perspectives in nutrition

The American JournalofClinical Nutrition 33: MARCH 1980, pp. 637-663. Printed in U.S.A. 637

The treatment of acute diarrhea in children

An historical and physiological perspective13

Norbert Hirschhorn, M.D.

ABSTRACT This review examines the historical, physiological, clinical, and epidemiohogical

evidence to support a method of therapy for children’s diarrhea that may be recommended for

general acceptance. The understanding and use of fluid and nutritional therapy of acute diarrheain childhood have progressed over the years to a point where acute mortality can be reduced tonearly zero. At the same time, the ill effects on electrolyte balance and nutrition may be reducedto a minimum. Through use of an oral glucose electrolyte solution with a carefully designed

composition, physiologically correct treatment may now be so simplified and inexpensive as to be

readily available to the remote, under-served areas of the world where most of the morbidity exists;

and be useful as well to more sophisticated settings. The method of therapy recommended in thispaper has several important departures from traditional teaching. It advocates rapid restoration of

extracehlular fluid with a polyelectrohyte solution containing sodium, base and potassium; use of an

oral glucose electrolyte solution for repletion of those not in shock and for maintenance; use of asingle oral glucose electrolyte solution for all age groups, regardless of diagnosis; and quite early

feeding with tolerated foods. Sodium loads given are generally higher than advocated by standard

pediatric teaching. The origins of that teaching and support for the newer approach come from adetailed analysis ofcurrent knowledge in the epidemiological, clinical, and physiological aspects of

diarrheal illness. Am. J. Clin. Nutr. 33: 637-663, 1980.

“Copying from one book, it is said, is plagiarism, whilecopying from two books is research.” (1)

Acute diarrhea affects nearly 500 miffionchildren annually worldwide (2), is the lead-ing cause of death in children under 4 yearsold (3), and is a substantial cause of under-

nutrition (4). This is the grim situation nowin the poor under-served parts of the world,but it was the same in the West 70 years ago(5). Since then, sanitation, protected watersupplies, and better medical therapy havedramatically reduced the incidence of acutediarrhea, with a nearly hundred fold drop inmortality (6).

Nonetheless, in the West, diarrhea stillranks second to respiratory diseases as thecause ofnonsurgical pediatric admissions (6);approximately one-half the children receiveintravenous therapy (7). Diarrhea causes one-fourth of the avoidable deaths in hospitalizedchildren (8).

Over the past three decades the study of

acute diarrhea in children (and adults) hasled to important knowledge ofthe physiologyof body fluids and the intestine, and of ther-

apy. Table 1 suggests how this knowledgerelates to the falling mortality rate. The es-

sential elements, known sinceDarrow’s work(18-20) are adequate replacement of sodiumchloride, base, potassium and volume losses,and maintenance of nutrition. Workers atclinical centers in Asia, Africa, and LatinAmerica recognized the need to translatethese elements into a rational treatment thatwas simultaneously simple, cheap, and appli-

‘ From The John Snow Public Health Group, Boston,Massachusetts 021 1 1.

2 Supported by Management Sciences for Health, a

nonprofit foundation, Boston, Massachusetts.

a Address reprint requests to: Norbert Hirschhorn,M.D., John Snow Public Health Group, Inc., 141 Tre-

mont Street, Boston, Massachusetts 02 1 1 1.

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Year Event Hospitalmortality

Over 75%

86%

33%

51%

12-33%

32%

6%

10%

1912 Sellards (10) describes acidosis in cholera and uses alkali.

Howhand and Marriot (1 l)describe acidosis in infantile diarrheaand give small doses of alkali, with brief improvement.

1926 Powers (12) uses intermittent blood, glucose, saline and bicar-bonate infusions, and prescribes prolonged fasting.

1928-1938 Hartmann (13) uses sodium lactate to relieve acidosis; recurrentdehydration, however, causes high mortality.

1931-1933 Kareitz and Schick (14-16) use continuous saline dextrose

infusions and recommend a 3-day fast.

1945 Mortality at Harriet Lane Home (Johns Hopkins) still quitehigh on regimen without potassium (17).

1946-1949 Darrow, at Hopkins, (17-20) does balance studies to measuresalt-H2O deficits in diarrhea; emphasizes use of potassium in

addition to saline, base and water. Prescribes 1-5 day fast.

1948 Chung (21) urges continued feeding in spite of diarrhea; mor-tality unaffected, disease not prolonged, nutrition enhanced,

but fluid balance more difficult to achieve.

1947-1958 Rapoport (22), Finberg and Harrison (23) and others (24)

describe hypernatremic dehydration.

1958 � Darrow’s solution (in mEq/L:Na�61,K�l8, base 27) as soleintravenous fluid in tropics (25, 26).

1959 Watten et al. (27) measure water and electrolyte loss in cholera.

1950’s-1960’s In the West, better understanding of hypernatremia (28, 29),careful tailoring of intake, and laboratory monitoring (30)

put treatment of diarrhea on a scientific footing.

l960’s-1970’s In Asia, simplified methods of treatment of cholera and non-cholera diarrheas developed at cholera research laboratories,

based on physiologic studies (31, 32) emphasize speed andlarge fluid volume for rehydration; simultaneous use of salt,

potassium, base; and early feeding.

1966-1979 Increasing use of oral glucose-electrolyte solutions in choleraand noncholera enteritis (33, 34).

0-5%

2-3%

0-2%

638 HIRSCHHORN

TABLE 1

Changes in hospital mortality of children’s diarrhea

1832 Latta (9) uses intermittent intravenous saline and alkali incholera. Most relapse when drip ceased.

12-24% for

hypernatremia

10%

cable under the adverse conditions and short-ages of the developing world.

The key elements ofthe method developedare: rapid restoration of salt and water deple-tion with simultaneous correction of acidosis,and administration of potassium; use of anoral glucose electrolyte solution for repletion4of those not in shock, and for maintenance;

use of a single polyelectrolyte intravenous

fluid and a single oral glucose electrolyte

4 “Volume repletion” and “volume depletion” are

more precise than “rehydration” and “dehydration.”

Still, the respective words will be used interchangeably

to mean electrolyte and water restoration or loss. The

word “fluid” also indicates solute and water rather thanwater alone.

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ACUTE DIARRHEA IN CHILDREN 639

8. Principal concerns Overhydration, hypernatremia,

persisting loose stools.

Under hydration, hyponatremia, un-

der-nutrition.

solution, for all age groups; and early feedingwith tolerated foods. This approach has beensuccessful both in well supplied hospitals (31-33), and, spectacularly, in Bangladesh refugeecamps under the worst of conditions (35).

But the approach deviates considerablyfrom conventional pediatric teaching. Table2 contrasts the differences in methods. Muchofcurrent pediatric teaching emphasizes slowrepletion of fluid losses; great concern overthe sodium load, especially for infants; tailor-ing of fluid therapy to each individual; andthe need to “rest the bowel” for several days.A classic presentation of this approach waswritten in 1974 by Blair and Fitzgerald (36).Given these differences, this paper has beenprepared with several aims in mind: to reviewthe historical development of current pediat-ric teaching about treatment of acute diar-rheal disease; to collect and synthesize in onereview the epidemiological, clinical, andphysiological data that explain both success-ful and unsuccessful treatment regimens; andon the strength of the synthesis, to reevaluatethe hypotheses upon which these differenttreatment regimens are based.

TABLE 2

Regimens and patients’ characteristics

The death rate in hospitals from acutediarrhea can and should be 2% or less,whether in a sophisticated urban hospital orin a makeshift tent ward in a rural area. Mostofthe excessive mortality that occurred in thepast (Table I) came soon after admission andwas due mostly to uncorrected volume deple-tion or electrolyte imbalance (3 1, 37-40).

Given the importance of the first day inthe fluid treatment ofsevere dehydration, theranges of a first 24-hr fluid regimen associ-ated with improved survival should be de-fmed. It is unlikely that such data will everbe generated prospectively, but a retrospec-tive analysis of reported experience may pro-vide clues. A literature search followed theserules for inclusion in the analysis: a study hadto specify clearly the first 24-hr volume andelectrolyte regimen (intravenous and oral)planned or actually received; the children hadto have been visibly dehydrated, requiring atleast some intravenous fluid; given the knownadverse effects of omitting potassium (Table1) and acidosis (41), regimens analyzed had

Comparison of two approaches to treatment of dehydrating diarrhea

1. The physiological model

2. Speed of rehydration

3. Choice of initial rehydratmg so-lution

4. Use of potassium

Traditional teaching

Varying degrees of dehydration

and tonicity require careful tal-

bring of fluid therapy.

24-48 hr

Hypotonic with sodium content

30-60 mEq/liter, especially for

infants.

Only after urination commences.

Recently dcveIo�

Within broad limits a simple and urn-

fled therapeutic approach may be

taken.

4-6 hr

Polyclectrolyte solution with sodium

content 80-130 mEq/liter for all

ages.

In polyelectrolyte solution.

5. Use of base Only for severe acidosis. In polyelectrolyte solution (bicarbon-

ate, lactate or acetate).

6. Use of oral fluids Small, infrequent sips of H20 in

first 24 hr.

Ad libitum intake of glucosc-elcctro-lyte solutions for those able to drink

(in mM/hiter:Na� 90, K�20,

HC0330, glucose 1 1 1). Need for

intravenous fluid can often be dim-mated.

7. Feeding Fasting for 24-48 1w, careful rein-

troduction of food.Tolerated feeds as soon as appetite

restored (usually within 6-24 hr) insmall frequent amounts.

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640 HIRSCHHORN

to specify inclusion of potassium and base atlevels of at least 1 mEq per kilogram bodyweight, respectively; and mortality reportedhad to be related to the diarrheal illness.Fifteen studies reporting 20 regimens metthese criteria (20, 25, 3 1, 32, 37, 38, 40, 42-49). All were published after 1945. Whenordered in terms of mortality, both higherand lower rates were described from Westernand tropical countries, in urban and ruralsettings, among infants and toddlers, and inchildren well or poorly nourished.

Five independent variables were analyzedagainst mortality: sodium load, total volume,“free water” volume, sodium load x totalvolume, and sodium concentration. All vari-ables were expressed as milliliters or miii-equivalents per kilogram of body weight asappropriate. Total volume and sodium loadincluded all intravenous and oral fluid andsodium intake in the first 24 hr of hospitali-zation. Free water was calculated as thatcomponent of fluid not bound to salt in termsof extracellular fluid sodium concentration(at a sodium concentration of 140 mEq/liter,a liter of solution has no free water, while oneat 70 mEq/liter has 500 ml free water); cal-culations for free water were further correctedfor the potassium given. A composite index,sodium load x total volume, was derived toexamine any augmenting effect of one on theother. Finally, the effective sodium concen-tration (in milliequivalents per liter) wascalculated by sodium load/total volume x1000.

The first four variables were plotted againstmortality. Since mortality cannot be less than0%, computer-calculated hyperbolic curvesrather than linear regressions were fitted tothe data (Fig. 1). This analysis is susceptibleto the hazards of a retrospective review ofmultiply disparate studies, and randomnesscannot be guaranteed since most outcomesare not published. Statistically significantnegative correlations with mortality werepresent for sodium load and the compositeindex, sodium load X total volume. A nega-tive correlation of borderline significance wasfound for total volume. A weakly positivecorrelation between free water volume andmortality was also found. The effective so-dium concentration of regimens associatedwith 6% mortality or greater averaged 60

mEq/liter; the effective sodium concentrationof regimens associated with 3% mortality orless averaged 77 mEq/liter; the difference,however, is statistically insignificant. At aminimum it can be said that, along withpotassium and base, the higher levels of so-dium-containing fluid administered werecompatible with improved survival, and mayhave contributed to it.

Although the successful regimens, higherin volume and sodium than generally advo-cated, have been used both in the West andthe tropics, it is often said that children fromthe tropics, or disadvantaged groups such asAmerican Indian children, represent a “dif-ferent type of infant” than the Western child(5 1-53); and that regimens developed for theformer are inappropriate for children gener-ally seen in American hospitals. Specifically,it is supposed that certain attributes renderWestern children less tolerant of fluid andsalt overload, or these other children moretolerant.

In an attempt to test this hypothesis, theclinical and biochemical attributes reportedfor Western and tropical children hospital-ized were examined. Table 3 reviews 7 1 re-ports written in the past three decades; fromthe West (generally from urban teaching hos-pitals); from tropical areas (urban and rural);and, for comparison, studies of children pre-senting exclusively with hypernatremia (in-cluding four from the tropics). For each ofthe attributes listed-dealing with clinical,biochemical and bacteriologic measure-ments-the mean values reported by eachstudy were ranked. Where five or more re-ports characterized an average attribute inthe group under study, a median value andthe interquartile range (IQR) were calcu-lated.5 Although differences in reporting existbetween series, this method of comparingmeans should reveal different tendencies be-tween the three groups.

Several fmdings are of interest. First, con-trary to accepted teaching, children with hy-pernatremia are, on the whole, neitheryounger nor better nourished than the pop-ulation with diarrhea from which they were

5 The IQR is a measure of dispersion about the me-dian and is defined as the third quartile minus the first

quartile. On Table 3, along with the medians, are pre-

sented the first and third quartile values.

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I”.

.

Sc%Vt4Y LOAD (mEq/kg) TOTAL VOLUMEx SXIUM (m/a�q/kq)

D36

32

28

24

20

16

12

8

4

r’-0.40

p< 0.08

.

r’ +026

p<0.2

.

.

�1 �168 192W 216 240 264 288

TOTAL VOLUME (rn//kg)

60 80 100 � 140 160

“FREE WATER” (rn//kg)

ACUTE DIARRHEA IN CHILDREN 641

FIG. 1. An analysis was made of 15 studies depicting 20 fluid regimens used in the 1st day treatment ofdehydrating diarrhea in children. Sodium load (A), total volume x sodium load (B), total volume (C), and “freewater” volume (D) are displayed against mortality. Hyperbolic curves were fitted to the data by computer, with the

general equation Y = ho + b,x’ where Y - mortality, bo � intercept, b, - regression coefficient and x - the

independent variable. Triangles represent two overlapping points.

drawn. Second, hypertonic dehydration doesoccur in tropical children, though not as com-monly as in the West. The incidence of hy-potonicity is several times greater in tropicalchildren with diarrhea. The differences, how-ever, are unlikely to be explained by differ-ences in evaporative water loss, the incidenceof parenteral infection, carbohydrate intoler-ance, or sodium loss in the stool. Third, thesevere consequences of diarrhea-markedvolume depletion, acidosis, and hypokale-mia-are seen with nearly equal prevalencein the tropical and hypernatremic series, andmore often than in the Western series. But,

once severe volume depletion occurs, as in-dicated by clinical shock, the mean weightloss in all the groups is approximately 10%;and accumulated sodium losses on admission,as measured by net retention studies, wereapproximately the same in the few Western,tropical, and hypernatremia studies recordingthese data. Traditional bacterial pathogens(shigella, salmonella, enteropathogenic Esch-

erichia coli) were more often isolated fromchildren hospitalized in the tropics, but reo-virus-like agents seem to be equally distrib-uted worldwide. The diagnosis of enterotox-igenic E. coil has been confused by a variety

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TABLE 3Clinical and biochemical attributes of children with diarrhea

from different parts of the world��b

weatem Tropical Hypernatremic

No. ofstudies 18 21 16

No. of children 2764 5607 323(median/series) 79 100 20

AttributeI . Mean age (mo)

Median ?_ !� 21QR ±:JP EL4

2. Malnutrition, % with weight 5, 30, 38 26, 37< 75% normal

Median

IQR

3. Volume depletion, % with 5-15%

loss body weightMedian �..2 �.4IQR 45-100 72-100 66-100

4. Mean % weight loss when clini-cally “severe” 4, 8, 10, 13 7, 9, 9, l0�

Median

IQR ELQ

5. Mean sodium loss, mEq/kg. in

severe dehydration 10, 10, 13 1 1 l3c, 8_l4c

6. Acidosis, % with pH < 7.3, or CO2< 15

Median � ThIQR a?.:?� �

7. Hypokalemia, % with K� < 3.5

(corrected for acidosis)Median � .�.!

IQR �L!�4 � .

8. ECF sodium on admission: % hy-pertonic (Na� > 150)Median j_4 IIQR 2z�

% Hypotonic (Na� < 130)Median 12 4!IQR �zai

9. Mean evaporative loss, ml/kg/day 64C 70 44, 44, 5 lc, 70C 50

10. % Children with parenteral infec-tion 19, 19, 40

Median iiIQR �:2� 11:42

1 1. Mean stool sodium, mEq/L (non-cholera, acute) 60, 71 46, 56, 91 20

12. % Children with carbohydrate in-

tolerance 6, 25, SOC 24, 25, 77

13. % Children with enteric bacterialpathogen 0, 0, 18Median 1.4IQR 1:11

14. % Children with rotavirusMedian 4�

IQR �

a Median values and IQR underlined. Single values, not underlined, are means from individual studies and

insufficient for calculation of median. b Reference numbers of studies included in Table 2: Western: 7, 18-20, 24,

37, 41, 45, 47, 50, 54-61; tropical: 32, 40, 44, 48, 62-78; hypernatremic: 22, 24, 45, 62, 66, 7 1, 79-87; C 88-

103. C Values indicate data from studies not otherwise included in total analysis.

642

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ACUTE DIARRHEA IN CHILDREN 643

of assay techniques; they are unlikely to becommon pathogens in Western children (104,105), but cause 10 to 20% of episodes intropical and American Indian children (102,106). In two studies ofApache children wherethe newer approach to treatment outlined inTable 2 was used exclusively (33, 107), theirclinical and biochemical attributes resembledboth Western and tropical children: nutri-tional status and severity of illness like theWestern children, hypotonicity like the trop-ical children; evaporative loss, stool sodiumconcentration and carbohydrate intolerancelike both.

None of the attributes examined, therefore,compel one to believe that tropical (orApache) children should be more tolerant ofsodium loads than Western children. Tradi-tional teaching has often dwelt on the differ-ences in these attributes, especially tonicity,as the basis for regimens tailored to eachcategory. This review will advance the hy-pothesis that, within broad limits, a simpler,unified approach is not only possible, butphysiologically correct. The support for suchan hypothesis must be built on the resolutionof four apparent paradoxes in the pathophys-iology of diarrheal dehydration.

The first seeming paradox is that despitethe fact that fluid losses in stool, sweat, andexpired air contain considerably more waterand less sodium than does the extracellularfluid (ECF), most children with diarrheapresent with a serum sodium concentrationequal to or less than normal.

The second paradox has to do with thesource of fluid loss. Darrow in the UnitedStates (19) and Mahalanabis in India (70)measured the retention ofelectrolyte and wa-ter during the recovery phase. Both showedthat the estimated deficits of sodium andpotassium on admission were roughly equiv-alent (total ion loss 3 18 to 353 mEq/literwater loss), which indicated that intracellular(ICF) and ECF fluid compartments areequally depleted in diarrhea. Yet measure-ments of the ECF compartment by the chlo-ride-space (18, 19, 70) or with inulin (54)show mostly ECF depletion.

The third paradox relates to the second:fluid regimens were designed to correct bothICF and ECF ion and water loss with ap-proximately equal concentrations of sodiumand potassium (limited by considerations of

safety to about 40 mEq/liter each). Yet chil-dren regularly respond well, perhaps better,to solutions closer in composition to the ECF(Fig. 1).

A fourth seeming paradox is that childrenfrom the tropics with diarrhea are predomi-nantly hyponatremic; yet their attributesclosely resemble those of hypernatremic chil-dren in severity of volume depletion, acidosisand hypokalemia.

To resolve the paradoxes requires an over-view of the pathophysiology of diarrheal de-hydration.

The pathophysiology of diarrhealdehydration

Figure 2 represents a synthesis of a widevariety of data on the effects of and the bodyresponses to diarrheal dehydration. Some ca-yeats are in order. The events depicted do notrepresent all the possible effects; neither isany weight assigned to predominant effects,or to the likelihood of interactions; and notall of the events have been investigated spe-cifically in children’s diarrhea. But the for-mulation is a reasonable synthesis of theknown and the likely responses to diarrhealfluid loss.

In the overall formulation (the top portion),

diarrhea first induces a major effect on thebody through salt and water depletion, withcompensatory responses by the vascular,renal, and hormonal systems. The secondmajor effect is on the intestine, inducing mal-absorption and (iatrogenically) fasting or im-proper intake; various metabolic, evaporativeand intestinal events follow. The first effectleads generally to hypotonic or isotonic de-hydration. This response may be considered“normal” or compensatory in a more helpful,homeostatic fashion. The second effect tendsgenerally toward hypertonicity. This responsemay be considered “pathological” or a moreharmful compensation.

Throughout the discussions that follow, thereader will be assisted by referring back toFigure 2.

Hyponatremic dehydration

Let us first consider the normal compen-satory events that follow quickly upon theloss of water, sodium, potassium and bicar-bonate in the stool (midportion of Fig. 2).

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�oseK�CeII No’ to ECF

[i�reosed Respootion�yper5Iycemio [�imonoty ESemo

Increosed _,� iii

Blood Volume Liet LosS

ARRHEAC �DI

Cotoboisin. �Th�eeDoys�0’� 5’�#{176}��;tolerance �......Cows Milk �E.ces$ Sugar

- Jo ___sad K’ Increased Gijt H�O and K’Loss,,,,,,,,,/’ �Rena Concentro’on � Urea Ac,deme: Hsgh Protein Feed �;;creosed Neat Stress

Increosed� �E’OS’�. ‘�C�OSd H � Reop P4�O Loss i� Eacess Salt �;‘[�;aseo easai H20 Heidi5od�um �eteflt�j Decreesid H20 intdie Le,ieo iCeil Sodium

� � Hyemgi�eesO. Aodo�s� � � irs inc�ased Heistri;;ereosed Sass’ L

� HYPERTONICITY LSolute Load ]FIG . 2. The events that follow onset of acute diarrhea are depicted to show how they may lead to volume

depletion that is hypo-, iso-, or hypernatremic. A, gives the general model; B, shows the predominant events generally

leading to hypo- or isonatremia; and C, shows the predominant events generally leading to iso- or hypernatremia.See text for particulars.

644 HIRSCHHORN

DIARRHEA

A

Rer,o -Vascuor Ion and Water Sugor Intolerance, IntestinoI�Evoporotive-

Responses Generolly � -Depletion, Imbalance 4 � Fosting,Inappropruote �- Metabolic Responses

Produce HypOtOniC and Compensation Intake Generally Produce

or ISO?Ofl�C Hypertonic or

Dehydration Isotonic Dehydration

DIARRHEA

B

No’, H� � �on and Water Losses �HCO3

�‘:=� � r�::::dRr;rIdo.AD;i////as/ r- Decieosed Acdf�cohon f

I ECF No’ I Inc�eosed hen Decreased � Lose SaltWater ___________________________F q c- NtC H T -4----� � IGtKdney L ng I

LoseK� � ‘VNo”�’ess � 120 Only HYPOTONICITY OR ISOTONICITY

� ‘ �

(References 18, 19, 78, 107a-l21 contain dataproviding the basis for the following ideas.)

With the loss of potassium from the ECFto the stool, a chemical gradient is createdthat facilitates potassium (and water) move-ment from the ICF to the ECF. Facilitatedby aldosterone, sodium (and water) tend tomove into the ECF. Protons (which accu-mulate in the ECF following bicarbonate lossin the stool, during tissue hypoperfusion, andwith ketosis of catabolism) also tend to dis-place ICF potassium. Since an effect of al-dosterone is to promote sodium retention andpotassium excretion via the kidney, a sub-stantial proportion of the potassium deficit indiarrheal disease may be accounted for in thisway. The effect of aldosterone may accountfor the observations of Darrow (19), andMann et al. (78), that potassium retention isinversely related to the volume of stool loss,even though potassium loss in the stool can-not account for the total deficit.

With even minimal ECF volume contrac-tion (loss of 2% of body weight or less), renin,angiotensin, aldosterone and antidiuretic hor-mone (ADH) secretions are increased, andthe glomerular filtration rate (GFR) is de-creased or redistributed. As GFR falls, acid-ification of the urine is also blunted andaccumulating protons tend to be retained,which in turn may further promote tubularsecretion of potassium.

These actions lead to a compensatory re-tention of salt and water, but proportionatelymore ofthe latter. The first palpable responseto ECF contraction is thirst. If water is taken,it will be mostly retained as ADH increasesdistal tubule and collecting duct permeabilityto free water, facilitating its reabsorption.Even without much intake, water may begenerated internally, and retained, in the re-sponse to stress by steroids and catecholamines which promote catabolism of bodytissue; the latter aggravated by fasting.

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ACUTE DIARRHEA IN CHILDREN 645

We may now suggest resolutions for threeof the four apparent paradoxes. First, thetendency to hypernatremia, due to loss ofmore water than sodium, is counteracted byavid retention of water (ingested or internallygenerated).

The second paradox is also explained: fluiddeficits in acute diarrhea, as measured by netretention studies, combine both ECF andICF losses in roughly equal proportions; butthe predominant contraction measured bychloride and inulin space takes place in theECF because sodium and hydrogen ions (andwater) replace ICF potassium (and water). Inother words, ECF space contracts in two di-rections: out in the stool, and into the cell; sothat the net measured loss of volume appearsto come mostly from the ECF.

A resolution to the third paradox follows:since it is continued ECF contraction that isat the root of these physiological changes,reversion to normal is more readily accom-plished by solutions more nearly approxi-mating the composition of ECF than ICF.The more hypotonic a fluid is with respect tosodium, the less well it can quickly correctECF contraction, unless proportionatelymore of that fluid is given (see Fig. 1B). Itshould be noted that hypotonic dehydration,once initiated, tends to be self-perpetuating,since vascular collapse and all the physiologicresponses thereto occur with less fluid lossthan seen in isotonic or hypertonic dehydra-tion (122). Preexisting, or uncorrected potas-sium deficit may also perpetuate hypotonicityby several possible mechanisms. There is cv-idence that potassium depletion causes anincreased secretion of renin (123), and pro-motes catabolism by impairment of insulinsecretion (124). Also, with potassium deple-tion but normal hydration, sodium (and wa-ter) may replace potassium (and water) in thecell causing ECF contraction and then ADHsecretion (1 17). The rational treatment thenshould reverse these events by restoring vol-ume quickly, correcting acidosis and reducingthe potassium deficit with solutions approxi-mating the composition of the ECF. Under-replacement of ECF fluid can perpetuate allthe events listed above. This has been shownempirically by studies comparing regimenshigher and lower in sodium (41, 44, 93).

It must be acknowledged that solutionsmore closely approximating ICF in compo-

sition have been used in rehydration therapyfor years. Their apparent success, however,derives in part from the avid retention of“maintenance” fluids over several days, andfrom the unproved view that severely dehy-drated children have lost, and thereforeshould be given, 15% or more of their weightin fluid (compare Reference 30, Table 3). Theuse of hypotonic solutions more nearly ap-proximating the ICF, however, explains thenecessity of the traditional practice to allowrehydration to proceed slowly over 24 to 48hr; a rehydrating fluid more nearly approxi-mating the ECF can be given more rapidly.

A hypothetical profile of a child most sus-ceptible to hyponatremia may now be drawn.It is a child with repeated bouts of diarrhea;with chronic potassium depletion; with per-haps slight, continued ECF volume contrac-tion; who is fasted; and who gets only salt-poor fluids once diarrhea starts. Many chil-dren in the tropics are found to suffer fromchronic or relapsing diarrhea at any timesurveyed (125, 126), and are predictably p0-tassium depleted (76). Malnourished chil-dren, with diarrhea much of the time, havechronically elevated levels ofrenin (127). Andfmally, the usual fluids given children in thetropics (as well as to Apache children) arehypocaloric and virtually salt-free: tea, bar-icy-water, rice-water, jello-water, or softdrinks. Clearly, not all of these features needbe present simultaneously to cause hypona-tremia in any one child.

A solution to the fourth paradox posed-how hyponatremic children in the tropics andhypernatremic children come to share severalcritical biochemical attributes-is yet to besupplied. This will require a more intensiveanalysis of how hypernatremia originates.

Hypernatremic dehydration

The dessication of the ICF in hypernatre-mia ( 128) can lead to serious neurologicalconsequences; therefore, hypernatremia is amatter of great concern. Since the regimenthis review has recommended contains moresodium than traditionally used, it is also nec-essary to examine the pathogenesis of hyper-natremia to determine if the newer regimenis as safe, from a theoretical point of view, asit seems to be in practice. We may analyzethe predisposing events by means of threecategories: The epidemiology of hypernatre-

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646 HIRSCHHORN

mia, augmenting mechanisms, and abnormalwater loss.

Epidemiology. Hypernatremia complicat-ing diarrhea is a condition of infants andtoddlers of either sex. The median age in 16reported series is 7 months. But the medianage of the general group of children hospital-ized with diarrhea in the West is also 7months (Table 3). Hypernatremia has beenreported both to have winter (28, 103, 129,130) as well as summer peaks (13 1, 132),suggesting that it reflects only the dominantdiarrheal seasonal pattern in a particular lo-cale. Hypernatremia occurs both in the trop-ics and in temperate zones, but is more com-mon in the latter (50, 66, 71, 73, 83, 84, 133,134). It is said that better-nourished childrenare more susceptible to hypernatremia (53).Data presented in two large series of hyper-natremia from the United States, however,found these children to suffer mild to severemalnutrition, not different from the largergroup at risk (22, 28). In the tropics, hyper-natremia is more common in large, bottle-fedinfants (73, 75, 83). The most important epi-demiological clue, however, is that while hy-pernatremia has been recognized for decades(23), there appears to have been a two-decadeepidemic, starting in the 1950’s and only nowabating (129, 133, 135, 137). Ifthe documen-tation is valid, it must mean that certainphysiological mechanisms reputed to causehypernatremia can only be predisposing, aug-menting, or perpetuating, but not initiating.

Augmenting mechanisms. Commonly citedpredisposing events include the large ratio ofsurface area to weight in children (138), andthe normally increased metabolic rate in cliii-dren 6 to 15 kg (139), both of which dictatea more rapid turnover of water. Small chil-dren are especially susceptible to metabolicwater loss, especially under heat stress andfever (72, 84). But these phenomena onlyserve to confirm that hypernatremia morecommonly affects infants and toddlers.

It has been suggested by several authorsthat immature renal function in infants is animportant contributing factor to hypernatre-mia (53, 140). If body surface area is used asthe basis for comparison of renal functions,particularly for GFR and urinary excretionof sodium, infants reach levels seen in youngadults by anywhere from 4 to 13 months (141,

142); but ifGFR per unit oftotal body water,or per unit extracellular fluid volume, or perunit kidney weight are calculated, valuesequivalent to those in adults are reached byone to two months of age (143, 144). Mc-Cance et al. (143), who first called attentionto the maturation question in 1941, decidedby 1957 that the latter method of comparisonwas more rational. Finally, maximal concen-trating ability reaches at least 85% of adultlevels by the second month of life (143, 145-147) in the majority ofchildren, and certainlyby 10 to 12 months in all. Any remainingdifference between adults and children wouldpermit conservation of only trivial amountsof water. So it would not seem that immaturerenal function plays an important role in theincidence of hypernatremia, where the me-dian age ofoccurrence is seven months (Table3).

A number of distinctly pathological renaland metabolic events do occur that, oncehypernatremia is initiated, serve to perpetuateit. Renal concentrating ability (i.e., the abilityto conserve water and excrete solute) doesnot keep pace with the hypertonicity, espe-cially as persisting volume depletion causesdecreased delivery of sodium to the distaltubule, and free water is thus not generatedfor retention. Potassium depletion (148) andhypertonicity itself (149) also affect the kid-ney’s ability to excrete salt.

Potassium depletion is generally not appre-ciated as a perpetuating factor in hypernatre-mia. Yet the tendency to retain sodium anddevelop edema in the face of body potassiumdeficiency has been described for nearly threedecades by Darrow and others (20, 41, 54,150). The effects are multiple: on the renal,( 148, 15 1), hormonal (123), and cellular levels(152, 1 13). Ramirez et al. (153) have demon-strated in children that a potassium-free dietis associated with cumulative weight gain andsodium retention beginning on the first day.

Severe acidosis is commonly found withhypernatremia (Table 3) and is a likely per-petuating factor. Acidemia stimulates therelease of nonextracellular sodium (154).With continued water loss, hypernatremiamay ensue. Hyperosmolarity, in turn, inducesfurther hydrogen ion secretion from cells( 155). With dehydration, the kidneys are lessable to excrete acid (156). The burden of

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compensation on the lungs is then increased;but with increased respiration, unfortunately,water loss also increases. Moreover, as aci-dosis becomes severe, (pH less than 7.1),blood is shunted from the peripheral vesselsto the lungs causing puLmonary congestion(157). If carbohydrates are poorly absorbed,additional protons are generated during bac-terial fermentation of the sugars in the gutand are either transferred to the body fluidsor remove bicarbonate already secreted intothe lumen (158, 159). Both acidosis and hy-perosmolarity cause hyperglycemia (86, 160-163) which, by an osmotic diuresis, can fur-ther force renal water loss.

We come back to our fourth, as yet unre-solved, paradox. Since many children in thetropics with diarrhea are seriously potassiumdepleted and acidotic, why is hypernatremianot more common?.Or, how can hypokalemiapredispose both to hypo- and hypernatremia?In fact, the known intolerance of malnour-ished children to sodium (164), as evidencedby the development of edema or congestivefailure, may have its roots in potassium defi-ciency (165). But the latter develops oversome time, allowing for compensatory waterretention. Hypernatremia, on the other hand,happens quickly (66, 84). Some event causingrapid and excessive water and potassium loss,in addition to sodium retention, is necessary.The next section examines this point.

Abnormal water loss. A search for a likelyinitiating cause of hypernatremia must startwith some of the early clinical observations.That drinking milk during diarrhea oftencauses clinical deterioration is quite an oldobservation. Howland (166), in 1921, notedthat “ . . . it is now generally appreciated thatsugars initiate and perpetuate diarrhea . ..“

Infantile diarrhea, with profuse stools, dehy-dration and shock, was often called “alimen-tary intoxication” and it was recognized thatcow’s milk initiated or worsened the condi-tion (12, 14, 164). When hypernatremia oc-curs in the tropics it is related to cow’s milkfeeding (7 1). Hypernatremia has been de-scribed in association with high-solute or hy-perosmolar feeds such as boiled skim milk(82), hypertonic (10 to 20%) glucose solution(168), tinned milk formulas (133, 134, 137),or commercial glucose-electrolyte solutionscontaining dextrose polymers in high concen-

tration (10%) (169, 129).6 � interesting con-comitant clue to the pathogenesis of hyper-natremia is the tendency of hypernatremicchildren to produce voluminous, watery stoollow in sodium (28, 169). Normally, as stoolrate rises, so does the stool sodium concentra-tion, approaching plasma levels; this occursin adults with cholera (170) as well as ininfants with noncholera enteritis (calculationof data presented by Darrow et al. (18, 19).Since stool fluid is rarely hypoosmotic toplasma, voluminous stool low in sodium mustcontain other solutes such as organic metabo-lites. Such metabolites are generated in thegut during malabsorption of carbohydrates(17 1). Intestinal bacteria degrade undigestedcarbohydrates into many osmotically activefragments that draw water into the lumen inthe upper intestine. This may cause the pro-duction of gas, distension and ileus and im-pair colonic absorption of salt and water

6 Several writers suggested that the sodium concentra-

tion of such formulas was to blame (24, 82). This is

difficult to accept. Taitz and Byers (133) found childrenwith hypernatremia had been fed improperly diluted

cow’s milk formula; the formulas, however, averaged a

sodium content of only 33 mEq/liter with a range of 22to 66; Chambers’ and Steel’s figures (134) were 37 mEq/liter, range 26 to 59. The original commercial sugar-

electrolyte formula contained 50 mEq Na/liter. Onereport, however, showed that boiling skimmed milkcould elevate the sodium content to as high as 165 mEq/

liter (85). Except for the latter, the sodium concentrations

of suspect formulas reported are really not exceptional,

especially when one considers the therapeutic range of

sodium used for rehydration (Fig. I).

Several other authors believe hypernatremia may be

related to inappropriate caloric and protein loads (133,134). An excessive caloric load increases evaporativewater loss, a situation dramatically worsened under heatstress (132). Decreased intake of a high-solute fluid dueto calorie satiation may make matters worse, as ingestion

oflarge volumes ofeven a high-solute fluid such as cow’s

milk allows the kidney to generate free water (173).Davies (174) has demonstrated, however, that a childwith mild diarrhea (30 ml/kg per day), receiving a

normal amount of twice concentrated cow’s milk, needonly to concentrate urine to 706 mOsm/liter to maintainwater balance. The recent decrease in the incidence ofhypernatremia may reflect better feeding with low solute

milk (136, 137); nonetheless, hypernatremia still occurs,even in children on low-solute milk (137). It is rare in

breast-fed children. The simplest reason why breast-fedchildren are less susceptible to hypernatremia (75), inspite of the high lactose concentration (7 g/100 ml), inaddition to its low protein content, is that breast milk,

unlike cow’s milk, is taken only in small quantities ateach feeding.

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(172). Voluminous, low sodium stools are theresult, in which potassium is also lost. Intes-tinal fermentation produces acidemia, whiledistension and ileus increase fluid loss andthe accompanying nausea reduces total in-take. If the incidence of hypernatremia hasfollowed an epidemic curve between the1950’s and 1970’s, perhaps it may be relatedto the common medical practice in that timewhich promoted boiled skim milk plus sugar,or dextrose polymer-salt solutions, as suitabletherapy for diarrhea. The hypothesis thatcarbohydrate intolerance is a principal initi-ating cause of hypernatremia awaits formaltesting.

An hypothetical profile of a child mostsusceptible to hypernatremia from diarrheamay now be drawn. It is a child under 1 yearofage, with a briefhistory ofdiarrhea, gettingcomplex carbohydrates at high concentration,and with reduced intake or considerable in-sensible loss of water. Once initiated hyper-natremia tends to be perpetuated by hypo-volemia, hypokalemia, and acidemia. Ra-tional treatment then should reverse theseevents be restoring volume, correcting aci-dosis, reducing the potassium deficit, andeliminating complex sugars from the diet (es-pecially lactose). Some caution must be usedin the speed with which serum sodium con-centration is reduced, but this caution shouldnot permit perpetuation ofthe hypernatremicbiochemical complex. A recent paper (175)reported the use of a 0. 18% sodium solutionover 48 hr, with base given only for “severeclinical acidosis.” The patients suffered a 13%death rate, slow rate of return to normalplasma osmolarity, and a high incidence ofedema and thromboses. However, Finberg,Rosenfield, et al. (87), who have studied hy-pernatremia for three decades, now recom-mend a regimen for the severely dehydrated(over 10% weight loss or greater) that pro-vides up to 50 nil/kg in the first 4 to 5 hr witha solution containing 80 mEq/liter sodiumand 25 mEq/liter base. In his most recentseries, only 2/67 (3%) died. The fluid andsodium load he recommends for hypernatre-mia is not remarkably different from whatthis review has suggested for all diarrhea inchildren.

The regimen suggested in this review(Table 2) does not, in fact, fit into any of thecontributing factors for hypernatremia. On

the contrary, with early prevention or correc-tion of volume depletion, acidosis and potas-sium loss, both hyponatremia and hyperna-tremia should be avoidable or easily cor-rected. Perhaps we are relearning Darrow’swisdom: “These patients with hypernatremiareceived.the usual fluid therapy used in othercases of diarrhea” (45).

It is now necessary to examine more closelysome of the origins ofcurrent pediatric teach-ing which emphasize that an absolute ceilingfor safe sodium intake exists, one regularlyexceeded by the regimen recommended inthis review.

Sodium: striking the balance

In the mid-l950’s, Talbot, Butler and theircolleagues (88, 176-182) presented an encom-passing framework for fluid therapy of adultsand children which established “floors andceilings” for the amounts of water and dcc-trolytes that could be safely administered.Their work came at the time when awarenessof hypernatremia was most acute and formedmuch of the intellectual underpinning fortraditional pediatric fluid therapy. Theirbasic concepts may be summarized as follows:There is a minimum and a maximum rate ofadministration of water and salt that can begiven without disturbance of body fluid com-position. The body’s adjustment to fluid ad-ministered between the limits is by the usualneuroendocrine and renal homeostatic mech-anisms, but the fluid administered should bebalanced as much as possible between mini-mal need and maximal tolerance (hence theoriginal use and meaning of the term “bal-anced solutions”). “Stress” due to injury, sur-gery, or illness lowers the ceiling for maximaltolerance. In treatment of dehydration, ICFand ECF losses are to be replaced simulta-neously with equal amounts of sodium andpotassium; it is unnecessary or undesirable toreplace all deficits within a few hours, onceshock is corrected.

Talbot and Butler suggested that the ceilingfor daily sodium administration to acutely illchildren would be 225 mEq/m2 surface area,with 150 mEq the “balanced” amount given,along with an equivalent amount of potas-sium, in no more than 3500 ml/m2 fluidvolume. In an 8-kg child, this works out to asodium load of 7.5 to 1 1.3 mEq/kg in 175

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ml/kg volume (sodium concentration 43 to64 mEq/liter). Such a child, if severely vol-ume depleted, will have lost approximately640 to 960 ml (80 to 120 mi/kg) of fluid andapproximately 90 mEq of sodium, or 11mEq/kg (see Table 3). The volume of fluidand sodium thus recommended for rehydra-tion is likely to be insufficient and only theceiling approaches adequacy (see Fig. 1). Onthe basis of his balance studies, Darrow hadarrived at a much higher value, supplying anaverage of 17 mEq/kg sodium in the first dayof rehydration (20) at an overall concentra-tion of 86 mEq sodium per liter fluid volume.How, then, did Talbot and Butler derive theirceiling for sodium administration for infants?Two references are cited in Talbot’s syllabus(88): Gamble et al. (1 83) and McCance andWiddowson (184). Gamble added salt to themilk and water diet of a normal 7-kg child,providing sodium at 12 to 13 mEq/kg perday for 8 days in a concentration probablyno greater than 90 mEq/liter. While the childretained an excess of 1. 1 mEq Na�/kg perday and gained water over eight days equiv-alent to 4% of body weight, it apparentlyremained well. McCance, however, gavethree premature neonates salted milk for 1 to2 days, providing sodium at 22 mEq/kg perday in a concentration range of 120 to 154mEq/liter. The neonates retained 10 to 14mEq/kg per day, gained water equivalent to10% of body weight, became puffy, oliguric,sick, and hypertonic. A key difference be-tween the two studies, in addition to theundoubted susceptibility of the prematures,may have been the fmal concentration ofsodium-hence the availability of water forexcretion-rather than the absolute amountsgiven. An important difference between thestudies of Gamble and McCance and thoseof diarrheal disease is, of course, the consid-erable existing deficit ofsodium on admissionin children with diarrhea.

Regimens that rehydrate slowly with fluidsmore like ICF in composition have severalconsequences, understandable from the gen-eral model described in Figure 2: rehydrationis not accomplished in the first day; hypona-tremia is likely to be produced or persist; andacidosis is prolonged, especially where diar-rhea continues during and beyond the firstday. All these consequences have been deter-mined empirically (41, 44, 54, 92).

So far this review has dealt principally withonly the first 24 hr of therapy. It is possiblethat adverse effects of excess sodium loadingmight be avoided if it occurs for only 1 day.In fact, the mainstay of the regimen thisreview recommends is the use of a singleintravenous or oral polyelectrolyte solution,both for initial deficit and continuing losses,with the addition of food and low-solute liq-uids. In practice, and on the average, this hasmeant providing sodium to (for example):Apache infants 14 mEq/kg per day for 2 to3 days (33, 107); Bengali children (averageweight 8 to 9 kg) with cholera, and giventetracycline, 1 1 mEq/kg per day for 2 days(32); Bengali children (average weight 1 1 kg)with cholera, on no antibiotic, 20 mEq/kgper day for 4 days (185); urban Americaninfants, 13 mEq/kg per day for 3 days (19).

In all these studies, however, enough waterwas supplied to reduce the fmal sodium con-centration (total sodium per total water) toapproximately 50 to 90 mEq/liter; and whiletransient puffmess (usually periorbital) wasnot uncommon, it was of no clinical conse-quence.

But pediatricians in general are more wor-ried about sodium retention and edema thanmoderate under-replacement of saline defi-cits. In the 1940’s, a syndrome of “postaci-dotic state of infantile diarrhea” (186) wasdescribed which followed vigorous saline andbicarbonate therapy without potassium. Thesyndrome included nonpitting edema, tetany,hypocalcemia, hypernatremia, hypokalemia,convulsions, and cerebral hemorrhage. Theseregimens included “normal” saline, or nor-mal saline plus 1/6 molar lactate, or thecurious “3: 1 regimen” (three parts normalsaline to one part 2% sodium bicarbonate)(22, 187, 188). None had potassium. The 3:1regimen (Na� at 177 mEq/liter) in one studywas associated with a 17% mortality and ahigh incidence of hypernatremia (187); witha changeover to lactated Ringer’s (Na� at 128mEq/liter) the mortality fell to 3% and hy-pernatremia was no longer documented (44,91). In the regimen recommended by thisreview, the “postacidotic” syndrome has notbeen reported. Marked edema, or puLmonarycongestion, may be associated with severeacidosis (157) or with potassium depletion(20); then it reflects a serious problem. Slightpuffmess about the eyes in a child otherwise

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clinically well is commonplace, is not relatedto electrolyte imbalance (13, 33, 54), and isnot a problem. Its presence indicates an cx-cess fluid volume isotonic to ECF amountingto I to 3% of body weight (33). Transientisotonic overexpansion after large doses ofNaC1 is seen both in adults (189-191) andchildren (183). The cause of delayed sodiumexcretion is complex but several explanationsmay fit: “Postloading antinatriuresis” de-scribes a brief period of renal tubular reab-sorption of sodium in response to a sodiumload (192); after chronic salt depletion, saltand water are retained even when a hypo-tonic salt solution is given (1 1 1); and fmally,the very handling of children during sam-pling procedures causes oliguria lasting up toan hour (193).

Talbot and Butler were also concerned thatthe stress ofiliness, through various hormonalmechanisms, would increase sodium reten-tion. This is quite true even to the extent thatlow sodium loads, given slowly, can induceedema and hypernatremia (41, 48, 82). Thesame may be said of hypernatremia: childrenwith this condition show intense retention ofsodium (54, 89). The relief of stress inducedby volume depletion, however, is achieved byrapid restoration of extracellular volume andelectrolyte deficits, which means using rathermore sodium than less. In fact, therapy thatjust removes clinical shock does little to stopthe responses to volume depletion (157).

The concepts developed by Darrow, Ta!-bot, and Butler and their colleagues, whilenot proved correct in all respects, had a pro-found effect on pediatric fluid therapy be-cause they were based on meticulous atten-tion to both physiologic and clinical infor-mation. A new concept in the treatment ofdiarrhea-oral therapy-is similarly based,and is the subject of the final section of thisreview.

Oral therapy with sugar-electrolyte solutions

Glucose-electrolyte solutions, taken bymouth for rehydration and maintenance ac-cording to carefully designed regimens (“oraltherapy” in shorthand), were developed toreplace diarrheal fluid loss in cholera andreduce the need for intravenous fluids indeveloping countries where cholera is preva-

lent. Data obtained from six independentlines of physiological and clinical research,however, have given oral therapy a broadersignificance with regard to both medical sci-ence and health care delivery.

A ctive cotransport of sodium and organic

substrates in the intestine

The details of this line of research havebeen well summarized (194-196). Briefly,several actively transported substances likeglucose, galactose, certain amino acids, somedisaccharides, and some dipeptides show anabsolute or partial dependence on sodium fortheir absorption, and the rate of sodium ab-sorption is considerably increased in the pres-ence of these substrates. While the kinetics ofthe sodium-substrate interactions vary bysubstrate class, a common effect, seen espe-cially in the intact intestine, is the simulta-neous enhancement of absorption of waterand of other salts, following electrochemicalgradients (197-200). How much of the in-duced transport is transcellular, or active, andhow much paracellular, or passive, is Un-known.

This effect on salt and water absorptionwas applied successfully to cholera patientswhen it was shown that the salt-substratecotransport was substantially intact, and thatoral therapy with sodium, potassium, bicar-bonate, chloride, and glucose in a single so-lution could maintain normal blood volumeand electrolyte concentrations (201-203). Thesuggested ideal composition of an oral ther-apy solution was derived in large part fromresearch done on isolated membranes, animalmodels and human subjects. First, there isconsiderable evidence that glucose and so-dium are absorbed at close to a 1: 1 molecularratio (204-206). Second, maximal water andsodium absorption take place at administeredglucose concentrations between 56 to 140mM/liter (197, 207, 208). At glucose concen-trations higher than 160 to 200 mM/liter,water and salt absorption are reduced, aneffect independent offluid tonicity (208-2 10).Third, when sodium concentration is consid-erably below that of the normal jejunal con-tents, secretion occurs even in the presence ofglucose (21 1). Fourth, bicarbonate, in addi-tion to correcting acidosis, also serves to en-hance sodium absorption (213), but the pres-

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ACUTE DIARRHEA IN CHILDREN 651

ence of chloride is necessary for the full so-dium-glucose effect (199). Fifth, glucose ismuch better absorbed in the jejunum than inthe ileum in man (213). Sixth, rapid flowrates of lumenal contents (over 10 mi/mm)reduce absorption substantially (209). 5ev-enth, the loss of sodium on admission inacute, severe diarrheal disease averages from76 to 109 mEq/liter of fluid loss in infantilediarrhea (19, 70); and up to 120 mEq/liter ofstool (17, 70). Potassium losses may be simi-larly extensive.

Taking these eight points together, a ra-tional solution for oral therapy should, there-fore, be sufficiently concentrated in sodiumto replace losses on a volume for volume basisso that patients do not need to drink exces-sively, thereby increasing flow rate and dcliv-cry of a large load of glucose to the ileum.The glucose concentration should closelymatch sodium on a molar basis. Potassiumand base should be added (empirically thishas worked out to be 4 to 6 mEq/kg per dayeach). Such a fluid would then contain, perliter, 75 to 100 mEq ofsodium, 20 to 30 mEqofpotassium, 20 to 30 mEq bicarbonate (withchloride as the other anion) and 75 to 100mM of glucose; the osmolarity would be 265to 360 mOsm/liter. The formula promotedby the World Health Organization contains,in millimoles per liter, Na�90, K�20, HCO330, C180, glucose 1 1 1; and 33 1 mOsm/liter.7The renal solute load is 220 mOsm/liter.Lytren (per liter: 30 mEq Na�, 556 m�t glu-cose, no bicarbonate, milliosmolarity 656),and Pedialyte (per liter: 30 mEq Na’�, 278mM glucose, no bicarbonate, milliosmolarity387), both in common use, are examples ofunphysiological solutions. They have too lit-tIe sodium, too much glucose and are tooconcentrated.

Two other phenomena may be relevant tothe discussion. One, described in rabbits, isthat sodium given by mouth stimulates natri-uresis five to 10 times greater than an equiv-alent amount given intravenously (215). Theeffect is seen in normal and in sodium-dc-pleted animals. The second observation, inhumans, is that a physiological dose of ADH,a level attained naturally in volume depletion,abolishes net salt and water absorption in thejejunum; but this effect is reversed when glu-cose is added to the oral mixture (216). These

two studies indicate that oral therapy may besafer than intravenous with respect to sodiumloading in children, and that any oral fluidwithout glucose (or some other appropriatesubstrate) will considerably worsen diarrheaif even a slight depletion of blood volumeexists. Diarrhea itself affects intestinal ab-sorption, as the next section discusses.

The effect of diarrhea on intestinal absorption

Morphological abnormalities in the intes-tine accompany acute bacterial and viral diar-rheas, the severity of which correlate withindices of malabsorption (217). Reversiblechanges in concentrations of enzymes asso-ciated with absorption (Na-K ATPase, di-saccharidases) have also been documented(218-221). Persistent disaccharidase defi-ciency (222, 223) and malabsorption of glu-cose (224) have been documented in selectedhospital cases. Malabsorption in children hos-pitalized with acute diarrhea spans a spec-trum from clinical intolerance to lactose inabout half (72), to sucrose in a third, and toglucose in about 5% (222). Intolerance toglucose can be made manifest by increasingthe concentration (225) and rate of adminis-tration (226) of the sugar. Sugar malabsorp-tion can lead to an increase in stool loss,continued morphological damage, bacterialovergrowth, gut ischemia, intolerance to allsubstrates and a downhill course in a minorityof children (159). From such clinical experi-ences came the general injunction to rest thebowel absolutely during the acute phase, withrestoration of full diet taking as long as amonth (36).

But there were always dissenters from thisapproach. Chung and Viscorova (227)showed in 1948 that children with acute diar-rhea fed milk and corn syrup (glucose poly-mers) recovered slightly faster and with betternutritional weight gain than those who fasted,even though the latter group had less totalstool output (227). A commercial formulacontaining casein hydrolysates plus glucose(Pregestimil) can replace stool salt and waterloss, and provide nutrition (33, 107). Evenchildren with “intractable” diarrhea, or withmalnutrition, gain weight and have less diar-rhea on diets that are predigested but not

7 In grams per liter: NaC1 3.5, NaHCO3 2.5, KC1 1.5,glucose 20.

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hypertonic (casein hydrolysates or commi-nuted protein, amino acids, glucose or glucosepolymers, etc.) even to the point of not re-quiring total parenteral nutrition (223, 228-233). It is possible that these organic sub-strates facilitate salt and water absorption bythe intestine. Since each class of substrate(sugar, dipeptide, amino acid, etc.) appears tointeract with separate sodium-carriers in theintestinal membrane, there may be an addi-tive effect when two or more substrate typesare used together. Such has been shown incholera when glucose and glycine are used(234). It also seems possible that one sub-strate, glucose for example, could reverse thenet secretion and attendant clinical symptomsinduced by malabsorption of another sub-strate, like lactose. Bedine and Bayless (235)have shown this experimentally in men withlactose intolerance.

Even so, feeding may increase stool output(34). If fasting caused no harm, feeding mightnot be worth the extra difficulties in calculat-ing fluid balance. Darrow et al. (18) wereparticularly concerned that this not happen.But, in fact, a third line of inquiry has shownthe rapidly deleterious effects of fasting oreven semistarvation.

Fasting and intestinal function

With as brief a fast as 3 to 5 days, glucose,salt, water and amino acid absorption aresubstantially reduced, as are disaccharidases,with or without changes in histology of theintestine (236-239). The effect is independentof nitrogen or caloric balance, as total intra-venous feeding alone causes depletion of in-testinal digestive enzymes and gut mass in aslittle as 3 days (240, 241). Since not all chil-dren with diarrhea are fasted for 3 days, it isimportant to know what fasting and diarrheaappear to be additive in their effects on di-saccharidases (242).

Apart from the intestinal effects, brief fast-ing has deleterious metabolic effects. For cx-ample, 3 days of no food causes an aldoster-one-resistant natriuresis (243) which couldlead to hyponatremia. A 10-day hypocaloricdiet in man causes a 42% decrease in venti-latory response to hypoxia, and a 25% de-crease in basal metabolic rate (244). This hasmeaning for marginally nourished childrenwho are particularly susceptible to pneu-

monia and other infections following boutsof diarrhea and reduction of intake.

It may still be argued that, although pro-longed fasting or reduced intake can be harm-ful, one should prove the positive effects offeeding during diarrhea. The fourth line ofresearch points the way.

The induction effect offeeding

It is clear from numerous animal and hu-man studies that intraluminal foodstuffs, car-bohydrate, and protein, increase intestinaldigestive enzymes and cell proliferation in adose-related way, even without prior fasting(237, 245-249). The inductions are somewhatspecific: sucrose is a better inducer of sucrasethan is glucose, for example. Diarrhea ap-pears to sensitize this effect. In rats, after aweek of mannitol-induced diarrhea, levels ofspecific disaccharidases showed increased de-pendence on corresponding dietary substratescompared to controls without diarrhea. Amixed carbohydrate diet was most protectiveagainst disaccharidase depletion during diar-rhea. The effects were independent ofchanges in histology, or number of epitheialcells (242).

The evidence so far presented suggests thatboth diarrhea and fasting affect intestinalabsorption that, when impaired, can lead tomore prolonged diarrhea, more severe mal-absorption, and possible malnutrition. A fifthline of investigation has recently related diar-rhea and malnutrition in whole populations.

The relationship ofdiarrhea to malnutrition

From Mexico, The Gambia, Uganda, Gua-temala, Papua New Guinea, and India (4,126, 250-254) have come longitudinal studieson cohorts of children which now prove thatdiarrhea directly causes malnutrition. First,diarrhea is the overriding correlate with se-quential weight loss in children, with malariaa distant second; episodes of respiratory ill-ness and fever do not correlate with perma-nent growth retardation (4, 126). Second, thecumulative difference in weight among six-month age-cohorts up to 84 months of ageamounted to 1 1% between children with low,and children with high frequency rates ofdiarrhea (4, 250); or the equivalent of about100 g body weight per month (25 1). Thesevalues account for a substantial proportion of

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ACUTE DIARRHEA IN CHILDREN 653

the weight deficits fmally incurred by chil-dren in the tropics, which are only partiallyreversed by generous supplementation witha high protein and calorie diet (4). Third,faltering of growth is acutely related to eachepisode of diarrheal illness (252), in part dueto catabolism and malabsorption, but also toanorexia and decreased food intake as well(253). Finally, nutritional deterioration aloneincreases the likelihood of a subsequent epi-sode of diarrhea (254). Can appropriate ther-apy reverse these events? The sixth line ofresearch has begun to defme the range ofeffectiveness of oral therapy, including itseffect on nutrition.

Current status of oral therapy

Oral therapy with glucose and electrolyteshas been used in the past. Darrow in the1940’s (19), Harrison in the 1950’s (255), andMeneghello in the 1960’s (65) recommendedthe use of oral therapy as a supplement tointravenous fluids, or as a first step to feeding,or for use in the outpatient department. None,however, appreciated the specific role of glu-cose, or described objective evidence of theusefulness of oral therapy, or developed anoptimal formula and method of administra-tion.

Such evidence followed the discovery ofthe biophysical principles involved. In 1967,under the tutelage of Robert A. Phillips, agroup from the Cholera Research Laboratoryin Dacca, Bangladesh reported that activelytransported sugars such as glucose and galac-tose (but not passively transported fructose)in a polyelectrolyte solution could consider-ably reduce the net volume of stool fluid incholera (201). Nalin et al. (202) then showedthat patients with cholera who received oraltherapy required 80% less intravenous fluidsfor cure; that children over 2 years old andadults, both with cholera, responded similarlyto an oral solution of the same composition(256); and that the amino acid glycine, whenadded to the glucose in the oral therapy mix-ture could reduce total stool output further(234). The Calcutta group, in the meantime,helped defme effective concentrations of so-dium and glucose (208, 257) for both adultsand children. The use of a single solution forany dehydrating diarrhea in all age groupsseemed to be a startling departure from usual

practice. In fact, it simply extended years ofexperience with a single intravenous solutionthat yielded the remarkably low mortalityrate of under 2% in children under 4 years ofage (31).

Oral therapy had a solid impact on mor-tality in situations where standard intrave-nous therapy was scarce. In Bangladesh ref-ugee camps in 197 1, the death rate fromdiarrheal diseases soared to 30%. Oral ther-apy, vigorously administered by family mem-bers (“give them as much as they will drink”)helped reduce the mortality rate to about 1%(35). Due to the severe shortage of materialsand staff, intravenous fluids were reserved toresuscitate those in shock.

In a home treatment program for AsianIndian children 0 to 3 years old, case fatalityrates fell from 3.2 to 1.4 per thousand afteroral therapy was introduced (258). The au-thors used a salt-sucrose solution, about 1 to2 liters/day, with a sodium concentration ofabout 100 mEq/liter.

Administration of oral therapy by lessertrained persons-whether in hospital, clinic,or home-became feasible when it was shownthat the majority of dehydrated infants andchildren would take oral therapy ad libitumup to the level of need as long as they werestrong enough to drink or suck, and the fluidswere offered freely (33). Children in shockwere rehydrated intravenously within a fewhours with a lactated Ringer-like solution(plus potassium), then put on oral therapy.

The capacity of children to absorb thefluid, taken either by mouth or delivered bynasogastric tube, is prodigious: reported rateshave ranged from 10 to 17 mi/kg per hour inthe first 1 to 2 days of hospitalization (33,256-262).

In Costa Rica, of 1 l 3 children (3 to 15months, mean age 5.5 months) averaging vol-ume depletion equivalent to 5% of bodyweight (one-third of them were 7 to 12%dehydrated), only six needed intravenousfluids (261, 262). The rest were totally treatedby oral therapy plus additional water. In tworeports from India (259, 260), 57 of 59 chil-dren (ages 3 months to 4 years, median age1 year) were managed solely by glucose-elec-trolyte fluids given intragastrically despite anacute fluid loss averaging 6 to 8% of bodyweight. Half the children had 24-hr stool

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654 HIRSCHHORN

volumes over 80 g/kg. Of99 Apache children(mean age 1 1 months; 28 were under 3months of age), one-half were moderately toseverely dehydrated, with stool losses aver-aging 6 ml/kg per hour for the first 6 hr (33,107). Only 10 required partial or total intra-venous rehydration; only one needed a na-sogastric drip because of failure to keep uporally with stool loss. The oral solutions usedcontained 80 to 90 mEq of sodium per liter(plus potassium, bicarbonate, and glucose)and corrected instances of both hypo andhypernatremia. In Bangladesh 57 children (5to 30 months old, mean age 12 months) withrotavirus diarrhea were treated completelywith oral therapy (World Health Organiza-tion formula) and compared to 44 treatedwith intravenous fluids. All did well (263).Twenty-five to 88% of the children in the sixclinical studies cited above were febrile onadmission. Theoretically this should increasethe risk of hypernatremia; but of the 328children, only three developed elevations ofserum sodium, 150 to 155 mEq/liter, noneclinically obvious. Mortality in the six reportswas nil.

Nichols and Soriano (264) have criticizedthe concept of a single solution for diarrhearegardless of etiology, indicating that differ-ent types of diarrhea produce stools withdifferent levels of sodium. Nonetheless, oraltherapy has proved equally effective in anydehydrating diarrhea of children (the limita-tions to be described below), whether due tocholera (46), where the stool sodium is high(80 to 120 mEq/liter) (214); to reovirus (261,263) where stool sodium is low (20 to 25mEq/liter); to shigella and other diarrheas(33, 107) where stool sodium is intermediate(40 to 50 mEq/liter).

An important principle followed in thesestudies was early feeding with tolerated foodsand fluid. In Apache infants, a casein hy-drolysate-glucose-medium chain triglycerideformula was started at full strength inter-spersed with oral therapy, within the first 24hr (107). Costa Rican children (261, 262)were given half-strength milk within 6 to 12hr of admission. Indian children (259, 260)were given dilute cow’s milk or breast milkwithin 12 to 24 hours. The criteria for whento begin feeding appear to be complete re-hydration, and appetite.8

A remarkable difference was noted in the

weights on discharge of Apache children onoral therapy and fed early, compared to thoseof the previous year treated with intravenousfluids, fasting, and slow return to diet (265).

The former group went home at 90 to 99% ofthe Harvard median (the average for Apacheinfants and children generally), the latter at70 to 79%. Associated with this was the din-ical perception that children rapidly rehy-drated with oral therapy were vigorous andhungry soon after. It was hypothesized thatoral therapy would help improve or maintainnutrition by restoring appetite quickly andhelping mothers (and doctors) see the valueof not fasting their children. Given the rela-tionship between diarrhea and malnutrition,such a fmding would be ofsignal importance.

The hypothesis was borne out in a studydone in collaboration with the Governmentof the Philippines and the World Health Or-ganization (266). An oral-glucose-electrolytesolution (the World Health Organization for-mula) administered at home to 464 Philippinechildren with diarrhea was associated with agreater average weight gain, both during anattack ofdiarrhea and over a 7-month period,when compared to a control group. Thelonger-term effect on weight, relative to astandard, was more pronounced in childrenwho had more than one attack of diarrhea inthe period of observation than in those whohad only one attack. The magnitude of thelonger-term weight gain was 3 to 5 percentagepoints towards the standard weight.

The limitations oforal therapy are partiallyknown. Vomiting has clearly not been limit-ing in the several hospital or field trials citedabove, except when those in shock have notbeen completely rehydrated intravenously(267), or in the earliest stages of severe chol-era (268). Nor have fever or high environ-mental temperatures affected good outcomes.Periorbital edema has been described rangingfrom 6 to 25% of hospitalized children (33,260), but was neither associated with hyper-natremia or any untoward consequences(therefore, not strictly a “limitation”). About5% of children in a hospital, and fewer than

8 A caveat is in order here. Feeding cow’s milk to a

population of children with intestinal damage and po-

tassium depletion is likely to cause hypernatremia, andhas (260); oral therapy when combined with breast milkappears not to cause hypernatremia, even in reovirus

diarrhea (263).

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ACUTE DIARRHEA IN CHILDREN 655

1% in a clinic setting have glucose intolerance(27, 33); they are made worse by oral therapy.The condition is easily suspected on clinicalgrounds (voluminous, watery stools; failureto rehydrate) and confirmed by simple bed-side measurements of stool-reducing sub-stances (33). Stool spillage of carbohydratecan be quite high, even with an adequateclinical response, however. In reovirus diar-rhea up to 30% of the administered glucoseload appears in the stool (261). Oral therapyalso fails in patients with very high rates ofstool loss, over 10 mi/kg per hour, perhapsdue to fatigue in drinking so much (269). Afinal possible limitation is the use of oraltherapy in neonates with diarrhea. There isinsufficient experience with this group to sup-port a recommendation at this time.

The study of oral therapy is now at thestage of finding the better strategies of dcliv-cry. For instance, sucrose is somewhat lesseffective than glucose in the oral solutions(262, 263, 271) in the sense that stool volumetends to be larger and duration longer, failurerates slightly higher, and correction of dehy-dration and biochemical abnormalitiesslightly slower. But where glucose is too costlyor unavailable, sucrose is the appropriate sub-stitute. The addition of magnesium for mal-nourished children is worthy of study. An-other area, just now being explored, iswhether the chemicals should be providedprepackaged or in the form of store-boughtsalt and sugar that the mother measures outherself for domiciliary treatment. Issues ofaccess, safety, cost, and effectiveness in pre-venting volume depletion and electrolyte im-balance are all important here. Even fmdinga suitable container for mixing will be aproblem in much of the world. More directcomparisons of oral fluids higher or lower insodium content (e.g., 90 versus 50 mEq/liter)are needed. One study (260) attempted this,but gave virtually the same amount of totalsodium to both groups. More recently, Nalinhas shown in Jamaican children that the so-lution lower in sodium resulted in persistent(days) hyponatremia in five of 24 children,while the one higher in sodium resulted intransient (6 hr), asymptomatic elevations ofserum sodium in three of 84 (D. Nalin, per-sonal communication).

In Western hospitals, the use of oral ther-apy instead of intravenous fluids can make

children more comfortable (33). It would beuseful to know how staff time is affected.

It has recently been demonstrated by thisauthor and colleagues that lightly trained andsupervised Philippine village women canteach mothers how to prepare and use oralfluids, and to feed their children at homeduring diarrhea. The clinical outcomes com-pared well to those in doctor-based clinics. Agratifying and significant increase in thenumber of mothers who kept on feeding theirchildren during the illness was seen in thecourse of a year (272).

The studies on oral therapy continue thedevelopment of knowledge of diarrheal dis-ease; their authors are conscious inheritors ofthe scientific and clinical fmdings of numer-ous workers, past and living. The advances inoral therapy also illustrate the felicitousphrase of Rohde and Northrup (2), “takingscience where the diarrhea is.”

The author thanks Howard S. Frazier, M.D., DavidR. Nalin, M.D., and Richard A. Cash, M.D. for their

careful reading ofthe manuscript, and Timothy N. War-ncr, Ph.D., for his help on statistical analyses.

References

1. HOWARD-JONES, N. Choleranomalies: The unhis-tory of medicine as exemplified by cholera. Per-

spective. Biol. Med. 15: 422, 1972.2. ROHDE, J. E., AND R.S. NORTHRUP. Taking science

where the diarrhea is. In: Acute Diarrhoea in Child-

hood. Ciba Fndn. Symp. 42: 339, 1976.3. PUFFER, R. R., AND C. V. SERRANO. Patterns of

mortality in childhood. Report of the Inter-Ameri-can Investigation of Mortality in Childhood. Pan

American Health Organization Scientific Publica-tion no. 262, 1973.

4. MARTORELL, F., i-P. HABICHT, C. YARBROUGH, A.

LECHTIG, R. E. KLEIN AND K. A. WESTERN. Acutemorbidity and physical growth in rural Guatemalan

children. Am. J. Diseases Children 129: 1296, 1975.

5. AYKROYD, W. R. Nutrition and mortality in infancy

and early childhood: past and present relationships.Am. J. Clin Nutr. 24: 480, 1971.

6. VAUGHAN, V. C., AND R. J. MCKAY. The field ofpediatrics. In: Textbook of Pediatrics (10th ed),

edited by W. E. Nelson. Philadelphia: W. B. Saun-ders 1975, p. 4.

7. MOFFET, H. L., H. K. SHULENBERGER AND E. R.

9 Pizarro of Costa Rica has just completed a study of

40 neonates, mean dehydration 6.6% of body weight.

treated with oral therapy and extra water; 39 requiredno intravenous fluids (270).

by guest on Decem

ber 23, 2010w

ww

.ajcn.orgD

ownloaded from

656 HIRSCHHORN

BURKHOLDER. Epidemiology and etiology of severe

infantile diarrhea. J. Pediat. 72: 1, 1968.

8. OAKLEY, J. R., P. M. MCWEENY, M. HAYES-ALLEN

AND J. L. EMERY. Possibly avoidable deaths in

hospital in the age group one week to two years.

Lancet 1: 770, 1976.

9. LATFA, T. A. Malignant cholera. Documents com-municated by the Central Board of Health, London,relative to the treatment of cholera by the copious

injection ofaqueous and saline fluids into the veins.

Lancet 2: 274, 1832.10. SELLARDS, A. W. Tolerance for alkalies in Asiatic

cholera. Philippine J. Sci. 5: 363, 1910.

1 1 . HOWLAND, J., AND W. M. MARRIOT. Acidosis oc-

curing with diarrhea. Am. J. Diseases Children 11:

309, 1916.12. Powers, G. F. A comprehensive plan of treatment

for the so-called intestinal intoxication of children.

Am. J. Diseases Children 32: 232, 1926.

13. HARTMANN, A. F., A. M. PERLEY, J. BASHMAN, M.V. NELSON AND C. ASHER. Further observations on

the metabolism and clinical uses of sodium lactate.J. Pediat. 10: 692, 1938.

14. KARELITZ, S., AND B. SCHICK. Treatment of toxi-

cosis with the aid of a continuous intravenous drip

of dextrose solution. Am. J. Diseases Children 42:

781, 1931.15. KARELITZ, S. AND B. SCHICK. Treatment of alimen-

tary toxicosis. J. Am. Med. Assoc. 99: 366, 1932.

16. KARELITZ, S. Continuous intravenous therapy inpediatrics with special emphasis on its use in ali-mentary toxicosis. Acta. Paedat. 16: 546, 1933.

17. GOVAN, C. D., JR., AND D. C. DARROW. The use ofpotassium chloride in the treatment of the dehydra-

tion of diarrhea in infants. J. Pediat. 28: 541, 1946.18. DARROW, D. C. The retention of electrolyte during

recovery from severe dehydration due to diarrhea.J. Pediat. 28: 515, 1946.

19. DARROW, D. C., E. L. PRATF, J. FLE1-F, JR., A. H.

GAMBLE AND H. F. WIESE. Disturbances of water

and electrolytes in infantile diarrhea. Pediatrics 3:129, 1949.

20. FLETF, J., E. L. PRATT AND D. C. DARROW. Meth-ods used in treatment of diarrhea with potassium

and sodium salts. Pediatrics 4: 604, 1949.2 1 . CHUNG, A. W. The effect oforal feeding at different

levels on the absorption of foodstuffs in infantile

diarrhea. J. Pediat. 33: 1, 1948.

22. RAPOPORT, S. Hyperosmolarity and hyperelectro-

lyternia in pathologic conditions ofchildhood. Am.J. Diseases Children 74: 682, 1947.

23. FINBERG, L., AND H. E. HARRISON. Hypernatremia

in infants. An evaluation of the clinical and bio-

chemical findings accompanying this state. Pediat-

rics 16: 1, 1955.24. COLLE, E., E. AYOUB AND R. RAILE. Hypertonic

dehydration (hypernatremia): the role of feedings

high in solutes. Pediatrics 22: 5, 1958.

25. BowlE, M. D. The management of gastroenteritiswith dehydration in outpatients. S. African Med. J.

34: 344, 1960.26. JELLIFFE, D. Diarrhoea in childhood. In: Medical

Care in the Developing World, edited by M. King.London: Oxford University Press, chapt. 15, 1966.

27. WATFEN, R. H., F. M. MORGAN, V. N. SONGKHLA,

B. VANIKIATI AND R. A. PHILLIPS. Water and dcc-

trolyte studies in cholera. J. Clin. Invest. 38: 1879,1959.

28. BRUCK, E., G. ABAL AND T. ACirro. Pathogenesis

and pathophysiology of hypertonic dehydrationwith diarrhea. Am. J. Diseases Children 115: 122,

1968.29. BRUCK, E. G., ABAL AND T. ACETO. Therapy of

infants with hypertonic dehydration due to diar-

rhea. A controlled study of clinical, chemical andpathophysiological response to two types of thera-

peutic fluid regimen, with evaluation of late se-

quellae. Am. J. Diseases Children 1 15: 281, 1968.30. WElL, W. B. A unified guide to parenteral fluid

therapy. I. Maintenance requirements and repair ofdehydration. J. Pediat. 75: 1, 1969.

31. NALIN, D. R. Mortality from cholera and otherdiarrheal diseases at a cholera hospital. Trop. Geog.

Med. 24: 101, 1972.

32. MAHALANABIS, D., J. B. BRAYTON, A. MONDAL

AND N. F. PIERCE. The use of Ringer’s lactate inthe treatment of children with cholera and acutenon cholera diarrhoea. Bull. World Health Organ46: 311, 1972.

33. HIRSCHHORN, N., B. J. MCCARTHY, B. RANNEY, M.A. HIRSCHHORN, S. T. WOODWARD, A. LACAPA,

R. A. CASH AND W. E. WOODWARD: Ad-libitumoral glucose-electrolyte therapy for acute diarrheain Apache children. J. Pediat. 83: 562, 1973.

34. Oral glucose/electrolyte therapy for acute diar-

rhoea. Lancet 1: 79, 1975.

35. MAHALANABIS, D., A. B. CHOUDHURI, N. G.

BAGCHI, A. K. BHATrACHARYA AND T. W. SIMP-

SON. Oral fluid therapy of cholera among Bangla-

desh refugees. Johns Hopkins Med. J. 132: 197,1973.

36. BLAIR, J., AND J. T. FITZGERALD. Treatment of

non-specific diarrhea in infants. Clin Pediat. 13:333, 1974.

37. ALEXANDER, M. B. Infantile diarrhea and vomiting.A review of 456 infants treated in a hospital unitfor enteritis. Brit. Med. J. 2: 973, 1948.

38. ORTIZ, A. Diarrheal diseases. Acute diarrhea inyoung children. In: Diseases of children in the

subtropics and tropics. Edited by: H. C. Trowell

and D. B. Jelliffe. London: Arnold, 1958, Chapter17.

39. KINGSTON, M. Electrolyte disturbances in Liberian

children with kwashiorkor. J. Pediat. 83: 859, 1973.40. AHMED, I., AND J. K. G. WEBB. Childhood diar-

rhoea in S. India with particular reference to fluid

and electrolyte disturbance. Ind. J. Child. Health12:85, 1963.

41. CHEEK, D. B. Changes in total chloride and acid-

base balance in gastroenteritis following treatmentwith large and small loads of sodium chloride.Pediatrics 17: 839, 1956.

42. Puyrr, H. The Maghazi Rehydration Center. Au-

gust-December 1961 Assessment Report. Courier

13: 73, 1961.

43. LAWSON, D. Management of gastroenteritis at the

Hospital for Sick Children, Great Ormond Street,

1948-49. Great Ormond Street J. 2: 1 10, 1951.

44. GUTMAN, R. A., D. J. DRUTZ AND G. E. WHALEN.

Double-blind fluid therapy evaluation in pediatric

by guest on Decem

ber 23, 2010w

ww

.ajcn.orgD

ownloaded from

ACUTE DIARRHEA IN CHILDREN 657

cholera. Pediatrics 44: 922, 1969.45. DARROW, D. C., AND J. S. WELSH. Recent experi-

ence in the treatment of diarrhea in infants. J.Pediat. 56: 204, 1960.

46. SACK, D. A., S. Isui.i, K. H. BROWN, A. IsL�i, A.K. M. I. KABIR, A. M. A. K. CHOWDHURY AND M.

A. ALl. Oral therapy of children with cholera: A

double blind comparison of sucrose with glucose-

electrolyte oral solution. J. Pediat. In press.

47. SMITH, H. L., AND J. N. EITELDORF. Parenteralfluid regimens in the treatment of severe diarrhea

in infants. J. Pediat. 58: 1, 1961.

48. BEATrY, D. W., M. D. MANN, H. DE V. HEESE AND

G. M. B. BERGER. Acute dehydrating gastroenteritis

in undernourished children. S. African Med. J. 48:

1563, 1974.49. RANIER-POPE, C. R. Fluid therapy in gastroenteritis

with severe dehydration. A biochemically con-trolled trial of regime in 40 patients. S. AfricanMed. J. 36: 1087, 1962.

50. IRONSIDE, A. G., A. F. TUXPORD AND B. HEY-

WORTH. A survey of infantile gastroenteritis. Brit.

Med. J. 3: 20, 1970.51. ABALLI, A. G. Single solution not ideal for oral

therapy of diarrhea. Lancet 2: 5 13, 1975.

52. WElL, W. B., JR. Editorial comment. J. Pediat. 83:571, 1973.

53. BART, K. J., AND L. FINBERG. Single solution for

oral therapy of diarrhoea. Lancet 2: 633, 1976.54. KATCHER, A. L., M. F. LEVITr, A. Y. SWEET AND

H. L. HODES. Alterations of fluid and electrolytedistribution and renal function in diarrhea of in-

fancy. J. Clin Invest. 32: 1013, 1953.55. KERPEL-FRONIUS, E., AND J. VONOCZKY. Signifi-

cance of changes in the tomcity of body fluids ininfantile diarrheal dehydration. Ann Paediat. Fenn.

3: 403, 1957.56 HALTALIN, K. C., J. D. NELSON, R. RING III, M.

SLADOSE AND L. V. HINTON. Double-blind treat-

ment study ofshigellosis comparing ampicillin, sul-

fadiazine and placebo. J. Pediat. 70: 970, 1967.

57. Sui-roN, R. E., AND J. R. HAMILTON. Tolerance ofyoung children with severe gastroenteritis to dietarylactose: A controlled study. Can. Med. Assoc. J. 99:980, 1968.

58. HALTALIN, K. C., H. T. KUMEISZ, L. V. HIr�rroN

AND J. D. NELSON. Treatment of acute diarrhea in

outpatients. Double-blind study comparing ampi-

dillin and placebo. Am. J. Diseases Children 124:554, 1972.

59. SHEPHERD, R. W., S. TRUSLOW, J. A. WALKER-

SMITH, R. BIRD, W. CurriNG, R. DARNELL AND C.M. BARKER. Infantile gastroenteritis: a clinical

study of reovirus-like agent infection. Lancet 2:

1082, 1975.

60. ECHEVERRIA, P., N. R. BLACKLOW AND D. H.SMITH. Role of heat labile toxigenic Escherichia

coli and reovirus-like agent in diarrhoea in Boston

children. Lancet 2: 1 1 13, 1975.61. TRIPP, J. H., M. J. WILMERS AND B. A. WHARTON.

Gastroenteritis: A continuing problem of child

health in Britain. Lancet 2: 233, 1977.

62. CARDELLE, G., R. M. JIMENEZ AND M. G. VAZQUEZ.

Alteraciones del metabolismo hidrosalino en el

curso de las diarreas infantiles. Rev. Cubana. Lab.

Clin. 8: 30, 1954.

63. MENEGHELLO, J., J. RossnLoT, F. MONCKEBERG

AND C. AGUILO. Algunos aspectos en el tratamiento

do la toxicosis del lactante. Boletin Medico Hosp.

InS. 13: 139, 1956.64. MENEGHELLO, J., J. ROSSELOT, F. MONCKEBERG, S.

RuBlo, E. SILVA AND J. GONZALEZ. Terapeutica de

Ia toxicosis. Influenca de algunas pautas terapeuti-cas en la evolucion de la toxicosis del lactante conespecial referencia al empleo de la solucion Darrow.Rev. Chilena Pediat. 28: 20, 1957.

65. MENEGHELLO, J., J. Rossai.oT, C. AGUILO, F. MON-

CREBERG, 0. UNDURRAGA AND M. FERREIRO. In-fantile diarrhea and dehydration: Ambulatory

treatment in a hydration center. Advan. Pediat. 11:

183, 1960.66. BowlE, M. D., D. MCKENZIE AND J. D. L. HANSEN.

Hyperosmolarity in infantile gastroenteritis. S. Af-

rican Med. J. 32: 322, 1958.67. TRUSWELL, A. S. Results of out-patient treatment

of infantile gastroenteritis. S. African Med. J. 31:446, 1957.

68. TRUSWELL, A. S., J. D. L. HANSEN, C. FREESMAN

AND T. F. SMIDT. Serum proteins in infants withsevere gastroenteritis. S. African Med. J. 37: 527,

1963.69. RANS0ME-KUTI, 0., 0. ELEBUTE AND T. B.

AGUSTO-ODUTOLA. Interperitoneal fluid adminis-

tration in children with gastroenteritis. Brit. Med.

J. 3: 500, 1969.

70. MAHALANABIS, D., C. K. WALLACE, R. J. KALLEN,

A. MONDAL AND N. F. PIERCE. Water and electro-

lyte losses due to cholera in infants and smallchildren. A recovery balance study. Pediatrics 45:374, 1970.

71. AHMED, I. AND T. B. AGUSTO-ODUTOLA. Hyper-

natremia in diarrhoeal infants in Lagos. Arch. Dis-

ease Childhood 45: 97, 1970.

72. LIFSHITZ, F., P. COELLO-RAMIREZ AND G. Gt.rrIER-

aEz-ToPEm. Carbohydrate intolerance in infants

with diarrhea. J. Pediat. 79: 760, 1971.

73. PRINSLOO, J. G., AND KRUGER, H. Electrolyte and

nutrition status of Bantu children with gastroenter-

itis. S. African Med. J. 44: 491, 1970.

74. WALKER, A. C., AND J. G. HARRY. A survey ofdiarheal disease in malnourished Aboriginal chil-dren. Med. J. Australia 1: 904, 1972.

75. KINGSTON, M. E. Biochemical disturbances in

breast-fed infants with gastroententis and dehydra-

tion. J. Pediat. 82: 1073, 1973.

76. GARCIA DE OLARTE, D, S. TRUJILLO H, 0. AGU-

DELO N, J. D. NELSON AND K. C. HALTALIN. Treat-

ment of diarrhea in malnourished infants and chil-dren. Am. J. Diseases Children 127: 379, 1974.

77. NICHOLS, B. L., J. ALVARADO M, J. RODRIQUEZ S,

C. F. HAZELWOOD AND F. VrraRI E. Therapeuticimplications of electrolyte, water and nitrogenlosses during recovery from protein-calorie malnu-trition. J. Pediat. 84: 759, 1974.

78. MANN, M. D., M. D. BowIE AND J. K. L. HANSEN.

Total body potassium acid-base status and serumelectrolytes in acute diarrheal disease. S. AfricanMed. J. 49: 709, 1975.

79. TARAIL, R., L. W. BASS AND A. S. RUNCO. Thefrequency and nature of hypertonicity of the body

by guest on Decem

ber 23, 2010w

ww

.ajcn.orgD

ownloaded from

658 HIRSCHHORN

fluids in infantile diarrhea. Am. J. Diseases Chil-

dren 86: 658, 1953.

80. WElL, W. B., AND W. M. WALLACE. Hypertonic

dehydration in infancy. Pediatrics 17: 171, 1956.8 1 . SKINNER, A. L., AND K. C. MOLL. Hypernatremia

accompanying infant diarrhea. Am. J. Diseases

Children 92: 562, 1956.

82. DEYour.�G, V. R., AND E. F. DIAMOND. Possibility

of iatrogenic factors responsible for hypernatremia

in dehydrated infants. J. Am. Med. Assoc. 173: 104,1960.

83. SLONE, D., AND S. E. LEVIN. Hypertonic dehydra-

tion and summer diarrhea. S. African Med. J. 34:

209, 1960.84. MACAULEY, D., AND M. I. BLACKHALL. Hyperna-

tremic dehydration in infantile gastroenteritis.

Arch. Disease Childhood 36: 543, 1961.85. BERENBERG, W., F. MANDELL AND F. X. FELLERS.

Hazards of skimmed milk, unboiled and boiled.Pediatrics 44: 734, 1969.

86. MANDELL, F., AND F. X. FELLERS. Hyperglycemia

in hypernatremic dehydration. Clin. Pediat. 13: 367,1974.

87. ROSENFIELD, W., G. L. DEROMANO, R. KLEINMAN

AND L. FINBERG. Improving the clinical manage-ment of hypernatremic dehydration. Observations

from a study of 67 infants with this disorder. Chin.Pediat. 16:411, 1977.

88. TALBOT, N. B., R. H. RICHIE, J. D. CRAWFORD

AND E. S. TAGRIN. Metabolic homeostasis. A Syl-

labus for those Concerned with the Care of Patients.

Cambridge: Harvard University Press, 1959.89. KERRIGAN, G. A. Disturbances ofsodium and wa-

ter homeostasis in hypernatremic infants. Am. J.Diseases Children 98: 608, 1959.

90. HEELEY, A. M., AND N. B. TALBOT. Insensible water

losses per day by hospitalized infants and children.

Am. J. Diseases Children 90: 251, 1955.91. GRIFFITH, L. S. C., J. W. FRESH, R. H. WArrEN

AND M. P. WILLAROMAN. Electrolyte replacement

in paediatric cholera. Lancet 1: 1197, 1967.

92. SPEROTFO, G., F. R. CARRAZZA AND E. MAR-

CONDES. Treatment of diarrheal dehydration. Am.J. Chin. Nutr. 30: 1447, 1977.

93. FLEWETr, T. H., H. DAVIES, A. S. BRYDEN AND M.

J. ROBERTSON. Diagnostic electron microscopy of

faeces. II. Acute gastroenteritis associated with reo-virus-like particles. J. Chin Pathol. 27: 608, 1975.

94. HOLMES, I. H., M. MATHAN, P. BHAT, M. J. ALBERT,

S. P. SWAMINATHAN, P. P. MAIYA, S. M. PEREIRA

AND S. J. BAKER. Orbiviruses and gastroenteritis.

Lancet 2: 658, 1974.

95. SEXTON, M., G. P. DAVIDSON, R. F. BISHOP, R. R.R. W. TOWNLEY, I. H. HOLMES AND B. J. RUCK.

Viruses in gastroenteritis. Lancet 2: 355, 1974.

96. CONKLIN, R. H., H. L. DUPONT AND J. T. R0DRI-

QUEZ. Viral agents in acute infantile diarrhea from

Houston and Guatemala. Chin. Res. 23: 26A, 1975.

97. BRYDEN, A. S., H. A. DAVIES, R. F. HADLEY, T. H.

FLEWETF, C. A. MORRIS AND P. OLIVER. Rotavirus

enteritis in the West Midlands during 1974. Lancet

2: 241, 1975.98. CAMERON, D. J. S., R. F. BISHOP AND G. P. DAV-

IDSON. Rotavirus infections in obstetric hospitals.Lancet 2: 124, 1975.

99. SCHOUB, B. D., H. J. KOORNHOF, G. LECTASAS, D.W. PROZESKY, I. FREIMAN, E. HARTMAN AND H.

KASSEL. Viruses in acute summer gastroenteritis inblack infants. Lancet 1: 1093, 1975.

100. DAVIDSON, G. P., R. F. BISHOP, R. R. W. TOWNLEY,

I. H. HOLMES AND B. J. RUCK. Importance ofa new

virus in acute sporadic enteritis in children. Lancet

1:242, 1975.101. CRUICKSHANK, J. G., B. ZILBERG AND J. H. M.

AXTON. Virus particles and gastroenteritis in black

and white children in Rhodesia. S. African Med. J.

49: 859, 1975.

102. RYDER, R. W., D. A. SACK, A. Z. KAPIKIAN, J. C.MCLAUGHLIN, J. CHAKRABORTY, A. S. M. M. RAH-

MAN, M. M. MERSON AND J. G. WELLS. Enteroxi-

genic Escherichia cohi and reovirus-like agent in

rural Bangladesh. Lancet 1: 659, 1976.103. KAPIKIAN, A. Z., H. W. KIM, R. G. WYATr, W. L.

CLINE, J. 0. ARROBIO, C. D. BRANDT, W. H. RoD-

RIGUEZ, D. A. SACK, R. A. CHANOCK AND R. H.PARROTF. Human reovirus-hike agent as the majorpathogen associated with “winter” gastroenteritis

in hospitalized infants and young children. New

Engl. J. Med. 294: 965, 1976.

104. GUERRANT, R. L., R. A. MOORE, P. M. KIRSCHEN-

FELD AND M. A. SANDE. Role of toxigenic and

invasive bacteria in acute diarrhea in childhood.

New Engi. J. Med. 293: 567, 1975.

105. GROSS, R. J., S. M. SCOTLAND AND B. ROWE.

Enterotoxin testing of Escherichia cohi causing ep-

idemic infantile enteritis in the U.K. Lancet 1: 629,

1976.

106. SACK, R. B., N. HIRSCHHORN, I. BROWNLEE, R. A.

CASH, W. E. WOODWARD AND D. A. SACK. Enter-

otoxigenic Escherichia coil-associated diarheal dis-ease in Apache children. New Engl. J. Med. 292:

1041, 1975.107. HIRSCHHORN, N., R. A. CASH, W. E. WOODWARD

AND G. H. SPIVEY. Oral fluid therapy of Apache

children with acute infectious diarrhoea. Lancet 2:15, 1972.

107a. DARROW, D. C., AND S. HELLERSTEIN. Interpre-

tation of certain changes in body water and electro-

lytes. Physiol. Rev. 38: 1 14, 1958.

108. LEAF, A. The clinical and physiologic significance

of the serum sodium concentration. New Engl. J.

Med. 267: 24, 77, 1962.

109. OPARIL, S., AND E. HABER. The renin-angiotensinsystem. New Engi. J. Med 291: 389, 446, 1974.

1 10. C0NN, J. W., D. R. ROVNER AND E. L. COHEN.

Normal and altered function of the renin-angioten-

sion-aldosterone system in man. Applications in

clinical research and medicine. Ann. Internal Med.

63: 266, 1965.

111. CH0U, S-Y., L. F. FERDER, D. L. LEVIN AND J. G.PORUSH. Evidence for enhanced distal tubule so-

dium reabsorption in chronic salt-depleted dogs. J.

Chin. Invest. 57: 1 142, 1976.112. GUR, A., P. Y. ADEFUIN, N. J. SIEGEL AND J. P.

HAYSLETF. A study of renal handling of water in

lipoid nephrosis. Pediat. Res. 10: 197, 1976.

113. DARROW, D. C., AND E. L. PRATF. Fluid Therapy.Relation to tissue composition and the expenditure

of water and electrolyte. J. Am. Med. Assoc. 143:

365, 1950.

by guest on Decem

ber 23, 2010w

ww

.ajcn.orgD

ownloaded from

ACUTE DIARRHEA IN CHILDREN 659

1 14. EKLUND, J., P-O. GRANBERG AND D. HALLBERG.

Clinical aspects of body fluid osomolahity. Nutr.

Metabol. 14: 74, 1972.I 15. HARRINGTON, A. R. Hyponatremia due to sodium

depletion in the absence of vasopressin. Am. J.Physiol. 222: 768, 1972.

116. MACKNIGHT, A. D. C. Epithehial transport of po-

tassium. Kidney hnternat. I I: 391, 1977.

117. HARRINGTON, J. T., AND J. J. COLTEN. Clinicaldisorders ofurine concentration and dilution. Arch.

Internal Med. 131: 810, 1973.1 18. EARLEY, L. E., AND T. E. DAUGHARTY. Sodium

metabolism. New Engl. J. Med. 281: 72, 1969.119. LEAF, A. Hyponatremia. Lancet 1: 1 1 19, 1974.120. LE,�F, A. Regulation of intracellular fluid volume

and disease. Am. J. Med. 49: 291, 1970.121. METCOFF, J., S. FRENK, T. YOSHIDA, R. T. PINEDO,

E. KAISER AND J. D. L. HANSEN. Cell compositionand metabolism in kwashiorkor (severe protein-calorie malnutrition in children). Medicine 45: 365,

1966.122. HIRSCHHORN, N. The management of acute diar-

rhea in children: an overview. In: Progress in DrugResearch. Tropical Diseases II, Vol 19, edited byE. Jucker. Basel: Birkhauser Verlag, 1975, p. 527.

123. FLEMING, B. J., S. M. GENUTH AND A. B. GOULD.

Laxative-induced hypokalemia, sodium depletion

and hyperreninemia. Effects of potassium and so-dium replacement on the renin-angiotension-aldos-terone system. Ann. Internal Med. 83: 60, 1975.

124. KNOCHEL, J. P. Role of glucoregulatory hormones

in potassium homeostasis. Kidney Internat. 1 1: 443,

1977.

125. JOSE, 0. G., AND J. S. WELCH. Growth retardation,

anaemia and infection with mahabsorption and in-festation of the bowel. The syndrome of protein-

calorie malnutrition in Australian Aboriginal chil-dren. Med. J. Australia 1: 349, 1970.

126. ROWLAND, M. G. M., T. J. COLE AND R. G. WHITE-

HEAD. A quantitative study into the role of infection

in determining nutritional status in Gambian vil-lage children. Brit. J. Nutr. 37: 437, 1977.

127. VAN DER WESTHUYSEN, J. M., E. KANENGONI, J. J.JONES AND C. H. VAN NIEKERK. Plasma renin

activity in oedematous and marasmic children with

protein energy malnutrition. S. African Med. J. 49:1729, 1975.

128. FEIG, P. U., AND K. K. MCCURDY. The hypertonicstate. New Engl. J. Med. 297: 1444, 1977.

129. FRANZ, M. N., AND W. E. SEGAR. The associationof various factors and hypernatremic diarrheal de-

hydration. Am. J. Diseases Children 97: 60, 1959.130. FINBERG, L. Hypernatremic (hypertonic) dehydra-

tion in infants. New Engl. J. Med. 289: 196, 1973.13 1. GAMSU, H. R. Medical evaluation of osmolar fac-

tors. Postgrad. Med. J. 51: 31, 1975.

132. DARROW, D. C., R. E. CooKE AND W. E. SEGAR.

Water and electrolyte metabolism in infants fedcow’s milk mixtures during heat stress. Pediatrics14: 602, 1954.

133. TAITZ, L. S., AND H. D. BYERS. High caloric/os-molar feeling and hypertonic dehydration. Arch.Disease Childhood 47: 257, 1972.

134. CHAMBERS, T. L., AND A. E. STEEL. Concentrated

milk feeds and their relation to hypernatremic de-

hydration in infants. Arch. Disease Childhood 50:

610, 1975.

135. HOGAN, G. R. Hypernatremia-problems in man-

agement. Pediat. Chin. N. Am. 23: 569, 1976.136. DAVIES, D. P., B. M. ANSAIR AND B. K. MANDAL.

Hypernatremia and gastroenteritis. Lancet 1: 252,

1977.

137. WHALEY, P., AND J. A. WALKER-SMITH. Hyperna-

tremi� and gastroenteritis. Lancet 1: 51, 1977.138. FINBERG, L. Hypernatremic dehydration. Advan.

Ped. 16: 325, 1969.139. HOLLIDAY, M. A., AND W. E. SEGAR. The mainte-

nance need for water in parenteral fluid therapy.Pediatrics.19:823, 1957.

140. APERIA, A., 0. BROBERGER, K. THODENIUS AND R.

ZETFERSTROM. Development of renal control of saltand fluid homeostasis during the first year of life.

Acta Paediat. Scand. 64: 393, 1975.141. MCCANCE, R. A., AND W. F. YOUNG. The secretion

of urine by newborn infants. J. Physiol. 99: 265,1941.

142. RUBIN, M. E., E. BRUCK AND M. RAPOPORT. Mat-

uration of renal function in childhood: clearance

studies. J. Chin. Invest. 28: 1 144, 1949.

143. MCCANCE, R. A., N. J. B. NAYLOR AND E. M.WIDDOWSON. The response of infants to a largedose of water. Arch. Disease Childhood 29: 104,

1954.144. WILKINSON, A. W. Some aspects of renal function

in the newly born. J. Pediat. Surg. 9: 103, 1973.145. EDELMANN, C. M., H. L. BARNE-I-r AND V. TROUP-

KOU. Renal concentrating mechanisms in newborn

infants. Effect of dietary protein and water content:

role of urea, and responsiveness to anti-diuretichormone. J. Chin. Invest. 39: 1062, 1960.

146. POLACEK, E., J. VOCEL, L. NEUGEBAUEROVA, M.

SEBKOVA AND E. VECHETOVA. The osmotic concen-trating ability in healthy infants and children. Arch.Disease Childhood 40: 291, 1965.

147. PRAI-r, E. L., B. BIENVENU AND M. R. WHYTE.

Concentration of urine solutes by young infants.Pediatrics 1: 181, 1948.

148. SCHWARTZ, W. B., AND A. S. RELMAN. Metabolicand renal studies in chronic potassium depletionresulting from overuse of laxatives. J. Chin. Invest.

32: 258, 1953.

149. FINBERG, L., B. F. RUSH, JR. AND C-S. CHEUNG.

Renal excretion of sodium during hypernatremia.

Am J. Diseases Children 107: 483, 1964.150. SCHLESINGER, B., W. PAYNE AND J. BLACK. Potas-

sium metabolism in gastroenteritis. Quart. J. Med.24: 33, 1955.

151. COOKE, R. E. Certain aspects ofthe renal regulation

of body composition. Pediatrics 14: 567, 1954.

152. SPATER, H., A. HUNT, R. TODD, P. MEARA, M.TERRY, J. D. CRAWFORD AND N. B. TALBOT. Dc-

velopment and therapy of cellular sodium intoxi-cation in potassium deficiency. Metabolism 8: 28,

1959.153. RAMIREZ, M. A., J. M. BAETRL, Y. A. DE MARTINEZ

AND G. G. GRAHAM. The effect of potassium andprotein intakes on sodium homeostasis of infants

and children. J. Trop. Pediat. Environ. ChildHealth 19: 275, 1973.

154. BERGSTROM, W. H., AND W. M. WALLACE. Bone as

by guest on Decem

ber 23, 2010w

ww

.ajcn.orgD

ownloaded from

660 HIRSCHHORN

a sodium and potassium reservoir. J. Chin. Invest.

33: 867, 1954.155. SoTos, J. F., P. R. DODGE AND N. B. TALBOT.

Studies in experimental hypertonicity. II. Hyper-

tonicity of body fluids as a cause of acidosis. Pedi-

atrics28: 180, 1962.

156. KILDEBERG, P. Metabolic acidosis in infantile gas-troenteritis. Acta Paediat. Scand. 54: 155, 1965.

157. HARVEY, R. M., Y. ENSON, M. L. LEWIS, W. B.

GREENOUGH, K. M. ALLY AND R. A. PANNO. He-

modynamic studies on cholera. Effects of hypovo-

lemia and acidosis. Circulation 37: 709, 1968.158. TORRES-PINEDO, R., E. CONDE, G. ROBILLARD AND

M. MACDONALD. Studies on infant diarrhea. III.

Changes in composition ofsaline and glucose-salinesolutions instilled into the colon. Pediatrics 42: 303,

1968.

159. LIFSHITZ, F. Clinical studies in diarrheal diseaseand malnutrition associated with carbohydrate in-

tolerance. In: Proceedings 9th International Con-

gress of Nutrition. Basel: Karger, 1975, vol. 1, p.

173.160. ROBERTS, W. Alimentary hyperglycemia simulating

diabetic ketosis. Lancet 2: 754, 1964.

161. NITZAN, M., AND S. ZELMANOVSKY. Glucose intol-

erance in hypernatremic rats. Diabetes 17: 597,1968.

162. STEVENSON, R. E., AND F. P. BOWYER. Hypergly-

cemia with hyperosmolal dehydration in non-dia-

betic infants. J. Pediat. 77: 818, 1970.

163. SPIRER, Z., AND H. BOGAIR. Blood sugar in infants

with diarrhea. Lancet 2: 131 1, 1970.

164. GARROW, J. S., R. SMITH AND E. E. WARD. Elec-

trolyte metabolism in severe infantile malnutrition.

Oxford: Pergamon Press, 1968.165. HANSEN, J. D. L., AND J. F. BROCK. Potassium

deficiency in the pathogenesis of nutritional oe-

dema in infants. Lancet 2: 477, 1954.166. HOWLAND, J. Prolonged intolerance to carbohy-

drates. Trans. Am. Pediat. Soc. 33: 1 1, 1921.167. FINKELSTEIN, H. Saughingskrankheiten. Amster-

dam: Elsevier, 1938, cited by D. C. Darrow: Ther-

apeutic measures promoting recovery from thephysiologic disturbances of infantile diarrhea. Pc-

diatrics 9: 519, 1952.

168. WARE, S. Hypernatremia and “glucose water”.Lancet 1: 494, 1976.

169. FINBERG, L. The possible role of the physician incausing hypernatremia in infants dehydrated from

diarrhea. Pediatrics 22: 2, 1958.

170. PHILLIPS, R. A. Water and electrolyte losses incholera. Federation Proc. 23: 705, 1964.

171. TORRES-PINEDO, R., M. LAVASTIDA, C. L. RIVERA,

H. RODRIGUEZ AND A. ORTIZ. Studies on infant

diarrhea. I. A comparison of the effects of milk

feeding and intravenous therapy upon the compo-

sition and volume ofstcol and urine. J. Chin. Invest.

45: 469, 1966.

172. CHRISTOPHER, N. L., AND T. M. BAYLESS. Role of

the small bowel and colon in lactose-induced diar-rhea. Gastroenterology 60: 845, 1971.

173. ZIEGLER, E. E., AND S. J. FOMON. Fluid intake

renal solute load and water balance in infancy. J.

Pediat. 78: 561, 1971.

174. DAVIES, D. P. Protein intake, osmohality, homeo-

stasis and renal function in infancy. Postgrad. Med.

J. 51: 25, 1975.

175. BANISTER, A., S. A. MATIN-SIDDIQI AND G. W.HATCHER. Treatment of hypernatremic dehydra-

tion in infancy. Arch. Disease Childhood 50: 179,1975.

176. TALBOT, N. D., D. CRAWFORD AND A. M. B�.rri�R.

Homeostatic limits to safe parenteral fluid therapy.New Engh. J. Med. 248: 1 100, 1953.

177. TALBOT, N. B., G. A. KERRIGAN, J. D. CRAWFORD,

W. COCHRAN AND M. TERRY. Application of ho-

meostatic principles to the practice of parenteral

fluid therapy. New Engl. J� Med. 252: 856, 892,1955.

178. TALBOT, N. B., J. D. CRAWFORD, G. A. KERRIGAN,

D. HILLMAN, M. BERTUCIO AND M. TERRY. Apphi-

cation ofhomeostatic principles to the management

of nephritic patients. New Engl. J. Med. 255: 655,

1956.

179. TALBOT, N. B., J. D. CRAWFORD AND C. D. CooK.

Application of homeostatic principles to the man-agement of nephrotic patients. New Engl. J. Med.

256: 1080, 1957.

180. TALBOT, N. B., AND R. H. RICHIE. The advantageof surface area of the body as a basis for calculating

pediatric dosages. Pediatrics 23: 495, 1959.181. BUTLER, A. M., AND R. H. RICHIE. Simplification

and improvement in estimating drug dosage andfluid and dietary allowances for patients of varying

sizes. New Engl. J. Med. 262: 903, 1960.

182. BUTLER, A. M. The use of glucose, electrolyte,albumin, and amino acid solutions and whole bloodin parenteral fluid therapy. Quart. Rev. Pediat. 15:34, 1960.

183. GAMBLE, J. L., W. M. WALLACE, L. ELIEL, M. A.HOLLIDAY, M. CUSHMAN, J. APPLETON, A. SHEN-

BERG AND J. PIorri. Effects of large loads of dcc-

trolytes. Pediatrics 7: 305, 1951.

184. MCCANCE, R. A., AND E. M. WIDDOWSON. Hyper-

tonic expansion of the extra-cellular fluids. ActaPediat. 46: 337, 1957.

185. LINDENBAUM, J., W. B. GREENOUGH, III AND M.R. ISLAM. Antibiotic therapy ofcholera in children.

Bull. World Health Organ. 37: 529, 1967.

186. RAPOPORT, S., K. DODD, M. CLARK AND I. SYLEM.

Postacidotic state of infantile diarrhea: symptoms

and chemical data. Postacidotic hypocalcemia and

associated decreases in levels of potassium, phos-

phorus and phosphatase in the plasma. Am. J.Diseases Children 73: 391, 1947.

187. UYLANGCO, C. V., R. N. CHAUDHURI AND J. A.VASCO. Lactated Ringer solution in the treatmentof pediatric cholera. J. Philippine Med. Assoc. 42:

861, 1966.

188. FRANT, S., AND H. ABRAMSON. Epidemic diarrhea

of the newborn. In: Therapeutics of Infancy and

Childhood, edited by H. R. Litchfield and L. H.

Dembo. Philadelphia; F. A. Davis & Co., 1947.

189. GRANT, H., AND F. REICHSMAN. The effects of theingestion of large amounts of sodium chloride on

the arterial and venous pressures of normal sub-jects. Am. Heart J. 32: 704, 1946.

190. CRAWFORD, B., AND H. LUDEMANN. The renalresponse to intravenous injection of sodium chlo-ride solutions in man. J. Chin. Invest. 30: 1456,

by guest on Decem

ber 23, 2010w

ww

.ajcn.orgD

ownloaded from

ACUTE DIARRHEA IN CHILDREN 661

1951.191. STEWART, J. D., AND G. M. Rou�tKE. The effects of

large intravenous infusions on body fluid. J. Chin.Invest. 21: 147, 1942.

192. ADKINS, T. G., AND V. M. BUCKALEW, JR. On themechanism of anti-natiuresis following acute saline

loading. Cliii. Res. 24: 34a, 1976.193. AMES, R. G. Urinary water excretion and neuro-

hypophyseal function in full term and premature

infants shortly after birth. Pediatrics 12: 272, 1953.194. Ga,�Y, G. M. Carbohydrate digestion and absorp-

tion. Role ofthe small intestine. New Engl. J. Med.292: 1225, 1975.

195. FIELD, M. New strategies for treating watery diar-rhea. New Engl. J. Med. 297: 1121, 1977.

196. DESJEUX, J-F., C. TANNENBAUM, Y-H TAI AND P.

F. CURRAN. Effects of sugars and amino acids on

sodium movement across small intestine. Am. J.Diseases Children 133: 331, 1977.

197. SLADEN, G. E., AND A. M. DAWSON. Interrelation-

ships between the absorptions of glucose, sodium

and water by the normal humanjejunum. Chin. Sci.

36: 119, 1969.

198. MODIGLIANI, R., AND J. J. BERNIER. Effects of

glucose on net and unidirectional movements ofwater and electrolytes in the human small intestine.Biol. Gastrol-Enterol. 5: 165, 1972.

199. FORDTRAN, J. S. Simulation of active and passivesodium absorption by sugars in the human jejunum.

J. Clin. Invest. 55: 728, 1975.

200. HELLIER, M. D., C. THIRUMAI AND C. D.HOLDSWORTH. The effect of amino acids and di-peptides on sodium and water absorption in man.

Gut 14: 41, 1973.201. HIRSCHHORN, N., J. L. KINZIE, D. B. SACHAR, R.

S. NORTHRUP, J. D. TAYLOR, S. Z. AHMAD AND R.A. PHILLIPS. Decrease in net stool output in choleraduring intestinal perfusion with glucose-containingsolutions. New Engl. J. Med. 279: 176, 1968.

202. NALIN, D. R., R. A. CASH, R. ISLAM, M. MOLLA

AND R. A. PHILLIPS. Oral maintenance therapy for

cholera in adults. Lancet 2: 370, 1968203. PIERCE, N. F., R. B. SACK, R. C. MITRA, J. G.

BANWELL, K. L. BRIGHAM, D. S. FEDSON AND A.

MONDAL. Replacement of water and electrolyte

losses in cholera by an oral-glucose electrolyte so-

lution. Ann. Internal Med. 70: 1173, 1969.

204. MALAWAR, S. J., M. EWTON, J. S. FORDTRAN AND

F. J. INGELFINGER. Interrelation between jejunal

absorption ofsodium, glucose and water in man. J.Chin. Invest. 44: 1072, 1965.

205. GOLDNER, A. M., S. G. SCHULTZ AND P. F. CUR-

RAN. Sodium and sugar fluxes across the mucosalborder ofthe rabbit ileum. J. Gen. Physiol. 53: 362,

1969.206. SCHEDL, H. P., AND J. A. CLIFTON. Solute and

water absorption by the human small intestine.

Nature 199: 1264, 1963.207. BIEBERDORF, H. P., 5. MORAWSKI AND J. S. FORD-

TRAN. Effect of sodium, mannitol, and magnesiumon glucose, galactose, 3-0 methylglucose and fruc-tose absorption in the human ileum. Gastroenter-

ology 68: 58, 1975.208. PIERCE, N. F., J. G. BANWELL, R. C. MITRA, G. J.

CARANASOS, R. I. KEIMOWITZ, A. MONDAL AND P.

M. MANJI. Effect of intragastric glucose-electrolyte

infusion upon water and electrolyte balance in

Asiatic cholera. Gastroenterohogy 55: 333, 1968.209. MODIGLIANI, R., AND J. I. BERNIER. Absorption of

glucose, sodium, and water by the human jejunum

studies by intestinal perfusion with a proximal oc-

cluding balloon and at variable flow rates. Gut 12:

184, 1971.

210. SAITO, Y., AND T. H0SHI. Effects of mucosal hy-

perosmoharity on active sugar-invoked potential inisolated small intestine of the toad. Japan. J. Phys-iol. 23: 419, 1973.

21 1. SANDLE, G. I., R. W. LOBLEY AND R. HOLMES. Oral

therapy in cholera. New Engl. J. Med. 298: 797,1978.

212. TURNBERG, L. A., J. S. FORDTRAN, N. W. CARTER

AND F. C. RECTOR, JR. Mechanism of bicarbonate

absorption and its relationship to sodium transportin the human jejunum. J. Clin. Invest. 49: 548,1970.

213. OLSEN, W. E., AND F. J. INGELFINGER. The role ofsodium in intestinal glucose absorption in man. J.

Chin. Invest. 47: 1 133, 1968.

214. NALIN, D. R., AND R. A. CASH. Sodium content in

oral therapy for diarrhea. Lancet 2: 957, 1976.

215. CAREY, R. M., J. R. SMITH AND E. M. ORrr.

Gastrointestinal control of sodium excretion in so-

dium-depleted conscious rabbits. Am. J. Physiol.230: 1504, 1976.

216. SOERGEL, K. H., G. E. WHALEN, J. A. HARRIS AND

J. E. GEENEN. Effect of antidiuretic hormone on

human small intestinal water and solute transport.J. Chin. Invest. 47: 1071, 1968.

217. KENT, T. H., AND J. LINDENBAUM. Correlation of

jejunal function and morphology in patients withacute and chronic diarrhea in East Pakistan. Gas-troenterology 52: 972, 1967.

218. HIRSCHHORN, N., AND I. H. ROSENBERG. Sodium-

potassium stimulated adenosine triphosphatase ofthe small intestine of man: studies in cholera andother diarrheal diseases. J. Lab. Chin. Med. 72: 28,1968.

219. HIRSCHHORN, N., AND A. MOLLA. Reversible je-

junaldisaccharidase deficiency in cholera and other

acute diarrheal diseases. Johns Hopkins Med. J.125: 291, 1969.

220. BISHOP, R. F., G. P. DAVIDSON, I. H. HOLMES AND

B. J. RUCK. Virus particles in epithehial cells ofduodenal mucosa from children with acute non-bacterial gastroenteritis. Lancet 2: 1281, 1973.

221. AGUS, S. G., R. DOLIN, R. G. WYATt. A. J. T0U-SIMIS AND R. S. NORTHRUP. Acute infectious non-

bacterial gastroenteritis: Intestinal histopathology,

histologic and enzymatic alterations during illness

produced by the Norwalk Agent in man. Ann.Internal Med. 79: 18, 1973.

222. LIFSHITZ, F., P. COELLO-RAMIREZ AND M. L. CON-

TRERAS-GUITERREZ. The response of infants to car-bohydrate oral loads after recovery from diarrhea.

J. Pediat. 79: 612, 1971.223. GREEN, H. L., D. R. MCCABE AND G. B. MEREN-

STEIN. Protracted diarrhea and malnutrition in in-

fancy: Changes in intestinal morphology and disac-

charidase activities during treatment with total in-travenous nutrition or oral elemental diets. J. Pc-

by guest on Decem

ber 23, 2010w

ww

.ajcn.orgD

ownloaded from

662 HIRSCHHORN

diat. 87: 695, 1975.

224. TORRES-PINEDO, R., C. L. RIVERA AND S. FERNAN-

DEZ. Studies on infant diarrhea: II. Absorption ofglucose and net fluxes ofwater and sodium chloride

in a segment of the jejunum. J. Clin. Invest. 45:

1916, 1966.

225. JAMES, W. P. T., B. S. DRASAR AND C. MILLER.

Physiologic mechanism and pathogenesis of wean-

ling diarrhea. Am. J. Chin. Nutr. 25: 564, 1972.

226. LUGO-DE-RIVERA, C., H. RODRIQUEZ AND R.

TORRES-PINEDO. Studies on the mechanism of

sugar malabsorption in infantile infectious diar-

rhea. Am. J. Chin. Nutr. 25: 1248, 1972.227. CHUNG, A. W., AND B. VISCOROVA. The effect of

early oral feedings versus early oral starvation on

the course of infantile diarrhea. J. Pediat. 33: 14,1948.

228. LARCHER, V. F., R. SHEPHERD, D. E. M. FRANCIS

AND J. T. HARRIES. Protracted diarrhoea in infancy.

Analysis of 82 cases with particular reference to

diagnosis and management. Arch. Disease Child-hood 52: 597, 1977.

229. HYMAN, C. J., J. REITER, J. RODNAN AND A. L.DRASH. Parenteral and oral alimentation in the

treatment of nonspecific protracted diarrheal syn-drome ofinfancy. J. Pediat. 78: 17, 1971.

230. LEAKE, R. D., K. C. SCHROEDER, D. A. BENTON

AND W. OH. Soy-based formula in in the treatmentof infantile diarrhea. Am. J. Diseases Children 127:374, 1974.

231. SHERMAN, J. 0., C. A. HAMLY AND A. K. KHACH-

ADURIAN. Use of an oral elemental diet in infants

with severe intractable diarrhea. J. Pediat. 86: 518,1975.

232. GRACEY, M., AND R. HENDERSON. The use of a

carbohydrate-free feeding formula in AustralianAboriginal children with chronic diarrhea. Austra-han Pediat. J. 10: 164, 1974.

233. MITCHELL, J. D., J. BRAND AND J. HALBISCH.

Weight-gain inhibition by lactose in Australian Ab-

original children. A controlled trial of normal andlactose hydrolysed milk. Lancet 1: 500, 1977.

234. NALIN, D. R., R. A. CASH, M. RAHMAN AND M.YUNUS. Effect of glycine and glucose on sodium

and water absorption in patients with cholera. Gut11:768, 1970.

235. BEDINE, M. S., AND T. M. BAYLESS. Modification

of lactose tolerance by glucose or a meal. Chin. Res.20: 448, 1972.

236. BILLICH, C., G. A. BRAY, T. F. GALLAGHER, JR., A.

V. HOFFBRAND AND R. LEVITAN. Absorptive ca-

pacity of the jejunum of obese and lean subjects.

Effect of fasting. Arch. Internal Med. 130: 377,1972.

237. KNUDSEN, K. B., H. M. BELLAMY, F. R. LECOCQ,

E. M. BRADLEY AND J. D. WELsH. Effect of fasting

and refeeding on the histology and disaccharidase

activity of the human intestine. Gastroenterohogy55: 46, 1968.

238. STEINER, M., G. C. M. FARRISH AND S. J. GRAY.

Intestinal uptake of valine in calorie and protein

deprivation. Am. J. Chin. Nutr. 22: 871, 1969.239. ADIBI, S. A., AND E. R. AuiN. Impaired jejunal

absorption rates of essential amino acids induced

by either dietary caloric or protein deprivation in

man. Gastroenterology 59: 404, 1970.240. LEVINE, G. M., J. J. DEREN, E. STEIGER AND R.

ZINNO. Role of oral intake in maintenance of gutmass and disaccharidase activity. Gastroenterology

67: 975, 1974.

241. GREEN, H. L., F. B. STIFEL, L. HAGLER AND R. H.HERMAN. Comparison of the adaptive changes indisaccharidase, glycolytic and fructose diphospha-tase activities after intravenous and oral glucose in

normal man. Am. J. Chin. Nutr. 28: 1 122, 1975.242. PERGOLIZZI, R., F. LIFSCHITZ, S. TEICHBERG AND

R. WAPNIR. Interaction between dietary carbohy-

drates and intestinal disaccharidases in experimen-tal diarrhea. Am. J. Chin. Nutr. 30: 482, 1977.

243. SPARK, R. F., R. A. ARKY AND P. R. BOULTER.

Renin, aldosterone and glucagon in the natriuresisof fasting. New Engl. J. Med. 292: 1335, 1975.

244. DOEKEL, R. C., JR., C. W. ZWILLICH, C. H. SCoo-

GIN, M. KRYGER AND J. V. WElL. Clinical semi-

starvation. Depression of hypoxic ventilatory re-

sponse. New Engl. J. Med. 295: 358, 1976.

245. ITZKOWITZ, S., S. B. CLARK AND N. S. ROSEN-

SWEIG. Ileal glucose perfusion increases net proxi-mal intestinal disaccharidases. Chin. Res. 25: 660A,

1977.

246. NICHOLSON, J. A., D. M. MCCARTHY AND Y. S.

KIM. The responses of rat intestinal brush borderand cytosol peptide hydrohase activities to variation

in dietary protein content. J. Chin. hnvest. 54: 890,1974.

247. ROSENWEIG, N. S., AND R. H. HERMAN. Control of

jejunal sucrase and maltase activity by dietary su-crose or fructose in man. J. Chin. Invest. 47: 2253,1968.

248. ROSENSWEIG, N. S., AND R. H. HERMAN. Dose

response ofjejunal sucrase and maltase to isocalorichigh and low carbohydrate diets in man. Am. J.

Chin. Nutr. 23: 1373, 1970.249. ASSAD, R. T., AND G. L. EAsi�wooD. Epithelial

kinetics in small intestine of orally versus intrave-nously alimented rats. Chin. Res. 24: 627A, 1977.

250. CONDON-PAOLONI, D., J. CRAVIOTO, F. E. JOHN-

STON, E. R. DE LICARDIF AND T. 0. SCHOLL. Mor-

bidity and growth of infants and young children in

a rural Mexican village. Am. J. Public Health 67:651, 1977.

251. COLE, T. J., AND J. M. PARKIN. Infection and its

effect on the growth of young children: A compar-ison of the Gambia and Uganda. Trans. Roy. Soc.

Trop. Med. Hyg. 71: 196, 1977.

252. BINNS, C. W. Food, sickness and death in children

of the Highlands of Papua New Guinea. J. Trop.Med. Environ. Child Health 22: 9, 1976.

253. MATA, L. J., R. A. KROMAL, J. J. URRUTIA AND B.GARCIA. Effect of infection on food intake and the

nutritional state: perspectives as viewed from thevillage. Am. J. Chin. Nutr. 30: 1215, 1977.

254. Gui�I, 0. P., AND V. N. JAISWAL. Relationship of

undernutrition to diarrhoea in infants and children.

hnd. J. Med. Res. 58: 789, 1970.255. HARRISON, H. E. The treatment of diarrhea in

infancy. Pediat. Chin. N. Am. 1: 335, 1954.256. NALIN, D. R., R. A. CASH AND M. RAHMAN. Oral

(or nasogastric) maintenance therapy for cholerapatients in all age groups. Bull. World Health Or-

by guest on Decem

ber 23, 2010w

ww

.ajcn.orgD

ownloaded from

ACUTE DIARRHEA IN CHILDREN 663

gan. 43: 361, 1970.257. SACK, R. G., J. CASSELLS, R. MITRA, C. MERRITF,

T. BUTLER, J. THOMAS, B. JACOBS, A. CHAUDHURI

AND A. MONDAL. The use of oral replacementsolutions in the treatment of cholera and othersevere diarrhoeal disorders. Bull. World HealthOrgan. 43: 351, 1970.

258. KIELMANN, A. A., AND C. MCCORD. Home treat-

ment of childhood diarrhea in Punjab villages. J.Trop. Pediat. Environ. Child Health 23: 197, 1977.

259. CHATrERJEE, A., D. MAHALANABIS, K. N. JALAN,

T. K. MAITRA, S. K. AGARWAL, D. K. BAGCHI AND

S. INDRA. Evaluation of a sucrose/electrolyte solu-

tion for oral rehydration in acute infantile char-

rhoea. Lancet 1: 1333, 1977.260. CHATrERJEE, A., D. MAHALANABIS, K. N. JALAN,

T. K. MAITRA, S. K. AGARWAL, B. DUTrA, S. P.

KHATUA AND D. K. BAGCHI. Oral rehydration ininfantile diarrhoea. Controlled trial ofa low sodiumglucose electrolyte solution. Arch. Disease Child-

hood 53: 284, 1978.

261. NALIN, D. R., M. M. LEVINE, L. MATA, C. DE

CESPEDES, W. VARGAS, C. LIZANO, A. R. CORIA,

A. SIMHON AND E. MOHS. Oral rehydration andmaintenance of children with rotavirus and bacte-

rial diarrhoeas. Bull. World Health Organ. 57: 453,

1979.262. NALIN, D. R., M. M. LEVINE, L. MATA, C. DE

CESPEDES, W. VARGAS, C. LIZANO, A. R. LORIA, A.SIMHON AND E. MOHS. Comparison ofsucrosc withglucose in oral therapy of infant diarrhea. Lancet2: 277, 1978.

263. SACK, D. A., A. M. A. K. CHOWDHURY, A. EUSOF,

M. A. ALl, M. M. MERSON, S. IsLAM, R. E. BLACK

AND R. E. BROWN. Oral hydration in rota-virusdiarrhea: A double blind comparison of sucrosewith glucose electrolyte solution. Lancet 2: 280,1978.

264. NICHOLS, B. L., AND H. A. SORIANO. A critique oforal therapy of dehydration due to diarrheal syn-

dromes. Am. J. Chin. Nutr. 30: 1457, 1977.265. HIRSCHHORN, N., AND K. M. DENNY. Oral glucose-

electrolyte therapy for diarrhea: A means to main-

tain or improve nutrition? Am. J. Chin. Nutr. 28:189, 1975.

266. International Study Group. A positive effect on thenutrition of Philippine children of an oral-glucose-

electrolyte solution given at home for the treatmentof diarrhoea. Bull. World Health Organ. 55: 87,1977.

267. MAHALANABIS, D., R. B. SACK, B. JACOBS, A. M0N-

DAL AND J. THOMAS. Use ofan oral glucose electro-

lyte solution in the treatment of pediatric cholera-a controlled study. J. Trop. Pediat. Environ. Child

Health 20: 82, 1974.268. NALIN, D., M. M. LEVINE, R. HORNICK, E.

BERGQUIST, D. Hoovea, H. P. Houiy, D. WAi�ea-

MAN, J. VAN Bwtx, S. MATHENY, S. SOTMAN AND

M. RENNELS. The problem of emesis during oralglucose-electrolytes therapy given from the onset ofsevere cholera. Trans. Roy. Soc. Trop. Med. Hyg.73: 10, 1979.

269. PALMER, D. L., F. T. Kosmi, A. F. M. R. Isw�i,

A. S. M. M. RAHMAN AND R. B. SACK. Comparison

of sucrose and glucose in the oral electrolyte ther-apy of cholera and other severe diarrheas. NewEngI. J. Med. 297: 1 107, 1977.

270. PIZARRO, D., G. PUSADA, L. MATA, D. NALIN AND

E. MOHS. Oral dehydration of neonates with de-hydrating diarrhocas. Lancet 2: 1209, 1979.

271. MOENGINAH, P. A., Supaiwro, J. Son�itTo, M.

BACHTIN, Ds. SirralsNo, SUTARYO AND J. E.

ROHDE. Oral sucrose therapy for diarrhea. Lancet2: 323, 1975.

272. INTERNATIONAL Sniu� GROUP. Beneficial effects

of oral electrolyte-sugar solutions in the treatmentof children’s diarrhea. 2. Studies in seven rural

villages. J. Trop. Pediat. Environ. Child Health. Inpress.

by guest on Decem

ber 23, 2010w

ww

.ajcn.orgD

ownloaded from