The most important medical advance of the past century

Antibiotics revolutionized medicine, but it is likely that no single antibiotic caused as big of a drop in deaths as a simple over-the-counter medicine that you have probably taken it at some point without appreciating how revolutionary it is.  It treats the ailment that was the biggest killer in the world for thousands of years until sometime in the mid 20th century.  Guess what ailment it is:

• Everyone in the world gets it occasionally, including you.
• It is an infectious disease that is caused by numerous different pathogens.  But the most important treatment is the same for all pathogens, so doctors rarely even bother to diagnose which pathogen is causing the disease. 
• It used to be particularly tragic because it mostly killed infants and children.
• Largely due to a new treatment its death toll dropped from 5 million children annually in the early 1980s, to only 1.5 million in 2004 (WHO).
• The treatment only costs pennies per day and can be produced at home by anyone with a rudimentary ability to follow a recipe.
• Although the new treatment has caused death rates to plummet, there is still a lot of work to be done and in 2008, it was still the world’s second leading cause of death in children under 5.
• Although it rarely kills anyone in rich countries today, it was still the fourth biggest killer of all ages in developing countries in 2001.

The world’s biggest killer for all of history until perhaps the 1980s is…. drum roll… diarrhea!*  Most Americans would never guess it because almost nobody dies from diarrhea in temperate nations like the US nowadays mostly due to improved sewage and water treatment, but it was still the third biggest killer in the USA in 1900 after influenza and pneumonia (#1) and tuberculosis (#2).  

Diarrhea was still the biggest killer in low-middle income nations in 1990 and it is disproportionately deadly among children.

Diarrhea is much harder to manage in poor, tropical nations because of bad sanitation.  Rich countries developed intravenous treatment a century ago which was effective, but it is expensive and requires medical professionals to administer.  So diarrhea remained the biggest killer in poor countries until the a new treatment was developed in the 1970s which almost magically eliminates over 90% of diarrheal deaths for pennies per treatment.  The British medical journal, the Lancet called it, “potentially the most important medical advance this century,” but most people don’t even know what it is.

As an economist, I rarely teach something practical that could save a life, but I have used this treatment many times for myself when afflicted with severe diarrhea while traveling in the tropics and for my children when they were little.  It may have already saved your life when you were a child because it is now the primary treatment for diarrhea in the US.  It is called Oral Rehydration Therapy (ORT – but there are several other acronyms like ORS).  It is basically water with a fairly precise amount of salt and sugar.  That’s right, salty water with sugar is the most important medical advance of the 20th century!  The WHO estimates that ORT has saved well over 60 million people and it continues to save millions every year.

The basic formula:  Just mix up these ingredients and drink as much as you can to replace the fluids lost due to diarrhea.

• 6 level tsp sugar (30 ml)
• 1/2 tsp salt (2.5 ml)
• 4.25 Cups of clean water (1 liter)

This is not the perfect formula, but if you cannot purchase a professional version, it is pretty good and certainly better than nothing.  It is very important to not mix in too much salt and sugar.  Too much salt and sugar is worse than not enough because it will increase dehydration and draw liquid out of the body instead of increasing absorption.  For example, sports drinks like Gatorade have too much sugar (more than double the optimal amount) and not enough salts (less than half the optimal amount), so they are far from optimal.  ORT should taste only VERY slightly salty and slightly sweet like 1/3-strength juice. A proper ORT mix tastes a bit unpleasant, but the flavor should be very mild if it is mixed correctly.

I prefer using apple juice.  It tastes better and provides some potassium too.  Other juices like orange juice or grape juice are probably ok to substitute, but don’t look good if you are vomiting.  The basic apple juice recipe is:

• 1C apple juice
• 3C water
• ½t salt

This treatment is largely responsible for the dramatic reduction in the number of children dying from diarrhea.  Diarrhea still causes nearly 1 in five childhood deaths  according to the World Health Organization and these deaths are mostly preventable if people had used ORT.  This treatment is so simple, the big problem with getting people to use it has been to convince them that something so trivial is really a miracle cure.  Historically, nobody was convinced that ORT could work until scientists figured out the mechanism of how diarrhea kills people.

People don’t literally get so ‘pooped’ that they die.  Diarrhea actually kills the same way that sweating too much could kill.  There are two main lethal mechanisms:

1. Dehydration
2. Salt (electrolyte) depletion

People can die when they lose about 10% of their fluid, but when diarrhea is severe, such as it is when caused by cholera, kids can lose up to 30% of their fluid in 24 hours which is absolutely fatal without treatment.  Imagine that you had a single massive sweat gland that is going to produce 10 to 20 liters (up to 5.2 gallons) of sweat over the next 24 hours.  It is easy to see how that could be life threatening.  (Or, for an alternative analogy, someone with a giant pimple that is pumping out gallons of fluid per day would probably forget about the social embarrassment of having a giant pimple and worry instead about mortality.) 

To put 10 to 20 liters of fluid loss into perspective, most people drink less than 2 liters/day (about 8 cups) and pee less than 1.5 liters/ day, so it is easy to see how a loss of 20 liters of fluid could cause lethal dehydration.  In addition, diarrhea pumps out salt and other electrolytes that are necessary for life.  An electrolyte shortage can directly cause death causing the heart, brain, or other vital organs to malfunction. Or an electrolyte shortage could indirectly cause death by weakening the immune system’s ability to fight infection.

Normally the intestines absorb more liquid than they excrete, but diarrhea turns the intestines into something like a giant sweat gland.  Both diarrhea and sweat glands are salty because they both work through osmotic transport.  The body’s cells move water across membranes using an osmotic salt pump.  For example, when the body wants to expel sweat, the cells in the sweat gland push salt out of the body. Then the salt attracts water from inside the body because osmotic pressure tries to equalize the salt concentrations.  The water then flows through the membranes and out of the body as a result.  I guess nobody tasted diarrhea to discover that it is a bit salty like sweat, but diarrhea pulls water out of the body using the same mechanism as a sweat gland and diarrhea is even saltier than ORT.  One significant difference between the sweat glands and the intestines is that the intestines use symporters that use both sugar and salt to pump water into the body.  That is why ORT contains both sugar and salt.  The sugar is pulled across your intestinal membrane into your bloodstream and each sugar molecule pulls one sodium ion which pulls some water.  This is why ORT formula should have an equal concentration of salt and sugar molecules for optimal functioning.  It only works when each molecule of salt is paired with a sugar.

Because the intestines are huge and have a lot bigger capacity for moving fluid than the body’s sweat glands, the intestines can squeeze ten liters of fluid out of an adult body per day.  Without replacement, that amount of water and salt would be lethal. ORT works by creating just the right amount of osmotic pressure in the intestines to push fluids back into the body to replenish both fluids and electrolytes.

HISTORY OF ORT:

There are many ancient traditions in India and elsewhere that developed home remedies using somewhat similar solutions, but nobody tested the optimal ratio of salt and sugar, so nobody knew what worked best and so success was haphazard and wasn’t replicated consistently. India has had a longstanding tradition of treating diarrhea by giving rice or coconut water with is fairly effective, but this traditional formula does not contain enough salt.  Sweden had a tradition of using a diluted carrot soup, but it didn’t always have the right ratio and often had too much salt. 

Without scientific understanding, the traditional remedies were often a little off and sometimes a lot off.  In this matter, more is not better:  If the solution has too much salt or sugar, it can be worse than plain water and is likely to be lethal.  There were several failed attempts that used overly-concentrated solutions.   For example, in the US in the 1950s powdered banana was mixed with water with varying degrees of success.  A 1968 article in The New England Journal of Medicine wrote about one of these solutions, but began by admitting that they didn’t understand how it worked.  They authors said, “the mechanisms for stool production are not, as yet, understood” because they can be so “massive”.  They didn’t even understand if diarrhea was due to “overproduction or underabsorbtion of fluid by the intestine”.   

Top researchers still weren’t even sure if diarrhea was squeezing out that reserve of fluid or simply the “underabsorbtion” of ingested fluids!  The mistaken idea that diarrhea is caused by the body rejecting drinking water has undoubtedly killed millions of people because it leads to people to drink less when they have diarrhea!

Atul Gawande explains:

Cholera is a violent and deadly diarrheal illness, caused by the bacterium Vibrio cholera, which the victim usually ingests from contaminated water. The bacteria secrete a toxin that triggers a rapid outpouring of fluid into the intestine. The body, which is sixty per cent water, becomes like a sponge being wrung out. The fluid pouring out is a cloudy white, likened to the runoff of washed rice. It produces projectile vomiting and explosive diarrhea. Children can lose a third of their body’s water in less than twenty-four hours, a fatal volume. Drinking water to replace the fluid loss is ineffective, because the intestine won’t absorb it. As a result, mortality commonly reached seventy per cent or higher. During the nineteenth century, cholera pandemics killed millions across Asia, Europe, Africa, and North America. The disease was dubbed the Blue Death because of the cyanotic blue-gray color of the skin from extreme dehydration.

In 1906, a partially effective treatment was found: intravenous fluid solutions reduced mortality to thirty per cent. Prevention was the most effective approach. Modern sewage and water treatment eliminated the disease in affluent countries. Globally, though, millions of children continued to die from diarrheal illness each year. Even if victims made it to a medical facility, the needles, plastic tubing, and litres of intravenous fluid required for treatment were expensive, in short supply, and dependent on medical workers who were themselves in short supply, especially in outbreaks that often produced thousands of victims.

Then, in the nineteen-sixties, scientists discovered that sugar helps the gut absorb fluid. Two American researchers, David Nalin and Richard Cash, were in Dhaka during a cholera outbreak. They decided to test the scientific findings, giving victims an oral rehydration solution containing sugar as well as salt. Many people doubted that victims could drink enough of it to restore their fluid losses, typically ten to twenty litres a day. So the researchers confined the Dhaka trial to twenty-nine patients. The subjects proved to have no trouble drinking enough to reduce or even eliminate the need for intravenous fluids, and none of them died.

Three years later, in 1971, an Indian physician named Dilip Mahalanabis was directing medical assistance at a West Bengal camp of three hundred and fifty thousand refugees from Bangladesh’s war of independence when cholera struck. Intravenous-fluid supplies ran out. Mahalanabis instructed his team to try the Dhaka solution. Just 3.6 per cent died, an unprecedented reduction from the usual thirty per cent. The solution was actually better than intravenous fluids. If cholera victims were alert, able to drink, and supplied with enough of it, they could almost always save their own lives.

One might have expected people to clamor for the recipe after these results were publicized. Oral rehydration solution seems like ether: a miraculous fix for a vivid, immediate, and terrifying problem. But [the miraculous results were mostly ignored for many years and have been slow to be adopted].

To understand why, you have to imagine having a child throwing up and pouring out diarrhea like you’ve never seen before. Making her drink seems only to provoke more vomiting. Chasing the emesis and the diarrhea seems both torturous and futile. Many people’s natural inclination is to not feed the child anything.

Furthermore, why believe that this particular mixture of sugar and salt would be any different from water or anything else you might have tried? And it is particular. Throw the salt concentration off by a couple of teaspoons and the electrolyte imbalance could be dangerous. The child must also keep drinking the stuff even after she feels better, for as long as the diarrhea lasts, which is up to five days. Nurses routinely got these steps wrong.   

Western medicine ignored the ancient wisdom even after numerous clinical experiments showed that it worked to save lives.  It wasn’t until researchers developed an understanding of the biological mechanism for why it works that doctors finally accepted the clinical evidence.  Medical doctors were unconvinced by the multiple studies that showed how well ORT worked until they also understood the osmotic mechanism of how diarrhea works.  Unfortunately, for many years the scientists who discovered the osmotic mechanism didn’t think about how their discovery might have clinical applications for diarrhea treatment and the clinical scientists who were testing various ORT formulas didn’t read the biology research to learn the mechanism explaining how it worked.  Nobody combined the understanding of the simple biological mechanism with the experimental evidence until the 1970s and once the two were combined, doctors were finally convinced and ORT finally caught on and began to spread across the world.  

In hindsight, you can see a mountain of evidence had been accumulating before mainstream medicine finally caught on, but the quality of medical “science” was horrifically bad before the 1970s, so it was hard for practitioners to know what was good science and what was bad.  The gold-standard in medical research is the randomized-controlled trial (RCT), but before the late 1960s, there were almost zero RCTs per year and most medical research was junk.  Even among RCTs, most medical research is still contradictory or misleading, so in an era before RCTs it was exceptionally hard to know what research to believe.  RCTs were almost unheard of until the 1970s.

Once medical professionals understood how ORT worked, they finally believed the research showing that it did indeed work. With both an understanding of the mechanism they finally believed the clinical evidence and ORT rapidly gained widespread acceptance in the 1980s.  Salty sugar water just didn’t seem like a technological breakthrough that could be a magic bullet.  The basic ORT formula sounds like something out of an ‘old wives tale’ that might be followed with the extract from the boiled toes of a newt.

Before ORT, the conventional scientific theory had been that diarrheal deaths were merely caused by the inability of the gut to absorb fluid.  That wouldn’t be nearly as big of a problem as the reality.  Diarrhea kills people by turning the intestine into something like a giant sweat gland that rapidly extracts fluid and electrolyte from the body.  Based on the old theory, IV treatment had been developed in 1920s and doctors thought that oral nutrients should actually be withheld from patients to help stop the flow of diarrhea and give the intestines a rest.  Even though the theory was faulty, the IV treatment worked well enough that it was not much problem that patents weren’t given enough to drink.  The success with expensive hospital IV treatment made it hard for medical science to change their thinking.  IV treatment seemed more scientific and technical than the traditional remedies like carrot soup or coconut water that work like ORT and the IV formula was easier to standardize than the traditional remedies. It was also a lot more profitable, but poor people cannot afford it and ORT works as well or better for almost all diarrhea cases.  A big advantage of ORT over IV therapy is that IVs can cause lethal infections, particularly in hospital settings.  ORT really is safer for most patients which is why it is the preferred treatment in rich countries today.

Unfortunately, even though ORT is an incredibly cheap and effective way to save lives, it still isn’t being used nearly enough.  The biggest problem is educating doctors and patients about how well it works.  One problem with cheap interventions like ORT is that it isn’t very profitable because it isn’t patented and there is little incentive for markets to disseminate it around the world to where it is needed most.  The Global Healthcare Information Network estimates that:

Only 1 in 10 children with diarrhoea in India receive increased fluids to prevent death from dehydration. Almost 4 in 10 receive less to drink than normal, thereby tragically increasing their risk of death. By contrast, more than 1 in 3 are inappropriately given antibiotics, which are not generally recommended for childhood diarrhoea. Almost half of children with diarrhoea in India are given little or no food, contrary to WHO recommendations. A thousand children die needlessly from diarrhoea every day in India alone, due to basic errors in care from parents and health workers.

And ORT use is much better in India than in many other nations in darker shades on the map below.  

Age-standardised disability-adjusted life year (DALY) losses from Diarrheal diseases per 100,000 inhabitants.

Ironically, if you have money and you get severe diarrhea in America, you are likely to get worse medical care than if you get it in a developing nation. American doctors are particularly lackadaisical about diagnosing the specific pathogen whereas in developing nations, pharmacies are commonly equipped to analyze a stool sample without even needing a prescription.  When my wedding reception caused a diarrhea outbreak (striking about half our guests), many people had trouble for weeks without doctors ever diagnosing the pathogen so that a cure could be prescribed.  Only one of the dozens of people who could have shortened the problem with antibiotics got tested to find out that it was campylobacter.  Plus, American doctors are more likely to go straight to an expensive, invasive IV treatment rather than using ORT.  Doctors in developing nations are much better at treating diarrhea because they are more experienced, so if you get diarrhea while traveling abroad, you are better off getting treated before coming home to America. 

Although ORT is an incredible success story that very few people have heard about, there is much work yet to be done.

*Note that some diseases like smallpox and bubonic plague are defined by one specific pathogen whereas diarrhea is caused by numerous different pathogens. So if you are defining the world’s biggest killer according to a specific pathogen, then smallpox has a much better claim than any of the numerous bacterias and viruses that cause diarrhea. But most diseases are not like smallpox and have multiple causes. For example, the biggest killers in the developed world are heart disease and cancer which have uncountable causes and much less consistent symptoms than diarrhea. Indeed, one of the causes of heart disease and cancer is our success at curing diarrheal disease! That has allowed people to get old enough to get heart disease and cancer.