Managing AGE Among ChildrenOral Rehydration, Maintenance, and

Nutritional Therapy

Chris Longhurst, MD, MS

Valley Journal Club

April 18, 2023

Background

• In 1992, CDC prepared the first national guidelines for managing childhood diarrhea

• Since the last recommendations were published in MMWR, new data have emerged regarding diarrhea treatment and the value of more effective oral solutions

• These recommendations update the previous report

Background

• Developed by specialists in managing gastroenteritis in consultation with CDC and external consultants.

• Relevant literature was identified through an extensive MEDLINE search by using related terms.

• Articles were then reviewed for their relevance to pediatric practice, with emphasis on U.S. populations.

Overview I

• Introduction– Background

– Epidemiology

– Historical perspective

– Physiologic Basis for Using ORT

• Fluid therapy– Home Management of Acute Diarrhea

– Therapy Based on Degree of Dehydration

– Clinical Management in the Hospital

Diarrhea

Introduction - Burden of Disease

• United States of America– >1.5 million outpatient visits– 200,000 hospitalizations– ~ 300 deaths/year– $1 billion/year in total costs to society for rotavirus

diarrhea alone!

• Worldwide– Diarrhea is leading cause of morbidity and mortality– 1.5 billion episodes and 1.5 - 2.5 million deaths occur

annually among children aged <5 years

Introduction - Making Progress

• Worldwide mortality decreased in the 1980’s and 1990’s– In 1982, 5 million deaths/year occurred– In 1992, deaths declined to 3 million/year

• A substantial portion of the decrease in mortality is attributable to worldwide campaigns to treat acute diarrhea with oral rehydration therapy (ORT)

Introduction - ORT

• Represents a case of reverse technology transfer, because protocols originally implemented to benefit patients in developing countries have changed the standard of care in industrialized countries as well.

– Santosham M, Keenan EM, Tulloch J, Broun D, Glass R. Oral rehydration therapy for diarrhea: an example of reverse transfer of technology. Pediatrics 1997;100:E10.

Introduction - ORT

• Two phases of treatment1. Rehydration phase, in which

water and electrolytes are administered as oral rehydration solution (ORS) to replace existing losses

2. Maintenance phase, which includes both replacement of ongoing fluid and electrolyte losses and adequate dietary intake

Historical Use of IVF

• Early attempts at treating dehydration resulting from diarrhea were described in the 1830s during epidemics of cholera

– Latta T. Malignant cholera: treatment by copious injection of aqueous and saline fluids into the veins. Lancet 1832;2:274

• Use of IV fluid did not become widespread until >100 years later

Historical Use of ORT

• In the 1940s, oral solutions were developed and the effect of potassium replacement in reducing mortality was recognized, which led to substantial decreases in case fatality rates

• Studies published in 1968 from Dhaka and Calcutta demonstrated the effectiveness of ORS for cholera patients, including those with high stool output

– Nalin DR, Cash RA, Islam R, Molla M, Phillips RA. Oral maintenance therapy for cholera in adults. Lancet 1968;2:370-3

Historical Use of ORT

• In 1971, oral electrolyte solutions were tested through the large-scale treatment of refugees

– Mahalanabis D, Choudhuri AB, Bagchi N, Bhattacharya AK, Simpson TW. Oral fluid therapy of cholera among Bangladesh refugees. Johns Hopkins Med J 1973;132:197--205

• The resulting success hastened development of the first WHO guidelines for ORT and the production of standard packets of oral rehydration salts

• ORT is now accepted as the standard of care for the clinically efficacious and cost-effective management of acute gastroenteritis

Physiologic Basis for ORT

• Although three principle mechanisms of sodium absorption have been described, the mechanism essential to the efficacy of ORS is the coupled transport of sodium and glucose molecules at the intestinal brush border.

– Curran PF. Na, Cl, and water transport by rat ileum in vitro. J Gen Physiol 1960;43:1137--48.

• This mechanism remains intact, even in patients with severe diarrhea.

Physiologic Basis for ORT

Physiologic Basis for ORT

• ORS in which additional co-transporters of Na (e.g., amino acids or cereals) were added has demonstrated promising results, but larger trials have not confirmed their efficacy.

• Bhan MK, Mahalanabis D, Fontaine O, Pierce NF. Clinical trials of improved oral rehydration salt formulations: a review. Bull World Health Organ 1994;72:945--55.

• Fontaine O, Gore SM, Pierce NF. Rice-based oral rehydration solution for treating diarrhoea. Cochrane Database Syst Rev 2000;2: CD001264.

Physiologic Basis for ORT

• Osmolarity is important!– Solutions with a high concentration of co-transporters

increase the risk from hypertonic solutions that decrease rather than improve sodium and water transport into the bloodstream.

– However, solutions of lower osmolarity, but that maintain the 1:1 glucose to sodium ratio, perform optimally as oral solutions for diarrhea management.

Barriers to ORT

• The full benefits have not been realized in countries with developed market economies

• Many reasons, including– ingrained use of intravenous (IV) therapy– reduced appeal of a technologically simple

solution– Ozuah PO, Avner JR, Stein RE. Oral rehydration,

emergency physicians, and practice parameters: a national survey. Pediatrics 2002;109:259--61

Barriers to ORT

• Especially true in America– Approximately 30% of practicing

pediatricians withhold ORT for children with vomiting or moderate dehydration

– Reis EC, Goepp JG, Katz S, Santosham M. Barriers to use of oral rehydration therapy. Pediatrics 1994;93:708--11

– The practice of continued feeding during diarrheal episodes has been difficult to establish as accepted standard of care

Home Management of Diarrhea

• Therapy should begin at home as long as caregivers are instructed properly regarding signs of dehydration or are able to determine when children appear markedly ill or appear not to be responding to treatment.

Home Management of Diarrhea

• Treatment with ORS is simple and enables management of uncomplicated cases at home, regardless of etiologic agent.

• Early administration of ORS leads to fewer office, clinic, and ED visits and to potentially fewer hospitalizations and deaths.

– Duggan C, Lasche J, McCarty M, et al. Oral rehydration solution for acute diarrhea prevents subsequent unscheduled follow-up visits. Pediatrics 1999;104:e29.

Home Management of Diarrhea

Assessment of Dehydration

• Dehydration and electrolyte losses associated with untreated diarrhea cause the primary morbidity of acute gastroenteritis

• Goal of assessment is to:– provide a starting point for treatment

– conservatively determine which patients can safely be sent home for therapy, which ones should remain for observation during therapy, and which ones should immediately receive more intensive therapy

Assessment of Dehydration

• Prior guidelines, including CDC's 1992 recommendations and the American Academy of Pediatrics (AAP) 1996 guidelines, divide patients with dehydration into subgroups for:– mild (3%-5% fluid deficit)– moderate (6%-9% fluid deficit)– severe (>10% fluid deficit, shock, or near

shock)

Assessment of Dehydration

• Studies that have evaluated the correlation of clinical signs of dehydration with post-treatment weight gain indicate that the first signs of dehydration might not be evident until 3%-4%, with more numerous clinical signs evident at 5% and signs indicating severe dehydration not evident until fluid loss reaches 9%-10%.

– Duggan C, Refat M, Hashem M, Wolff M, Fayad I, Santosham M. How valid are clinical signs of dehydration in infants? J Pediatr Gastroenterol Nutr 1996;22:56--61.

Assessment of Dehydration

• Because of this threshold effect, these updated recommendations group together patients with mild to moderate dehydration over a relatively wide range of fluid loss (i.e., from 3%-9%)

• Nevertheless, the goal of assessment is the same:– to provide a starting point for treatment– to conservatively determine which patients can safely

be sent home for therapy, which ones should remain for observation during therapy, and which ones should immediately receive more intensive therapy

Assessment of Dehydration

Assessment of Dehydration

• Supplementary laboratory studies, including serum electrolytes, to assess patients with acute diarrhea are usually unnecessary.

– Teach SJ, Yates EW, Feld LG. Laboratory predictors of fluid deficit in acutely dehydrated children. Clin Pediatr (Phila) 1997;36:395--400.

• Stool cultures are indicated in cases of dysentery (bloody diarrhea) but are not usually indicated in acute, watery diarrhea for the immunocompetent patient.

Therapy of AGE

Therapy of AGE

Therapy of Minimal Dehydration

• Minimal dehydration (<3% loss of body wt)– Encourage use of ORS– Nutrition should not be restricted

Therapy of Mod. Dehydration

• Mild to moderate (3-9% loss of body wt)– ORS: 50-100 cc/kg over 2-4 hrs

– “Small, frequent feedings”

• A randomized trial of ORS versus IV rehydration demonstrated shorter stays in EDs and improved parental satisfaction with oral rehydration

– Atherly-John YC, Cunningham SJ, Crain EF. A randomized trial of oral vs intravenous rehydration in a pediatric emergency department. Arch Pediatr Adolesc Med 2002;156:1240--3

Therapy of Mod. Dehydration

• Nasogastric (NG) feeding allows continuous administration of fluid at a slow, steady rate, particularly for patients with persistent vomiting or oral ulcers.

• Rapid rehydration by nasogastric fluid can be well-tolerated, more cost-effective, and associated with fewer complications than IV rehydration.

– Nager AL, Wang VJ. Comparison of nasogastric and intravenous methods of rehydration in pediatric patients with acute dehydration. Pediatrics 2002;109:566--72.

Therapy of Severe Dehydration

• Severe dehydration constitutes a medical emergency requiring immediate IV rehydration.

• As soon as the severely dehydrated patient's level of consciousness returns to normal, therapy can usually be changed to the oral route, with the patient taking by mouth the remaining estimated deficit.

Management in the Hospital

• When is hospitalization indicated?– caregivers cannot provide adequate care at home

– substantial difficulties exist in administrating ORT, including intractable vomiting, ORS refusal, or inadequate ORS intake

– concern exists for other possible illnesses complicating the clinical course

– ORS treatment fails, including worsening diarrhea or dehydration despite adequate volumes

Management in the Hospital

• When is hospitalization indicated?– severe dehydration (>9% of body weight) exists– social or logistical concerns exist that might

prevent return evaluation, if necessary– such factors as young age, unusual irritability

or drowsiness, progressive course of symptoms, or uncertainty of diagnosis exist that might indicate a need for close observation

Management in the Hospital

• Risk factors for suboptimal outcomes– Prematurity– Young maternal age– Black race– Rural residence

– Ho MS, Glass RI, Pinsky PF. Diarrheal deaths in American children. Are they preventable? JAMA 1988;260:3281—5

Therapy of AGE

Overview II

• Other therapies– Dietary Therapy during AGE

– Pharmacologic Therapy of AGE

– Supplemental Zinc Therapy

– Functional Foods

• Choice of ORS– New solutions

– Barriers to ORT

– Limitations of ORT

• Conclusion

Dietary Therapy of AGE

• Breastfed infants should continue nursing on demand

• Formula-fed infants should continue their usual formula immediately upon rehydration

Dietary Therapy of AGE

• A meta-analysis of clinical trials indicates no advantage of lactose-free formulas over lactose-containing formulas for the majority of infants, although certain infants with malnutrition or severe dehydration recover more quickly when given lactose-free formula.

– Brown KH, Peerson J, Fontaine O. Use of nonhuman milks in the dietary management of young children with acute diarrhea: a meta-analysis of clinical trials. Pediatrics 1994;93:17--27.

Dietary Therapy of AGE

• Although medical practice has often favored beginning feedings with diluted (e.g., half- or quarter-strength) formula, controlled clinical trials have demonstrated that this practice is unnecessary and is associated with prolonged symptoms and delayed nutritional recovery.

– Santosham M, Foster S, Reid R, et al. Role of soy-based, lactose-free formula during treatment of acute diarrhea. Pediatrics 1985;76:292--8.

– Brown KH, Gastanaduy AS, Saavedra JM, et al. Effect of continued oral feeding on clinical and nutritional outcomes of acute diarrhea in children. J Pediatr 1988;112:191--200.

Dietary Therapy of AGE

• Formulas containing soy fiber have been marketed to physicians and consumers in the United States, and added soy fiber has been reported to reduce liquid stools without changing overall stool output.

– Brown KH, Perez F, Peerson J, et al. Effect of dietary fiber (soy polysaccharide) on the severity, duration, and nutritional outcome of acute, watery diarrhea in children. Pediatrics 1993;92:241--7.

Dietary Therapy of AGE

• A reduction in the duration of antibiotic-associated diarrhea has been demonstrated among older infants and toddlers fed formula with added soy fiber.

– Burks AW, Vanderhoof JA, Mehra S, Ostrom KM, Baggs G. Randomized clinical trial of soy formula with and without added fiber in antibiotic-induced diarrhea. J Pediatr 2001;139:578--82.

Dietary Therapy of AGE

• The BRAT diet is unnecessarily restrictive and, similar to juice-centered diets, can provide suboptimal nutrition for the patient's nourishment and recovering gut.

• Severe malnutrition can occur after gastroenteritis if prolonged gut rest or clear fluids are prescribed.

– Baker SS, Davis AM. Hypocaloric oral therapy during an episode of diarrhea and vomiting can lead to severe malnutrition. J Pediatr Gastroenterol Nutr 1998;27:1--5.

Pharmacologic Therapy

• Because viruses are the predominant cause of acute diarrhea in developed countries, the routine use of antimicrobial agents for treating diarrhea is not indicated.

• Nonspecific antidiarrheal agents, antimotility agents, antisecretory drugs, and toxin binders (e.g., cholestyramine), are commonly used among older children but none of these drugs address the underlying causes of diarrhea, specifically increased secretion by intestinal crypt cells.

Pharmacologic Therapy

• Reliance on pharmacologic agents shifts the therapeutic focus away from appropriate fluid, electrolyte, and nutritional therapy, can result in adverse events, and can add unnecessarily to the economic cost of illness.

• Because acute diarrhea is a common illness, cost-effective analyses should be undertaken before routine pharmacologic therapy is recommended.

Supplemental Zinc Therapy

• Multiple reports have linked diarrhea and abnormal zinc status, including increased stool zinc loss, negative zinc balance, and reduced tissue levels of zinc.

• In India, zinc supplementation was associated with a decrease in both the mean number of watery stools per day and the number of days with watery diarrhea.

– Sazawal S, Black RE, Bhan MK, Bhandari N, Sinha A, Jalla S. Zinc supplementation in young children with acute diarrhea in India. N Engl J Med 1995;333:839--44.

Supplemental Zinc Therapy

• Prophylactic zinc supplementation in India has been associated with a substantially reduced incidence of severe and prolonged diarrhea, two key determinants of malnutrition and diarrhea-related mortality.

– Bhandari N, Bahl R, Taneja S, et al. Substantial reduction in severe diarrheal morbidity by daily zinc supplementation in young north Indian children. Pediatrics 2002;109:e86.

Supplemental Zinc Therapy

• In Peru, zinc administration was associated with a reduction in duration of persistent diarrhea.

– Penny ME, Peerson JM, Marin RM, et al. Randomized, community-based trial of the effect of zinc supplementation, with and without other micronutrients, on the duration of persistent childhood diarrhea in Lima, Peru. J Pediatr 1999;135(2 Pt 1):208--17.

Supplemental Zinc Therapy

• In developing countries, zinc supplementation was beneficial for treating children with acute diarrhea and as a prophylactic supplement for decreasing the incidence of diarrheal disease.

– Bhutta ZA, Black RE, Brown KH, et al. Prevention of diarrhea by zinc supplementation in children in developing countries: pooled analysis of randomized controlled trials. Zinc Investigators' Collaborative Group. J Pediatr 1999;135:689--97.

– Bhutta ZA, Bird SM, Black RE, et al. Therapeutic effects of oral zinc in acute diarrhea in children in developing countries: pooled analysis of randomized controlled trials. Am J Clin Nutr 2000;72:1516--22.

Supplemental Zinc Therapy

• A number of trials have supported zinc supplementation as an effective agent in treating and preventing diarrheal disease.

• Further research is needed to identify the mechanism of action of zinc and to determine its optimal delivery to the neediest populations.

Functional Foods - Definitions

• Functional foods can be defined as foods that have an effect on physiologic processes separate from their established nutritional function.– Probiotics are live microorganisms in fermented foods

that promote optimal health by establishing an improved balance in intestinal microflora.

– Prebiotics are complex carbohydrates used to preferentially stimulate the growth of health-promoting intestinal flora.

Functional Foods - Probiotics

• Reviews have evaluated studies of probiotic use in preventing or reducing the severity or duration of diarrheal illnesses among children.

– Vanderhoof JA, Young RJ. Use of probiotics in childhood gastrointestinal disorders. J Pediatr Gastroenterol Nutr 1998;27:323--32.

• One meta-analysis concludes that Lactobacillus species are both safe and effective as treatment for children with infectious diarrhea.

– Szajewska H, Kotowska M, Mrukowicz JZ, Armanska M, Mikolajczyk W. Efficacy of Lactobacillus GG in prevention of nosocomial diarrhea in infants. J Pediatr 2001;138:361--5.

Functional Foods - Probiotics

• A positive recommendation emerges from a meta-analysis of probiotic use in antibiotic-associated diarrhea.

– D'Souza AL, Rajkumar C, Cooke J, Bulpitt CJ. Probiotics in prevention of antibiotic associated diarrhoea: meta-analysis. BMJ 2002;324:1361--6.

Functional Foods - Prebiotics

• The oligosaccharides in human milk have been called the prototypic prebiotic because they foster growth of lactobacilli in the colon of neonates.

– Dai D, Walker WA. Protective nutrients and bacterial colonization in the immature human gut. Adv Pediatr 1999;46:353--82.

• Early data linked higher intake of breast milk oligosaccharides with a lowered incidence of acute diarrhea.

– Morrow A, Ruiz-Palacios G, Altaye M, et al. Human milk oligosaccharides are associated with protection against diarrhea in breast-fed infants. Ped Res 2003;53:167A.

Functional Foods - Prebiotics

• Two randomized trials of prebiotic supplemented infant cereal did not demonstrate a reduced incidence of diarrheal disease among infants and children living in an urban economically depressed area.

– Duggan C, Penny ME, Hibberd P, et al. Oligofructose-supplemented infant cereal: 2 randomized, blinded, community-based trials in Peruvian infants. Am J Clin Nutr 2003;77:937--42.

• Specific recommendations regarding their use should await further well-controlled human trials.

Choice of ORS

Choice of ORS

• In 1975, WHO and the United Nations Children's Fund (UNICEF) agreed to promote a single ORS (WHO-ORS) containing (in mmol/L) sodium 90, potassium 20, chloride 80, base 30, and glucose 111 (2%) for use among diverse populations.– This composition was selected to allow for a single

solution to be used for treatment of diarrhea caused by different infectious agents.

– WHO-ORS has been demonstrated during >25 years of use to be safe and effective for children and adults with all types of infectious diarrhea.

Choice of ORS

• However, a reduced osmolarity ORS has been associated with less vomiting, less stool output, and a reduced need for unscheduled intravenous infusions.

• Subsequent clinical research, documented in multiple controlled trials and summarized in a meta-analysis, has supported adoption of a lower osmolarity ORS.

– Hahn S, Kim Y, Garner P. Reduced osmolarity oral rehydration solution for treating dehydration due to diarrhoea in children: systematic review. BMJ 2001;323:81--5.

Choice of ORS

• On the basis of those and other findings, UNICEF and WHO organized a consultation on oral rehydration that recommended a reduced osmolarity solution for global use.

– World Health Organization. Reduced osmolarity oral rehydration salts (ORS) formulation. New York, NY: UNICEF House, 2001.

Choice of ORS

• In May 2002, WHO announced a new ORS formulation consistent with these recommendations, with 75 mEq/L sodium, 75 mmol/L glucose, and total osmolarity of 245 mOsm/L.

– World Health Organization. Oral rehydration salts (ORS): a new reduced osmolarity formulation. Geneva, Switzerland: World Health Organization, 2002.

• The composition of available oral rehydration solutions is distinct from other beverages frequently used inappropriately for rehydration.

Choice of ORS

Barriers to ORS

• An informal survey of hospital Internet sites revealed outdated recommendations for treating diarrhea that include nonstandard fluids.

• A case report of one child whose care was compromised by following advice obtained from a prominent pediatric hospital's Internet site highlights the continued gap between knowledge and practice and the ongoing need to disseminate accurate information regarding oral rehydration.

– Crocco AG, Villasis-Keever M, Jadad AR. Two wrongs don't make a right: harm aggravated by inaccurate information on the Internet. Pediatrics 2002;109:522--3.

Barriers to ORS

• The advice on the Internet site specified:– “Give clear fluids every 2 to 3 hours. These

may include Pedialyte (Abbott Laboratories, Abbott Park, IL), flat cola, ginger ale, tea with sugar, Kool Aid (Kraft Foods, East Hanover, NJ), or Jello (Kraft Foods, East Hanover, NJ)”

– “Stop all regular foods and fluids”– “For children drinking regular milk, give no

milk or milk products for 1 week”

Barriers to ORS

• Among patients, barriers to using ORS and continued nutrition during diarrheal disease include:– cultural practices– lack of parental knowledge– lack of training of medical professionals– cost of commercially available ORS

• Among physicians, preference for IV hydration, even where evidence indicates improved results from oral rehydration remains a major barrier

Future Possibilities for ORS

• Potential future additives to ORS include– substances capable of liberating short-chain

fatty acids and partially hydrolyzed guar gum– probiotics– prebiotics– zinc– protein polymers / amino acids

Conclusions I

• Treatment of acute diarrhea can rely upon the simple and effective therapy of oral rehydration.

• The critical co-principle of early resumption of feeding of children immediately upon rehydration has also gained wide acceptance.

• Recent advances include recognition for the role of zinc supplementation in reducing disease severity and occurrence, and development of an oral rehydration solution of lower osmolarity for global use.

Conclusions II

• ORT is suitable for use among children throughout the world.

• If the principles of therapy outlined in this report are accepted by all levels of the medical community and if education of parents includes teaching them to begin ORT at home, numerous deaths and unnecessary clinic visits and hospitalizations can be avoided.

ShiloThat’s all folks!