History of cholera treatment

(See How to treat hangovers for an introduction to ORS.)

Given that the solution to dehydration is so simple (just mix some salt and sugar in water!), it’s kind of amazing to see how long it took science to figure it out.

Cholera

Among the most deadly causes of dehydration are diarrheal diseases like cholera. Prior to the invention of ORS, it’s estimated that “500 million annual episodes of diarrhea in children under the age of five resulted in at least five million deaths per year.”¹

Cholera is a bacterial infection of the small intestine. The classic symptom is extreme watery diarrhea, leading to severe dehydration and electrolyte imbalances. Without treatment, the case fatality rate (CFR) is very high, 40-60%! There have been 7 pandemics over the last 200 years. The seventh continues to this day, mostly in developing countries.

The intravenous technique

O’Shaughnessy and Latta: 1830-1833

Efforts to treat diarrhea in a semi-recognizably modern way began in 1830 with the administration of saline solution in creative ways, including by rectal enema, by steam bath, and by mouth. None of these experiments worked. Though today we know that oral saline solution is not effective without glucose, at the time practitioners did not have any theory to guide them and just tried random things. Some doctors didn’t even realize that the problem was dehydration and instead focused on irrelevant properties like the color of the patient’s blood.²

In 1831, the Irish physician William O’Shaughnessy performed lab experiments on the blood of cholera patients.³ From these experiments, he correctly theorized that the main problem was loss of water and salt, and proposed intravenous (IV) injections as a treatment.⁴ After reading O’Shaughnessy’s theory, Thomas Latta tried IV saline injections on his cholera patients and saw immediate success in resuscitating cholera patients near death. However, his results were inconsistent, and many of his patients died soon after the initial revival.

With the benefit of hindsight, we know today that Latta was missing two pieces. First, he didn’t know how to safely perform sterile IV injections. Second, his feedback control algorithm was too crude, as he would give further injections only when clinical observation indicated the patient was doing poorly (e.g. “Next day pulse failed, injection repeated.”⁵).

With Latta’s death in 1833, progress on effective diarrhea treatment pretty much stalled for 75 years. His work is the first widely documented demonstration of a medical intervention reversing cholera collapse, even temporarily. Nevertheless, the CFR refused to budge, remaining at 40-60%.

Leonard Rogers: 1908-1912

After a long gap in the historical record, Leonard Rogers resumed and popularized IV injections for cholera in the early twentieth century.⁶ By then, Louis Pasteur had developed germ theory, and Joseph Lister had successfully demonstrated antiseptic surgery techniques.⁷ Rogers was able to leverage this knowledge, as well as better procedures for excluding air from the IV line, to safely perform IV injections without risk of air embolism or infection.⁸

Rogers’ most important innovation in cholera treatment was to refine the feedback mechanism used to control the amount of IV fluid administered. Whereas Latta relied on his own clinical observation of patients, Rogers monitored blood pressure⁹ and density¹⁰ to determine the patient’s hydration status. Rogers would give injections “as needed” to maintain blood pressure above 70 mmHg and blood specific gravity below 1.063.

Combined with the improved IV injection technique, this more quantitative method of feedback control was enough to improve the CFR from 40-60% to 10-30%, the first documented instance of humanity successfully reducing the death rate from cholera.

Robert A. Phillips: 1947-1961

After another gap in the historical record, the intravenous technique was refined to near perfection by Robert A. Phillips over the course of a career that spanned more than 20 years and multiple cholera epidemics around the world.¹¹

Phillips’ most impactful advances were to further refine feedback control of injection amounts. During the 1947 Egyptian cholera epidemic, he used bladder catheters to measure urine output. Maintenance fluids were given only when urine output fell, indicating severe dehydration. During the 1958 Thailand cholera epidemic, he did “complete balance studies” on his patients, in which he measured the volume and electrolyte content of all output and input. These measurements led to the idea of replacing all lost fluids and electrolytes, the key insight necessary to successfully treat cholera. By the 1961 Philippine cholera epidemic, Phillips was able to essentially eliminate fatalities in cases where IV therapy was started promptly.

At this point in the story, it’s worth stopping and reflecting on all the steps on the way to perfecting the intravenous technique. To recap:

Time period	Cholera CFR (%)	Researchers	Technique
Pre-1831	40-60	N/A	Ineffective or actively harmful “treatments” like bloodletting
1831-1833	40-60	O’Shaughnessy and Latta	IV saline, administered by clinical judgment
1908-1912	10-30	Rogers	Improved IV technique, primitive monitoring blood density and pressure
1947	5-8	Phillips	More precise monitoring of fluid loss via urine output
1961	0-1	Phillips	Even more precise monitoring of fluid loss via diarrhea/vomit output
Today	0-1	N/A	More reliable injection hardware, computerized control of infusion rate, faster feedback of blood status via point-of-care testing

A scalable oral solution

Phillips and the tragic clinical trial: 1962

By the time of the 1961 Philippine cholera epidemic, Phillips had come to realize that his work on IV injections, while essential in hospital settings, was impractical for mass application. As such, in summer 1962 he began experimenting with oral saline solutions. For two patients, Phillips randomly added glucose to the solution and was amazed to find that the addition greatly enhanced sodium absorption.

Excited by this finding, Phillips attempted a clinical trial in September 1962, but the study was poorly designed and several of the patients unexpectedly died of heart failure. We now know that the oral solution, administered in combination with IV fluids and without careful patient monitoring, was too much. Had he tested the oral solution alone and with more careful control of the dosing, he likely would have been successful.¹

A most productive decade: 1962-1972

The failure of the 1962 clinical trial threw Phillips into a depression and soured him on the prospects of oral therapy. As one of the most prominent cholera researchers, Phillips’ opposition represented a formidable obstacle. Nevertheless, over the next couple of years, his staff and others would conclusively demonstrate that ORS could treat cholera just as effectively as IV treatment, even in extreme conditions.¹

• In spring 1966, David Sachar showed that glucose-dependent sodium transport was intact in cholera patients. This finding disproved Phillips’ earlier theory that his 1962 clinical trial failed because cholera “poisoned” intestinal sodium pumps.
• In winter 1966, Norbert Hirschhorn at the Cholera Research Laboratory in Dhaka successfully showed that glucose strongly affected fluid intake by administering a fixed rate of solution (1 liter/hour) and observing that the addition of glucose reduced diarrhea output. As the solution was perfused intragastrically (directly into the stomach via a tube), this was not quite an oral treatment, but it was close.
• In summer 1967, Nathaniel Pierce at the Johns Hopkins Center in Calcutta (a rival to the Cholera Research Laboratory) confirmed Hirschhorn’s results. They also applied some feedback control, setting the perfusion rate equal to 100-200 mL/hour greater than the measured diarrhea rate. With this, they were able to show that cholera patients could be rehydrated by an intragastric glucose solution alone, without any intravenous injection.
• In winter 1967, Rafiqul Islam experimented with giving patients a fixed rate of 1 liter of intragastric glucose therapy per hour, but the study failed.
• In spring 1968, Richard Cash and David Nalin repeated Rafiqul Islam’s experiment with the addition of feedback control to match the patient’s diarrhea losses. They were successful.
• From 1968-1970, Nalin and Cash expanded their results, showing that ORS alone could treat cholera, that it could be successfully administered by field staff, and that it worked in both adults and children.
• In 1971, Dilip Mahalanabis showed that ORS could be used successfully even in a disaster zone and even when administered by untrained family members instead of medical staff. This study in particular greatly increased the public and political visibility of ORS.
• In 1972, Cash and Hirschhorn showed that children instinctively knew how much ORS they needed and would drink until hydration. This discovery underlines a key advantage of ORS over intravenous treatment, which is that the patient can successfully control their own dosing, reducing the risk of error.

Parallel research

Above we looked at the mainline history of cholera treatment, but there are some interesting side plots as well.

John Snow and the water pump

At the time of the 1854 London cholera epidemic, scientists held two competing theories about the spread of cholera. The then-dominant “miasma theory” claimed that particles in the air were the root cause of the disease, while “germ theory” claimed that some particle was transmitted from person to person.

The physician John Snow was a proponent of the germ theory, and hypothesized specifically that cholera was spread by waterborne particles. By interviewing victims of the 1854 outbreak and studying the geographic pattern of the cases (which all tightly clustered in a particular London neighborhood), Snow concluded that a particular water pump was the source of the outbreak.

He also found other corroborating evidence for his theory, such as that the rate of cholera incidence depended on which company the water came from (different companies sourced their water from different spots along the river), and that none of the workers at a nearby brewery contracted cholera (since the beermaking process involves boiling the water, which sterilizes it).

For this work, Snow is widely regarded as a founder of modern epidemiology.¹²

Robert Koch and the discovery of the causal organism

In August 1883, the German government sent Robert Koch to Egypt to investigate a cholera epidemic there. Koch had previously made monumental advances in the study of bacteria, including how to culture them and how to observe them under a microscope.

Upon reaching Egypt, Koch began bacteriological investigations of cholera victims and found a multitude of different organisms in their stool, without any obviously dominant suspect. However, tissue samples from their intestinal linings were dominated by one specific bacterium. Koch believed there was a link between this bacteria and the cholera disease, but it was unclear whether the link was coincidental or causal. He collected the bacteria and attempted without success to infect monkeys, dogs, mice, and hens.

By November 1883, the cholera epidemic in Egypt had died down, and Koch made his way to India. There, he would make great progress in studying the bacteria he had previously observed in Egypt. Over several months, Koch successfully isolated and cultured the bacteria. He was then able to observe its shape under a microscope, its ability to proliferate in moist linen, and its susceptibility to dry, acidic conditions. He also observed that the bacteria existed in great numbers in the stool of sick cholera patients, but that its prevalence decreased as the patients recovered.

Partly for this work, Koch is regarded as a founder of modern bacteriology.¹³ Interestingly, the discovery of the cause of the disease didn’t help patients much. Leonard Rogers himself even mentioned “great disappointment at the absence of any material improvement in the treatment of the disease as a direct result of Koch’s discovery of the causative organism”.¹⁴

At least two people nearly invented ORS decades before

In the 1940s, Daniel Darrow developed an oral rehydration solution shockingly similar to the modern formulation, consisting of potassium, sodium chloride, and glucose. He successfully used this solution to treat infant dehydration.¹

Hemendra Chatterjee has a similar story. In 1953, he published a recipe for an oral saline solution with glucose in The Lancet, but it failed to gain traction.

How much credit these two deserve in the history of ORS is a point of controversy. On the one hand, they did in fact develop effective methods for oral rehydration. However, lacking large-scale studies demonstrating efficacy or a physiological explanation, their work failed to lead directly to the development of modern ORS.

The biochemical mechanism behind ORS

In 1953, Fisher and Parsons excised a section of a rat’s intestinal wall and observed that only certain cells were permeable to glucose, suggesting that there might exist specific receptor sites for glucose. Much biochemical research followed: in 1960, Robert Crane proposed the sodium-glucose cotransport mechanism, and in 1970 Schultz and Curran conclusively demonstrated the validity of Crane’s model.¹

These physiological and biochemical findings helped popularize ORS by providing a mechanistic explanation for why it was so effective at treating cholera. In particular, it explained why the presence of glucose was so critical. However, the relevance of this research to ORS was recognized only in hindsight. At the time, Robert Phillips and the other practitioners who developed ORS were ignorant of the sodium-glucose cotransport literature.

A triumph of medical science

Today, oral rehydration solution is on the World Health Organization’s List of Essential Medicines. It saves the lives of at least one million children each year and has been hailed as “the most important medical advance of the 20th century”.¹⁵

A couple of reflections come to mind:

• The world is a museum of passion projects. None of the people involved in the development of ORS got rich off of their work. They did it for the love of the game.
• The “establishment” can be dogmatic. Many of the researchers involved in the development of ORS were “outside” of the establishment. During the 1960s, most of the medical establishment considered cholera to be “solved” since the refined intravenous technique was able to essentially eliminate fatalities. Never mind that millions of children were still dying due to lack of access to medical care.
• You have to sell the work too. Both Darrow and Chatterjee administered effective ORS-like concoctions to their patients. But without large-scale studies to convince the rest of the medical world, their innovations lapsed into obscurity.
• Technological progress doesn’t have to be linear. There’s no fundamental reason why the oral solution had to come after the intravenous solution. ORS could have been developed hundreds of years earlier by a doctor armed with water, salt, sugar, a desire to experiment, and detailed recordkeeping.
• Free markets are bad at incentivizing knowledge production. The capitalist techno-economic machine is good at incentivizing the production of many goods, but knowledge is not one of them. There are too many positive externalities.
• Knowledge is the scarcest resource of all. Water, sugar, and salt have long been in abundance. The only missing ingredient was the knowledge of what to do with them.