Oral rehydration therapy

Nurses encouraging a patient to drink an oral rehydration solution to combat dehydration caused by cholera.

Oral rehydration therapy (ORT) is a simple treatment for dehydration associated with diarrhoea, particularly gastroenteritis or gastroenteropathy, such as that caused by cholera or rotavirus. ORT consists of a solution of salts and sugars which is taken by mouth. It is used around the world, but is most important in the developing world, where it saves millions of children a year from death due to diarrhea, the second leading cause of death (after pneumonia) in children under five.^[1]

History

Prescriptions from the ancient Indian physician Sushruta date back over 2500 years with treatment of acute diarrhea with rice water, coconut juice, and carrot soup. However, this knowledge did not carry over to the Western world, as dehydration was found to be the major cause of death secondary to the 1829 cholera pandemic in Russia and Western Europe. In 1831, William Brooke O'Shaughnessy noted the loss of water and salt in the stool of cholera patients and prescribed intravenous fluid therapy (IV) to compensate. The results were remarkable, as patients who were on the brink of death from dehydration recovered. The mortality rate of cholera dropped from 70% to 40% with the use of hypertonic IV solutions.^[2] IV fluid replacement became entrenched as the standard of care for moderate/severe dehydration for over a hundred years. ORT replaced it with the support of several independent key advocates that ultimately convinced the medical community of the efficacy of ORT.^[3]

In the late 1950s, ORT was prescribed by Dr. Hemendra Nath Chatterjee in India for cholera patients.^[4] Although his findings predate physiological studies, his results failed to gain credibility and recognition because they did not provide scientific controls and detailed analysis.^[3] Credit for discovery that in the presence of glucose, sodium and chloride became absorbable during diarrhea (in cholera patients) is typically ascribed to Dr. Robert A. Phillips. However, early attempts to translate this observation into an effective oral rehydration solution failed, due to incorrect solution formula and inadequate methodology.^[3]

In the early 1960s, biochemist Robert K. Crane discovered the sodium-glucose cotransport as the mechanism for intestinal glucose absorption.^[5] Around the same time, others showed that the intestinal mucosa was not disrupted in cholera, as previously thought. These findings were confirmed in human experiments, where it was first shown that a glucose-saline oral therapy solution administered in quantities matching measured diarrhea volumes was effective in significantly decreasing the necessity for IV fluids by 80%.^[6] These results helped establish the physiological basis for the use of ORT in clinical medicine.^[2]

The events surrounding the Bangladesh Liberation War in 1971 convinced the world of the effectiveness of ORT.^[3] As medical teams ran out of intravenous fluids to treat the spreading cholera epidemic, Dr. Dilip Mahalanabis instructed his staff to distribute oral rehydration salts (ORS) to the 350,000 people in refugee camps. Over 3,000 patients with cholera were treated, and the death rate was only 3.6%, compared to the typical 30% seen in intravenous fluid therapy.^[2] The fact that ORT was delivered primarily by family members instead of trained staff across such a large population in an emergency fashion was demonstrative proof of the utility of ORT against cholera.^[3]

Between 1980 and 2006, ORT decreased the number of worldwide deaths from 5 million a year to 3 million a year.^[7] Death from diarrhea was the leading cause of infant mortality in the developing world until ORT was introduced.^[8] It is now the second leading cause of mortality for children under 5, accounting for 17% of all deaths, second only to pneumonia, at 19%.^[1] Its remarkable success has led to naming the discovery of its underlying physiological basis as "potentially the most important medical advance [of the 20th] century."^[8] ORT is part of UNICEF's GOBI program, a low cost program to increase child survival in developing countries, including growth monitoring, ORT, breastfeeding, and immunization.^[9] Despite the success and effectiveness of ORT, its uptake has recently slowed and even reversed in some developing countries. This raises concerns for increased mortality from diarrhea and highlights the need for effective community-level behavioral change and global funding and policy.^[10]

The individuals and organizations involved in the development of ORT have been recognized widely. The 2001 Gates Award for Global Health was awarded to the Centre for Health and Population Research, located in Dhaka, Bangladesh, for its role in the development of ORT.^[11] In 2002, the first Pollin Prize for Pediatric Research was awarded to Dr. Norbert Hirschhorn, Dr. Dilip Mahalanabis, Dr. David Nalin, and Dr. Nathaniel F. Pierce for their contributions in the discovery and implementation of ORT.^[12] For promoting the use of ORT, the 2006 Prince Mahidol Award was awarded to Dr. Richard A. Cash of Harvard School of Public Health, Dr. David Nalin, and Dr. Dilip Mahalanabis in the field of public health; and to Dr. Stanley G Schultz in the field of medicine.^[13]

Availability

The World Health Organizations states that some home products can be used to treat and prevent dehydration. This includes salted rice water, salted yogurt drink, and salted vegetable or chicken soup. A home-made solution of one liter of plain water with 3 grams table salt and 18 grams common sugar can also be made. And a medium amount of salt can also be added to water in which cereal has been cooked, unsalted soup, green coconut water, unsweetened weak tea, and unsweetened fruit juice. What should be avoided are commercial soft drinks, commercial sweetened fruit juices, and coffee.^[14]

ORT is available anywhere that adequate nutrition is available. ORS, on the other hand, is typically packaged in pre-measured sachets that are ready to be mixed in with water (generally 1L). These are available via commercial manufacturers^[15] or supplied by local/regional governments or relief agencies such as UNICEF. In 1996, UNICEF distributed 500 million sachets of ORS to over 60 developing nations.^[16] Commercial suppliers produce a variety of formulations, and there is no restriction as to what formulation can be marketed as ORS. As such, some vendors include extra sugar or other flavoring to make the product more palatable, popular examples in the US being the various flavors and formulations of Pedialyte.

Scheduled to start in October 2011, there is a pilot program in Zambia to piggyback onto Coca-Cola distribution channels using the empty spaces in cases to include Colalife, which are wedge-shaped packets of medicines including oral rehydration salts.^[17]

Definition

The definition of ORT has changed over time, broadening in scope and encompassing a definition of a specific therapy appropriate for rehydration. Initially, in the early 1980s, ORT was defined only as the solution prescribed by the WHO/UNICEF. It was later changed in 1988 to encompass recommended home fluids, because the official preparation was not always readily available. It was amended once again in 1988 to include continued feeding as appropriate management. In 1991, the definition was changed to define ORT as any increase in administered fluids. The final change came in 1993, and is the definition used today, which states that ORT is an increase in administered fluids and continued feeding.^[18]

Basic Solution

Where ORS sachets are not available, home-prepared solutions are typically used. While many different recipes exist to increase palatability (e.g. adding flavor, citrus, savory, etc.), all are based on a standard ratio of water, sugar, and salt.

A basic oral rehydration therapy solution is composed of:^[19][20][21]

• 30 ml (6 level tsp) of sugar
• 2.5 ml (1/2 level tsp) of salt, dissolved into
• 1 litre (4.25 Cups) of clean water

(Note that these expedient rehydration mixtures do not replenish potassium, and usage over long term may result in hypokalemia.)

WHO/UNICEF definition of ORS

Concentrations of ingredients in reduced osmolarity ORS^[22]

Ingredient	g/L	Molecule/ion	mmol/L
sodium chloride (NaCl)	2.6	sodium	75
glucose, anhydrous (C6H12O6)	13.5	glucose	75
potassium chloride (KCl)	1.5	potassium	20
		chloride	65
trisodium citrate, dihydrate Na3C6H5O7·2H2O	2.9	citrate	10

The WHO and UNICEF jointly maintain the official guidelines^[23] for the contents of reduced osmolarity ORS packets. These guidelines are used by manufacturers of commercial ORS packets that are available for purchase and were last updated in 2006.^[24] The reduced osmolarity ORS has a total osmolarity of 245 mmol/L.^[22]

Switch to reduced osmolarity ORS

In 2003, WHO/UNICEF changed the ORS formula to a reduced osmolarity version from what it had been recommending for over two decades prior.^[22] This change was in response to numerous studies that showed that the standard ORS formula was ineffective in reducing diarrheal stool output compared to other solutions, including rice water.^{[25][26][27][28][29]} Additionally, further studies showed that a reduced osmolarity solution not only decreased stool output, but also resulted in less vomiting and fewer unscheduled intraveneous therapy cases.^[30][31][32] Although UNICEF certifies reduced osmolarity ORS for all forms of dehydration,^[22] at least one study cautions that for high stool output cholera-based diarrhea, reduced osmolarity ORS may not sufficiently replenish electrolyte levels, leading to hyponatremia. Though the actual consequence of this appeared negligible, further study was recommended.^[33]

The change reduced the osmolarity of the ORS from 311 mmol/L to 245 mmol/L. The ingredients reduced in concentration were glucose and sodium chloride. Potassium and citrate concentrations remained the same.^[22] The benefits of the reduced osmolarity ORS are reducing stool volume by about 25%, reducing vomiting by nearly 30%,^[34] and reducing the need for unscheduled intraveneous therapy by 33%.^[35]

Many Indian pharmacy manufacturers lobbied to oppose this change as the reduction in glucose and sodium chloride concentrations degraded the taste of the ORS solution and hence adversely affected their sales. Dr Dinesh Kumar Tiwari lead a decade long campaign against the old high osmolarity formula, he called "Sweet Killer". The recommendations were at last adopted by CDSCO.

Administration

Pouring of an ORS sachet into a bottle

Current WHO/UNICEF guidelines,^[36] recommend that ORT should begin at home with "home fluids" or a home-prepared "sugar and salt" solution at the first sign of diarrhea to prevent dehydration.^[37] Feeding should be continued at all times.^[18] After initial fluid volume has been restored, the regimen should be switched to official preparations of oral rehydration salts (ORS) at the appropriate dosing times to maintain adequate hydration and proper electrolyte balance.

During the home-prepared stage, care should be taken to select the proper type of fluid to administer. The fluids given must contain both sugar and salt in the proper amounts. Liquids without salt can lead to low body salt (hyponatremia) because the diarrheal stool contains salt that must be replenished. Additionally, sugar must also be present in the administered fluid because salt absorption is coupled with sugar in the intestine via the SGLT1 transporter.^[37]

Appropriate drinks to administer during the home-prepared stage include official ORSs, salted rice water, salted yogurt-based drinks, and vegetable or chicken soup with salt. Clean water should always be used when preparing a solution. Drinks to be avoided include soft drinks, sweetened fruit drinks, sweetened tea, coffee, and medical tea infusions with diuretic effects due to high sugar content and/or caffeine. In addition, drinks with a high concentration (osmolarity) of sugar can worsen diarrhea as they draw water out of the body and into the intestine because of their hypertonicity.^[37]

If dehydration ensues even when ORT is begun with a home-prepared solution, if available, a qualified health professional should manage further rehydration with ORS to ensure proper electrolyte balance and to facilitate rapid rehydration, and treatment of the underlying cause of dehydration if appropriate.^[35]

Food and supplements

An adult or child with child with diarrhea should continue to eat, and infants should continue to breast-feed.^[14][38] In a 2005 publication for doctors regarding the treatment of diarrhea, the World Health Organization states: "When food is given, sufficient nutrients are usually absorbed to support continued growth and weight gain. Continued feeding also speeds the recovery of normal intestinal function, including the ability to digest and absorb various nutrients. In contrast, children whose food is restricted or diluted lose weight, have diarrhea of longer duration, and recover intestinal function more slowly."^[14]

Zinc supplementation^[39] is recommended for the management of diarrheal disease in addition to ORS, particularly for pediatric patients. For children under five, zinc supplementation significantly reduces the severity and duration of diarrhea and is strongly recommended as a supplement with ORS for dehydrated children.^[35] Preparations are available as a zinc sulfate solution for adults,^[40] a modified solution for children,^[41] and also a tablet form for children.^[42]

Treatment when malnourished

The treatment of diarrhea and dehydration in child or adult who is also malnourished is somewhat different from standard treatment. Dehydration may be over-estimated in a marasmic/wasted child and under-estimated in a kwashiorkor/edematous child. The diagnosis is based instead on whether the person has been having diarrhea.^[43][14] The standard reduced-osmolarity oral rehydration solution needs to be modified so that it will have somewhat less salt and somewhat more sugar and potassium than standard in order to produce what is called a Rehydration Solution for Malnutrition (ReSoMal). Or, if diarrhea is severe, the standard reduced-osmolarity solution can be used.^[43] In addition, the World Health Organization recommends that all malnourished persons with diarrhea be treated with a course of broad-spectrum antibiotics.^[14] Supplemental zinc is still recommended, and a dehydrated person should still continue to be given food.^[14]

Physiological basis

Fluid from the body is normally pumped into the intestinal lumen during digestion. This fluid is typically isosmotic with blood because it contains a high concentration of sodium (approx. 142 mEq/L). A healthy individual will secrete 20-30 grams of sodium per day via intestinal secretions. Nearly all of this is reabsorbed by the intestine, helping to maintain constant sodium levels in the body (homeostasis).^[44]

Because there is so much sodium secreted by the intestine, without intervention, heavy continuous diarrhea can be a very dangerous and potentially life-threatening condition within hours. This is because liquid secreted into the intestinal lumen during diarrhea passes through the gut so quickly that very little sodium is reabsorbed, leading to very low sodium levels in the body (severe hyponatremia).^[44] This is the motivation for sodium and water replenishment via ORT.

Sodium absorption via the intestine occurs in two stages. The first is at the outermost cells (intestinal epithelial cells) at the surface of the intestinal lumen. Sodium passes into these outermost cells by co-transport via the SGLT1 protein.^[44] From there, sodium is pumped out of the cells (basal side) and into the extracellular space by active transport via the sodium potassium pump.^[45][46]

The co-transport of sodium into the epithelial cells via the SGLT1 protein requires glucose or galactose. Two sodium ions and one molecule of glucose/galactose are transported together across the cell membrane through the SGLT1 protein. Without glucose or galactose present, intestinal sodium will not be absorbed.^[44] This is the reason glucose is included in ORSs. For each cycle of the transport, hundreds of water molecules move into the epithelial cell, and this brings about the rehydration.

References

1. ^ ^{a b} UNICEF (December 2007) (pdf). The State of the World’s Children 2008: Child Survival. p. 8. ISBN 978-92-806-4191-2. http://www.unicef.org/publications/files/The_State_of_the_Worlds_Children_2008.pdf. Retrieved 2009-02-16. 
2. ^ ^{a b c} Guerrant, Richard L.; Benedito A Carneiro-Filho, Rebecca A. Dillingham (August 2003). "Cholera, Diarrhea, and Oral Rehydration Therapy: Triumph and Indictment". Clinical Infectious Diseases 37 (3): 398–405. doi:10.1086/376619. PMID 12884165. http://www.journals.uchicago.edu/doi/full/10.1086/376619. Retrieved 2008-07-15. 
3. ^ ^{a b c d e} Ruxin, Joshua Nalibow (1994). "Magic bullet: the history of oral rehydration therapy.". Medical History 38 (4): 363–397. ISSN 4. PMC 1036912. PMID 7808099. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1036912. Retrieved 2009-02-16. 
4. ^ Chatterjee, Hemendra Nath (1957). "Reduction of Cholera Mortality by the Control of Bowel Symptoms and Other Complications". Postgraduate Medical Journal 33 (380): 278–284. doi:10.1136/pgmj.33.380.278. PMC 2501333. PMID 13431557. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2501333. Retrieved 2009-02-16. 
5. ^ Robert K. Crane, D. Miller and I. Bihler. “The restrictions on possible mechanisms of intestinal transport of sugars”. In: Membrane Transport and Metabolism. Proceedings of a Symposium held in Prague, August 22–27, 1960. Edited by A. Kleinzeller and A. Kotyk. Czech Academy of Sciences, Prague, 1961, pp. 439-449.
6. ^ Nalin, David R.; Richard A. Cash, Rafiqul islam, Majid Molla and Robert A.Phillips (August 1968). "Oral Maintenance Therapy for cholera in Adults". The Lancet 2: 370–373. 
7. ^ Gerline, Andrea (October 8, 2006). "A Simple Solution". Time Magazine. http://www.time.com/time/printout/0,8816,1543876,00.html. 
8. ^ ^{a b} "Water with Sugar and Salt" (pdf). The Lancet 312 (8084): 300. 1978. doi:10.1016/S0140-6736(78)91698-7. http://www.sciencedirect.com/science?_ob=MImg&_imagekey=B6T1B-49HF0GB-K0-1&_cdi=4886&_user=145269&_orig=search&_coverDate=08%2F05%2F1978&_sk=996871915&view=c&wchp=dGLbVlW-zSkWA&md5=238bad325d6a98acb8bc07ea56bd7a3a&ie=/sdarticle.pdf. Retrieved 2009-02-16. 
9. ^ UNICEF (November 2006) (pdf). 1946-2006 Sixty Years for Children. UNICEF. ISBN 92-806-4053-4. http://www.unicef.org/publications/files/1946-2006_Sixty_Years_for_Children.pdf. Retrieved 2008-06-07. 
10. ^ Ram, Pavani Kalluri; Misun Choi, Lauren S Blum, Annah W Wamae, Eric D Mintz, Alfred V Bartlett (2008). "Declines in case management of diarrhoea among children less than five years old". Bulletin of the World Health Organization 86 (3): 240–240. doi:10.2471/BLT.07.041384. PMC 2647400. PMID 18368194. http://www.who.int/bulletin/volumes/86/3/07-041384/en/index.html. Retrieved 2009-02-16. 
11. ^ Bill & Melinda Gates Foundation. "Centre for Health and Population Research - 2001 Gates Award for Global Health Recipient". http://www.gatesfoundation.org/gates-award-global-health/Pages/2001-centre-for-health-and-population-research.aspx. Retrieved 2009-02-21. 
12. ^ NewYork-Presbyterian Hospital. "First Pollin Prize in Pediatric Research Recognizing Developers of Revolutionary Oral Rehydration Therapy". http://nyp.org/news/hospital/2002-pollin-prize.html. Retrieved 2009-02-22. 
13. ^ Prince Mahidol Award Foundation. "Prince Mahidol Award 2006" (pdf). http://www.princemahidolaward.org/publications/PMA_Program06.pdf. Retrieved 2009-02-22. 
14. ^ ^{a b c d e f} THE TREATMENT OF DIARRHEA, A manual for physicians and other senior health workers
    World Health Organization, 2005. See page 9 (13 in PDF) for home products and recipes that can be used to treat and prevent dehydration. See chapter "8. MANAGEMENT OF DIARRHEA WITH SEVERE MALNUTRITION," pages 22-24 (26-28 in PDF). This manual is quite emphatic about the importance of continuing to feed the patient with page 10 (14 in PDF) stating: “Food should never be withheld and the child's usual foods should not be diluted. Breastfeeding should always be continued."
15. ^ "Worldwide Suppliers of ORS - rehydrate.org". http://rehydrate.org/resources/suppliers.htm. Retrieved 2009-02-19. 
16. ^ UNICEF (1996). "The State of the World's Children 1996". http://www.unicef.org/sowc96/joral.htm. Retrieved 2009-02-19. 
17. ^ Coke's supply chain could distribute aid to the needy, Marc And Craig Kielburger, Times Colonist, [Victoria & Vancouver Island, Canada], October 2, 2011.
18. ^ ^{a b} Cesar G. Victora; Jennifer Bryce, Olivier Fontaine, & Roeland Monasch (2000). "Reducing deaths from diarrhoea through oral rehydration therapy" (pdf). Bulletin of the World Health Organization (WHO) 78 (10): 1246–55. PMC 2560623. PMID 11100619. 00-0747. http://www.who.int/entity/bulletin/archives/78(10)1246.pdf. Retrieved 2009-02-17. 
19. ^ World Health Organization, Global Task Force on Cholera Control, WHO position paper on Oral Rehydration Salts to reduce mortality from cholera
20. ^ "ORS Made at Home - rehydrate.org". http://rehydrate.org/solutions/homemade.htm. Retrieved 2009-02-19. 
21. ^ "How to Make an Oral Rehydration Salts Drink (ORS)". http://www.wikihow.com/Make-an-Oral-Rehydration-Salts-Drink-(ORS). Retrieved 2011-02-26. 
22. ^ ^{a b c d e} "UNICEF: New formulation of Oral Rehydration Salts (ORS) with reduced osmolarity". http://www.supply.unicef.dk/catalogue/bulletin9.htm. Retrieved 2009-02-16. 
23. ^ WHO. "Pharmacopoeia Library: Oral Rehydration Salts". http://www.who.int/phint/en/p/docf/. Retrieved 2009-02-16. 
24. ^ UNICEF. "Improved formula for oral rehydration salts to save children's lives". http://www.unicef.org/media/media_31825.html. Retrieved 2008-07-15. 
25. ^ Wong, HB (1981). "Rice water in treatment of infantile gastroenteritis". Lancet 2 (8237): 102–103. doi:10.1016/S0140-6736(81)90462-1. PMID 6113434. 
26. ^ Wong, HB (1981). "Gastroenteritis: III. Rice-water in the management of infantile gastroenteritis in Singapore.". Journal of Singapore Paediatric Society 23 (3-4): 113–117. PMID 7052847. 
27. ^ Mehta, MN; Subramaniam S. (1986). "Comparison of rice water, rice electrolyte solution, and glucose electrolyte solution in the management of infantile diarrhoea.". Lancet 1 (8485): 843–845. doi:10.1016/S0140-6736(86)90948-7. PMID 2870323. 
28. ^ Molina S; Vettorazzi C, Peerson JM, Solomons NW, Brown KH (1995). "Clinical trial of glucose-oral rehydration solution (ORS), rice dextrin-ORS, and rice flour-ORS for the management of children with acute diarrhea and mild or moderate dehydration". Pediatrics 95 (2): 191–197. PMID 7838634. 
29. ^ Bhattacharya SK; Dutta P, Dutta D, Chakraborti MK (1990). "Super ORS". Indian Journal of Public Health 34 (1): 35–37. PMID 2101384. 
30. ^ Santosham M; Fayad I, Abu Zikri M, Hussein A, Amponsah A, Duggan C, Hashem M, el Sady N, Abu Zikri M, Fontaine O (1996). "A double-blind clinical trial comparing World Health Organization oral rehydration solution with a reduced osmolarity solution containing equal amounts of sodium and glucose.". The Journal of Pediatrics 128 (1): 45–51. doi:10.1016/S0022-3476(96)70426-2. PMID 8551420. http://www.jpeds.com/article/S0022-3476(96)70426-2. 
31. ^ Kim Y; Hahn S, Garner P (2001). Hahn, Seokyung. ed. "Reduced osmolarity oral rehydration solution for treating dehydration caused by acute diarrhoea in children". Cochrane Database of Systematic Reviews (2): CD002847. doi:10.1002/14651858.CD002847. PMID 11406049. CD002847. http://mrw.interscience.wiley.com/cochrane/clsysrev/articles/CD002847/frame.html. Retrieved 2009-02-16. 
32. ^ CHOICE Study Group (2001). "Multicenter, randomized, double-blind clinical trial to evaluate the efficacy and safety of a reduced osmolarity oral rehydration salts solution in children with acute watery diarrhea". Pediatrics 107 (4): 613–618. doi:10.1542/peds.107.4.613. PMID 11335732. http://pediatrics.aappublications.org/cgi/content/full/107/4/613. Retrieved 2009-02-16. 
33. ^ Murphy C; Hahn S, Volmink J (2004). Murphy, Colleen K. ed. "Reduced osmolarity oral rehydration solution for treating cholera". Cochrane Database of Systematic Reviews (4): CD003754. doi:10.1002/14651858.CD003754.pub2. PMID 15495063. CD003754. http://mrw.interscience.wiley.com/cochrane/clsysrev/articles/CD003754/frame.html. Retrieved 2009-02-16. 
34. ^ UNICEF. ""New ORS" Q&A". http://www.supply.unicef.dk/catalogue/NewORSQ&A.pdf. Retrieved 2009-02-16. 
35. ^ ^{a b c} WHO (2005) (pdf). The treatment of diarrhea: A manual for physicians and other senior health workers. ISBN 9241593180. WHO/FCH/CAH/05.1. http://whqlibdoc.who.int/publications/2005/9241593180.pdf. Retrieved 2009-02-16. 
36. ^ WHO, UNICEF. "Oral Rehydration Salts: Production of the new ORS" (pdf). http://libdoc.who.int/hq/2006/WHO_FCH_CAH_06.1.pdf. Retrieved 2009-02-16. 
37. ^ ^{a b c} WHO: Programme for the Control of Diarrhoeal Diseases. "WHO/CDD/93.44: The selection of fluids and food for home therapy to prevent dehydration from diarrhoea: Guidelines for developing a national policy" (pdf). http://whqlibdoc.who.int/hq/1993/WHO_CDD_93.44.pdf. Retrieved 2009-02-16. 
38. ^ Community Health Worker Training Materials for Cholera Prevention and Control, CDC, slides at back are dated 11/17/2010. Page 7 states " . . . Continue to breastfeed your baby if the baby has watery diarrhea, even when traveling to get treatment. Adults and older children should continue to eat frequently."
39. ^ WHO. "The International Pharmacopoeia". http://www.who.int/medicines/publications/pharmacopoeia/ors/en/. Retrieved 2008-07-15. 
40. ^ WHO. "Zinc Sulfate for ORS for adults" (pdf). http://www.who.int/entity/medicines/publications/pharmacopoeia/QAS07_194rev1Zinc-sulf_FINAL.pdf. Retrieved 2008-07-15. 
41. ^ WHO. "Pediatric zinc sulfate oral solution" (pdf). http://www.who.int/entity/medicines/publications/pharmacopoeia/QAS07_195rev1Zinc-sulf-oral-solFINAL.pdf. Retrieved 2008-07-15. 
42. ^ WHO. "Pediatric zinc sulfate tablets" (pdf). http://www.who.int/entity/medicines/publications/pharmacopoeia/QAS07_193_rev1Zinc-sulf-tabFINAL.pdf. Retrieved 2008-07-15. 
43. ^ ^{a b} National Guidelines for the Management of Severely Malnourished Children in Bangladesh, Institute of Public Health Nutrition, Directorate General of Health Services, Ministry of Health and Family Welfare, Government of the People’s Republic of Bangladesh, May 2008. See esp. pages 21-22 (pages 22-23 in PDF)
44. ^ ^{a b c d} Guyton, Arthur C.; Hall, John E. (2006). Textbook of Medical Physiology. Philadelphia: Elsevier Saunders. pp. 814–816. ISBN 0-7216-0240-1. 
45. ^ Canadian Paediatric Society, Nutrition Committee (2006). "Oral rehydration therapy and early refeeding in the management of childhood gastroenteritis". Paediatrics & Child Health 11 (8): 527–531. http://www.cps.ca/english/statements/N/N06-01.htm. Retrieved 2009-02-17. 
46. ^ Guyton, Arthur C.; Hall, John E. (2006). Textbook of Medical Physiology. Philadelphia: Elsevier Saunders. pp. 330. ISBN 0-7216-0240-1.