Trainer Attachment 5D: Oral rehydration therapy: the scientific and technical basis

DR. NORBERT HIRSCHHORN
John Snow Public Health Group Inc.
Boston, Massachusetts
Resident Technician
National Control of Diarrheal Diseases Program
Egypt

When a child has diarrhea it loses body fluids - mainly essential minerals and water - and becomes dehydrated. So mix up some salts and sugar in water, and feed the solution to the child, as much as he/she will take until the child is no longer dehydrated, and diarrhea has slowed down or stopped. Make sure the child continues to take food or breast milk.

This is oral rehydration therapy, and it seems so simple (compared, say, to manipulation of genes or artificial hearts) that one may wonder what science has had to do with ORT, or why we need continue scientific studies on ORT. Many older physicians, nurses, or mothers have protested, "This is nothing new, we have been practicing ORT for years" Some of the great clinicians wrote about ORT thirty to forty years ago - Darrow, Harrison, Chatterjee. But this is precisely the point: they wrote about using ORT, but did not know how ORT works (nor to be fair, could they have them and so there was no further development or spread of their anecdotal experience until some decades later. Even today, when we fail to understand and use the scientific approach, we continue erroneous or wasteful methods of therapy; actually, this is the case in all fields of medicine and public health. Not everyone who practices ORT must be a scientist, but the spirit of inquiry and joy of discovery which suffuses science may be shared by all. The spirit of inquiry is present in five stages:

1. Observation - using all one's senses to capture events and think about them: it was noticed that children with dehydration drank the oral rehydration solution vigorously and greedily and, when nearly hydrated, slowed down and often went to sleep.

2. Measurement - taking one's observations and gauging some values on scales of time, length, amount, and degree: children who drank oral rehydration solution at will tended to drink close to what their initial deficit was, as measured by intake, output, and change in body weight.

3. Creative hypotheses - thinking through the implications of a measured observation and asking interesting questions: who can choose more closely the correct amount of fluid for rehydration, the dehydrated child or the physician?

4. Testing experimenting - within the ethical boundaries of conduct, designing, with proper statistical force and safeguards against bias, a test of the hypothesis: in certain situations, children freely drinking oral rehydration solution became hydrated faster and reached better fluid and mineral balance than those on intravenous solutions controlled by physicians.

5. Application - using the results of scientific testing for the widest possible benefit. It is as Jon Rohde and Robert Northrup have written, "taking science where the diarrhea is" Human information must be shared across all political and other boundaries.

The data and information I will present in this paper have gone through several of these five stages of scientific inquiry.

ORT developed from two streams of inquiry, if I may use a liquid metaphor. The first established what dehydration actually meant, how it related to the clinical picture of the dying child, and what was needed to reverse the situation. Believe it or not, this line of inquiry has taken nearly eighty years to come to satisfactory resolution. The second line, still ongoing, is the discovery of how the intestinal tract handles the movement of salts, nutrients, and water between the body and the outside world.

The picture of the dying child is hauntingly familiar. The baby has lost about 10% of its weight in fluid. This amounts to one liter of fluid in a ten-kilogram child, or about a quart in a twenty-two pound baby. Now the child has hollow, sunken eyes; its pulse is feeble or absent; its breathing is deep and rapid; the skin, when pinched, tends to remain dented and inelastic; the abdomen many be distended; urine has ceased to flow; the mouth is parched; the eyelids do not quite shut properly; there are no tears. Dry as the child may be, vomiting and watery diarrhea persist nearly to the end, and this stage may be reached in as little as ten to twenty hours after onset of illness.

Virtually all these signs are due to loss of salt, water, potassium, and sodium bicarbonate, all essential ingredients for life. Most of the loss is in the watery stool, and some, especially in the case of potassium, is from the urine. Regardless of the cause of diarrhea (rotavirus, cholera, E. coli, etc.) or whether in Baltimore or in Bengal, once the child reaches these clinical signs the amount of loss of water and minerals is roughly the same (Table 1) This is fortunate in a way, because the replacement therapy may be uniform and does not require us to know which specific microbe is doing the mischief. Incidentally, while the loss of potassium is of the same magnitude as that of sodium, the body stores of potassium are several times larger. So replacement of sodium is more urgent and also helps conserve potassium.

Although the extreme case I have portrayed is present in 1% to 2% of all bouts of diarrhea, it is sobering realize that with very few visible signs of dehydration beyond thirst, the child may have already lost 5% of body weight, halfway to death, in as little as five to ten hours. By the time parents become alarmed, there may be only a few hours left in which to find competent help. The majority of children who die, however, do linger for two to three days: they have received some fluid, probably of dubious value, by mouth or intravenously; the diarrhea may have slowed a little if various medicines are tried. But by this time the parents may have exhausted their money or the skills and resources of the local practitioner, and the nearest hospital is miles away. The child needs fluid therapy: effective, affordable, trustworthy, nearby.

But we learned about ORT only after we knew how to apply intravenous therapy. Beginning in the mid-1940s, diarrhea research centers in Dhaka, Calcutta, Manila, Cairo, Baltimore, and Taipei proved that intravenous solutions containing sodium chloride, potassium chloride, sodium bicarbonate (or lactate or acetate) in a well-determined combination could be given rapidly so that severely dehydrated children could, Lazarus-like, be resuscitated within two to four hours. Lives are saved by the use of a polyvalent solution, administered quickly with the correct proportion of ingredients. ORT is successful foremost because of this principle, first discovered for intravenous therapy. And we must still rely on intravenous fluids if the child is so severely dehydrated that it cannot drink at all. With this principal exception, what then makes ORT preferable to the intravenous route?

- It can be given by persons with little formal education, even in the home.

- It needs no sterile equipment.

- It is inexpensive (a boon, incidentally, even to well-equipped hospitals)

- It is safer and, under most circumstances, more effective.

- In a pinch, a less-effective formula can be prepared at home from table salt and table sugar (sucrose)

- It allows parents to participate in the care of their children.

- It is comforting to the child and to the parents.

Let us now consider the second stream of inquiry that led to the development of ORT: how the intestine handles salts and water

"What a piece of work is man," given form by skeleton, powered by muscles, coordinated and programmed by a chemical-electric skein of nerves and brain, nourished and defended by a red liquid distantly related to the primordial sea.

The intestine is but a hollow tube connected to the outside world at both ends, the core around which the rest of the body is wrapped. The intestine does many things, but its prime job is to take food, break it into basic molecules that are usable by the body's cells, and transport these molecules across the one-cell-thick lining that separates inside from out. To digest food, it seems necessary to increase the surface area of the tube by multiple folds on the surface of the tube and by fingerlike projections from these folds, called "villa," which carry multiple digestive enzymes at or near their surface. If the surface area is much reduced, as occurs in the disease called "spree," key nutrients and vitamins are not absorbed. It also seems necessary to suspend the particles in liquid and let digestive enzymes do their chemical work. The ultimate source of the digestive liquid is the blood stream, from which the intestine abstracts and secretes salty water free of blood or serum. Secretion of salts and water seems largely to be the function of the youngest cells in the lining, called the "crypt cells" end is controlled by a marvelously organized sequence of enzymes, minerals, and small chemical messengers which ´'know" just when to turn the flow on and off. Infectious agents which cause diarrhea are able to turn the cell mechanisms for secretion to a fixed "on" state until new cells replace the infected ones, usually in two to four days, or until the microbes and toxins are cleared out by the defense mechanisms of the body.

It has been estimated that the intestine of a healthy adult secretes one hundred liters - 264 U.S. gallons - or more of fluid each day; amazing, of course, but, given the total surface area of two million square centimeters (the size of a ballroom carpet seventy by thirty feet), one hundred liters represents but one drop per square centimeter per day Since the well nourished adult body contains only forty-five liters of fluid altogether and the adult would die if just seven to ten liters were permanently lost, there must be a rapid, certain mechanism to put the digestive fluid back into the bloodstream nearly as quickly as it is secreted. In what is surely one of the neater bits of engineering, the very molecules produced by the liquidy digestion are the ones that help transport the salts and water back across the intestinal cell, from there to return to the inner pools of body fluid. The molecules that work this way are principally glucose, the simple sugar derived from starch or table sugar; galactose, a component of milk-sugar; and amino acids and peptides, the products of protein digestion. Each of these molecules combines with sodium, probably in close to a one-to-one ratio, and these dyads cross the cell membrane, per haps by linking in a menage-a-trots to carrier protein molecules anchored in the membrane. Water is pulled along by osmosis, and other minerals (potassium, bicarbonate, more sodium) follow along, caught up in the stream, as it were. Most of this absorption appears to take place in the upper, more exposed regions of the villi, so that if there is extensive damage to villi from, say, viral diarrhea, oral rehydration may fail: failure occurs in about 5% to 10% of seriously ill children.

What is rather elegant about this system is that glucose, amino acids, and peptides seem to enter the cell linked to sodium, but each class of molecules joins with different carrier molecules or finds separate entrances specific to each. One predicts that if one adds an amino acid - glycine, say - to glucose in an oral rehydration solution, more fluid will be absorbed than if glucose or glycine are used alone. This is just what happens, and, as you shall hear shortly, this phenomenon promises a major advance in oral rehydration therapy. But for the moment, let us leave the alimentary canal and return to the child.

The formula for the oral rehydration solution was originally devised to combat epidemic outbreaks of cholera in which both adults and children are affected and where lifesaving intravenous fluids are scarce. The salts are packed in flat aluminum foil packets, paid for and stockpiled by UNICEF ready for shipment to any country on demand. The formula, often referred to as the "WHO formula,' was originally devised as a compromise between what adults needed and children could tolerate. The composition, however, is more inspired than that suggests (Table 2). The amount of salt is sufficient to replace sodium and water losses in severe de: hydration (Table 1), although adults may need to drink extra amounts. Glucose at 2% is optimal, as many studies suggest that water is best absorbed when glucose and sodium are in the ratio of one-to-one, and glucose does not exceed a concentration of 2 1/2%. Potassium deficit is only partially met by this formula because it is unsafe to completely replace losses so fast, but initial replacement must be started quickly (some suggest increasing the replacement rater Acidosis is corrected much faster with bicarbonate than without This formula has proved surprisingly versatile in the treatment of hundreds of thousands of children and adults, with documented success in #5% to 95% of cases, under the following range of situations:

- in persons who are able to drink;

- in malnourished children and the well nourished;

- in bacterial and viral causes of dehydrating diarrhea;

- with serum sodium levels as low as 110 milliequivalents per liter to as high as 165 extremes immediately threatening to life;

- with severe derangement of the blood alkaline-acid balance to the acid side (a condition called acidosis);

- in tropical climates and Baltimore winless;

- with no visible dehydration up to loss of body fluid equivalent to 10% of body weight.

- with voluminous, continuing loss of diarrhea, up to 10 milliliters per kilogram body weight per hour.

Even vomiting does not bar success except in a few instances; in fact, vomiting decreases in direct proportion to the degree of rehydration with ORT what makes ORT so versatile, in addition to its balanced formula, is that most children drink as much oral rehydration solution as is offered up to nearly the amount of which they are deficient. When they are hydrated, or nearly so, they seem to lose their taste for the fluid, then they either fall asleep, or cry for food.

Crying for food: we must think of ORT as more than simply rehydration with a solution of salts and sugar. ORT also means restoration, quickly, of a normal diet. It is now well established that a principal cause of malnutrition in children of the Third World is repeated episodes of diarrhea. The reasons are several and interactive:

- children lose their appetite for food because of salt and water loss and acidosis;

- children are often made to fast when they have diarrhea, sometimes for several days, because it is feared that food makes diarrhea worse;

- potassium loss may make muscle tone too weak for eating and digestion;

- when a child is ill, anxiety and restlessness burn up calories from the child's own stores of fat and protein (which may be already seriously depleted;

- diarrhea and fasting independently damage digestive enzymes in the intestinal tract, leading to malabsorption and loss of food that is eaten.

- with each serious bout of diarrhea, a child loses weight and may never catch up to its potential for growth and good nutrition.

In well-designed studies in the Philippines, Iran, Turkey, India and Panama, ORT appeared to protect against acute weight loss with an episode of diarrhea when the parent was also encouraged to continue to feed the child despite the diarrhea. Breast milk, soft foods and porridges, even fish and fruit and breads were advised. ORT restores a child's appetite u within a few hours, so suddenly this advice made sense to parents. The protective effect was most apparent in those already undernourished, and in those with repeated episodes of diarrhea and protection seemed to last several months. But of course no food, no protection.

We do not know, exactly how ORT works to protect nutrition, but we observe regularly that rapid restoration of fluid and mineral balance restores appetite. Potassium may play a key role here; there is also an intriguing possibility, based on studies of adults who go without food, that the glucose in ORT may help restore or protect intestinal digestive enzymes. The parent certainly finds feeding the child more acceptable, and the child becomes more settled.

Oral rehydration therapy is, thus, two therapies: rehydration and continued feeding. ORT has already been proved to reduce mortality from diarrhea. It would be an amazing achievement if ORT could also reduce the prevalence of malnutrition.

This hope leads me to consider an impending development in ORT. Often, parents" and physicians' prime concern is to stop the diarrhea, and until they see otherwise, they do not believe that rehydration is the first order of business. ORT does not stop diarrhea, which generally runs its own course of a few days; we spend a lot of effort getting that point across. Perhaps we soon will have the means to slow stool loss even while rehydrating the child.

You will recall, back in the alimentary canal, that the different breakdown products, or metabolites, of digestion (sugars, peptides, amino acids) linked up to sodium and promoted salt and water absorption through different gates in the intestinal cell membrane. There is now sufficient evidence that if we combine these metabolites in a single oral solution, we not only rehydrate but can actually decrease the total loss of stool. Peptides and amino acids are particularly necessary in the combination because they act on absorption all along the small intestine, whereas the action of glucose is more confined to the upper portion. Absorption of peptides and amino acids are also far less susceptible than glucose to damage by diarrhea. So the next step is to develop an enriched ORT, one that combines salt, potassium, bicarbonate, glucose or a simple starch, and peptides or a simple protein. Here are some expected advantages of such a formula.

- Diarrhea is lessened.

- With less diarrhea, there will be less waste of nutrients in regular food, and possible more protection of intestinal enzymes.

- Common local foods, already familiar to parents, may be adapted to form an enriched ORT.

Early studies with such a formula are encouraging. We look forward now to a burst of research to define its optimal composition, the range of severity of illness it can be used for, its advantages over the WHO solution and food given separately, its cost and distribution. We will need to consider, also, how we can enlist parents to prepare and use an enriched ORT at home.

Where does all this take us? From a global public health view, it is possible that ORT is nothing more than a palliative until research produces effective antidiarrheal vaccines. Now. sadly, for many children, ORT merely postpones death. Optimists among us hope ORT programs will enable people to trust other health services, such as family planning, to encourage better nutrition and hygienic practices, to improve the health worker's morale, and to help achieve "Health for All".

We hope these hopes prove true; they need testing. But little can be advanced, I believe, as long as nations fail to make human welfare the first priority.

This brings me full circle to the beginning of this paper.

The international agencies sponsoring this conference have done a lot for our children. They support research; they supply services and technicians; through a generous network of information they link scientists from Boston to community health workers in Bangladesh; but most of all they demonstrate that the global village exists: in helping our neighbor's child survive we establish our common humanity.

Table 1

AVERAGE WATER AND SALT LOSSES IN SEVERE DIARRHEA OF A 10-KILOGRAM CHILD BEFORE TREATMENT (milliequivalents)

Table 2
COMPOSITION OF THE "WHO FORMULA" FOR ORAL REHYDRATION SOLUTION

Grams per Liter Solution

Chemical Concentration in Millimoles per Liter Solution