CHERRY TREES AND ADRENALIN

     Washington’s gorgeous cherry trees were in full bloom recently, a beautiful welcome to spring in our capital city.

Cherry trees, Washington (National Park Service photo)

     Ever wonder where the trees came from? The answer has a lot to do with adrenalin and progress in endocrinology and pharmacology.

     In the winter of 1893-4 George Oliver and Edward Schäfer in London showed that extracts of adrenal medulla tissue injected into dogs produced sudden hypertension and arterial

Edward Schafer (left) and George Oliver (right)
(from Wikipedia)

constriction. A few years later Bayliss and Starling demonstrated secretin, a substance from the intestine that stimulated secretion of pancreatic enzymes. And something in thyroid tissue produced metabolic effects.  Starling, in 1905, introduced the word “hormone”, Greek for “I excite”, as a label for these secretions.

     What was the blood-pressure-active adrenal hormone? The search was on in several laboratories, but only two “benchmen” will be highlighted here. The first is John J. Abel.

     Born near Cleveland in 1857, Abel studied mainly chemistry and physiology at the University of Michigan and Johns Hopkins.

John J Abel (Wikipedia)

Then he made the pilgrimage to Europe, where he studied under the physiologist Karl Ludwig (who trained a legion of Americans, including William Welch, a founder of Johns Hopkins), and Oswald Schmiedeberg. Schmiedeberg was a founding father of a new discipline, experimental pharmacology, whose students eventually occupied chairs of some forty different pharmacology departments. While in Europe Abel obtained an MD degree and accepted the chair of a new pharmacology department at the University of Michigan Medical School, where he built a laboratory and introduced hands-on German teaching methods. It was the first such department in the U.S. (as distinct from old, didactic departments of “Materia Medica”). Two years later, in 1893 William Osler enticed him to Johns Hopkins to head their new department.

     At Hopkins, after considerable hard work Abel obtained crystals of a substance from adrenals that was physiologically active. He named it “epinephrine” in a publication in 1897, believing it to be the natural compound. Unfortunately, though he was close he had actually isolated a benzoyl derivative. And he had lost an eye in a laboratory explosion, a loss he never complained about.

     Abel made many contributions, including isolation of poisons from Amanita Phalloides mushrooms, and, most famously, the crystallization of pure insulin. He helped found three journals. He invented a dialysis procedure to remove toxins from the blood of animals and developed a plasmapheresis process. Both ideas, ahead of their time, gained clinical use later. He did not believe in patenting his discoveries.

     The second protagonist is Jokichi Takamine, born in Japan in 1857 to a physician father. Jokichi started in medical school but switched to chemistry, in which he excelled. He worked for the

Jokichi Takamine (Wikipedia)

Japanese government on industrial projects, and was sent in 1884 to represent Japan at the New Orleans World Exposition. There he met, and later married, his landlord’s daughter and eventually took up residence in the U.S. Before long Jokichi patented the first digestive enzyme for human use (an amylase), and Parke-Davis marketed it under the name Taka-Diastase. Since Jokichi had set up his own lab Parke-Davis soon asked him to try to purify the active substance in adrenals. He visited Abel’s lab and, using a different chemical approach, proceeded to isolate the pure compound. He named it “adrenalin” in 1902 – after taking out a patent. Careful review indicates that he did not “steal” any ideas from Abel, nor did Abel accuse him of it.

     Adrenalin was a “blockbuster drug” in today’s parlance, used topically for all sorts of bleeding or inflammatory lesions, asthma, hay fever, and systemically for anaphylaxis. Quacks peddled it for cancer, etc. Royalties from sales of Adrenalin (the trade name) and enzymes made Takamine a rich man. He was one of the first “biotech entrepreneurs”. 

     Takamine’s wealth and business accomplishments helped him establish important social and political contacts and he became a sort of unofficial Japanese ambassador. In 1909, hearing that President Taft’s wife was interested in planting cherry trees in Washington, Takamine secured her acceptance of 2,000 trees as a gift from the mayor of Tokyo, though Takamine quietly paid for them. Unfortunately they were diseased and had to be destroyed, but Takamine financed, behind the scenes, a second lot of 3020 carefully grown trees. They have persisted, been added to, and are in bloom today.

    The contrast between Abel, a dedicated academic researcher and teacher who refused to patent ideas, and Takamine, an equally brilliant laboratory man who used his wealth from patents to foster cross-cultural amity, is striking.

Addenda:

     1. The name “epinephrine” is the approved one in the U.S. in recognition of Abel. “Adrenaline” is approved in the U.K., and in Japan a change was made in 2006 from “epinephrine” to “adrenaline” in honor of Takamine.

     2. The H K Mulford drug company marketed its own adrenalin, arguing that since it was a natural substance it was not subject to patent. Parke-Davis sued them. The Parke-Davis v Mulford case ended in a decision by Learned Hand in 1911 holding that the isolation/purification of a natural substance rendered it patentable. The decision was cited often in the recent Myriad Genetics case about the patentability of naturally occurring genes.

     3. The study of adrenalin effects opened the way to the discovery of chemical neurotransmitters.

SOURCES CONSULTED:

Hoffman, B. B. Adrenaline. 2013. Harvard Univ Press.

Kawakami, K. K. Jokichi Takamine: A Record of his American  

    Achievements. 1928. W E Rudge, NY.

Parascandola, J. The Development of American Pharmacology:  

   John J Abel and theShaping of a Discipline. 1992. Johns Hopkins  

   Press.

Voegtlin, C. “John Jacob Abel”. 1939. Journal of Pharmacology 

    and Experimental Therapeutics. 67: 373-406.

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FRANCE’S MIDWIFE EXTRAORDINAIRE

     Plague ravaged Europe for the last time in Marseilles in 1720, causing an outbreak that cost around 50-100,000 lives. Some commentators, Montesquieu among them, worried that the population of France was seriously declining. This became a national concern, especially during the Seven Years War (1754-63) when typhus exacted a heavy toll. But the Age of Enlightenment was underway, emphasizing rational and scientific approaches to social problems. So, in addition to encouraging more babies, attention focused on improvements in what would today be called public health. Inoculation against smallpox was promoted and better methods of handling epidemics were encouraged. (Ironically, historians later determined that the population actually grew during the century.)

      Another population-enhancer aimed at better survival at birth. Unlicensed midwives were targeted as part of the problem; they were labeled old, crude, superstitious, poorly trained, and a reason for the falling population. The first volume of the Encyclopédie (1751) carried an article disparaging midwives. A new cadre, properly trained, was needed. Male “accoucheurs” had already been sanctioned by Louis XIV, and some surgical professors taught and wrote about obstetrics but the numbers were limited. In 1730 a national system of examinations for midwives administered by surgeons was introduced, though many midwives still slipped through the net. 

     In 1740 a twenty-five year old unmarried woman, Angelique

Angelique Marguerite Le Boursier du Coudray
(from Wikipedia)

Marguerite Le Boursier du Coudray, was licensed in Paris after she had finished her three-year apprenticeship, passed the rigorous midwife examination, and supplied testimony on her good morals and Catholic faith. Virtually nothing is known of her earlier life. At first she practiced midwifery in Paris. After eleven years she took on her first apprentice, who paid 300 livres for a three-year course. She also made the acquaintance of Jean Basilhac, better known as Frère Côme, a monk-surgeon well known for new approaches to surgery for bladder stones, for cataract surgery, for connections with court surgeons, and for his great humanitarian activities. He admired and supported du Coudray throughout her career, and on his recommendation she was invited to teach midwifery in

Jean Basilac (Frère Côme)
(from BIU Santé)

Auvergne, instructing young women from poor families and few resources.   

     She was a successful teacher, but two more steps cemented her reputation. The first was the creation of a “machine”, a model of a female pelvis, complete with reproductive organs, used for teaching. Wood or real skeletal bones formed the pelvis, the rest was constructed out of leather, cloth, and other materials. Various birth maneuvers were  demonstrated using a flexible doll as the baby. Du Coudray took the machine to Paris where court surgeons, including André Levret, Royal Accoucheur and inventor of improved forceps, examined and praised it. She appears to be the first to use such a device, and so clear were her presentations that even surgeons took lessons from her. She could now teach entire classes instead of one-on-one apprentices.

     Her other step was to publish a short text, the Abrégé (synopsis, summary) de l’Art des Accouchements. It was concise but

Abrégé,  ?fourth edition (from Internet Archives)

complete, and well received. She states clearly that this is not a text on obstetrics but a manual for women of less education, that she is not a doctor, and that midwife services are primarily for situations where doctors are not available or affordable.  Later editions were illustrated and included details on duties beyond delivery, such as ethical behavior, care after birth, etc. Forceps came into vogue during the mid-century, though midwives were prohibited from using them. They depended on manual maneuvers. 

Illustration of normal birth in the Abrégé
 (from Internet Archives)

     A midwife, in fact, had multiple duties. She took the newborn to the church for baptism. She was consulted in legal cases such as paternity suits, whether a baby died before or after delivery, determination of virginity, suspected rape, etc. Often the midwife concealed unwed pregnant women in apartments until they gave birth, sparing them humility or abortion, and took the unwanted child for baptism and subsequent nursing in a foundling home. Discretion was important and valued.

     During prenatal care various ointments were applied to the breasts and abdomen, the mother was bled frequently (today she receives iron), and enemas or laxatives given to prevent hemorrhoids.

     Du Coudray’s success at teaching midwifery, along with her machine and book, induced Louis XV to issue a brevet in 1759 commissioning her to go “wherever she judges appropriate” in France to teach midwifery. This carte-blanche enabled her to travel widely through France, teaching her art to thousands. Soon her students were training others. Though she met resistance from some in the surgical community, overall her program was a major success. She trained over 5,000 midwives and near the end of the century her trainees comprised about two thirds of the country’s midwives.

     By the time of the French Revolution Le Boisier du Coudray was retired on a pension granted by the king, living in Bordeaux with her niece’s family. Her niece had taken over the teaching duties and written her own manual. Unfortunately in the chaos of the Revolution her pension went unpaid and she lived in terror of arrest because of her former royal connections. She died quietly, however, in 1794 at age 79. Her intelligence, long hours of work, court contacts, and persistence combined with tact were crucial elements of her brilliant career.

SOURCES:

Gelbart, Nina R. The King’s Midwife: A History and Mystery of 

   Madame du Coudray. U of Calif Press, 1998.

Brockliss, L, Jones, C. The Medical World of Early Modern  

   France. Oxford U Press, 1997.

Hibbard, Bryan M. The Obstetrician’s Armamentarium: Historical

    Obstetrical Instruments and their Inventors. Norman Pub, 2000.

Hickey, B B. “Jean Baseilhac (Frère Côme)”. Brit J Urology 1953. 

    v25(3): 252.

THE YEAR OF THE THREE KAISERS

THE YEAR OF THREE KAISERS

                                                                            by
                                                             Arthur Lyons

     The importance of political or military figures in history is often speculated on and thinking of alternate scenarios can be a fascinating exercise. What, for instance, would the world be like absent a Jesus Christ, Henry VIII, Napoleon, or George Washington?

      If the great man theory of history needs an example the events in Berlin in 1888 will serve as well as any. In 1888 Europe was relatively stable. The various powers were at peace and existed under more or less constitutional monarchies. The various large and petty states making up the German Federation had agreed to unify in 1871 under the leadership of Prussia in the exuberance following the Franco-Prussian War.

     A hero of the Franco-Prussian War was the able and relatively liberal Crown Prince of the Empire of Germany, Frederick III of

Frederick III, by Heinrich von Angeli
(Wickipedia)

Prussia, son and heir of the aging emperor Wilhelm I (1797-1888). Frederick was married to Queen Victoria’s daughter, the Princess Royal Victoria, and both were progressives. Though under effective control of Otto von Bismark, the 91 year-old Wilhelm’s talented and conservative chancellor, Germany was looking forward to a more open society under the upcoming reign of the liberal Frederick.

     In early 1887 Frederick, or “Fritz” as he was known, a non-smoker, complained of hoarseness. He was treated symptomatically for several months but when his hoarseness persisted he was examined by several prominent physicians. They concluded that the Crown Prince was suffering from a potentially lethal cancer of the larynx. Curative surgery, to open the larynx and resect the cancer or the entire larynx, was recommended. The operation was risky, and both medical and political issues were at stake.

Princess Royal Victoria by Heinrich
von Angeli (Wickepedia)

     Frederick’s wife, Victoria, insisted that another specialist be called in. The most famous laryngologist of the day was the London surgeon Morell Mackenzie (1837-1892). He had written several books including a definitive text on diseases of the throat and nose, and invented a number of surgical instruments. With the agreement of Frederick’s physicians Mackenzie was called to Berlin. After examining the Prince he recommended a biopsy using a laryngoscope, the first of the Prince’s physicians to do so. None of the attendings had used the laryngoscope for this, and Mackenzie had to find a suitable one in a local shop. He sent the biopsy specimen to Rudolf Virchow, the famous pathologist at Berlin’s Charité Hospital, but Virchow, using available techniques, could not make a diagnosis of cancer. A second and then a third biopsy were done. The second contained insufficient tissue but the third was an adequate

Sir Morell Mackenzie (Wickepedia)

specimen. None showed cancer, and Mackenzie could not recommend surgery. Syphilis was considered as a diagnosis, not unusual at the time.

     Over the next few months Frederick worsened, and two more specialists, one from Berlin (Dr. Krause) and one from Vienna (Dr. von Schrötter), were called in. The unanimous opinion now was that the Prince had cancer and would not live long. His father, Wilhelm, died in March, 1888, and the weakened Frederick assumed the throne. He reigned only 99 days before succumbing to his cancer. An autopsy was done by Virchow, assisted by Paul Langerhans (also to become famous). This time cancer was found.

     The press, partly controlled by Bismark, blazed the case across the headlines in a largely partisan manner. Articles harshly critical of Mackenzie and favorable to the German doctors abounded. A supposedly “official” German report turned out also to be a polemic. Mackenzie was stung. After initial praise and having gained a knighthood he was now humiliated, though both Frederick and Victoria affirmed that he had acted appropriately. His esteem was shattered and his practice dwindled. Trying to save his

Mackenzie's answer to attackers
(Hathi Trust)

tarnished reputation, Mackenzie published a self-serving book, The Fatal Illness of Frederick the Noble, stating his case, revealing patient details, and denigrating the skill of the German doctors. It was unprofessional and the Royal College of Surgeons censured him for it. Mackenzie only partly recovered his practice and, being an asthmatic, died four years later, in 1892, of influenza pneumonia.

     Kaiser Wilhelm II (1859-1941), after Frederick’s death, was the third German emperor that year of 1888. With his paranoia, withered left arm, and an abiding hatred for all things English he managed to rule Germany with his reactionary policies until his abdication in 1918. He fired Bismarck and started Germany on a militaristic course that led to two 20th C. World Wars, the Russian Revolution, and the other horrors of the next century. It is reasonable to assume that had the pacifistic Frederick been Kaiser for long enough the futures of Germany and Europe would have been entirely different.

      Mackenzie should not be forgotten, though. He founded the Hospital for Diseases of the Throat in London, the first of its

From text on laryngoscopy. Note candle
as light source (Hathi Trust)
(You can zoom in on this image)

kind in the world. He had learned laryngoscopy from Johann Czermak in Budapest and published the first English text on the subject, which went into three editions and was widely translated (as was his text mentioned above). He invented new instruments. He was a cofounder of the Journal of Rhinology and Laryngology and, in the year of his return from Germany, founded the British Rhinolaryngology Association (Otology added in 1895). Many of his numerous students became leaders in the field. It was the very skill he was known for that ensnared him in the tragic events around Prince Frederick.

SOURCES:

Thorwald, J. The Century of the Surgeon 1954 New York. Pantheon
McKenzie, Sir M. The Fatal illness Frederich the Noble 1888 London.    

    Low, Marston, Searle

Stevenson, R Scott. Morell Mackenzie: The Story of a Victorian 

     Tragedy. 1947 New York, Henry Schuman

Weir, Neil. Otolaryngology: An Illustrated History. 1990. Butterworths,

     London

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DR. DREW AND EARLY TRANSFUSION SERVICES

     Careening through the streets of London in the fall of 1940 were vans carrying a precious cargo – blood. The blitz was on and at night the vans raced without lights, dodging debris and bomb craters almost by instinct. The blood, all type O (universal donor), met London needs but was difficult to store and transport in large quantities to the front.

     The answer to these problems was plasma – easy storage and no blood typing. John Elliot of North Carolina was the first to study the use of plasma (1936). He convinced the American Red Cross to consider it. In 1940 the Red Cross (that had a limited person-to person transfusion service at the time) and the Blood Betterment Association of New York (a larger blood donation service in New York and the first in the U.S. - that used paid donors) jointly rolled out a program in New York called “Plasma for Britain” to help England. The Red Cross rounded up donors, the BBANY collected and processed the blood, and the Red Cross shipped it to England. The program grew exponentially but technical problems developed, primarily bacterial contamination. The Board needed a medical director to streamline the processing and appointed Dr. Charles Richard Drew.  

Charles Drew (courtesy National
Library of Medicine)

     Dr. Drew was an African-American born in 1906 in a middle class interracial community in Washington DC. He attended Amherst College and was accepted at McGill University’s Medical School where he excelled. After an internship and year of residency at McGill he obtained a faculty position at Howard University Medical School, where he also completed a surgical residency. His excellent work earned him a research position at the surgery department of Columbia-Presbyterian Hospital, under Allen Whipple. There he worked with John Scudder on fluid balance, shock, and transfusion therapy. He also ventured into the new field of blood storage and wrote a dissertation on “Banked Blood”. (The first “blood bank” in the world was started at Cook County Hospital in Chicago in 1937 by Dr. Bernard Fantus, who coined the name.) Drew was granted a Doctor of Science in Medicine degree and then returned to Howard Univ. as a faculty member. He was called from there in September, 1940, to be Medical Director of the program.

     As Medical Director Drew standardized blood collection procedures at 

Unpacking plasma in England (courtesy
National Library of Medicine)

participating hospitals, improved the separation techniques, created a completely closed system to pool the plasma (in a dust-proof, ultraviolet-lit room). To further avoid contamination merthiolate was added, and cultures done at every step. Results improved dramatically. In all, over 5,000 liters of plasma from over 14,000 donors were shipped abroad.

     Drew also drew up a detailed program for mass production of dried plasma, something already under investigation by Sharp and Dohme Co. and others. After England opened their own plasma facility the Red Cross set up a dried plasma program at Presbyterian Hospital for the military, with Drew as assistant director. During this period he introduced the use of mobile blood units (later called “bloodmobiles”).  

Charles Drew with bloodmobile unit
(courtesy National Library of Medicine)

      But the story had its dark side. Racial segregation was still a fact in American life. The scientists knew that blood from blacks and whites was the same, but transfusion services were new and the public was less sure. The Plasma for Britain directors made the political decision to accept all donors but label the plasma as to origin. Not much later the military, still rigidly segregated, decided to not collect African-American blood at all, and the Red Cross acquiesced. But when African-American blood donors were turned away after the Pearl Harbor bombing both the black and white press expressed outrage, impelling the military to change their minds – partly. All donors were accepted but the blood remained labeled and segregated.

     Drew resigned from the Red Cross job before his term was up to take over as chief of surgery at Howard and be chief surgeon at Freedmen’s Hospital, Washington’s only black hospital. He said little of blood donor discrimination at the time but later

Freedmen's Hospital, Washington DC
(courtesy National Library of Medicine)

wrote and spoke about it more often. He faced other barriers. To be a member of the AMA one had to join the local AMA chapter, an impossibility in the South. Strong letters to Morris Fishbein, JAMA editor, had no effect. Drew was both board certified and an examiner for the American Board of Surgery, but refused membership in the American College of Surgeons for their prejudicial policies. He spoke out on many other obstacles black physicians faced.

     Every year Drew and other African-American doctors gathered at a hospital in Tuskegee, Alabama to man a free clinic for underprivileged blacks in the South. On April 1, 1950, he and three colleagues set off by car at midnight from Washington. Reaching North Carolina in early morning Drew was driving when the car ran off the road and rolled over three times. Drew’s companions were not seriously injured, but Drew was. He was taken to the nearest hospital but after two hours of intensive efforts, he expired.

     A tireless worker (everyone commented on that), an agreeable, gregarious person, an author of 25 scientific papers, a gifted surgeon and teacher, a pioneer in the study of transfusion and blood bank technology, an early spokesman for civil rights, and the subject of a number of biographies, Charles Drew’s career tragically ended much too soon.

SOURCES

Starr, D: Blood. 1999.

Love, S: One Blood: The Death and Resurrection of Charles R. Drew.

      1996.

Wynes, C E: Charles Richard Drew: The Man and the Myth. 1988.

Rutkow, I M: “Charles Richard Drew”. JAMA 2000. v135: 1233.

Stetten, D: “The Blood Plasma for Great Britain Project”. Bull NY Acad

     Med. Jan, 1941. pp27-38.

Telischi, M: “Evolution of Cook County Hospital Blood Bank”.

      Transfusion, 1974. 14: 623-8.

U.S. National Library of Medicine: “Profiles in Science: The Charles R.  

     Drew Papers” at

https://profiles.nlm.nih.gov/ps/retrieve/Narrative/BG/p-nid/336

Russian Surgery in the Crimean War:

NIKOLAy PIROGOV and the first anesthesia

     “Stretcher parties were constantly arriving with casualties, setting them down one beside the other on the floor – which was already so packed that the wretched men were jostling one another and smearing one another with their blood – and then leaving to fetch more… Gloomy-faced surgeons in their rolled up shirtsleeves knelt beside wounded men while an apothecary assistant held up the candle, pushing their fingers into bullet wounds and searching them or turning over severed limbs that still hung by a thread…” . Thus described an eyewitness, Leo Tostoy, the main hospital in his Sebastopol Sketches about the Crimean War. The hospital was

Siege of Sebastopol by Franz Roubaud (from Wikipedia)

 set up in the large “Noble’s Club”, where the billiard room morphed into the operating room and the ballroom into an open ward for the wounded. Moving within this grim scene was an eminent surgeon who greatly advanced the knowledge of battle surgery: Nikolay Pirogov.

     Pirogov was born in 1810, the thirteenth child of a Moscow

Nikolay Pirogov by Ilya Repin (from
Wikipedia)

family whose house perished when Napoleon set fire to the city in 1812. His father died early, but being a quick learner Nikolay raced through school and was admitted to Moscow University at age 14 to study medicine. He found the curriculum inadequate but won a scholarship for further training at Dorpat University (now in Estonia) under a German faculty. There he learned experimental

physiology, did numerous anatomy dissections, and rose to become Professor of Surgery, publishing an atlas of surgical anatomy shortly thereafter (see illustration below). He studied briefly in Paris and Germany. At the age of 30 he won the Chair of Surgery at St. Petersburg’s Medico-Surgical Academy and directorship of the Surgical Department at the Army Hospital. During 14 years there he performed about 12,000 autopsies and, utilizing the cold weather, made frozen sections of the human body at various levels to produce a 5 volume Anatomia Topographica, a highly praised work. “Pirogov’s triangle” (the hypoglossohyoid triangle in the neck) is described there. The young and restless surgeon, as one might expect, battled an entrenched and reactionary medical staff jealous of his growing fame.    

From: Chirurgische Anatomie der
Arterienstämme und Fascien,2nd ed, orig pub'd
1840 (from Internet Archives)

     In 1846 ether was first demonstrated at the Massachusetts General Hospital and only a few months later Pirogov published a manuscript describing his own research on both animals and humans (himself first). He tested ether by inhalation, intravenously, and by enema, realizing its wonderful potential. In the spring of 1847 he was appointed by the Tsar to provide ether anesthesia for the Army fighting in the Caucasus, both to relieve suffering and to boost the morale of men terrified of painful surgery if wounded. Pirogov designed a tight-fitting inhalation mask employing a valve to regulate the ether-air mix, and did not hesitate to perform amputations in the presence of other soldiers, who indeed were relieved to witness the painless surgery. This was the first use of anesthesia in wartime.

     On return Pirogov experimented with chloroform, finding it easier to transport and store, and safe if used properly. The supreme test came in the Crimean War, in which the Russians lost over 250,000 men during the eleven-month siege of Sebastopol alone. Pirogov volunteered his services and with the influence of Grand Duchess Elena Pavlovna was appointed chief surgeon. Pavlovna

Grand Duchess Elena Pavlovna, by
Karl Briullov (from Wikipedia)

was the originator of the Russian nursing service, called the “Holy Cross Community”, whose volunteers worked tirelessly under Pirogov’s direction in the besieged city (Florence Nightingale’s nurses were far away from fighting). At Sebastopol Pirogov instituted a system of triage still used today. He freely gave anesthesia (the British used it sparingly), mainly chloroform, used plaster casts frequently for severe fractures (avoiding amputations), and was a believer in the transmission of sepsis, requiring hand washing by his surgeons and limited wound probing for bullets. He advised prompt treatment in the field whenever possible, an innovation still observed. He also invented an amputation of the foot that saved higher leg amputations. His experience was distilled into the monumental, Principles of War Surgery (available in German), a work studied until WW II.

     (Little known is that 36 American surgeons worked under Pirogov and in the Caucasus during the siege. They were volunteers, though paid, and at their request the American representative in the Tsar’s court, an ex-Governor of Connecticut, arranged the details. About half of them died of typhus or cholera, but lessons learned were later helpful in the American Civil War.)

     After the war, as educational reforms were introduced by Tsar Alexander II, Pirogov resigned from the Medico-Surgical Academy and became an education advisor, working in Odessa, Kiev, and later as advisor to Russians studying in Germany. While in

Memorial statue of Pirogov, Moscow
(from Himetop, creative commons license)

Heidelberg he consulted on a bullet wound in Garibaldi’s ankle. In 1870 he was invited by the Red Cross to inspect the military hospitals in the Franco-Prussian War, and found that most of his recommendations from the Crimean War were being observed. A similar evaluation was performed in 1877 in the Russo-Turkish War, at which he now emphasized even more the importance of antisepsis.

     Between these assignments and in his waning days Pirogov retired to an estate near Vinnytsia (now in Ukraine) where he was a country doctor and farmer. There he composed, but did not finish, his memoirs, a mix of diary, autobiography, and reflective philosophy.

     He died in 1881, and was mourned as a hero throughout Russia. The Society of Russian Physicians, formed in 1884 in Pirogov’s honor, was influential in Russian medicine until abolished in 1918 by personal order of Lenin. The same fate met the Russian Red Cross, a direct descendent of the innovative use of wartime

Entrance to Pirogov Estate and Museum, Vinnystia,
Ukraine (from Wikipedia)

volunteer nurses organized by Grand Duchess Pavlovna. Pirogov’s reputation was revived under the later Soviets.

     Nikolay Pirogov is an underappreciated pioneer in anesthesia and battle surgery, a gifted anatomist and educator, and a humanitarian supporting the highest ideals of his profession. Sadly, few of the works by or about him are available in English.

    

SOURCES:

     Pirogov N: Questions of Life: Diary of an Old Physician. 1991 (orig. in 1885)

     Tolstoy L: Sebastopol Sketches. 1986 (orig 1855-6)

     Raymond E A: “American Doctors in the Crimean War”. 1974. Connecticut Medicine, 38: 373-6.

     Hendriks IF, Bovil JG, Boer F, Houwaart ES, Hogendoom PCW: “Nikolay Ivanovich Pirogov: A Surgeon’s Contribution to Military and Civilian Anaesthesia". 2015. Anaesthesia 70: 219-27.

     Pirogov, N: Recherches Partiques et Physiologiques sur l’Etherisation. 1847

     Sorokina, T: “The Great Russian Surgeon Nikolay Ivanovich Pirogov (1810-1881)”. 2011. Vesalius 17: 10-15.

     Halperin G. “Nikolai Ivanovich Pirogov – Surgeon, Anatomist, Educator”. 1956. Bull Hist Med 30: 347-55.

     Fried BM. “Pirogoff in the Crimean Campaign, 1854-55” 1955. Bull NY Acad Med 31: 519-36.

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ARSENIC POISONING:

 MEDICINE IN THE COURTROOM

     Imagine wanting to eliminate a rival, whether for love or for money. What better way than poison. No violence needed, just cunning. And so it was in early 19^th century Europe, where poisoning, especially with arsenic, was fairly common. Arsenic was everywhere - as rat poison, in dyes for paints, clothing, and wallpaper, and in medications.  Sheep dipping required large amounts and it was even found in flypaper. You could buy it at the local chemist or grocer. “White arsenic” (arsenic trioxide), the common form, was odorless and tasteless, ideal for lacing food or coffee.

     In the courtroom the decision to send an accused to freedom or to the hangman often relied on circumstantial evidence rather than science. In 1815 England was shaken when a 22 year old servant, Elizabeth Fenning, crying to the last that she was innocent, was hanged for poisoning (non-fatally) the family where she worked. Circumstantial evidence alone convinced the jury, in spite of lack of hard evidence of arsenic in those affected. Thousands turned out for her funeral and a public outcry ensued, making it clear that better science, and evidence collection, were needed.

     Two years before, in France, a young physician and chemist, Mateu Orfila, noted that white arsenic powder in coffee or other organic fluids failed to precipitate with standard reagents. He correctly saw the importance of this in criminal cases. Orfila, born on the island of Minorca, had studied medicine in Valencia and

Mateu Orfila (from Wikipedia)

then chemistry in Barcelona and Paris. He was quick, bright, self-confident, and an excellent lecturer, traits that catapulted him rapidly into influential chemistry and medical circles. He was helped by a superb baritone voice (said to be adequate for the Paris Opera) that gained him entry into select Paris salons. He was a constant proponent of the value of chemistry to medicine, a theme resisted by many clinicians at the time. Orfila soon was able to isolate arsenic in organic material and rapidly widened his research. He published the first full book in years on toxicology, Traité des Poisons, in 2 volumes over 1814-5, a popular book translated into several languages. In 1819 he was appointed professor of legal medicine at the Paris Faculty of Medicine, and was consulted frequently in criminal poisoning cases. Later in life he was president of the Royal Academy of Medicine.

     One of Orfila’s students, a Scot named Robert Christison, on returning to Scotland noticed there an absence of knowledge of toxicology and published the first English language text on the

Robert Christison (from Wikipedia)

subject. He too was frequently consulted on court cases and became professor of medical jurisprudence in Edinburgh. 

     Better science soon came. In 1833, John Brodle was accused of poisoning his grandfather by placing arsenic in his coffee. The coffee grounds and stomach contents of the victim were sent off to Michael Faraday for testing, who passed them on to his assistant, James Marsh, whose findings were inconclusive - Brodle went free. Marsh appreciated that the usual precipitation methods could not detect arsenic in tiny amounts. He knew from Carl Wilhelm Scheele, an important Swedish chemist, that the combination of arsenic, zinc, and nitric acid produced a gas, arsine. He devised an apparatus (see insert) featuring a tube with a

stopcock at the top through which the arsine could pass. When the arsine was flamed a precipitate of metallic arsenic formed on a glass plate held over the stopcock. At first tricky to use, with modification it became the standard test for arsenic. Little is known of Marsh’s life except that he was a respected scientist for the military and had invented a vibrating interrupter to turn circuits off and on.

      A few years later, in 1840, in the village of Beyssac, south-central France, a Marie Lafarge was accused of poisoning her husband. Tests for arsenic on his remains were inconclusive, and when repeated were negative. The juge d’instruction ordered the body exhumed, 10 months after burial, for more tests. This time the “Marsh test”, applied to the putrid remains, was negative. But a physician who relied on the clinical picture still doubted the results so the juge ordered a fourth assay, appointing experts, including Mateu Orfila, to do the tests. Orfila’s team found arsenic this time, landing Madame in jail for life. Orfila claimed that the previous team had performed the test improperly. It was the first criminal trial decided by the Marsh test. Madame LaFarge’s case was another that evoked a media blitz which

Madame LaFarge (from Wikipedia)

divided the country “as much as the Dreyfus case”, according to some. LaFarge’s memoirs, written in jail, were a best seller.

      Aware of the sensitivity of the Marsh test, Orfila realized that he could now assay blood and tissue levels for arsenic at levels unheard of before. He was aware of experiments done a few years earlier by Francois Magendie on strychnine, proving that it was absorbed through the venous system and not the lymphatics. Orfila did similar experiments, now measuring levels in blood and tissues, something impossible for Magendie who relied on clinical effects. Testing for organic poisons, such as strychnine and nicotine, soon followed. Forensic science, and experimental pharmacology, were now established.

     “Medical jurisprudence” chairs were established in many of Europe's medical centers in succeeding years. In the U.S., by contrast, the first full time position in “legal medicine” was not until 1937 at Harvard. The physician chosen for the position, Alan Moritz, was first sent to Europe for two years to study at already existing departments. Moritz pushed the AMA to advocate for physician medical examiners. In 1944 only seven states had medical examiners - in others the coroners were laymen. The AMA agreed with Moritz and exerted its influence. Gradually medical examiners replaced lay coroners, and forensic pathology is now a board specialty in the U.S.

      

SOURCES:

           Bertomeu-Sanchez, JR, and Nieto-Galan, A, eds: Chemistry, Medicine, and Crime. 2006.

           Jentzen, JM. Death Investigation in America. 2009

           Stratmann, L. The Secret Poisoner: A Century of Murder. 2016.

           Chaille, SE. 1949.  “Origin and Progress of Medical Jurisprudence, 1776-1876”. J Crim Law and Criminology, 40: 397-444.

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