George Liarczek | Romania
This is a series of flashes to cover the evolution of medicine from its beginnings until anaesthesia appeared and later developed to what it is today.
Actually Anaesthesia is considered to have 4 pillars: analgesia, hypnosis (sleep, unconsciousness), muscular relaxation and homeostasis. In previous flashes we discussed some of the main substances considered as anaesthetics. But modern anaesthesia uses much more and different kind of drugs to cover the pharmacological needs of the 4 pillars. Some of them are not included in one of the 4 mentioned classes like for instance the neuroleptics, different drugs acting on the vegetative nervous system, antihistamines, tranquilizers, etc. which we include in this category of ancillary drugs.
So this time history cannot start until after Morton’s first anaesthesia in 1846.
The necessity to add ancillary drugs to an anaesthetic already in course, preceding or following it, came from unexpected phenomena appearing during anaesthesia, and the need to avoid or treat accidents and improve the security and quality of the procedure.
The curare revolution
First of all we have to mention that there was no clear pharmacological concept about anaesthesia until very late, in the fifth decade of the last century when Jackson Rees and Cecil Gray invented the concept of the “anaesthetic triangle”: analgesia, sleep, and relaxation. This rather new concept became a reality only after the introduction of the first muscle relaxant, tubocurare, by Griffith (Canada) in 1942. The triangle was soon transformed into a square a few years later when the notion “anti shock” effect showed up. It soon got the name of “anti-stress” and later on it was accepted as a more comprehensive notion, that of “homeostasis”, a term which includes all methods and medication to maintain in normal parameters the vital functions of the organism, respiration, circulation, temperature, excretion, cerebral function, etc.
Starting with Morton, the first trend of development was to look for other anaesthetics which were discussed in a previous flash.
The first two drugs to be added to the already existing anaesthetics (ether, chloroform and ethyl chloride) were morphine, introduced as pre-medication by Al. Wood in 1853, and atropine introduced by Heidenhein in 1872 for its anti-salivary effect and later on for its tachycardic properties . We have to mention also a curious method of improving the quality of anaesthetic mixtures, the so called ACE (alcohol, chloroform, ether) or the Schleich (ethyl chloride, chloroform, ether) mixtures. Both have been abandoned until Lundy in 1926 introduced the concept of “balanced anaesthesia” using different hypnotics and analgesics from an already long list of drugs at his time. Much later (around 1960) the azeotropic mixture (halothane, ether) was tried for short time. But one cannot forget that much earlier, in 1872, intravenous anaesthesia was inaugurated by Ore who used chloral-hydrate in animals and 2 years later in humans.
In 1903 the first barbiturate (barbitone, Veronal®) was synthesised by E. Fischer inaugurating a long list of compounds used first in premedication and later in anaesthesia for induction and even, in high doses, for maintenance, during the first years after their introduction.
An interesting and a long reaching concept was proposed by G. Crile in 1910 the “annoci association” combining light general anaesthesia with regional block of the operating site. This concept was used in Romania by N. Hortolomei, a very well known surgeon, who associated general or spinal anaesthesia with local infiltration of the vagus and splanchnic nerves for upper abdominal surgery. In modern times this concept is materialised in the association of thoracic epidural and light general anaesthesia.
The year of 1927 brought the introduction of ephedrine by Ochenblad and Dillon as a circulatory stimulating drug, very largely used, especially for correcting the hypotension induced by spinal block.
Hypovolemia, was it good??!!
For long time the compensation of blood lost during trauma and surgery was not at all a concept ! On the contrary, wounded individuals were bled by venesection, and just look back at the fate of Lord Byron! Later on, due to authors like Crile, Henderson, Cannon, Bayliss, Blalock, Wiggers Rushmer, Shoemaker (1890-1975) and others the cause of traumatic shock was revealed as being in major part due to loss of blood or any body fluid.the compensation of blood lost was started with saline and blood, after anti-coagulation with citrate became available. At the beginning of the 20th century saline was administered either with syringes or with pressuriSed devices like the Potain, usually subcutaneously. Only in 1935 was the intravenous drip proposed by Mariott and Kekowick, and shortly after it became standard procedure in the US army, being included in the dried plasma kit during World War II. Blood transfusions were performed by syringes or pumps in quick direct transfer, before clotting occurred. Only in 1914 A. Hustin used citrate to prevent coagulation of blood and thus could introduce blood conservation, which of course had to be kept at temperatures around 4-6 degrees Celsius. So suitable volemic solutions were searched for, and the first one was plyvinyl-pyrollhidon (Periston), discovered by Weese in 1939. Lyophilised plasma was also extensively used during World War IIby the US army. Dextran, another artificial solution, was discovered accidentally in a soft drink where it was produced by bacteria was found to be a good plasma substitute by A. Groenwall and B. Ingelman and was largely used in the 1950-53 Korean war.
Before reaching the next big step in the evolution of anaesthesia I have to mention the synthesis of meperidine (pethidine) by Schauman and Eisleb in 1939.
Back to square one: the curare
However, the big step was the introduction of curare to produce muscle relaxation in surgery.
As mentioned before, it was achieved by H.R. Griffith and G.E. Johnson in Canada in 1942. The history of curare is a long one, starting in the 16th century, after the discovery of America (1492) by Columbus. The first reports came from South America and were mentioned by an Italian Pietro Martire d’Angheira in his work “De Orbe Novo” (1514), and then by Vasquez d’Espinosa and Lucas Fernandez de Pietrahita (1688) who reported about an expedition lead by Alonso Perez de Tolosa (1548). It seems that this one was the first to report the use of poisoned arrows and mentioned the paralysis effect of the poison. Later W. Raleigh’s visits in the Guyanas and reports about similar poisons called by the natives “ourari” described similar effects. In the 18th century father Jose Gumilla told stories about his journey on the Orinoco and of the use of “curare”. The toxic drug was brought to Europe and was studied first by father Fontana in Florence (1781) who published a book on poisons including a chapter on curare.. Von Humbold, during his South American voyages, made the observation that the source of curare was different in different tribes and regions. He, in fact, discovered that even the symptoms of intoxication were different. Later on three important plant families were identified as being the main source of the flash poison, the Menispemacaea, producing d-tubocurarine; the Loganiacaea, producing toxiferin I and II and c-curarine I and the Erytrydinaea, producing c-toxiferin I and erytroydine. The first half of the 19-th century brought light into the place and mode of action of d-Tubocurarine which was proved to act only on the neuro-muscular junction and that the action was related to dosage.
The introduction of curare in the anaesthesia arsenal led Cecil Gray and Geddes to conceive a new model of anaesthesia: the “relaxant anaesthesia” (1951) in which they used a premedication with papaveretrum/atropine or even scopolamine, induction with thiopental and apnoeic dosage of d-tubocurarine, tracheal intubation, and maintenance with N2O andO2 under controlled ventilation and slight hyperventilation which was proved to potentiate analgesia. New types of relaxants showed up, some of them produced as natural extraction, semi-synthetic or synthetic. Two groups emerged: depolarising or leptocurare and non-depolarising or pachycurare products. Time filtered them out, and today synthetic, non-depolarising compounds are preferred and largely used.
The useful combinations
The next decade 1950-1960 was a very prolific one, both in products and in new concepts. It started already after 1945 with the concept of vegetative storm described by Wiggers and Robertson, and the use of the first sympatholytic drugs acting on the pre-synaptic ganglion, the ganglioplegics, penta and hexamethonium, by Patton and Zaimis.
This concept was largely developed by H. Laborit and P. Huguernard, with their theory of the “oscillating postagressive syndrome”, meaning an exaggerated physiological reaction which creates the state of shock in its form and mechanisms described already by Wiggers. Later, Laborit et Huguenard introduced anaesthetic combinations in order to prevent the appearance of shock:-potentialised anaesthesia (diethazine, promethezine and pethidine) and the “Lytik cocktail” (chlorpromazine, prometazine, pethidine), which later on became the famous neurolept-anaesthesia. When coupled with hypothermia the method was called “hybernotherapy”.
A next important event was the synthesis by Janssen of a series of opioid type analgesics, more potent and less aggressive than morphine and its derivatives: dextromoramide (Palfium), phenoperidine and fentanyl which were firs used by Joris deCastro in association with non-sedative neuroleptics ( haloperidol and droperidol). As part of the neurolept-anaesthesia technique. Later deCastro recurred to analgesic subconscious anaesthesia (anaesthesie analgesique) in which he eliminated the neuroleptic and increased the dosage of analgesic.
Further progress was made by introduction of benzodiazepines (diazepam, midazolam) to replace barbiturates in induction. They were later joined by etomidate and propofol /
Propofol became the most preferred induction (and not only) anaesthetic drug and its increasing use led to what is called today TIVA (Total Intra Venous Anaesthesia)
The new volatiles, sevoflurane and desflurane with their rapid dynamics led to the concept of VIMA (Volatile Induction Maintenance Anaesthesia) resuscitating the work of Morton, who could not have imagined that in fact he was more than 150 years ahead to practice VIMA with his ether administration.