THE LIFE AND DEATH

OF CHLOROFORM

 

      Ether burst onto the medical stage in October of 1846 when a dentist, William Thomas Green Morton, administered the volatile compound to twenty-year-old Edward Abbott while the noted Boston surgeon, Dr. John Warren removed a neck tumor. Painless surgery had arrived.

         News of the dramatic effect of ether flew across the Atlantic. That December, Dr. James Simpson, Professor of Midwifery in

James Simpson (Wikipedia)

Edinburgh, traveled to London to witness its use in an operation by his old teacher, Robert Liston. Liston took 28 seconds (surgeons before anesthesia had to be quick) to amputate a leg without any complaint from the etherized patient. He announced after the procedure, “This Yankee dodge, gentlemen, beats mesmerism hollow.” Simpson eagerly took up ether anesthesia to ease the pains of labor as well as in surgeries. He ignored objections from clergy and other quarters that pain was natural in childbirth and should not be suppressed.

But difficulties administering and transporting ether led Simpson to assess many other agents. After trying somewhat indiscriminately, primarily on himself, various volatile compounds, a chemist friend suggested chloroform. On the evening of November 4, 1847, Simpson and two assistants sat at his dining room table and inhaled a small amount of the sweet-smelling substance. Simpson soon found himself on the floor along with his two semiconscious companions. The trio were so delighted with the result that they inhaled the substance several times more, finally heading home at 3 AM, determined to use it.

Cartoon of Simpson's home trial of chloroform (Wellcome Library)

Chloroform, like ether, had been around for a while before its anesthetic potential was realized. Credit for the first synthesis goes to an American, Samuel Guthrie. Trained as a physician, Guthrie became more interested in business and set up a gunpowder plant and other enterprises near the shore of Lake Ontario. Interested in chemistry, he read in writings of the Yale University chemist,

Samuel Guthrie (Wikipedia)

Benjamin Silliman, about a compound named “chloric ether,” whose sweet aroma might have uses in medicine. Dr. Guthrie devised a simpler method, in 1831, of making it by combining “best whisky” with chloride of lime and distilling the result. What he actually made was an alcoholic solution of chloroform. Sippers of this solution became pleasantly tipsy, sometimes drunk. Silliman chemically removed the alcohol, producing pure chloroform, but the mild alcoholic solution was used by American doctors for its pleasant and seemingly beneficial effects. Its anesthetic properties remained unknown.

Just over one year following Dr. Warren’s first use of ether and five days after Simpson’s chloroform experiment at home, a young woman in Edinburgh, Scotland, entered her second labor. She had previously endured an agonizing three-day labor resulting in a dead child. Simpson was her accoucheur, as he was called, and, anxious to avoid a second tortuous labor, he anesthetized her with chloroform – its first use in a patient. The young lady delivered a healthy child after a three-hour, painless labor. Within a few weeks Simpson helped over 50 women avoid labor pains and surgeons quickly adopted it for operations. His successful experience made him an enthusiast of the new agent and he publicized it relentlessly. It was cheap, easy to administer, acted rapidly, had a pleasant smell, lacked the irritating qualities of ether, and was not flammable. 

In London, when ether was first in use, the highly educated but relatively obscure practitioner, John Snow (later of cholera fame), took an interest. He had worked on respiratory physiology and

John Snow (Wikipedia)

surmised that the varying results with ether might be due to varying dosage. He measured the amount of ether in air at varying temperatures, devised a breathing apparatus that produced a predictable amount for administration, and characterized five levels of anesthesia. Later, responding to the enthusiasm for chloroform, Snow devised a similar breathing apparatus to administer an exact dose. He helped Queen Victoria through two labors with the new agent, though without the apparatus since she was lightly dosed. Most practitioners, in fact, continued to pour chloroform onto a sponge or cloth-covered cone. During the American Civil War and the Crimean War chloroform was the chief anesthetic employed. The agent also made headlines as an instrument in kidnappings, rapes, and other crimes, though much of this was exaggerated.

Before long, reports of sudden death during chloroform anesthesia appeared, often during induction, that were unrelated to dose or underlying medical problems. The Lancet criticized Snow for using it on Queen Victoria, citing reports of unexpected deaths. Not until 1911 did Goodman Levy show that ventricular fibrillation occurred in cats under chloroform, suggesting a mechanism. He later published data showing that over two decades chloroform use constituted between 72 and 90 percent of all anesthetic deaths in Britain. In these cases British doctors were obliged to testify at a coroner’s inquest, but none were charged with anesthetic

Henry J. Bigelow (Wikipedia)

malpractice throughout the nineteenth century. In the northern United states, however, doctors were sued for anesthetic deaths and, additionally, Henry J. Bigelow, Professor of Surgery at Harvard, used his influence to champion the use of ether as the safer choice. Chloroform usage died quickly in the north, though in the southern states its use continued for some time. 

Levy’s publications were persuasive and eventually the mortality statistics could not be ignored on either side of the Atlantic. Chloroform usage declined everywhere, replaced by ether and eventually newer agents.

Pierre Louis in Paris pioneered the use of statistical methods in the early 1800s to question the value of bloodletting as treatment for pneumonia. His methods, after over half a century, finally convinced chloroform users to choose another anesthetic.

 

SOURCES:

Stratmann, Linda, Chloroform: The Quest for Oblivion, Sutton Publishing, 2003

 

Johansen, Peter V, et al, Cholera, Chloroform, and the Science of Medicine: A Life of John Snow, Oxford University Press, 2003.

 

Shepherd, John A, Simpson and Syme of Edinburgh, E&S Livingston, 1969.

 

Snow, Stephanie J, Blessed Days of Anaesthesia: How Anaesthetics Changed the World, Oxford University Press, 2008.

 

Levy, A. Goodman, Chloroform Anesthesia, William Wood & Co. 1922

 

Bigelow, Henry J, “Death by Chloroform and Alleged Death by Ether,” Boston Med Surg Journal, 1872; 86: 277-9.

 

Holmes, Oliver Wendell, “Henry Jacob Bigelow,” Proc Amer Acad Arts Sci 1891; 

26; 339-51.

 

Thomas, K B, “The Early Use of Chloroform,” Anesthesia” 26(3): 348-62, 1971.

 

 

 

 

 

 THEODOR ESCHERICH AND HIS BACTERIUM

 

         Last month the CDC reported on an outbreak of diarrhea due to a strain of Escherichia coli, thought to be associated with the consumption of romaine lettuce. Certain strains of this bacterium frequently cause diarrheal illness while others are innocuous inhabitants of the lower intestinal tract. This tongue-twister of a name derives from its discoverer, Theodor Escherich, a pioneering pediatrician who originally called the organism Bacterium coli. 

  

Theodor Escherich (Wikipedia)

       Escherich was born in 1857 in Ansbach, Germany. His father was a district health officer, concerned with health of the poor and high infant mortality rates, passing these concerns on to his son. Theodor completed his medical education in different German cities, as was the custom at the time, served briefly in the military, and became an assistant to Prof. Karl Gerhardt in Würzburg. Although Gerhardt was an internist, he was interested in pediatrics and eventually wrote a large, sixteen-volume work on the subject.
Inspired by Gerhardt and by the newly developing science of bacteriology, Escherich studied further at the St. Anna Children’s Hospital in Vienna, where he attended lectures by Hermann von Widerhofer, who held the city’s first Chair of Pediatrics at the University of Vienna. After a brief time in Paris, he moved to Munich where he learned bacteriology skills from a former student of Robert Koch. He learned well, and focused his efforts on

Hermann von Widerhofer

examining the intestinal bacteria of the newborn. He characterized two distinct new bacteria that he called Bacterium coli commune (now known as Escherichia coli) and Bacterium lactis aërogenes (now called Klebsiella pneumoniae). He determined that at birth the intestinal canal was sterile but acquired these and other bacteria almost immediately. His thesis paper on the subject was published and a translated version eventually saw print in the U.S in 1988.

         In 1890, at age 33, he moved to the St. Anna Children’s Hospital in Graz, as a professor of pediatrics, soon being elevated to a full professor and director of the hospital. In this capacity he supervised an expansion of the hospital, including laboratories and incubator rooms. He and a colleague demonstrated antitoxin in children recovering from diphtheria, he promoted Emil von Behring’s diphtheria antitoxin treatment, and he wrote a book on diphtheria. He also established Bacterium coli as a cause of diarrheal disease and urinary tract infections in children. After Roentgen’s discovery of X-rays, he installed an X-ray camera. He attracted numerous students, including Clemens von Pirquet and Bella Schick. These two studied and described in detail serum sickness, a complication of serum therapy. Pirquet also developed the tuberculin skin test, and Schick developed the Schick test for diphtheria, then widely used but now obsolete. 

         Escherich’s talents as a teacher, researcher, and humanitarian did not go unnoticed. After the death of his old teacher, von Widerhofer, in 1901, he accepted an offer from the University of Vienna to fill his shoes as Chair of Pediatrics and Director of the St. 
Anna Children’s Hospital (separate from the one in Graz), where he had studied 18 years previously. Escherich did not slow down in his new role. He expanded the hospital laboratories and X-ray facilities and instituted training of pediatric nurses. Infant mortality in Vienna was still high and Escherich combatted it by establishing organizations enhancing the hygiene and welfare of children, such as an infant welfare society, a Society for Children’s Research, and the Association of Pediatricians in Vienna. He continued his interest and research in infectious diseases and was considered the best pediatric bacteriologist in Europe. The Emperor Franz Joseph named him Court Counselor in 1906 and invited him to dine at court several times. 

St Anna Hospital, Vienna, 1850s (Wikimedia Commons) 

         His accomplishments in pediatrics and his connections were essential in the construction of a new Imperial Institute for Maternal and Infant Care in Vienna and the first human milk bank. Escherich’s bacteriologic studies of neonatal stool of breast-fed and non-breast-fed infants taught him the importance of breast feeding. Boston opened a similar bank the next year and as of 2017 about 500 milk banks were operating worldwide. In short, his influence was global. 

Sadly, in 1911, as he was making ward rounds, he began to uncontrollably speak in several languages. It was the first sign of a cerebrovascular accident that ended his life the next day. Numerous obituaries lamented his loss and praised his contributions to medical science and his humanity toward children. He had published several works: on infant intestinal flora, on tetanus, and on diphtheria, authored numerous articles, and trained a generation of pediatricians. 

In 1919, Drs. Castellani and Chalmers, in a text on tropical diseases, proposed that the name Escherichia coli replace Bacterium coli, but the change was not official until 1958. E coli has been a popular laboratory organism for years. Studies of the bacterium have yielded three Nobel Prizes. One was for the mechanism of transfer of genetic material, one for mechanisms of enzyme control, and one, using phages, for the replication and genetic structure of viruses. Interestingly, a sample of the original strain studied by Escherich turned up in the National Culture Type Collection in London (formerly the Lister Institute), a collection that holds strains from the beginnings of bacteriology. Theodor Escherich’s brother-in-law had sent it to a laboratory in Cambridge in 1900 and it eventually landed in the Lister Institute. Its presence was “rediscovered” in 2015.

Theodor Escherich’s work in bacteriology and pediatrics resulted in major contributions to medicine and child health. Authors of a paper in 2007 felt that he could justifiably be considered “the first pediatric infectious disease physician,” a fitting and well-deserved designation.

 

SOURCES:

Schulman, S T, et al, “Theodor Escherich: The First Pediatric Infectious Disease Physician?” 2007; Clin Infect Dis 45: 1025-9.

 

Méric, G, et al, “From Escherich to the Escherichia coli Genome.” 2016; Lancet Inf Dis 16 (6): 634-36.

 

 Friedmann, H C, “Escherich and Escherichia.” 2006; Advances Appl Microbiol 60: 133-196.

 

Escherich, Theodor, “The Foundations and Aims of Modern Pediatrics.” 1905; American Medicine 9 (2): 55-62.

 

 

 

 

A FAMOUS NAVAL HOSPITAL:

HASLAR

 

         By the mid-eighteenth century, Britain had established colonies around the world. To protect the new possessions and maintain the trade routes that rendered the colonies profitable required an expanded navy. Larger ships, into which hundreds of crewmen were crowded in close quarters, sailed ever-longer routes far from land. Though the seamen’s diet, measured in calories and meat content, was richer that that found in most homes at the time, it did not included perishable fruits or vegetables.

         The diet rendered the crews susceptible to scurvy, brought on by the lack of vitamin C, and the killer of more men than combat wounds and other diseases combined. Crowding also permitted infectious diseases to flourish. Among the latter, typhus was the most common, though smallpox and yellow fever appeared intermittently.

         In the early years of naval expansion, the sick arriving in a port were placed in homes, lodging houses, or small private hospitals contracted to care for them. Such a system, however, failed. Fraud was rampant; the host facilities padded the bills and provided minimum care. Alcohol was traded for clothing and the few contract doctors available were often busy with private patients. Faced with over 15,000 men yearly invalided ashore, the Navy decided to build substantial hospitals to provide better care. The largest, Haslar Hospital, went up across the bay from Plymouth, home of the Navy’s principal docks.

         Originally designed as a large four-sided building around a large square central court, only three sides were constructed to allow more ventilation. The central portion was primarily for

Plan of Haslar Hospital (from Tait, History of Haslar Hospital)

administrative functions (the administration was civilian) and the side wings featured double pavilions three stories high and separated by a small, aerated area. The building opened in 1754, allowing accommodation for 1200 patients, and was the largest brick building in England and perhaps in Europe. Lighting was by gas, replaced by electricity in 1905. Water closets were installed at the end of each ward, and sewage emptied into Portsmouth Harbor via a nearby creek. Wells supplied fresh water. The first chief physician was James Lind, a civilian at the time.

James Lind (Wikipedia)

         Lind was a Scot who learned surgery as an apprentice and went to sea as a surgeon’s mate at age 23. While serving in the Channel Fleet he conducted his famous trial of remedies for scurvy, noting that the most effective curative was juice from lemons and oranges. He then left the Navy to earn an MD degree at Edinburgh, entered private practice, and found time to write A Treatise on Scurvy, published in 1753, in which he detailed his success with citrus juice to prevent scurvy. Strangely, though, Lind did not emphasize citrus juice for the treatment of scurvy, believing it to have other causes. Lind held the post at Haslar until 1783, succeeded by his son.

         By the time of the American revolt against England, Haslar held 2100 patients, making it four times the size of Guy’s Hospital in London. Not all seamen wanted to be there. Many had been impressed into service out of prisons or poorhouses and frequently escaped during the night or had alcohol smuggled in. To discourage desertion, bars were put on the windows, a wall twelve feet high surrounded the hospital, and guards patrolled outside. Yet in1794, 226 still managed to escape. Nursing care was unreliable, with alcohol often bartered for clothing, and sometimes nurses or attendants coaxed sick patients into willing their property over. Mortality overall was substantial. In 1780, 909 deaths were recorded.

         The few doctors assigned to the hospital were allowed to engage private practice and when needed might be miles away with a patient. Only after 1797, was private practice forbidden. At first, surgeons operated without anesthesia on the wards, but after patients objected a separate operating room was installed. Surgeries were infrequent, however, until the arrival of anesthesia in the 1850s.

         In the early days, scurvy and typhus were the most common medical problems in the hospital. Typhus most commonly broke out on a ship after men from jails or from other ships carrying typhus were put aboard as crewmembers. Most medical men considered it “contagious,” not recognizing the role of the louse in its

Thomas Trotter (Wikipedia)

transmission. Thomas Trotter, appointed Physician to the Hospital in 1793, improved hygiene enormously. New patients were bathed (as before), shaved, their hair cut short, and given clean clothes. Thereafter they were washed daily and given twice-weekly changes of hospital gowns, which undoubtedly helped prevent new typhus cases. Trotter halted the treatment of bleeding for fevers and supplied a rich diet, speeding recovery. By this time, the value of fruits and vegetables for scurvy was evident. Trotter also revised the administrative structure, pleaded for more personnel to attend the sick, and recommended that the Navy take over the previous civilian administration.

         The Navy did assume responsibility for the hospital and introduced a teaching program aimed at medical problems peculiar to shipboard life. Courses in new subjects, such as bacteriology, were introduced. Anesthesia allowed a more active surgical service. The hospital, over time, cared for casualties from the Napoleonic wars, the Crimean War, and both World Wars. The country’s first blood bank opened there in 1940. The National Health Service took over the site in 2007 and closed it in 2009. The hospital now contains flats for retirees. Over 10,000 bodies are believed to be buried on the grounds. Forensic scientists have recently examined a few skeletal remains and documented osseous signs of scurvy, once a persistent threat to a seaman’s life.

 

Modern view of the hospital, showing a guard tower (Wikipedia)

SOURCES:

 

William Tait, A History of Haslar Hospital, 1906; Griffin & Co.

Kenneth J. Carpenter, The History of Scurvy and Vitamin C, 1986; Cambridge Univ Press.

Bryan Vale and Griffith Edwards, Physician to the Fleet: The Life and Times of Thomas Trotter. 2011; Boydell Press, Woodbridge.

James Lind, A Treatise on the Scurvy, 3^rd ed. 1772; London.

Eric Birbeck, “Royal Naval Hospital Haslar: Paragon of Nautical Medicine.” The Grog Ration 5 (2): 2-5, 2010.

Eric Birbeck, “The Royal Hospital Haslar: from Lind to the 21^st century.” The James Lind Library, accessible at: https://www.jameslindlibrary.org/articles/the-royal-hospital-haslar-from-lind-to-the-21st-century/

 

 

                     THE VIBRANT LIFE AND TRAGIC DEATH OF

RENÉ FAVALORO

 

            René Favaloro, an Argentinian cardiac surgeon, is best known to the world as the “father” of coronary artery bypass surgery. His life in medicine, however, ranges well beyond cardiac surgery.

         René was born in La Plata, Argentina, in 1923, the son of an artisan carpenter of Sicilian origin. After medical school and internship in La Plata, he decided on a career in surgery. But he declined a residency when he was required to sign a declaration of allegiance to the Peronist party. Coincidentally, a letter came from an uncle in a remote village in the Pampa asking him to fill in while the local doctor was absent for medical treatment. René accepted and traveled to Jacinto Aráuz, a village in flat, desolate land whose inhabitants, mainly of German descent, labored at raising livestock and farming in barren land with unpredictable weather conditions. The previous doctor soon died, and René brought in his brother,

René Favaloro (Wikipedia)

recently graduated from medical school, to set up a more modern clinic. They expanded their area of activity, acquired used X-ray equipment, medical books and journals, a reliable automobile, and materials for local and spinal anesthesia. They taught midwives to be nurses and others to educate villagers about hygiene, clean water, and ways to stay healthy. Cesarian sections, gallbladder surgery, hernia repair, and many other procedures became possible. He tabulated the blood types of all the residents, thus establishing a “mobile blood bank” in case of emergencies. René married and built a house, but after twelve years of hard work and little vacation, decided to broaden his horizons. He wanted to study thoracic surgery.

         His old professor of surgery, José María Mainetti, encouraged him to go to the Cleveland Clinic. René took some quick English lessons and flew north. George Crile, one of the Clinic's founders, greeted him and referred him to the cardiac surgery service under Dr. Donald Effler. Effler found that Favaloro had not passed any U.S. exams and spoke halting English and told him he could work only as an unpaid aid. Using modest savings, René carried out aid duties and earned enough confidence to be allowed to scrub in on operations. He learned English, crammed every night to pass the National and State Board exams, and was accepted as a cardiac surgery resident. 

The timing was propitious. A brilliant cardiologist at the Cleveland Clinic, Mason Sones, was the first to use a rapid frame motion picture camera to photograph dye in the coronary arteries and clearly demonstrate obstructive lesions. Favaloro worked with Sones

Mason Sones with Favaloro (Wikimedia Commons)

intensively and before long tried bypassing the lesions using a saphenous vein graft. The coronary artery bypass graft (CABG), as the procedure was called, replaced the less effective Vineberg operation (implanting a mammary artery in the myocardium) and became a favored operation worldwide. Favaloro justifiably earned many honors, especially for his rigorous collection of data to establish the value of the procedure. 

During his time at the Cleveland Clinic, he was still mindful of the lagging state of surgery in his native city and wanted no less than to bring the Cleveland Clinic to La Plata. At the height of his fame, he resigned his position at the Clinic, moved to La Plata in June of 1971, and began to assemble a cardiac institute. As Chief of Cardiac Surgery at the Clinica Güemes Hospital, he and his brother put together, in 1975, the Favaloro Foundation, a nonprofit organization devoted to cardiology and cardiac surgery. Tragically, René’s brother died in an accident one year later and René helped raise his four children, two of whom became physicians. In 1978 an eight-story building was donated to the Foundation as a research institute. Two years later, René performed the first cardiac transplant in Argentina and established a teaching unit in the hospital. 

René's worldwide reputation helped him raise funds for a new institute that combined cardiology, teaching, and research into one unit: The Institute of Cardiology and Cardiovascular Surgery. It resembled the National Heart, Lung, and Blood Institute in the U.S. and opened in 1992 as part of the Favaloro Foundation. It was a nonprofit entity, providing care to all, regardless of ability to pay. About 25% of surgical patients had no insurance. By the seventh year, the Institute had trained at least 400 cardiologists and cardiac surgeons for work throughout South America and beyond.

Planet Heart (Corazón Planetario), by Gyula Kosice, at the Favaloro Foundation 
(Wikimedia Commons)

Outside his medical work, René was an active member of the National Commission on the Disappearance of Persons, a group investigating the tragedies of thousands of “disappeared” citizens during the military Junta regime. He took an interest in Argentina’s history and wrote two books on the life of its founding father, San Martín. He wrote a book on his life as a country doctor and another on his life at the Cleveland Clinic. His favorite fictional character was said to be Don Quixote, and many friends felt his entire life resembled a quixotic quest.

Maintaining a nonprofit foundation requires money, and when times were prosperous the Institute received adequate funds. However, in the late 1900s Argentina’s finances fell into serious trouble. The usual subsidies from government and private agencies dried up. René struggled with the Institute’s increasing debt, but to no avail. Letters to the government went unheeded. In desperation, on July 29, 2000, at the age of 77, René shook the conscience of Argentina to the core when he pointed a revolver to his chest and ended his life. He left a long letter detailing his accomplishments in his home country and the corruption he was surrounded with. He said a goodbye to his family and ordered that his body be cremated and his ashes scattered in the hills near Jacinto Aráuz, where he had labored for twelve years as a rural physician.

Public outrage helped the Favaloro Foundation survive the crisis and René would be happy to know that the Foundation now is a major cardiac center in Argentina, as he dreamed it would be.

 

SOURCES:

 

Captur, Gabriella, “Memento for René Favaloro.” Texas Heart Institute Journal 2004; 31(1): 47-60.

Favaloro, René, “Landmarks in the Development of Coronary Bypass Surgery.” Circulation 1998; 98(5): 466-78.

Favoloro suicide letter, available at:    https://web.archive.org/web/20160305021334/http://www.avizora.com/publicaciones/biografias/textos/textos_f/0013_favaloro_rene_anexo_01.htm

Fye, Bruce, Caring for the Heart: Mayo Clinic and the Rise of Specialization, 2015; Oxford Univ Press, pp 315-342.

Rubenstein, Robyn, et al, “René Gerónimo Favaloro (1923-2000): A Man Who Struggled with Matters of the Heart.” American Surgeon, January 2018, 7-11.

Favaloro, R, Recuerdos de un Médico Rural, 2^nd edition, Editorial Sudamericana, 2018.

Favaloro, R, De la Pampa a Los Estados Unidos, digital edition, Random House, 2012.

"Argentina Searches it Soul over a Suicide," New York Times, August 7, 2000.

 

 

         

        IMMUNOLOGICAL CAPITAL IN NEW ORLEANS

 

                Much has been written about the impact that disease has on the course of human affairs. Typhus, for example, decimated Napoleon’s army as it retreated from Russia. Plague ravaged Europe in the fourteenth century to such an extent that the population dropped by about one third. Malaria and cholera have crippled military campaigns. Influenza killed millions toward the end of the Great War.

                One more disease deserves mention: yellow fever. In 1802, when Napoleon sent an army to St. Dominique (now Haiti) to put down a revolution, yellow fever carried off so many troops that the effort failed. After the failed invasion, Napoleon decided to sell the French possessions in America to the new United States. Thomas Jefferson, suddenly responsible for the management of the Louisiana Purchase, acted to bring it and its most important city, New Orleans, under American governance. He filled the various administrative offices with men to whom he owed political favors.

                Before long, however, his appointees expressed reluctance to accept the new jobs. Their predecessors were dying of yellow fever. The fever season lasted from June to the end of October or early November and the mortality among the newcomers hovered around fifty percent. A new book, Necropolis: Disease, Power, and Capitalism in the Cotton Kingdom, by the Stanford historian Kathryn Olivarius, relates the dominance that yellow fever exerted on the rhythm of life in New Orleans during the antebellum years and the importance of “immunological capital.”

                The city, by all accounts, was filthy. Local government, controlled by the planter and merchant class, funded the most meager civic improvements possible. Sewage was virtually absent. Cesspools stank in the summer. Butchers slaughtered animals in the street and left the carcasses behind. Diseases of poor sanitation were common. All this was in spite of the predominant medical opinion that yellow fever was not contagious but arose from the miasmas produced during hot months. Travelers were astonished at the nonchalance of the inhabitants living among such foulness, stench, and, in the summer, death. Newspapers and publications, on the contrary, ignored the truth and painted the city as healthful and prosperous.

                Importantly, there were fortunes to be made in New Orleans (mainly on the backs of slaves) and new immigrants kept coming from both the United States and from Europe. Young, optimistic arrivals often felt they could weather a bout of the fever and then, being immune, seek greater opportunity. A man was much more likely to be hired after surviving yellow fever, especially in a job with long-term prospects. Surviving “yellow jack” is how he earned his “immunological capital.” Immunity to yellow fever was a ticket to a social and business world of privilege that tended to exclude those who had not crossed this threshold. An immune person could rise in business, hold office, be a member of clubs and associations, buy life insurance more easily, and even marry the daughter of a father who rejected any nonimmune suiter. It was common for employers and insurance companies to ask for a doctor’s certificate verifying immunity to yellow fever. The doctor, of course, had no laboratory test or visible sign to buttress his opinion. He relied on the patient’s history, focusing especially on how long the individual had lived in the city.

                It was almost a universal belief that the black population had a natural, inborn, immunity to yellow fever. Doctors believed it too. For slaves born in Africa that may have been partially true since they grew up in a yellow fever environment. But slaves and free blacks born in the United States were as susceptible as anyone else. Planters, of course, knew the truth. They lost slaves to the fever during epidemics, sometimes in large numbers, seeing it as a cost of business. Slaves known to have survived yellow fever commanded higher prices.

                Some residents profited from the epidemics. Doctors, for instance, charged a higher “yellow fever rate” during epidemics. They often became wealthy enough to invest in a plantation or slaves, prospects that attracted more doctors to town. Gravediggers, usually blacks, charged higher rates during outbreaks. Even so, they were often overwhelmed. Undertakers, coffin makers, pharmacists, and irregular practitioners all did well during epidemics. Residents of French and Spanish background usually called on French-trained physicians, who tended to prescribe baths, rest, and hydration. American-trained doctors, in contrast, were more aggressive, employing generous purges, copious bleeding, and blistering. Medical care for poor people was more haphazard. Charity Hospital, founded back in 1736, was overloaded with patients and lacked the money for decent nursing, bathing, and even adequate diet. Numerous private charities and the Catholic Church filled the gap for the poor as best they could. Irregular practitioners, even Voodoo doctors, were also active.

                The deadliest yellow fever epidemic in antebellum New Orleans came in 1853. Up to 1000 people a week were dying and an estimated 10% of the city population (of 120,000) perished, even as newspapers reported on everything except the epidemic. Amazingly, the deaths and misery of that terrible outbreak still failed to persuade the city to establish a permanent health department or a quarantine regimen. The filth, stench, and repeated yellow fever tragedies continued until the Civil War, when Union forces under General Butler cleaned up the city and enforced a quarantine. Yellow fever cases dropped dramatically, paradoxically reinforcing the general belief that the disease arose from filth and miasmas. It took a massive epidemic in 1878 to finally convince New Orleans to institute definitive measures. Mosquito transmission was not confirmed until 1900.

 

                                     A MIRACLE DRUG, MAYBE

       She was known only as Mrs. G, a twenty-seven-year-old woman with debilitating rheumatoid arthritis that largely confined her to a bed and chair existence. Grasping at straws, she had already undergone a trial of streptomycin, based on theories of an infectious cause for her arthritis, without any improvement. In July 1948, she journeyed to the Mayo Clinic after hearing about a possible new approach to the disease: inducing jaundice.

        The chief of the rheumatology service at the Mayo Clinic was Philip Hench. He had founded and directed the first rheumatology

Philip Hench (Wikipedia)

service at the Clinic. An alert clinician, Hench noticed that the pain and immobility of rheumatoid arthritis sometimes improved for weeks to months in patients who were jaundiced from various causes (except hemolysis). Sensing a treatment opportunity, he infused bilirubin in large doses into patients and even transfused blood from jaundiced individuals, but with little or no improvement (1938). Noticing that pregnancy also helped rheumatoid arthritis in women, Hench transfused blood from pregnant women and administered female hormones, but without success. Some women even deliberately became pregnant again, hoping to make permanent the improvement in pain and stiffness.

This time Hench gave Mrs. G, and another patient, lactophenin, a substance that induced jaundice. But Mrs. G never turned yellow, though her companion did, and was released from the study. She refused to leave, however, badgering the Mayo doctors for another possible therapy. 

Based on the jaundice and pregnancy results, Hench had proposed a “substance X” present in the blood in these conditions that rendered rheumatoid arthritis potentially reversible. Since it appeared not to be a sex hormone or released from the liver, attention turned to the adrenal cortex. During WWII, research on extracts from the adrenal cortex had accelerated. Rumors proliferated that German scientists had isolated a substance from the adrenal cortex that increased tolerance to oxygen deprivation in fighter pilots and that submarines were transporting large quantities of bovine adrenal

Edward Kendall (Wikipedia)

glands from Argentina to Germany. Edward Kendall, at the Mayo Clinic, who had already isolated thyroxine and glutathione, and a Swiss chemist, Tadeusz Reichstein, had both isolated compound E from the adrenal cortex in 1936. The procedures were laborious and the quantities small. Because compound E, unlike other isolates, kept adrenalectomized rats alive and might be valuable for stressed pilots, the U.S. prioritized efforts to synthesize it.

       Mrs. G’s pleas for another treatment touched Hench. He turned to Edward Kendall, who had isolated compound E, who persuaded Merck, the owner of the scarce

Tadeusz Reichstein (Wikipedia)

substance, to release 5 grams for use. Hench, not optimistic about the outcome, left the trial to two younger rheumatologists working on the service, Charles Slocum and Howard Polley. 

       Mrs. G received the first of twice daily injections of 50 mg of compound E on September 21. By the 23^rd she felt better and by the 24^th she was walking around and doing light exercise. By the 28^th she went shopping for three hours, saying “I have never felt better in my life.” Hench, stunned, was about to leave for London at this critical moment to give the prestigious Heberden Lecture. He swore everyone involved to complete secrecy until he returned. On the way to London, he detoured to New York to meet with Merck executives to swear them to secrecy and to obtain more of the scarce compound E.

       Meanwhile, Mayo doctors tried compound E (soon to be called cortisone) on more patients, including some with lupus and other rheumatic diseases, with equally startling results. Merck, before publicizing such extraordinary findings, wanted the security of involving experts beyond the Mayo group. Hench coaxed a group of five prominent rheumatologists from around the country to come to Rochester. One of them, Dr. Richard Freyberg, from New York’s Hospital for Special Surgery, recalled the event years later. Hench had turned his large house into a clinic, complete with X-ray viewers, microscopes, and movie projectors, and plenty of food. Two patients were examined carefully, then injected once with 300 mg of cortisone. Over the next three days the same miraculous transformation from an almost immobile status to a freely moving one amazed the onlookers. Back home, the experts tried it on their own patients, with the same astonishing results, but always with relapses after the cortisone ceased. 

       The rheumatologists reported their findings at the International Congress of Rheumatology. One of them, Walter Bauer from

Nobel Medal, showing a figure gathering water from a spring 
to help an ailing young woman (Wikipedia)

Harvard, recalling Boston’s ether story, declared, “Gentlemen, this is no humbug.” During the Congress, however, Hench received a phone call alerting him to side effects that were to mar cortisone’s reputation. In particular, Mrs. G had become bloated, developed a moon-like face, lost bone density, and suffered a depression and psychosis so serious she was transferred to a locked psychiatric ward. After recovery, she refused to take cortisone ever again. She died in 1954 of pulmonary edema during a course of ACTH in Indiana. 

Similar side effects from cortisone in others shattered the euphoria of the doctors and their arthritic patients. In the end, cortisone, used safely, offered little benefit over aspirin. Only the later introduction of prednisone provided a safer alternative.

       In 1950, two years after Mrs. G received her first dose of cortisone, the Nobel Prize in physiology or medicine was awarded to Hench, Kendall, and Reichstein. 

Was the Nobel prize premature? Maybe, since cortisone proved to be a disappointment. On the other hand, its use led to improved steroids and opened vast new avenues of research, considerably improving the lives of those with rheumatic diseases.

 

SOURCES:

Rooke, Thom, The Quest for Cortisone. Michigan State University Press, 2012.

 

Burns, C M, “The History of Cortisone Discovery and Development.” 2016; Rheum Dis Clin North Am 42: 1-14.

 

Warner, M E, “Witness to a Miracle: The Initial Cortisone Trial: An Interview with Richard Freyberg, MD.” 2001; Mayo Clin Proc 76: 529-32.

 

Hench, P S, “Effect of Spontaneous Jaundice on Rheumatoid (atrophic) Arthritis.” Brit Med J 1938; Aug 20: 394-8. 

 

Benedek, T G, “History of the Development of Corticosteroid Therapy.” 2011; Clin Experim Rheumatol 29(Suppl 68): S5-S12.