A Simple Solution

On a sultry June evening in 1971, Thomas Simpson, MD, and his wife Doris celebrated their 30th wedding anniversary with a lively dinner in the private garden of their flat in Calcutta, India. Celebrating with them were professional staff, both American and Indian, from the Johns Hopkins International Center for Medical Research and Training (ICMRT) in Calcutta, a joint project of the School of Public Health and the School of Medicine, which Simpson led as resident coordinator. Seated on a porch where the Simpsons were sometimes visited by vagabond snake charmers, keepers of trained monkeys, and multitudes of stray cats, the party dined on lamb shish kabob with rice and red pepper sauce. The summer monsoon season had started, and the mosquitoes were out in force.

While the occasion for the dinner was a happy one, much of the night’s discussion was not. Early in the year, an independence movement in East Pakistan (now Bangladesh) had been brutally put down by the West Pakistani army. A massacre of the educated middle and upper classes—including doctors, professors, and students—ensued. Terrorized survivors fled the country and poured over the border into India; by June 2, as many as 9 million refugees were amassing near Calcutta. 

The discussion at dinner centered on reports from the camps: horribly overcrowded conditions, with almost no sanitation. Refugees had no shelter from the monsoon rains. Some families were constructing houses from sections of sewer pipes. “There was nothing but privation and injuries,” remembers Simpson, now an associate professor emeritus at Hopkins. Worst of all, India’s annual cholera epidemic had begun.

The cholera—an extreme form of diarrhea—already had a fatality rate of 80 percent in the refugee camps (under normal circumstances, it was 30 to 40 percent). The health professionals at ICMRT knew, perhaps better than anyone, how bad the situation was. Research on cholera had been one of the Center’s main projects since its inception in the early 1960s. While effective intravenous (IV) treatments—which could drop fatality rates to under 1 percent—had been successfully developed, the chaotic, destitute, and nearly inaccessible camps precluded treating a massive outbreak among the refugees with IV fluids.

After his dinner guests had left, Simpson went to bed worried. In the night, he woke and remembered another conversation that had taken place at dinner. It involved the results of a test in another cholera research lab in nearby Dhaka, East Pakistan. The team there had successfully completed a clinical test of an oral, rather than intravenous, treatment for cholera using a simple solution of water, glucose, and salt. Because the Dhaka team’s experiment had been conducted under much more favorable, controlled conditions, with plenty of IV fluids available as back-up, no one at dinner had drawn a link between the clinical trial’s results and the refugee crisis.

Says Simpson, 85, in his coastal Georgia drawl, “I woke up. I thought: Cholera comes here every year. We know what’s coming. But instead of thousands of [potential victims], we’ve got 9 million.” Then, as he wrote in his memoirs, “The answer came to me with unbelievable clarity: oral fluids!”

Today, oral rehydration therapy, or ORT, is a common process. Add one packet of powder—containing salt, glucose, and other electrolytes—to water, and give people suffering from diarrheal dehydration as much as they can drink until they get better.

But while ORT is revolutionary in its simplicity, the story of how it came into being is anything but. It’s a saga that involves at least a century of lethal missteps, international strife, global cooperation, physiological science, hard work, luck, difficult personalities, and the decades-long dedication of scores of medical professionals—many of whom had affiliations with the School.

The morning after Simpson’s revelatory night, he called colleague Dilip Mahalanabis, ICMRT’s cholera expert, and shared his idea of using the still-experimental oral fluid therapy. The two decided that, based on the positive results from the Dhaka team, they would try it. Simpson approached the Indian Ministry of Health, which was eager to try the new therapy. Simpson cabled the National Institutes of Health, one of the funding sources for the ICMRT, and requested that the Center’s funds be diverted for use in the refugee crisis. NIH okayed it. 

Then the work began. Researchers converted the ICMRT library into a makeshift factory. They mixed local ingredients—table salt from the market, baking soda from a chemist’s shop, and glucose from a soft drink manufacturer—in packets and sent them to the camps, with directions to mix them  with any water that could be found. It wasn’t feasible to use sterilized water, since it wasn’t available in the necessary quantities and severely dehydrated patients could die waiting for water to boil. 

“A lot of the water had Ganges River sand in it. We told them, ‘Just let the soil settle out,’” says Simpson.

It worked. Using only ORT, the fatalities due to cholera in the camps were less than 4 percent. When he saw the statistics sheets, says Simpson, “That was when the feeling of exhilaration came on. We’d really proved that oral rehydration worked.”

Did he think, then, that ORT would change the world? Simpson leans over, his blue eyes still bright, and nods. “Uh-huh,” he says.

ORT did change the world. The dramatic results from using ORT in the refugee crisis attracted the attention of both the World Health Organization (WHO) and the United Nations Children’s Fund (UNICEF). ORT’s uses were soon expanded to include treating an even greater threat than cholera, childhood diarrhea. By the mid-1970s, WHO passed a resolution making ORT the world’s standard treatment for childhood diarrhea. By the 1980s, WHO and UNICEF had worked together to bring ORT to 130 countries and 99 percent of all children in the developing world.

Between 1980 and 2000, ORT treatment decreased the number of children under five dying of diarrhea from 4.6 million worldwide to 1.8 million—a 60 percent reduction. Last year, the accomplishment garnered four of ORT’s developers, all of whom have been affiliated with the School of Public Health, the prestigious Pollin Prize for Pediatric Research (see sidebar). But the development of ORT, from its inception to its use in the refugee camps in India in 1971, was neither seamless nor direct.

But the development of ORT, from its inception to its use in the refugee camps in India in 1971, was neither seamless nor direct. 

As early as 1830, a saline injection was used with success on a cholera patient, yet the practice did not catch on. Common, and often lethal, 19th-century remedies for cholera instead included blood letting—precisely the wrong thing to do for someone dying of dehydration—and, in one doctor’s office, intravenous injections of cow’s milk. “Starving” patients to give the gut a rest, also a wrong-headed and deleterious approach, was common into the 1950s. The physiological mechanisms of acute diarrhea were not yet understood.

“Almost every culture has a grandmother cure, like chicken soup,” that may be useful but lacks the optimal mix of sugars and salts that ORT has, explains William Greenough, MD, a professor of International Health at the School who was a physician at the Dhaka lab starting in 1962. But if the patient doesn’t ingest enough of the chicken soup to replace what he’s losing, it won’t work. In the 1950s, somewhat effective therapies, like carrot soup, were tried clinically. These were hit-or-miss concoctions, however, rather than a scientifically formulated replacement for the exact substances being lost in acute diarrhea.

Throughout the 1940s, ’50s, and ’60s, scientists made advances in determining exactly what happened when a person was inflicted with acute diarrhea: what is lost with the diarrhea and the mechanisms through which, using a specific combination of glucose and sodium, fluids and nutrients could be replaced. These physiological discoveries would make it possible to develop effective intravenous treatments and, later, an effective oral rehydration solution.

A second integral part of the ORT story is the unusual degree of cooperation and healthy competition that developed between two laboratories, both of which were launched in the early 1960s and both of which drew researchers from the School of Public Health. The Johns Hopkins International Center for Medical Research opened in Calcutta, while, just 150 miles away, the Dhaka Center (officially known as the Pakistan-SEATO Cholera Research Laboratory and later the International Centre for Diarrhoeal Disease Research, Bangladesh) was established under NIH’s direction. These two centers, often in tandem, played pivotal roles in finding a treatment for cholera in adults, and then acute diarrhea in children. 

The first step was to perfect IV therapy. This, according to Greenough, was accomplished fairly quickly. The mortality rate dropped from 30 to 40 percent for untreated villagers to less than 1 percent with IV treatment. “They were like resurrections,” he recalls. “Families would bring a dying relative in, and we would take them off the rickshaw, lay them down on the sidewalk, and hydrate them there. Everyone in the family watched what would happen—they’d come back to life.” 

But in the developing world, resources for IV treatment were scarce. The treatments required prohibitively expensive supplies, from needles to sterilization equipment, as well as trained workers. “In the 1962–63 period there were very large outbreaks in several refugee situations. With no IV solution, they were just dragging the sick out to die,” says Greenough. “It was clear there was no way to get IVs” to the victims. A simpler technique was needed.

By 1962, NIH researchers learned of the work of Robert A. Phillips, a Navy doctor who had treated cholera patients in the Philippines with an oral fluid. NIH saw the potential, but Phillips’ experiment had been based on an incorrect physiological hypothesis, and the resulting mixture resulted in the death of five patients. These deaths “weighed heavily” on Phillips, writes Joshua Nalibow Ruxin in his book, Magic Bullet: The History of Oral Rehydration Therapy. When Phillips took over the Dhaka Lab in the mid-1960s, he brought with him a deep-seated bias against oral rehydration.

In spite of the authoritarian Phillips’ resistance, some ORT research continued, in part because of the persistence of Norbert Hirschhorn, MD, who worked under Phillips at the Dhaka lab (and would later join the faculties of the Hopkins Schools of Public Health and Medicine in the early 1970s). 

Phillips, says Hirschhorn, only trusted the researcher who was also his personal physician. “He appointed me to be his physician—he had high blood pressure—so he trusted me.” Hirsch-horn is now a poet and consultant for the Yale/World Health Organization Collaborating Center on Health Promotion Policy and Research at Yale’s School of Medicine. 

When Hirschhorn proposed re-opening investigation into oral rehydration, Phillips initially said, “We can’t ever do that again.” Hirschhorn replied: “Let me see your data.” Phillips relented. “He brought me into his office and locked the door. He said, ‘Here’s my safe, with all the data. I’m going to leave you alone for an hour.’ Then he left, locking the door,” recalls Hirschhorn. Hirschhorn read the data and saw where Phillips’ formula had gone wrong—too much salt—and convinced Phillips to let him try again, with an adjusted formula. Phillips agreed on the condition that Hirschhorn sleep next to the patients to make sure they didn’t die.

At about the same time, researchers at the Calcutta Lab, led by Hopkins’ Nathaniel Pierce, MD, professor of International Health at the School, were also having success with oral rehydration. By 1967, the scientific groundwork was laid for ORT by these two competing labs. Until the refugee crisis in 1971, the labs kept leapfrogging one another in ORT advances. 

The first clinical trials were conducted by Dhaka’s David Nalin (later a School faculty member) and Richard Cash, MD, MPH ’74. In an experiment using some 20 patients, they showed that ORT worked, and the two doctors were eager to do larger-scale field experiments. Phillips, however, was against it. “They [then] came to me,” recalls Henry Mosley, MD, MPH ’55, a professor of Population and Family Health Sciences at the School who was then working in the Dhaka lab for the CDC. “They had finally gotten a working model, the clinical trial showed it could be done, and they wanted to know if you could take it to the field.” Mosley was particularly interested because he was working in a hospital outside Dhaka where IV fluid was hard to come by. Working with Mosley, Nalin and Cash performed a successful field trial. This was the trial that came up at the pivotal anniversary dinner party in Calcutta and helped prompt the landmark use of ORT to save refugees in 1971.

“It was very important that we confirmed one another’s findings,” says Greenough of the two labs’ competition. “The basic science agreed in the two centers. And if it had not been taken to the field [in a controlled test] in Bangladesh, maybe it would not have been tried in [the 1971 refugee crisis] in Calcutta. That was the yin and yang of Dhaka and Calcutta.” 

“Calcutta was a key event,” Pierce agrees. “It was the first real demonstration of how effective ORT could be. In the worst possible field setting, with basically no equipment, ORT worked.” 

Today, ORT still has tremendous appeal. Says Pierce, “It’s so simple. A packet costs three to four cents to produce.” Efforts are now focused on convincing doctors in developed nations (including the United States) that ORT is preferable to IVs for treating dehydrated children, adults, and the elderly. And the search for the perfect solution continues. 

“The story,” declares Greenough, “is not over.”