"A pinch of salt with a fistful of gur"
Every letter which went through the Bangladesh post office from 1993-1994 was stamped with a printed rhyme.

Translated into English, it read:

Mix with much care,
Good water, a liter,
A pinch of salt with a fistful of gur,
Remove the menace for good.

We might think this simple poem, calling for the careful mixing of water, salt, and "gur", a raw sugar often made at home by Bengali women from sugarcane or date juice, is a quaint folk remedy. Actually, the postmark poem marked a successful revolution in modern medicine.

This is the story of a 'simple solution', Oral Rehydration Therapy (ORT), for an age-old killer ­ fluid loss in diarrhea from diseases such as cholera. ORT was pioneered in the late 1970s in Bangladesh, then one of the most impoverished, heavily populated, disease-plagued, and war-torn places on earth. Over the course of a decade in this small country neighboring India, a remarkable collaboration between medical science and local people inaugurated a new era in emergency treatment, one that continues to save lives around the world.

Cholera, as of March 2000, is in the midst of a worldwide pandemic. It began in Indonesia and spread through East Asia in the sixties, through Africa in the 70s and 80s, and Latin America in the 90s. A new form of cholera has recently broken out in India and Bangladesh. These bacteria are becoming resistant to antibiotics, the treatment of choice for most acute cases.

People, especially children, living in hot climates with large populations are particularly vulnerable.
Many of the world's most pernicious diseases are always present in the environment in warm climates where there is no winter freeze to kill or interrupt the life cycle of disease-causing organisms. Many molecular reactions go more quickly where it is very warm. Water-borne diseases are the greatest threat to health there.

The world's population, unfortunately, is more concentrated in the tropical climate zones spanning the Americas, Africa, Asia, and the Indo-Pacific. Dense populations make it hard to contain a disease. The more a sick person contacts other people, clearly, the more they spread the disease to others in the environment. Population density, therefore, contributes to prolonging diseases in developing countries.

Why are children at greater risk?
Diarrheal diseases cause the body to lose too much fluid. Children exchange about a 1/5th their body fluids daily normally, a turnover amount far higher than that of adults (1/7th), so they are at a much higher risk of dehydration from diseases which cause the body to expel fluids. Children will quickly show secondary symptoms of life-threatening dehydration, including thirst, sunken eyes, dry tongue, shriveled fingertips, and weakness. If untreated, especially in young children, loss of consciousness and death can follow rapidly.

The World Health Organization estimated in 1970 that there were about 500 million cases of diarrhea per year in children under 5 alone. Five million of these children died. Because diarrheal diseases are still a major cause of death in many parts of the world, the World Health Organization (WHO) <htto://www.who.int/>, a member of the United Nations, has for several decades given high priority to a Diarrheal Disease Control Program. This program has reached 99% of people in developing countries.

A Three-Part Success Story
There are three exciting steps in the "success story" of rehydration:
1. The discovery of what was going on at a molecular level, and therefore what could be done to treat a dehydrating disease ­ the development of intravenous solutions (V);
2. The discovery that a simple solution of sugars and salts made many IV solutions unnecessary;
3. The discovery of how best to get this vital information to the people who needed it the most.

Part I: The Molecular Level

IVs, and the Power of Gatorade
People with cholera and similar diseases can die from dehydration. Let's think about what happens when body fluid is lost. If more water than electrolytes (salts) are lost, the concentration will increase of everything that had been dissolved in the remaining fluid. This could be potentially toxic.

Can't a person just drink a lot of water? We instinctively drink when we 'feel dehydrated' from sweating a lot. But the concentration of essential electrolytes in body fluid would become too dilute. So the goal is to restore fluid at just the proper concentration.

Back in the 1940s a doctor at Yale University investigated the question, "What is in body fluids being lost that would need to be replaced? He took samples to the lab for analysis. He discovered that the body fluid being lost was salty and very similar to sweat. This salty stuff our bodies lose through sweating, diarrhea, or even tears, is dissolved electrolyte salts (Some people speculate that since we evolved from cells in the primordial ocean, our cells are mostly made of water with the same concentrations of salts.)

The use of intravenous fluid replacement therapy is based on these findings. Interviewed in his office at Harvard University, Dr. Cash, an innovator in replacement therapy, says with a laugh, "Now you can buy soft drinks that replace electrolytes. These specially formulated sports drinks, like Gator-ade, are basically flavored sweat!"

Success Story, Phase Two: Sodium & Glucose Found To Be Molecular Hitchhikers
If we want to understand how oral rehydration actually works at a molecular level, we need to travel to the 1950s. Researchers then working with samples of animal membranes found that the transportation of sodium (salt) and glucose (sugar) across the small intestine were coupled, linked togetheruj. Each improved the way the other was absorbed.

When glucose, for example, is added to an electrolyte salt solution, the absorption of both sodium ions and sugars dissolved in water is increased. We have other examples in the body of such mutually beneficial pairings: Vitamin D, for example, helps us absorb Calcium, so many people take them together when they take their vitamins.

Keep this pairing in mind as we return to the next challenge: Dehydration can be treated relatively easily by administering intravenous (IV) rehydration solutions with both sugars and salts directly into the bloodstream of the patient. But many people cannnot receive the IV treatments they need. Either they live too far from medical centers with the right equipment or trained staff, or they cannot afford the high cost of the treatment. What more is needed? What is they simply drank the mixture?

A setting for epidemic disease
Bangladesh is a heavily populated agricultural country where over half the land goes under water during the annual monsoon season, creating ideal conditions for water-borne diseases like cholera to flourish.

During the war resulting in independence from Pakistan in 1971, enormous numbers of people fled from their homes and farms over the border into India. After the war 10 million refugees began trekking home to an impoverished country that was unable to provide them with adequate sanitation and clean water. Diarrhea is the most common cause of death among refugees anywhere. A way to treat huge numbers of people, far from medical facilities, had to be found or millions would die.

American doctors make a contribution
When two 26 year old American doctors, Richard Cash and his colleague David Nalin, both arrived in Dhaka (the capital of East Pakistan, as Bangladesh was known before gaining independence) in 1967 to do cholera research, they found themselves facing an enormous challenge. Oral Rehydration Therapy (ORT), involving simply drinking a solution of salts and sugars in perfect balance, appeared to be the 'solution' to many patient's problems, and a way to save expensive IVs, but they had to prove that it worked well.

In order to prove that the new treatment worked, they had to test it on large numbers of sick people. They faced considerable opposition from senior researchers. In order to meet the highest standards of scientific investigation, they developed a strict procedure, and conducted a clinical trial. It worked, and they then went on to conduct more trials in parts of the country that had very little medical support. After that, they tested the ORT therapy with patients with other dehydrating, diseases, also with success.

After them, a Calcutta team started a large-scale test of ORT in Bengali refugee camps. By the 1980s, scientific confirmation of the superior efficacy of oral rehydration therapy (ORT) by laboratories in Bangladesh and India had demonstrated that use of oral solutions could reduce by 80% the use of intravenous (IV) fluids used to treat diarrhea. The World Health Organization (WHO) launched a large campaign.

Getting the solution right
Knowing the exact concentrations of what the body is losing is the key to making an oral rehydration drink that will restore the right fluid balance. An awful thing happened when sick children were given early oral treatment solutions, and even infant formula, that had very high concentrations of sodium and glucose. Their diarrhea got worse. We know now that the high level of salt and sugar caused even more water to be drawn out of the body by osmosis into the gut. In addition, loss of more water from the body must have caused the concentration of salts in the body to rise to dangerous levels. Richard Cash explains that we now know a range of solutions which will work on both children and adults.

A Molecular Aside: What is a safe concentration?
Remember that oral rehydration must replace fluids that match the normal concentration of electrolytes found in the body fluids. This means that the oral rehydration solution must be "isotonic" ­ it should have the same osmotic pressure as that of blood. Ions will tend to move across a membrane to achieve an isotonic state ­ with equal concentrations on each side.

A solution with a higher concentration than that of blood would be "hypertonic"- with a higher concentration of electrolytes than the normal concentration maintained by the body. This will cause water molecules to leave the body by osmosis, increasing dehydration, and creating a higher and potentially dangerous concentration of electrolytes in the blood. The opposite would occur if a "hypotonic" solution ­ with lower osmotic pressure than that of the bloodstream ­ were given. In this case more water molecules would be drawn into the body, diluting the body fluids and resulting in a lower than normal concentration of electrolytes in the blood.

The World Health Organization recommends a solution with 90 mmol/l sodium. Less than 30 mmol/l sodium is not very effective, and over 120 is dangerous. Since a sodium concentration over 100 is considered potentially harmful, a program to teach village women to make oral rehydration solutions at home set 50 mmol/l as the salt solution target level. Right about in the middle of the safe range, which is between 30-90 mmol/l sodium.

Maximum water absorption is achieved with a glucose level of 56 mmol/l, and glucose 'pulls' a maximum of sodium with it at a concentration of 140 mmol/l. The World Health Organization solution splits the difference at 111 mmol/l glucose.

Success Story, Part III: Taking the therapy to the villages

Over the course of a decade following Drs. Cash and Nalin's work on ORT, a Bengali non-governmental organization taught women and girls in over 12 million households to prepare safe and effective ORS (oral rehydration solutions) at home. The founder, Abed Fazle Hasan, initially conducted a series of experiments in his own kitchen, using various combinations of measurements of sugar and salt. These were sent to the lab to be analysed. He found that using a 3-finger pinch of salt and two finger-scoops of sugar reliably produced solutions with the target concentrations, and this became the basis for measurement in the training program.

Abed Fazle Hasan is the founder of the NGO that developed the massive outreach/training campaign. It began as a post-war relief org. and evolved into a reconstruction organization. One of the funny things the ORT workers had to overcome when they began going out into the villages to teach women to make ORS was getting people to understand that they were not 'family planning' workers (mixing up sterilization solutions.

Women were revisited periodically over the years to re-test samples of solutions they were making. At one point it was discovered that sometimes the measurements got mixed up, using two pinches of sugar and one scoop of salt ­ a potentially dangerous combination! The women who were working as trainers suggested a way to improve making the solution to avoid possible confusion: one pinch of salt and one fistful of sugar.

The amount of water used to make the solution was also found to vary since most people did not have standard measuring cups. Another innovation which came from the field workers was to carry a standard _ litre measure, pour the right amount of water into a pot in each household visited, and scratch a line so that pot could be used to guage the proper measure every time oral rehydration solution was made.

What can new research add?
For over 20 years the World Health Organization has recommended a standard packaged solution based on glucose and 3 salts, which has proven highly effective in treating dehydration from diarrhea from all causes and in all age groups worldwide. Both this therapy and the home-made solution treat the dehydration but do not stop or reduce the severity of diarrhea, so there is still room for more scientific investigation and possible improvement.

Research in several groups of villages in south India a decade ago found almost no use of packaged salt solutions, but discovered several locally-prepared food-based solutions in use. The use of rice-water, ragi-water, and arrowroot-water were all found to be effective in decreasing cholera-induced secretion of water, and in the case of all but arrowroot resulted in more water absorbed than lost. Ragi-water produced the best results, far exceeding water absorption achieved with commercial solution packets. Further laboratory testing of new solutions, using locally available foodstuffs, show promise for the development of alternative and perhaps even better solutions.

P.S. The discovery that sugars added to a solution will 'pull' more salts across a membrane is due to a relationship known as "co-transport." Not all cells in the intestinal membrane are permeable to glucose. Only certain cells have 'receptor sites' for glucose, and glucose absorption at these sites depends on the presence of sodium ions. When both glucose and sodium are present, more sodium is absorbed from the solution because it hitch-hikes through the glucose receptor sites. A major obstacle to the use of ORT was the belief among medical professionals that since diarrheal diseases strike in the intestines and cause the body to expel fluids, absorption must not be possible and the gut should be rested. This thinking formed the basis for intravenous treatment.

It is now known that sodium and glucose absorption continue in the intestines despite the severe diarrhea from cholera and E. coli infections, and even after damage to the gut from rotavirus, another widespread diarrheal disease in developing countries.]

Understanding the mechanisms of osmosis and the ability of sugars to pull salts across a membrane in solution form the laboratory basis for this breakthrough, but it is the field research in Bangladesh - which proved it is possible to teach even illiterate mothers to make safe effective oral rehydration solutions out of simple salt and sugar - that has actually saved so many lives.

*Contaminated water is the most likely cause; the cholera bactera has been found living in algal blooms.

Bibliography
Chowdhury, A. Mushtaque R., and Richard Cash. A Simple Solution ­ Teaching Millions to Treat Diarrhoea at Home. Dhaka. The University Press Limited. 1998.

Ruxin, Joshua Nalibow. Magic Bullet : the History of Oral Rehydration Therapy. Medical History, 1994, 38: 363-397.