By Jenny (Jia) Tang, MD, MBA
The CSA Committee on the History of Anesthesia congratulates Dr. Jenny (Jia) Tang, the 1st place winner of the 2024 CSA History of Anesthesia Essay Contest!
Dr. Tang, who was born in Singapore and raised in Fremont, California, is a CA-2 resident physician at UCLA. She loves traveling, scuba diving, and cats.
On the morning of January 23, 1942, Drs. Harold Griffith and Enid Johnson kept a watchful eye on their patient, a 20-year-old presenting for appendectomy, during what appeared to be a routine induction of cyclopropane anesthesia. Business here would not proceed as usual, however. When closure of the peritoneum proved difficult in the setting of tense abdominal muscles, Griffith administered 5 milliliters of the experimental drug, Intocostrin, a purified preparation of the paralytic curare. Within a minute, the abdomen became “soft as dough,” remained so despite lightening of the inhaled anesthetic, and the operation was completed smoothly.1,2 Griffith and Johnson would reproduce these results in 25 patients by July of that same year, and the adoption of curare would revolutionize anesthetic practice. Finally, rapid muscle relaxation was possible without the complications of deep anesthesia.
While curare’s benefits to the field of anesthesia appear obvious from this landmark case, its debut in the operating room was anything but fated. Indeed, its momentous journey from the remote rainforest to modern medicine would have been impossible without the synergistic contributions of numerous explorers, scientists, indigenous tribes, and animal subjects. Curare’s tale begins five centuries ago and a continent away…
Spanish New World explorers, venturing deep into the Amazonian jungle, noted as early as 1516 the use of poisoned arrows by indigenous South and Central American tribes. Used mainly for hunting, these arrows were shot from either longbows or blowguns, and “albeit the [wounds] were not great, [the victims] died immediately.”3 The resinous poison,curare (or wourali), was therefore nicknamed “the flying death.” Intriguingly, its production process was shrouded in ritual and superstition. Curare was only concocted by brujos (witchdoctors) in secluded locations away from areas of habitation, as not to curse other community members.4 The root and bark of certain vines were combined in designated clay pots, and the mixture was continuously boiled until reaching a “tar-like consistency,” into which the tips of arrows were carefully dipped.4
Curare remained relatively unknown until the findings of French mathematician, Charles de la Condamine. On an expedition to Peru to confirm Newtonian theory in 1735, de la Condamine (also a naturalist and apparent daredevil) decided to return home not by traditional routes but via a spontaneous rafting detour down the Amazon River.It was during this adventure that he witnessed the use of curare and desired to study its captivating properties. He discovered that a hen injected with curare died swiftly from respiratory failure, yet he was able to eat the animal without ill effects. Thus, he deduced cheerfully that “the venom of this poison is only mortal when absorbed by the blood.”5 Ultimately, he carried back samples to Europe, facilitating the first scientific studies of curare.
In 1814, Englishmen Benjamin Brodie and Charles Waterton successfully demonstrated that a curarized animal could be kept alive with artificial ventilation. In their experiment, a donkey (affectionately named Wouralia), was injected with curare and artificially ventilated using bellows via tracheotomy. After 4 hours, the donkey recovered and “walked about, [and] seemed neither in agitation nor pain.”6 In 1850, French physiologist Claude Bernard observed that a curarized frog still retained electrical impulses in its nerves, thereby concluding that the site of action must be at the neuromuscular junction.3 These revelations sparked interest in curare as a potential therapeutic agent for humans suffering from spastic diseases such as tetanus, epilepsy, and rabies. Unfortunately, early patients suffered high mortality rates from respiratory failure, and titration was exceedingly difficult due to inconsistent preparations of the drug. Furthermore, due to insufficient amounts of crude curare, biological standardization was impossible.
Interest and usage of curare, therefore, waned until 1937, when self-taught American botanist Richard Gill embarked on a 5-month expedition to Ecuador in hopes of securing a larger supply of crude curare. Suffering from severe spasms and paralysis following a fall, Gill dreamed of a standardized drug derived from curare that could alleviate spastic diseases. Luckily, he had forged close relationships with several indigenous tribes while previously residing on a ranch in the Andean wilderness and felt confident that they could assist him in locating and obtaining quality samples.
His endeavor was a resounding success. He not only secured 12 kg of crude curare, but also 75 meticulously preserved botanical specimens, all of which were bought in 1939 by the pharmaceutical company E.R. Squibb and Sons. Squibb scientists were able to purify and standardize this supply as the drug Intocostrin, as well as identify the active compound as d-tubocurarine from the vine Chondodendron tomentosum.7
Now that Intocostrin represented a form of curare with adequate supply and predictability of effect, physicians were less hesitant to trial it in human patients. The first documented application was by psychiatrist Abram E. Bennett in 1940 for patients undergoing convulsive shock therapy for psychotic disorders. Until then, such treatments were executed without paralytic, a practice associated with a 40-50% chance of traumatic fracture.8 Bennett reported that intravenous injection of Intocostrin at 1/10 the lethal dose five minutes prior to initiation of convulsions significantly decreased contractions and associated traumatic injury without interfering with the therapeutic effect of the treatment.9 Incredibly, none of his patients required artificial ventilation for respiratory failure, presumably due to the low dose administered.
Bennett’s success caught the attention of Lewis H. Wright, an anesthesiologist who worked as a consultant for Squibb. Wright thought the proper use for curare lay in the specialty of anesthesiology, and he persuaded Griffith to use the drug during surgery. His suggestion inspired Harold Griffith to experiment with Intocostrin during that fateful appendectomy case in 1942.
By 1950, curare was cemented into standard general anesthetic practice as the first neuromuscular blocking agent, facilitating optimal conditions for intubation and surgery even with lighter depths of anesthesia. It would later prove to be integral in ICU care, where it enabled patients to tolerate prolonged mechanical ventilation in a safer and more comfortable manner. Within two decades, curare would be replaced by faster and safer agents, such as succinylcholine and pancuronium, thus ending its role in active anesthetic practice. Nonetheless, its enchanting legacy endures. A lecture in honor of Lewis Wright, the Wood Library-Museum Lewis H. Wright Memorial Lecture, is given each year at the American Society of Anesthesiologists Annual Meeting.
1. Griffith HR, Johnson GE. The use of curare in general anesthesia. Anesthesiology. 1942;3(4):418-420. doi:10.1097/00000542-194207000-00006
2. Dillane D, Chartrand D, Maltby R. Harold Griffith’s legacy: A tribute on the 75th anniversary
of the introduction of curare into anesthetic practice. Figure 2: Original Anesthesia Record from January 23, 1942. Canadian Journal of Anesthesia/Journal canadien d’anesthésie. 2017;64(6):559-568. doi:10.1007/s12630-017-0864-6
3. Sykes K, Bunker J. Chapter 8: Curare: the Indian arrow poison. In: Sykes K, Bunker J, ed. Anaesthesia and the Practice of Medicine: Historical Perspectives. Royal Society of Medicine Press; 2011:105-120.
4. Humble RM. The Gill-Merrill expedition. Anesthesiology. 1982;57(6):519-526. doi:10.1097/00000542-198212000-00014
5. Fernie JD. Marginalia: The Shape of the Earth. Part II. American Scientist. 1991;79(5):393-395.
6. Micheletti S. Exotic Poisons and Resurrected Donkeys: Charles Waterton and Physiological Experiments with Curare in Early Nineteenth-Century England. Pharmaceutical Historian. 2017;47(3):47-56.
7. Sykes K, Bunker J. Chapter 9: Spasms and convulsions: the role of curare. In: Sykes K, Bunker J, ed. Anaesthesia and the Practice of Medicine: Historical Perspectives. Royal Society of Medicine Press; 2011:121-135.
8. Dewald PA. Vertebral fractures as a complication of electroconvulsive therapy. Journal of the American Medical Association. 1954;154(12):981-984. doi:10.1001/jama.1954.02940460013005
9. Bennett AE. Preventing traumatic complications in convulsive shock therapy by curare. Journal of the American Medical Association. 1940;114(4):322-324. doi:10.1001/jama.1940.02810040032009