Research Paper

Therapeutics of Kidney Diseases
Am J Nephrol 2002;22:284–289

Now and Then, the History of Parenteral Fluid Administration
Noha Barsoum Charles Kleeman
UCLA School of Medicine and West Los Angeles VA Medical Center, Los Angeles, Calif., USA

Key Words History of medicine W Intravenous fluids W Blood W Blood transfusion W Cholera W Bloodletting

The Circulation

Abstract The use of blood and intravenous fluid therapy is now considered routine therapy. The level of sophistication that we now perceive as standard has resulted from centuries of legends, religious beliefs, pseudo-science, nonscientific supposition, experimentation and error. The purpose of this article is to review the evolution of parenteral fluid and transfusion therapy through history. Data were collected via online search through the medical literature (ovid-medline), historical journals, medical history books as well as visits to historical medical libraries. We express our appreciation and gratitude to the hundreds of scientists whose work has allowed us to practice medicine, as we know it.
Copyright © 2002 S. Karger AG, Basel

Long before William Harvey’s description of the circulation, ancient healers across many cultures debated and speculated the nature of man’s blood circulation. In the ancient culture of Mesopotamia the liver, being most vascular, represented the center of life. Ancient Chinese medicine was perhaps the closest to describe the modern circulation accurately. The medical compendium of Nei Ching, an ancient Chinese medical text, describes that ‘all the blood is under the control of the heart, the blood current flows continuously in a circle that never stops’. Imenhopt I, an ancient Egyptian physician, described the ‘metu’ or channel theory where air, blood and other body fluids traveled together in body channels and were eventually excreted through the anus. Aristotle believed that blood was manufactured in the heart then distributed to other tissues. Galen, however, believed that blood was made in the liver, then moved back and forth until it was consumed, this continued to be the theory regarding circulation for many years to follow.

‘The life of the body is the blood’ (Lev.17:11; Gen. 9:4). From the earliest history of medicine to the days of Galen, blood and other body fluids have held a mystical quality. Blood represented life and was therefore regarded as the greatest gift, and hence the custom of sacrificial offerings to the deities.

Bloodletting

The ancient custom of bloodletting also derives its origins from prehistoric times. It possibly started with the observation of premenstrual women whose pain was relieved by menstruation, suggesting a therapeutic benefit from bloodletting. It is clear that bloodletting, blood sucking and the use of leeches was widely employed in the ancient Egyptian and Arabic cultures, where the Arabs

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Noha Barsoum, MD Va Medical Center West Los Angeles Nephrology Section WIIIL Wilshire and Sawtelle Blvds., Los Angeles CA 90073 (USA) Tel. [phone], Fax [phone]

Fig. 1. Blue stage of spasmodic cholera. A girl who died of cholera in Sunderland, November 1831. Lancet 1832.

had scales designed to guide the amount of bloodletting. During the 13th through the 16th centuries bloodletting became more sophisticated and its use more popular. The medicinal use of blood and fluids also goes as far back as ancient Egyptian times; blood drinking as well as oral intake of medicinal herbs was widely employed. Egyptian royalty were routinely offered blood baths for different ailments. This was true for most of the ancient cultures with the exception of ancient Hebrew medicine where blood drinking was forbidden: ‘avoid the temptation of eating blood’. Pliny, the great Roman writer depicted the custom of rushing into the arena to drink the fresh flowing blood of the gladiators to gain youth and strength. In ancient Rome, epileptics were allowed to drink the blood of beheaded criminals in the public arena under the direction of physicians. Famous Greek mythology describes how Odysseus, Homer’s hero, was said to have regained consciousness by drinking blood when he was in the realm of the dead.

Earliest Attempts at Intravenous Therapy

The journey starts at the end of the 16th and the beginning of the 17th century. William Harvey’s report on the circulation coupled with the curiosity, patience and dedication of other scientists allowed the first steps towards establishing IV therapy. More than half a century later, frustration and disappointment from poor outcomes resulted in the cessation of efforts at IV and transfusion therapy throughout the 18th century. Bloodletting and the medicinal use of leeches reached unprecedented popularity and sophistication. This continued until the end of the century when Pierre Alexander Louis (1787–1872), a French physician, performed the first literature review and analysis of the practice of bloodletting and showed it to be harmful.

Interest Revived Dawning of Intravenous Therapy

Perhaps the first hint of intravenous (IV) therapy lies in the classical story of the Argonauts. Ovidius, a Roman poet, relates that princess Medea rejuvenated her husband’s father Aeson by a magic potion. She was said to have cut the elder’s throat, emptied his veins then refilled the vessels with her solution. In 1492, the ailing Pope Innocent VIII, 250th successor of the Apostle Peter was ‘given blood’ from three healthy youths in an attempt to save his life after a stroke, but all died. Although a few historical references refer to this incident as first attempt at blood transfusion, most texts believe blood was given orally as was the custom at that time.

The early part of the 19th century was quiet until the outbreak of the cholera epidemic sparked a renewed interest in the use of parenteral therapy. It would take physicians and scientists almost 3 years to recognize that the sequelae of cholera were a result of dehydration and not a ‘blood disease’. Cholera started in India in 1827, spread to Russia in 1829, England in 1831, and the US in 1832. The impact of the disease was devastating with approximately 15,000 cases reported in England alone in 1832, a third of whom died. Perhaps the best description of cholera is illustrated in figure 1, Tilted Blue Stage of Spasmodic Cholera, originally published in the Lancet on February 4, 1832, by William O’Shaughnessy, who later founded principles on IV fluid therapy. ‘On the bed lay an expiring

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Table 1. The history of blood transfusion and intravenous therapy
1492 First attempted blood transfusion? First description of a blood transfusion The circulation First animal to animal transfusion First intravenous injection in an animal Ailing Pope Innocent VIII, 250th successor of the apostle Peter ‘given’ blood from 3 heatlthy youths to save his life after a stroke. All died. Much speculation exists on the route of blood administration. Andreas Libavius of Saxony, a Chemist, physician and director of the College at Coburg: ‘the arterial blood of the healthy one will leap into the sick one and immediately bring him the fountain of life’. William Harvey (1578–1657) Physician-In-Ordinary to Kings James I and Charles publishes his description of the circulation in ‘Exercitiato anatomica de moto cordis’. Francis Folly, a Florentine physician, claims to have performed the first successful animal to animal transfusion before Grand Duke Ferdinand II. He ‘inserted a silver tube into the artery of the donor and a canola of bone into the vein of the recipient’. Never published his work. Sir Christopher Wren, London architect of Saint Paul’s Cathedral describes ‘a way to convey liquid poison into the mass of blood’. He fahioned a quill and a pig’s bladder to instill wine, ale, opium and liver of antimony into a dog’s veins. An intoxicated dog was a successful endpoint. Wren taught Willis who later described the circle of Willis. Johann D. Major, a German graduate of Padua University injected an unpurified compound into a man’s vein. Poor outcome resulted in cessation of any more attempts for many years to follow. Richard Lower (1631–1691), a graduate of Westminster School, London, a microscopist, physiologist, cardiologist and architect publishes the first successful animal to animal transfusion. Lower claims to have transfused a man named Arthur Coga with sheep blood. Coga suffered from a ‘benign form of insanity’ and sheep blood was meant to ‘calm him’. Lower published his work in 1669 in ‘Tactus de Corde’. Jean Baptiste Denis, a Montpellier philosopher, professor of mathematics and physician to Louis XIV of France, transfused a 16-year-old boy suffering from fever with 3 oz of sheep blood. He published his work in a letter in the Philosophical Transactions of the Royal Society on July 22, 1667, No. 2. Denis transfuses his 4th patient, Antoine Mauroy, with calf’s blood. On his 2nd transfusion ‘felt a sensation of heat traveling up his arm, tightness in the chest and kidneys, an irregular heart beat, 1 day later he suffered a nose bleed and dark urine then finally died’. Denis was tried for manslaughter then later acquitted. Philip Syng Physick, an American physician from Philadelphia, claims but does not publish the first human to human blood transfusion. Cholera started in India, spread to Russia by 1829 then England in 1831 and the United States by 1832 claiming thousands of lives. It was initially thought to be a blood disorder ‘black, thick and cold’ and treated by bloodletting. Finally, in 1831 22-year-old William Brook O’Shaugnessy of Edinburgh University recognizes that dehydration and ‘universal stagnation’ of blood is the primary pathology. Williams Blundell (1790–1878), an English physician and obstetrician, graduate of Edinburgh University and Fellow of the Royal College of Physicians, transfuses a man named Brazier suffering from intractable vomiting. With the help of Henry Cline, a famous surgeon, blood was drawn from several witnessing physicians in increments of 1−1.5 oz then ‘thrown in’ to a total of 14 oz. Brazier died. Blundell successfully transfuses a woman dying of severe postpartum hemorrhage after obtaining blood from his assistant Dr Davies using 8-oz syringes. Herman and Jaehnichen, Russians physicians desperate in the face of cholera, injected 6 oz of water into a patient in Moscow who died 2 h later. Thomas Latta, assistant to O’Shaugnessy and a practicing physician in Leith, Scotland, injects 6 pints of a solution of ½ concentration of soda and subcarbonate soda (58 mEq Na, 49 mEq Cl, 9 mEq HCO3) into an elderly woman over 30 min who dies shortly after. Latta’s 2nd patient, a 52-year-old woman who had ‘reached the last moments of her earthly existence’ receives 330 cm3 of fluid over 12 h and survives. Latta transfuses 25 patients, ‘a third of my patients have been restored to life’. John Mackintosh, Scottish physician and student of Latta comments that ‘it would be advisable to make the fluid resemble as much as possible the serum of blood, by adding albumin obtained from egg’. After the infusion ‘the pulse would become perceptible, then strong and the cramps would cease and the secretion of urine returned’.

1615

1616 1654

1656

1662

First intravenous injection in humans First published animal to animal transfusion First animal to human transfusion First published animal to human transfusion

1665 1665

1667

1667– First documented transfusion 1669 reaction

1795 1827

First human to human blood transfusion? The cholera epidemic strikes

1829

The first documented blood transfusion

1830 1830 1832

First successful blood transfusion First intravenous use of water First saline infusion

1833

First successful saline infusion First use of intravenous albumin

1834

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Table 1 (continued)
1840 1849 First transfusion in hemophilia Blood transfusions deemed acceptable Samuel Armstrong Lane, a physician at St George’s School in London transfuses the first hemophiliac. Walton, a famous English physician reviewed all transfusions to date and concluded the procedure a success with a mortality rate of 30%. He judged that the quantity of blood transfused should be no less than 6 oz and no more than 16 oz (roughly 1 unit blood). With the advent of the second cholera epidemic, milk became the primary infusate. The first attempts were done by James Bovell, physician and mentor to Osler, and Edwin Hodder in Toronto. Bovell and Hodder injected 12 oz of cows milk into 7 patients, 5 of whom died. Goat then later human milk was used by Howe in New York and Meldon in England until 1884 when Bull reported that saline appeared to be overall more beneficial than milk infusions. Sydney Ringer, graduate of London University and one of the first clinical pharmacologists was the first to observe the different physiological effects of the various electrolytes while studying a frog’s heart. He introduced Ringer’s solution, a solution containing 8 g NaCl, 0.3 g KCl and 0.33 g CaCl in 1 liter of distilled water and determined that composition to be most physiologically beneficial. 35 years later, Alexis Hartman, an American pediatrician, added lactate to this solution to make what is now known as lactated Ringer’s solution. Sir Almroth Wright, an English pathologist introduces the use of citrate as an anticoagulant. It will be almost 30 years later that citrate becomes available as an anticoagulant. Karl Landsteiner of Austria discovered three of the four major blood groups and is awarded the Nobel Prize for his work in 1930. Jansky from Chekoslovakia discovers the fourth blood group. By 1908 blood typing become commercially available. Ottenberg, a biochemist at Colombia University describes the concept of the universal donor and the universal recipient. In 1913 Ernest Unger, later a pioneer in kidney transplantation, devises an apparatus with a 4-way stopcock for direct transfusion. Reported by Albert Hustin in Belgium then shortly followed and confirmed by Agote in Argentina, Weil and Lewishon in England. Oswald Robertson, a medical officer in the Canadian Army in World War I successfully transfuses 22 wounded soldiers. By 1925 blood transfusions also used in the treatment of burns. The first blood bank was established in Leningrad. 2 years later the first American blood bank is established in Cook County in Chicago, Ill., by Bernard Fantus. Fantus is recognized as the ‘Father of Blood Banks’. K. Landsteiner, A. Wiener, P. Levine and Stenson all report the Rh system. Edwin Cohen, a professor of biological chemistry at Harvard University develops cold ethanol fractionation which enables the isolation of albumin, Á-globulins and fibrinogen. Isodor Ravidin, a Philadelphia surgeon, becomes the first to use albumin clinically in the treatment of shock and burn victims of Pearl Harbor. Carl Walter, a Harvard surgeon and later a pioneer in kidney transplantation introduces the plastic bag for blood collection. Walter was also responsible for the introduction of the concept of aseptic technique. Needles in the first half of the 20th century were steel reusables with a stylet to keep the lumens open and barbs were sharpened by hand with a flint stone. IV fluid therapy or ‘feedings’ were reserved only for the critically ill patients. In 1950 David Masa, an anesthesia resident at the Mayo Clinic, introduced the plastic needle that, in combination with the introduction of the aseptic technique by Walters then the autoclave in 1958, resulted in an explosion in the use of IV fluids. E. Cohen introduces the blood separator allowing the separation of erythrocytes, leukocytes, platelets and plasma. Max Perutz of Cambridge discovers the molecular structure of hemoglobin. Stanley Dudrick, a surgical resident at the University of Pennsylvania, experiments with intravenous hyperalimentation using a mixture of protein hydrosylates and concentrated dextrose on 6 puppies. His puppy mixture was successful and was used to provide nutrition to a newborn infant until age 15 months. This was the foundation for TPN, and intralipid was added in 1975 after FDA approval.

1854– The transfusion of milk 1884

1876

Ringer’s solution introduced

1894 1901 1907 1911

Citrate introduced as an anticoagulant Blood groups identified Blood groups identified Universal donors and recipients identified First use of citrated blood for transfusion Blood transfusion accepted in the treatment of shock First blood bank established

1914 1918 1932

1939 1940

The discovery of the Rh system Cold ethanol fractionation developed

1950

The plastic bag is introduced

1930

The Rochester plastic needle

1951 1959 1969

The blood separator is developed The molecular structure of hemoglobin TPN

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woman ... presenting an attitude of death which ... I never saw paralleled in terror ... on the floor, extended on a palliasse ... lay a girl of slender make and juvenile height, but with a face of a superannuated hag. She uttered no moan, gave expression of no pain, but she languidly flung herself from side to side ... the color of her countenance was that of lead – a silver blue, ghastly tint; her eyes were sunk deep into sockets, as though they had been driven an inch behind there natural position; her mouth was squared; her features flattened; her eyelids black; her fingers shrunk, bent and inky in their hue. All pulse was gone at the wrist and a tenacious sweat moistened her bosom.’ Motivated by the devastating disease, scientists once again started experimenting with IV and transfusion therapy. In 1831, William Brooke O’Shaugnessy, a 22-yearold graduate of Edinburgh University described cholera as ‘universal stagnation of the venous system and rapid cessation of the arterialization of blood’. He went on to wonder whether ‘alteration of this black and thickened condition of the blood to the state of arterialization prevent the sequel of exhaustion’. He proposed that if they were to ‘bring certain salts of highly oxygenated constitution into contact with the black blood of cholera ... such blood lost a large proportion of its water and a great proportion of its neutral saline ingredients ... of the free alkali contained in healthy serum, not a particle in some cholera cases’. Once again overwhelmed by poor outcomes and complications, and with the resolution of the cholera epidemic, IV therapy would once again take a secondary role until the advent of the second cholera epidemic in the second half of the century. Disappointed from prior experience from the first cholera epidemic, scientists now enter the era of milk transfusions which would continue until the end of the century when milk therapy was shown to be harmful. In 1885, Went published the views of Hayem, a famous hematologist of that era summarizing the views of that century. Hayem ‘strongly urges the employment of saline solutions ... extensive transudation of serum into the intestines, the blood is greatly reduced in volume ... circulates but slowly into the system ... carbonic acid accumulates to the extent that it may even become acid in reaction ... quantity of water equal to the entire mass of the blood may be added without causing any serious inconvenience ... about 2 liters must be injected if the proportion of RBC increased to 7–8 million/cm3.’ He went on further to say that ‘in certain cases of vascular collapse ... one would throw the injection into the cavity of the peritoneum’.

Although the importance of IV solutions was well recognized, the complications related to access and sepsis made progress slow in the first half of the 20th century. ‘IV feedings’, as they were called, were only given to critically ill patients. Fluids were poured into an open glass flask covered with gauze, in the neck was a rubber stopper attached to glass tubing then rubber IV tubing. Various methods of introduction of IV fluids were employed including proctoclysis in which a liter of fluid would be poured into the rectum of supine patients. Hypodermoclysis or subcutaneous injection of large amounts of fluid was also popular although limited since only isotonic fluids could be successfully used.

Final Success

The 20th century started with a breakthrough in transfusion therapy with Landsteiner’s discovery of the blood groups. News of successful cases of human to human transfusion encouraged the use of transfusion therapy during World War I. Later, the introduction of citrate as an anticoagulant, the discovery of pyrogens in 1923 and the introduction of plastic bags, then shortly thereafter the plastic needle would take transfusion and IV fluid therapy to another level. The advent of the Second World War allowed clinical and useful application of IV and transfusion therapy and would once and for all establish an indisputable role for IV therapy as routine medical practice. The second half of the 20th and the beginning of the 21st century were marked for their continued sophistication both scientifically and technically. In 1990 it was estimated that 185% of hospitalized patients in the US needed IV accesses and some form of IV fluid therapy. About 40 million patients in the US alone receive IV therapy annually. About 32,000 units of packed red blood cells are transfused daily and 23 million units of blood products yearly. Today there are over 40 different IV fluid preparations and at least 15 different blood and blood components. As for the future, research continues targeting different aspects of IV and transfusion therapies, the use of oxygen carriers, enzyme-converted O red blood cells and solventdetergent treated frozen plasma are some of the examples of current ongoing research. As we review the history of blood transfusion and IV therapy, we wish to acknowledge the hundreds of scientists who dared to question and pursue their dreams. We commend their efforts which allow us to practice medicine as we now know it.

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Bibliography: 1 Hasselgren P-O: Total Parentral Nutrition and the Surgical Patient: History, Definitions, and Applications. Astra, USA, Inc. 1994. 2 Barger C: Some of Carl Walter’s contributions to Harvard Medical School and hospitals. Am J Surg 1984;148:578–580. 3 Bartecchi CE: Intravenous therapy: From humble beginnings through 150 years. South Med J 1982;75:61–64. 4 Bendiner E: The revolutionary physician of kings: William Harvey. Hosp Pract 1978;13: 129–148. 5 Bjeletich J, Hickman RO: The Hickman indwelling catheter. Am J Nurs 1980;80:62–65. 6 Blundell J: Observations on transfusion of blood – With a description of his gravitator. Lancet 1828–9;ii:321–324. 7 Blundell J: Successful case of transfusion. Lancet 1829;i:431–432. 8 Bovell J: On the transfusion of milk, as practiced in cholera, at the cholera sheds, Toronto 1854. Can J Med 1855;3:188. 9 Boyle R: Tryals proposed by Mr Boyle to Dr Lower to be made by him, for the improvement of transfusing blood out of one live animal into another. Philos Trans R Soc Lond 1666;1:353– 358. 10 Broviac JW, Cole JJ, Scribner BH: A silicone rubber atrial catheter for prolonged parentral alimentation. Surg Gynecol Obstet1973;136: 602–606. 11 Bull WT: On the intravenous injection of saline solutions as a substitute for blood. Med Rec 1884;25:6. 12 Carrel A: The surgery of blood vessels. Johns Hopkins Hosp Bull 1907;18:18–28. 13 Cosnett JE: The origins of intravenous fluid therapy. Lancet 1989;i:768–771. 14 Crile G: The technique of direct transfusion of blood. Ann Surg 1907;46:329–332. 15 Davies MK, Hillman A: William Harvey (1578–1657). Heart 1996;76:11–12. 16 Debauchee M: A simple continuous flow blood transfusion instrument. 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