623

Management of Acute Diarrhoea

ACUTE diarrhoeal disease exacts a high toll in

morbidity and mortality, particularly in childrenunder three years of age in the less developed countries,where longitudinal studies of infants record incidencerates of 6-8 separate episodes of acute diarrhoea perchild per year.l,2 Rotavirus, the major viral pathogen,can account for 5-15% of episodes of infant diarrhoeain villages and about 30-40% of cases seen at a

treatment centre.2,3 The remaining diarrhoealinfections in infants are mainly bacterial, of whichenterotoxigenic Escherichia coli (ETEC),Campylobacter jejuni, shigella, and enteropathogenic Ecoli (EPEC) are the chief culprits. 1-6 The incidence ofdiarrhoea due to these bacteria is much lower in olderchildren and adults, indicating acquired immunity. Incontrast, when adults from industrialised countriesvisit less developed countries they often have diarrhoeadue to ETEC, shigella, and C jejuni, the major bacterialpathogens of infant diarrhoea in those countries. Theprincipal clinical manifestations of acute diarrhoealdisease are watery diarrhoea and dysentery (i.e., blood,pus, and mucus in stools), watery diarrhoea being farthe more common. Fever, nausea, vomiting, malaise,and abdominal cramps are variable and relate to the

offending pathogen. Loss of body water and

electrolytes can lead to dehydration, acidosis, shock,and death. Great strides have been made in thetreatment of diarrhoeal dehydration by means of oralglucose/electrolyte or sucrose/electrolyte solutions.’-"

1 Mata LJ. The children of Santa Maria Cauque: a prospective field study of health andgrowth. Cambridge, Massachusetts: MIT Press, 1978.

2 Black RE, Brown KH, Becker S, Abdul Alim ARM, Huq I. Longitudinal studies ofinfectious diseases and physical growth of children in rural Bangladesh. II.Incidence of diarrhea and association with known pathogens. Am J Epidemiol 1982;115: 315-24.

3 Black RE, Merson MH, Rahman ASMM, Yunus M, Alim ARMA, Huq I, Yolken RH,Curlin GT. A two-year study of bacterial, viral and parasitic agents associated withdiarrhea in rural Bangladesh. J Infect Dis 1980; 142: 660-64.

4 Blaser MJ, Glass RI, Huq MI, Stoll B, Kibriya GM, Alim ARMA Isolation of

Campylobacter fetus subsp. jejuni from Bangladeshi children. J Clin Microbiol 1980;12: 744-47.

5 Robins-Browne RM, Still CS, Miliotis MD, Richardson NJ, Koornhoff HJ, Freiman I,Schoub BD, Lecatsas G, Hartman E. Summer diarrhoea in African infants andchildren. Arch Dis Childh 1980; 55: 923-28.

6 de Mol P, Brasseur D, Hemelhof W, Kalala T, Butzler JP, Vis HL. Enteropathogenicagents in children with diarrhoea in rural Zaire. Lancet 1983; i: 516-18.

Oral rehydration is simple, practical, highly effective,and technologically appropriate for less developed aswell as developed countries, and is the keystone ofnational diarrhoeal disease control programmes.’-"Sugar/electrolyte solutions, while highly effective incombating dehydration and its consequences, do notdiminish the rate or volume of diarrhoeal stools; stoolvolume may in fact be increased with such therapy,though net balance is greatly on the side of absorption.In patients with extremely high rates of stool losses (asin patients with severe cholera early in their illness),especially if nauseated and vomiting, it is often not

possible to maintain fluid balance with oral

glucose/electrolyte solution alone.l2 Thus, health

workers, as well as the patients themselves, have beengreatly attracted by the concept of a pharmacologicalagent that would rapidly and effectively control thediarrhoea. For maximum impact in those areas of theworld where diarrhoea takes its greatest toll, the drugwould have to be highly effective, inexpensive, readilyavailable, and safe for use in children (especially at thevillage level) without close supervision.What is the place of adjunct therapy-that is,

measures in addition to sugar/electrolyte oral

rehydration solutions-in the treatment of diarrhoea?In particular, what is the value of antimotility andantisecretory agents and antibiotics? The four broadcategories of drug that have been used in man areantimicrobials (to eradicate the offending pathogen),antimotility agents, antisecretory drugs, andadsorbents. Few controlled studies have been done toevaluate the role of antibiotics in diminishing theseverity and duration of infant diarrhoea where thecausal agents are known. Numerous clinical studieshave shown that, in general, infants with non-choleradiarrhoea can be managed with oral therapy alone,without antibiotics.’-" By contrast, if dysentery is theclinical presentation, antibiotics effective againstshigella are indicated since they shorten the course andlessen the severity of shigellosis, as well as curtailingexcretion of the pathogen.13 Black et a1.l4 showed thatearly trimethoprim/sulphamethoxazole (TMP/SMZ)

7. Nalin DR, Levin MM, Mata LJ, DeCespedes C, Vargas W, Lizano C, Loria AR,Simhon A, Mohs E. Oral rehydration and maintenance of children with rotavirusand bacterial diarrhoeas. WHO Bull 1979; 57: 453-59.

8. Nalin DR, Levine MM, Mata LJ, DeCespedes C, Vargas W, Lizano C, Loria AR,Simhon A, Mohs E. Comparison of sucrose with glucose in oral therapy of infantdiarrhoea. Lancet 1978; ii: 227-29.

9. Palmer DL, Koster FT, Islam AFMR, Rahman ASM, Sack RB. Comparison of sucroseand glucose in the oral electrolyte therapy of cholera and other severe diarrheas. NEngl J Med 1977; 297: 1107-10.

10. World Health Organization. A manual for the treatment of acute diarrhoea. Geneva:WHO, 1980.

11. Santosham M, Daum RS, Dillman L, et al. Oral rehydration therapy of infantilediarrhea. A controlled study of well-nourished children hospitalized in the UnitedStates and Panama. N Engl J Med 1982; 306: 1070-75.

12. Nalin DR, Levine MM, Hormck RB, Bergquist EJ, Hoover D, Holley HP, WatermanD, van Blerk J, Matheny S, Sotman S, Rennels M. The problem of emesis duringoral glucose-electrolytes therapy given from the onset of severe cholera. Trans RoySoc Trop Med Hyg 1979; 73: 10-14.

13. Levine MM. Bacillary dysentery mechanisms and treatment. Med Clin N Am 1982; 66:623-38.

14. Black RE, Levine MM, Clements ML, Cisneros L, Daya V. Treatment of

experimentally induced enterotoxigenic Escherichia colt diarrhea with

trimethoprim, trimethoprim-sulfamethoxazole or placebo. Rev Infect Dis 1982; 4:540-45.

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therapy in adult volunteers with experimental ETECinfection significantly reduced the severity andduration of diarrhoea. In field studies of traveller’s

diarrhoea, DuPont et al.I5 applied this approach withsimilar success. Early TMP/SMZ treatment oftraveller’s diarrhoea (beginning after passage of thethird loose stool) is more rational than prophylaxis anddoes not interfere with an immune repsonse.Furthermore, TMP/SMZ is highly effective againstboth ETEC and shigella. Other specific indications forantimicrobials include known cholera (tetracycline),Giardia lamblia infection (quinacrine, metronidazole,or furazolidone), and Entamoeba histolytica infection(metronidazole). The effectiveness of antibiotics in

campylobacteriosis is still controversial. 16 I

Drugs that affect the motility of the intestine arecommonly used to treat chronic non-infectiousdiarrhoea in industrialised countries, sometimes withgood results. However, in less developed countriesthey are unnecessary and potentially harmful in

endemic or traveller’s diarrhoea because of an adverseeffect on the course of infections due to invasivebacterial enteropathogens such as shigella.13 For

example, guineapigs are ordinarily resistant to oralinfection with shigella;" however, if the animals arepretreated with antimotility agents such as paregoric,the same inoculum of shigella induces fatal enteritis."Another antimotility agent, diphenoxylate, extendedthe duration of fever and prolonged excretion of

shigella in experimental infection in man.18 Incontrolled trials in adults with cholera’9 and in infantswith non-cholera diarrhoea 20 diphenoxylate decreasedneither the number or volume of stools nor the

requirements for rehydration solutions.Many drugs have been reported to have antisecretory

properties in animal models of infectious or toxigenicdiarrhoea but few have been tested by controlled trialsin man. There is no adequate experimental basis onwhich to recommend the use of these agents in acutediarrhoeal disease; moreover, all have notable side-effects or a low therapeutic index and their efficacy ismarginal at best. Chlorpromazine in cholera has shownthe most impressive effects but the doses that give thegreatest antisecretory effects can cause sedation thatinterferes with the patient’s ability to drink oral

rehydration solutions.2l,22 Bismuth subsalicylate givento young adults with traveller’s diarrhoea greatly

15. DuPont HL, Reves RR, Galindo E, Sullivan PS, Wood LV, Mendiola JG. Treatmentof traveler’s diarrhea with trimethoprim/sulfamethoxazole and with trimethoprimalone. N Engl J Med 1982; 307: 841-44

16. Anders BJ, Lauer BA, Paisley JW, Reller LB. Double-blind placebo controlled trial oferythromycin for treatment of Campylobacter enteritis. Lancet 1982; i: 131-34.

17. Formal SB, Abrams GD, Schneider H, Spnnz H. Experimental shigella infections. VI.Role of the small intestine in an experimental infection in guinea pigs. J Bacteriol1963; 85: 119-25.

18. DuPont HL, Hornick RB. Adverse effect of lomotil therapy in shigellosis JAMA 1973;225: 1525-28.

19. De S, Sircar BK, De SP. Diphenoxylate hydrochloride (lomotil) in the management ofcholera. Ind J Med Res 1975; 63: 469-74.

20 Portnoy BL, DuPont HL, Pruitt D, Abdo JA, Rodriguez JT. Antidiarrheal agents inthe treatment of acute diarrhea in children. JAMA 1976; 236: 844-46.

21 Rabbani GH, Greenough WB III, Holmgren J, Lonnroth I. Chlorpromazine reducesfluid loss in cholera. Lancet 1979; i: 410-12.

22. Rabbani GH, Greenough WB III, Holmgren J, Kirkwood B Controlled trial of

chlorpromazine as antisecretory agent in patients with cholera hydratedintravenously. Br Med J 1982; 284: 1361-64

decreased the number of unformed stools and

subjective complaints; 3 there was, however, no

difference in stool water or total weight of stools passedby the bismuth-subsalicylate group versus the controlgroup, suggesting that the effect may not have involvedan antisecretory mechanism.23 Moreover, the doses ofbismuth subsalicylate used in the 31/2 h course oftreatment were quite high (240 and 480 ml), probablyruling out comparable studies in children.In view of the antisecretory effect of loperamide

against cholera toxin and other secretagogues, and itsrelative absence of central nervous system effects incontrast with other opioid derivatives,24 much debatehas raged over a possible role for loperamide intreatment of acute infectious diarrhoeas in infancy.However, the few controlled paediatric studiesconducted so far do not show this drug to be effective.Owens et al.25 gave loperamide in a dose of0’2 2 mg/kgor placebo to children three months to four years of agewith acute (mainly rotavirus) diarrhoea in Benghazi(Libya) and Liverpool. While causing no adversereactions, loperamide at this dosage did not diminishduration of diarrhoea or hospital stay, nor did itenhance weight gain.Adsorbents such as kaolin and charcoal are thought

to act by binding free bacterial enterotoxin. However,results in clinical studies have been disappointing ininfectious diarrhoea. Kaolin was completelyineffective in cholera.26 In infants with non-choleradiarrhoea kaolin made the stools look more formed butstool weight and stool water content did not differ fromthose in controls.2O Stoll et a1. 27 reported some successin oral treatment with a charcoal GMl gangliosidepreparation (GMl is the enterocyte receptor for choleratoxin). It is difficult to see any practical application forthis finding.Thus oral rehydration in watery diarrhoea, together

with antibiotics in dysentery, remains the mainstay oftherapy. However, several reports suggest that oralrehydration solutions can be modified to enhanceintestinal absorption so greatly that stool volumedecreases by up to 50%. Nalin et al .21 reported in 1970that an oral rehydration solution containing bothglucose and glycine (as the actively transportedsubstrates to promote water and electrolyte absorption)was significantly better than a solution containing onlyglucose and electrolytes. They showed that stoolvolume and duration of watery diarrhoea were lessenedin the glucose/glycine group. Mahalanabis29 in

23. DuPont HL, Sullivan P, Pickering LK, Haynes G, Ackerman PB. Symptomatictreatment of diarrhea with bismuth subsalicylate among students attending aMexican University. Gastroenterology 1977; 73: 715-18.

24. Sandhu BK, Tripp JH, Candy DCA, Harries JT. Loperamide: studies on its

mechanism of action. Gut 1981; 22: 658-62.25. Owens JR, Broadhead R, Hendrickse RG, Jaswal OP, Gangal RN. Loperamide in the

treatment of acute gastroenteritis in early childhood. Report of a two centre, double-blind, controlled clinical trial. Ann Trop Paediatr 1981; i: 135-41.

26. Nalin DR, Cash RA. Kaolin and cholera. J Pak Med Ass 1970; 20: 177-82.27. Stoll B, Holmgren J, Bardhan PK, Hug I, Greenough WB III, Fredman P,

Svennerholm L. Binding of intraluminal toxin in cholera: trial of GM, gangliosidecharcoal Lancet 1980; ii: 888-91.

28. Nalin DR, Cash RA, Rahman M, Yunus Md. Effect of glycine and glucose on sodiumand water absorption in patients with cholera. Gut 1970; 11: 768-72.

29. Mahalanabis D. In search of a super oral rehydration solution: can optimum use oforganic solute mediated transport lead to the development of an absorptionpromoting drug? Unpublished.

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Calcutta has lately re-examined the efficacy of aglucose/glycine electrolyte solution, this time in oralrehydration of infantile diarrhoea. The glucose/glycinecombination was superior to the standard

glucose/electrolyte solution. Most notable was theobservation that the stool volume in the

glucose/glycine group was significantly less than in theglucose group. Other reports describe rice powder as asubstrate.29-32 Rice powder provides both sugars andaminoacids that are actively transported, therebypromoting electrolyte and water absorption. Thedecade of the 1970s saw oral rehydration with

sugar/electrolytes become established as the life-savingbasis of diarrhoeal therapy. The 1980s should see thedevelopment of oral rehydration "super-solutions"that enhance intestinal absorption so potently that theyalmost turn off diarrhoeal stool losses ofbody water andelectrolytes.

Diet and Hepatic EncephalopathyTHE connection between hepatic encephalopathy

and nitrogen metabolism is undisputed, but its exactnature remains contentious. In the 1930s VanCaulaert’ and Kirk2 showed that encephalopathy andraised blood ammonia levels could be provoked incirrhotic patients by administration of ammoniumsalts. Several groups expanded3-9 these observations,such that by the mid 1950s it was generally acceptedthat dietary nitrogen, particularly protein and urea,could induce encephalopathy in susceptible patientswith liver disease. The biochemical pathway by whichthis occurred was not clear, but two features

emerged-firstly, that the toxins were partly derivedfrom bacterial action on the nitrogenous substrate inthe intestine;’"’" and, secondly, that ammonia, thougha strong contender, could not be solely responsible

30. Wong HB. Rice water in treatment of infantile gastroenteritis. Lancet 1981; ii: 102-03.31. Molla AM, Sarker SA, Hossain M, Molla A, Greenough WB III. Rice-powder

electrolyte solution as oral in diarrhoea due to Vibrio cholerae and Escherichia coli.Lancet 1982; i: 1317-19.

32 Patra FC, Mahalanabis D, Jalan KN, Sen A, Banerjee P Is oral rice electrolyte solutionsuperior to glucose electrolyte solution in infantile diarrhoea? Arch Dis Childh 1982;57: 910-12.

1 Van Caulaert C, Deviller C, Halff M Troubles provoqués par l’ingestion de selsammomacaux chez l’homme atteint de cirrhose de Laennec. Comptes Rendus SocBiol 1932; 111: 739-40.

2. Kirk E. Amino acid and ammonia metabolism in liver diseases. Acta Med Scand 1936;77: 147 (suppl)

3. Gabuzda GJ Jr, Phillips GB, Davidson CS Reversible toxic manifestations in patientswith cirrhosis of liver given cation-exchange resins. N Engl J Med 1952; 246:124-30

4 Phillips GB, Schwartz R, Gabuzda GJ, Davidson CS. The syndrome of impendinghepatic coma in patients with cirrhosis of the liver given certain nitrogenoussubstances. N Engl J Med 1952; 247: 239-46.

5. Schwartz R, Phillips GB, Seegmiller JE, Gabzuda GJ, Davidson CS. Dietary protein inthe genesis of hepatic coma N Engl J Med 1954; 251: 685-89.

6 Gaustad V. Transient hepatargy. Acta Med Scand 1949; 135: 354-63.7 Summerskill WHJ, Davidson EA, Sherlock S, Sterner E. The neuropsychiatric

syndromes associated with hepatic cirrhosis and an extensive portal collateralcirculation Quart J Med 1956; 25: 245-66.

8 Mcdermott WV Jr, Adams RD. Episodic stupor associated with an Eck fistula in ahuman subject with particular reference to the metabolism of ammonia. J Clin Invest1954, 33: 1-9.

9 Sherlock S, Summerskill WHJ, White LP, Phear EA. Portal-systemic encephalo-pathy-Neurological complications of liver disease Lancet 1954; ii: 455-57.

10 Silen W, Harper HA, Mawdsley DL, Weirich WL. Effect of antibacterial agents onammonia production within the intestines. Proc Soc Exp Biol Med 1955; 88: 138-40.

11 McDermott WV. Metabolism and toxicity of ammonia. N Engl J Med 1957, 257:1076-81

since blood levels correlated poorly with the degree ofencephalopathy. 4, 9This new information led to a therapeutic dilemma.

Until then, patients with chronic liver disease, oftenmalnourished and hypoalbuminaemic, had beentreated with a high-protein diet. The obvious step wasto try to reduce toxin production by dietary nitrogenrestriction and bowel cleansing, and Sherlock,9Summerskill,12 and Dawson" established the nowaccepted routine in hepatic encephalopathy of low-protein diet and oral broad-spectrum antibiotics. Savefor the introduction of lactulose,14 the interveningyears have seen no great therapeutic progress, thoughsome advances have been made in clarifying themetabolic abnormalities. Many reviewerslS-17 haveexamined the putative toxins and mechanisms. Thetoxins include mercaptans, short-chain fatty acids,aromatic aminoacids, and "middle molecules" as wellas ammonia. The evidence is strongest for ammoniabut Zieve’ persuasively argues that various toxins mayact synergically to augment ammonia’s toxicity. In thepast few years interest has centred more on aminoacidimbalance and several groups have recorded a relativeincrease in aromatic and decrease in branched chainaminoacids in the blood of patients with hepaticencephalopathy.ls-2l It is postulated that the

hyperammonaemia and increased amounts of aromaticaminoacids together induce a cerebral depletion ofdopamine and noradrenaline while at the same timecausing an accumulation of false neurotransmitters(octopamine and phenylethanolamine).22 At presentthere are data both to support and to contradict this

theory. Do any of the new data indicate that furtherdietary modifications may be beneficial? The standardhepatological23-ZS texts are at odds here. All adviseplentiful calories in the form of carbohydrate andrestriction of total protein intake to about 40 g a day,but some23,25 suggest greater benefit may be gained byaltering the nature of the dietary protein. Thisfundamental question has attracted little attention.

12. Summerskill WHJ, Wolfe SJ, Davidson CS. The management of hepatic coma inrelation to protein withdrawal and certain specific measures Am J Med 1957; 22:59-75.

13. Dawson AM, Mclaren J, Sherlock S. Neomycin in the treatment of hepatic coma.Lancet 1957; ii: 1263-68

14. Conn HP, Lieberthal MM The hepatic coma syndromes and lactulose. Baltimore:Williams and Williams, 1979 5-8.

15. Zieve L. The mechanisms of hepatic coma. Hepatology 1981; i: 360-65.

16. Schalm SW, De Groot GH. Hepatic encephalopathy In: Arias IM, Frankel M, WilsonJHP, eds. The liver annual. Amsterdam: Excerpta Medica, 1982: 250-62.

17. Crossley IR, Wardle EN, Williams R. Biochemical mechanisms of hepaticencephalopathy. Clin Sci 1983; 64: 247-52.

18. Smith A, Rossi-Fanelli F, Ziparol V, James H, Keane J, Soeters P The effect ofnormalization of plasma amino acids on hepatic encephalopathy in man. Surgery1976; 80: 77-91.

19 Iber F, Rosen H, Levenson S, Chalmers T. The plasma amino acids in patients withliver failure J Lab Clin Med 1957; 50: 417-25

20. Morgan MY, Milsom JP, Sherlock S. Plasma ratio of valine, leucine and isoleucine tophenylalanine and tyrosine in liver disease. Gut 1978; 19: 1068-73.

21. Eriksson LS, Persson A, Wahren J Branched-chain amino acids in the treatment ofchronic hepatic encephalopathy. Gut 1982; 23: 801-06.

22. Fischer JE, Baldeosarini RJ False neurotransmitters and hepatic failure. Lancet 1971;ii: 75-79.

23. Sherlock S. Diseases ofthe liver and biliary system, 6th ed. Oxford: Blackwell ScientificPublications, 1981

24. Fischer JE Portasystemic encephalopathy. In: Wright R, Alberti KGMM, Karran S,Millward-Sadler GH, eds. Liver and biliary disease. Philadelphia Saunders, 1979:973-1001.

25. Zieve L. In SchifF L, Schiff E, eds. Diseases of the liver, 5th ed. PhiladelphiaLippincott, 1982.