war and was awarded the Military Medal for gallantry at the battle of Vimy Ridge. Griffith qualified from McGill University in 1922. After spending a year studying homoeopathic medicine, he joined his father's general practice and became the anaesthetist to the Homoeopathic Hospital in Montreal. He succeeded his father as Medical Director of the hospital (now renamed the Queen Elizabeth Hospital) in 1936 and retired in 1966. Griffith was a superb clinical anaesthetist. He was an early advocate of detailed anaesthetic records, and was responsible for the introduction of both ethylene and cyclopropane into Canadian practice, later teaching himself to intubate under these two agents. Griffith was one of the first to be concerned with standards of patient care. He introduced postoperative recovery and intensive care units into Canadian practice and played a major role in postgraduate teaching. He was unstinting in his support of organisations designed to further the progress of anaesthesia and was the first President of the Canadian Anaesthetist's Society. He was one of those responsible for inaugurating the World Federation of Societies of Anaesthesiology and was President of the First World Congress of Anaesthesiology in 1955. It is remarkable that the introduction of curare into anaesthetic practice was delayed until 1942, since curare had been used in anaesthesia some 30 years previously. However, it was probably Griffith's confidence in his own clinical abilities which enabled him to seize the opportunity when it was offered.

Harold King. A notable contributor to anaesthesia.

Harold King was an analytical chemist of distinction, who worked with Sir Henry Dale and his colleagues in the Medical Research Institute, later the Medical Research Council. He helped to quash the theory that the anaesthetic action of ether was attributable to its impurities. Interest in alkaloids led to the elucidation of the structure of hyoscine, the synthesis of muscarine and the first isolation of crystalline tubocurarine for which he proposed a structural formula, work which influenced Bovet in the synthesis of gallamine. He proposed the synthesis of the homologous series of methonium compounds which included relaxant and hypotensive drugs. His collaboration with Rosenheim was outstanding and opened the way for synthesis of cholesterol and the steroids. He was always encouraging clinicians, and gave a sample of tubocurarine to Ranyard West who was the first to inject d-tubocurarine into a human patient.