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with which they are often associated. In practical terms,since they may be easier to diagnose retrospectively inpatients with meningitis, if there is any doubt whatsoever atthe time of presentation it is probably wisest to investigateand treat them as fits, until proved otherwise.
CHRONIC DIARRHOEA IN CHILDREN—ANUTRITIONAL DISEASE
CHRONIC diarrhoea of infancy is a symptom, not adisease. It has a heterogeneous aetiology, is often difficult tomanage, and still carries a considerable mortality. In youngchildren the condition can be alarming and has sometimesbeen labelled "intractable diarrhoea of infancy".1 Avery’sdefinition required an onset within the first three months oflife, a persistence of more than three stools per day for over 2weeks, and the absence of detectable bacterial pathogens.Not all published series fulfil these criteria. Failure to thriveand malnutrition are basic components and it has been called"a nutritional disease". In such small infants the mortalityrate may exceed 50% and intractable may be the
appropriate description since all attempts to replace lostfluid and provide enough nourishment fail.
Increasing attention has rightly been paid to thenutritional consequences of prolonged diarrhoea and theneed for vigorous alimentation in treatment.2,4 Chronicdiarrhoea is a nutritional disorder but the network and
pathways of this association are complex. The
pathophysiology is, in brief, either absorption failure fromvillous injury or excessive enterocyte secretion, or both.Mucosal damage may be the result of infections, abnormalbacterial colonisation of the small intestine, hypersensi.tivityto dietary proteins, bile-acid malabsorption, andmalnutrition itself. An inflammatory response may initiateabnormal secretion in the presence of crypt-cellproliferation and villous-cell atrophy. The latter leads tosecondary disaccharidase deficiencies and carbohydrateintolerance. Structural damage results in a protein-losingenteropathy. Malabsorption of fats, proteins, and
carbohydrates contributes to osmotic diarrhoea and luminalbacterial overgrowth.
In order to break this vicious spiral various therapies areindicated. Specific treatments are required for a number ofconditions and drugs are effective in some cases.5.6 Theinitial steps, as with acute diarrhoea, is the replacement offluid and electrolytes, but without adequate nourishmentthe condition can only deteriorate. After the development ofelemental nutrients and the possibility of central venousfeeding, total parenteral nutrition. (TPN) was introduced.7,8TPN, particularly in children with impaired defence
mechanisms, carries a high risk of infection as well asmechanical and metabolic complications. Thus catheters
1. Avery GB, Vallavicencio D, Lilly JR, Randolph JG. Intractable diarrhea in earlyinfancy. Pediatrics 1968; 41: 712-22.
2. Lo CW, Walker WA. Chronic protracted diarrhea of infancy, a nutritional diseasePediatrics 1983; 72: 786-800
3. Larcher VF, Shepherd R, Francis DE, Harries JT Protracted diarrhoea in infancy.Analysis of 82 cases with particular reference to diagnosis and management. Arch
Dis Child 1977; 52: 597-605.4 Walker-Smith JA, McNeish AS, eds Diarrhoea and malnutrition in childhood.
London. Butterworths, 1986.5. Sandhu BK, Tripp JH, Milla PJ, Harries JT. Loperamide in severe protracted
diarrhoea. Arch Dis Child 1983; 58: 39-43.6. Hill ID, Mann MD, Househam KC, Bowie MD. Use of oral gentamicin,
metronidazole and cholestyramine in the treatment of severe persistent diarrhoea ininfants. Pediatrics 1986; 77: 477-81.
7 Lloyd-Still JD, Shwachman H, Filler RM. Protracted diarrhea of infancy treated byintravenous alimentation Am J Dis Child 1973; 125: 358-64.
8. Winters RW Total parenteral nutrition in pediatrics. The Borden Award address.Pediatrics 1975; 56: 17-23.
can slip, fracture, become malpositioned, and cause localthrombosis, and resting the bowel from the role of absorbingnourishment often results in deterioration rather than
improvement in its function. Intraluminal food stimulatesthe mucosa in a number of ways: it provides nutrients for theenterocytes, enhances cellular proliferation, and inducesenzymes. Feeding also initiates non-luminal factors, bothneuronal and hormonal, which stimulate the bowel. Restingthe bowel results not in healing but atrophy.9 In acutediarrhoea, initial starvation was the accepted managementfor many years. As long ago as 1948 Chung presentedevidence that this practice was detrimental10.11 and morerecent studies confirm that early reintroduction of milk isbeneficial. 12,13 Molla et al have shown that even in acutediarrhoea over 50% of ingested nutrients are absorbed.14The only genuine reason for TPN is in patients withinadequate length and function of the bowel, but in
protracted diarrhoea enteral feeding is still very valuable.9,ls- Controlled comparisons between TPN and differentforms of alimentary nourishment suggest that use of thealimentary tract is both safer and more effective.16-18 InOrenstein’s small study 13 infants with protracteddiarrhoea were randomly allocated to one of three regimens- TPN, continuous enteral nutrition (CEN), or
intermittent oral nutrition (ION). Of the more severely illchildren, those on CEN had a return to normal stools and animprovement of their nutritional state in an average of 2-8weeks, while those on the TPN regimen took an average of9-8 weeks to show the same clinical improvement. Severityof malnutrition was measured by a standard D-xylose test.Those on the CEN regimen improved in 2-4 weeks, whilethose treated with TPN took 7-12 weeks to respond. TheTPN group undoubtedly had a smaller stool output than theCEN group during the first 2 days of treatment (57 ml/dayvs 214) but ultimately those who were nourished via thebowel recovered more rapidly and completely. ION wasused only in milder cases and small numbers did not permitany useful comparisons. Complications were almost
exclusively limited to the TPN group and TPN was moreexpensive because of higher pharmacy costs and longer stayin hospital. Glick and Hollander19 have lately pointed outthat although it is possible to maintain individuals for longperiods on TPN, even if this is undertaken at home the risksare considerable and the cost in the USA is$800-$1600/week. ’
9. Greene HL, McCabe DR, Merenstein GB Protracted diarrhea and malnutrition ininfancy: changes in intestinal morphology and disaccharidase activities duringtreatment with total intravenous nutrition or oral elemental diets J Pediatr 1975,87: 695-704.
10. Chung AW. The effect of oral feeding at different levels on the absorption of food stuffsin infantile diarrhea. J Pediatr 1948; 33: 1-13.
11. Chung AW, Viscorova B. The effect of early oral feeding versus early oral starvation onthe course of infantile diarrhea. J Pediatr 1948; 33: 14-22.
12. Dugdale A, Lovell S, Gibbs V, Ball D Refeeding after acute gastro-enteritis: acontrolled study. Arch Dis Child 1982; 57: 76-78
13 Maudgal DP, Bradshaw J, Wansbrough-Jones MH, Lambert HP Management ofacute gastroenteritis in children. Br Med J 1985; 290: 1287
14 Molla AM, Molla A, Sarker SA, Rahaman MM Food intake during and afterrecovery from diarrhoea in children. In. Chen LC, Scrimshaw NS, eds. Diarrhoeaand malnutrition. New York Plenum, 1983 113-23.
15. Weizman Z, Schmueli A, Deckelbaum RJ Continuous nasogastric drip elementalfeeding. Am J Dis Child 1983; 137: 253-55.
16 Parker P, Stroop S, Greene H A controlled comparison of continuous versusintermittent feeding in the treatment of infants with intestinal disease J Pediatr1981; 99: 360-61.
17. Bennegard K, Lindmark L, Wickstom I, Schersten T, Lundholm K A comparativestudy of the efficiency of intragastric and parenteral nutrition in man Am J ClinNutr 1984; 40: 752-57
18. Orenstein SR. Enteral versus parenteral therapy for intractable diarrhea of infancy: Aprospective randomised trial. J Pediatr 1986, 109: 277-86.
19. Glick ME, Hollender D. Nutrition-selected issues. In Kem F, Blum AL, eds Thegastroenterology annual 3. Amsterdam Elsevier, 1986 514-27
What are the safest and most effective nutrients for enteralnutrition in children with chronic diarrhoea? A formulabased on comminuted cliicken3 and elemental diets2O.21 are
being used, but there is some evidence that free aminoacidsare less well absorbed.22 Human milk has been foundeffective in some cases when other enteral nutrients havefailed.23Most cases of protracted diarrhoea of infancy occur in the
tropical countries with poor environmental hygiene.24 Theresearch findings about the benefits of enteral nutrition areespecially relevant for these countries in which mostchildren with chronic diarrhoea live and die. In
suboptimum conditions the dangers of TPN are magnifiedand the method is contraindicated. Giving fluid by mouthhas transformed the management of acute diarrhoea 25 andlikewise the alimentary tract is the most effective way to treatthe malnutrition of chronic diarrhoea. Use the bowel, this isboth the natural and the best way to treat diarrhoea.
THE CHEMORECEPTOR TRIGGER ZONEREVISITED
EVERY medical student since the 1950s has learned of the
importance of the chemoreceptor trigger zone (CTZ) in thevomiting reflex to certain blood-borne chemicals.12 Locatedon the floor of the 4th ventricle within the area postrema, it
presents an incomplete blood-brain barrier and senseschemical stimuli such as apomorphine (classically) as well asother opioids, ipecacuanha, digoxin, nicotine, levodopa, andvarious cytotoxic agents which can provoke emesis whenpresent in the blood in sufficient concentration. Ablation ofthe CTZ interferes with this vomiting reflex but leavesintact the vomiting provoked by intragastric coppersulphate.
In some ways the CTZ has stood the test of time; itsclinical importance has been emphasised by reports ofpatients with brain tumours localised to this area who
presented with vomiting that was relieved by discreteplacement of surgical tensions.3 However, it seems doubtfulthat initiation of chemically mediated vomiting is its onlyfunction. Moreover, it is but one of several inputs to thenearby vomiting centre; the roles of afferent informationfrom the gastrointestinal tract, other viscera, the labyrinth,vestibular nuclei, cerebellum, and cortex as well as otherareas of the central nervous system are in many instancesunclear. Even for the CTZ the mechanisms by which it isstimulated by chemically unrelated substances are largelyunknown.The many doubts and few certainties about the
mechanism of nausea and vomiting have lately been
20. Tim LO, Odes HS, Duys PJ, Novis BR, Bank S, Helman CA The use of an elementaldiet in gastro-intestinal diseases. S Afr Med J 1976, 50: 1752-56.
21. Gobio-Casali L, Gambaretto G, Astolfi R. Constant flow enteral feeding with anelemental diet in the treatment of severe protracted diarrhea in early childhoodPediatr Med Chir 1985; 7: 85-99
22 Lindblad BS, Rahimtoola RJ, Hafiz-ur-Rehman, et al Plasma free aminoacid levelsduring the initial rehabilitation of protein-energy malnutrition with protracteddiarrhoea using a free aminoacid-glucose diet. Acta Paediatr Scand 1978, 67:335-43.
23 Macfarlane PI, Miller V Human milk in the management of protracted diarrhoea ofinfancy. Arch Dis Child 1984; 59: 260-65.
24 Synder JD, Merson MH The magnitude of the global problem of acute diarrhoealdisease: a review of active surveillance data. Bull WHO 1982; 60: 605-13
25. Editorial Water with sugar and salt. Lancet 1978, ii 300-01.1 Borison HL, Brizzee KR. Morphology of emetic chemoreceptor tngger zone in the cat
medulla ablongata Proc Soc Exp Biol Med 1951; 77: 38-42.2 Borison HL, Wang SC Physiology and pharmacology of vomiting. Pharmacol Rev
1953; 5: 193-230.3. Lindstrom PA, Brizzee KR. Relief of intractable vomiting from surgical lesions in area
postrema. J Neurosurg 1962; 19: 228-36.
rehearsed in the proceedings’ of a symposium on the subjectwhich was held in Oxford in 1984. Some of the areas ofdoubt are profound. Thus, the problems of motion sicknessare all too obvious, whether to the man on the Claphamomnibus, the naval recruit, or the majority of astronauts, butthe evolutionary advantage is far from clear. Suggestionsthat motion sickness is due to discord between different
sensory stimuli are not illuminating, but the topic is
fundamentally important. Susceptibility to motion sicknessseems to predict both postoperative and chemotherapy-induced nausea and vomiting,5,6 perhaps because motionsickness itself depends on an intact chemoreceptor triggerzone.’ The function of this cubic millimeter of brain tissuetherefore seems to extend beyond the mediation of
chemically induced emesis.Vomiting induced by cytotoxic chemotherapy may help
understanding of the nature of its function. Its severity andspeed of onset relate to the speed with which different drugsinhibit enzyme activity. Thus, cisplatin and streptozotocin,which affect proteins directly, induce severe vomitingrapidly in most people, whereas vincristine and vinblastine,which inhibit cell division, are among the least emetogenic,and drugs whose major impact is on RNA synthesis,(actinomycin, cyclophosphamide, adriamycin &c) are
intermediate. Harris4,8 has advanced the provocativehypothesis that emesis occurs because of interference withenzymes responsible for breakdown of a neurotransmitter(possibly enkephalins). Like all the best hypotheses this isnovel, surprising, and specific, but its testability is limitedby the possibility that enkephalins (in different neural sites)both stimulate and inhibit emesis.9 Moreover, suchobservations leave unresolved the question of how non-cytotoxic chemicals induce emesis.The symposium touched very little on how stimuli acting
within the stomach provoke emesis. Might there be achemoreceptor trigger zone within the stomach or intestinewhose membrane potential and rate of neuronal firing aredirectly influenced by chemicals such as copper sulphate?The idea, whilst speculative, is not unlikely. Certainly thereis at least one intragastric pacemaker with intrinsic
rhythmicity located to the mid-portion of the greater curvewhose normal activity is important for gastric emptying andwhose dysfunction may be associated with nausea andvomiting.10 Does this trigger zone (and there may be others)provide afferent information to the brain? Would inhibitionof protein synthesis affect the firing of such trigger zones?Would irradiation affect their activity since irradiation to theupper abdomen is especially emetogenic?"Much research in this area has traditionally been of
interest to and funded or conducted by the military becauseof the impact of motion sickness on their effeciveness.Perhaps, likewise, the problem of radiation vomiting maystimulate much needed advances in basic and appliedresearch and provide a silver lining to the nuclear cloudunder which we all live.
4 Davis CJ, Lake Bakaar GV, Grahame-Smith DG, eds Nausea and vomiting:mechanisms and treatment. Berlin Springer, 1986.
5 Purkis IE. Factors that influence post operative vomiting. Can Anaesth Soc J 1964; 11:335-48.
6. Frytak S, Moertel CG, Fallon O Jr. Delta-9-tetrahydrocannabinol as an antiemetic forpatients receiving cancer chemotherapy. Ann Intern Med 1979; 91: 825-30.
7. Wang SC, Chinn HI. Experimental motion sickness in dogs. Functional importance of chemoreceptor emetic trigger zone Am J Physiol 1954; 178: 111-16.
8 Harris AL. Cytotoxic-therapy-induced vomiting is mediated via enkephalin pathwaysLancet 1982; i: 714-16
9 Costello DJ, Borison HL Naloxone antagonises narcotic self blockade of emesis in thecat. J Pharmacol Exp Ther 1977; 203: 222-30
10. Vantrappen G, Janssens J, Coremans G, Jian R Gastrointestinal motility disorders.Dig Dis Sci 1986; 31: 5S-25S.
11 Gerstner HB Reaction to short term radiation in man. Ann Rev Med 1960; 11:389-402.