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Refeeding of infants with acute diarrheal disease
Refeeding of infants with acute diarrheal disease Fima Lifshitz, MD, Ulysses F a g u n d e s N e t o , MD, Carlos A l b e r t o G a r c i a Olivo, MD, A n g e l C o r d a n o , MD, a n d Silvia Friedman, PhD From the Department of Pediatrics, North Shore University Hospital, Cornell University Medical College, Manhasset, New York; Hospital Umberto I, Escola Paulista de Medicina, SOo Paulo, Brazil; and the Mead Johnson Research Center, Bristol-Myers United States Nutritional Group, Evansville, Indiana The purpose of this study was to determine which infant formula a m o n g five would be the most efficacious for the refeeding of infants during an a c u t e episode of diarrhea. Fifty male infants less than 42 months of a g e with severe diarrhea and at least 5% dehydration were a d m i t t e d to a m e t a b o l i c unit and studied in a prospective, single-blind protocol. Ten infants randomly received one of five types of formula: two-thirds diluted c o w milk, c o w milk formula (Nanon, Nestle, Inc., Sao Paulo, Brazil), Portagen, Pregestimil, or Prosobee ( M e a d Johnson & Co. Division, Evansville, Ind.). They c o n t i n u e d to receive the same formula for 72 hours unless dehydration occurred. There were no associated infections, and they r e c e i v e d no prior antibiotic treatment. Oral hydration together with intravenous fluid therapy was given to all patients during the initial treatment. During the first 72 hours of refeeding, patients fed Portagen e x c r e t e d the least amount of stool and required r e d u c e d quantities of intravenous fluids or oral hydration. In contrast, patients fed diluted c o w milk or any other formula had more severe diarrhea. Nine of the 40 patients fed Portagen c o m p l e t e d the 72-hour treatment, whereas only 2 of 10 fed diluted c o w milk tolerated it. Similarly, the cumulative proportions for high purging rate, dehydration, c a r b o h y d r a t e intolerance, and vomiting were more f a v o r a b l e for Portagen and least a c c e p t a b l e for diluted c o w milk. No differences were found a m o n g the remaining three formulas tested. These d a t a show that diluted c o w milk is poorly tolerated by infants with severe diarrhea, whereas Portagen is more effective. (J PEDIATR1991;418:$99-408)
There is a general agreement that breast-feeding should continue during acute diarrhea, 1 Additionally, the use of oral rehydration solutions to replace the fluid and electrolyte losses is now considered essential during acute diarrheal episodes. 24, However, the choice of diet to be used for refeeding non-breast-fed infants who have acute diarrhea remains controversial. Lactose intolerance and prolongation of the diarrheal illness have been described in infants
Reprint requests: Fima Lifshitz, MD, Department of Pediatrics, North Shore University Hospital, Cornell University Medical College, Manhasset, NY 11030. 9/0/2"7126
who were fed cow milk. 57 For these reasons the American Academy of Pediatrics has recommended a lactose-free formula, s However, the World Health Organization (WHO) continues to recommend diluted cow milk or cow milk formula as the first choice for refeeding non-breast-fed infants who have acute diarrhea. 9 This prospective, randomized, single-blind study was designed to determine which of five formulas would be the most efficacious for refeeding infants during an acute episode of severe diarrhea. The response to formula feedings was measured by timing the recovery, evaluating the purging rates, and noting the complications during the refeeding trial. Complications measured included the development of dehydration, the presence of carbohydrate intolerance, and vomiting. $99
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The Journal of Pediatrics April 1991
Table I. N u t r i e n t composition of five formulas Formulos*
Cow milk'l"
Nanon
Calories Carbohydrate (gm) Type
100 7.7 Lactose
100 11.0 Lactose
Percent of calories Protein (gm) Type
30.8 5.5
44 2.5
Percent of calories Fat (gm) Type
22 5.5 Animal
Percent of calories Linoleate (gin) Linolenic (gm) Percent of calories Vitamin A (I.U.) Vitamin D (I.U.) Vitamin E (I.U.) Vitamin C (rag) Folic acid (#g) Thiamine (mg) Riboflavin (mg) Niacin (mg) Vitamin B6 (mg) Vitamin B12 (~g) Biotin (~g) Pantothenic acid (mg) Vitamin K (#g) Choline (mg) Inositol (rag) Calcium (mg) Phosphorus (mg) Iodine (#g) Ir0n (mg) Magnesium (mg) Copper (mg) Zinc (mg) Manganese (mg) Chloride (mg) Potassium (rag) Sodium (mg) Renal solute load Osmolality (mOsm/kg H20)
47.2 0.13 0.08 49.5 207 1.69 #g 0.06 mg 1.55 8.07 0.06 0.27 20.6 0.06 0.58 5.81 0.52 9.67 32.3 6.61 195 153 5.9 0.08 21 0.02 0.63 0.004 169 250 80.6
52 298 59 1.18 8.04 9.02 0.06 0.14 0.75 0.08 0.22 2.2 0.45 3.06 7.45 4.51 78.4 45.1 5.10 1.18 7.65 0.06 0.75 7.06 76.44 111.72 25.5
300
300
10.0 5.1 80% Milk fat, 20% corn oil 46 0.67
Portagen
Pregestimll
Prosobee
100 11.5 73% Corn syrup solids; 25% sucrose 46 3.5 Sodium caseinate
100 13.5 85% Corn syrup solids, 15% modified tapioca starch 54 2.8 Casein hydrolysate with added L-cysteine, cystein, L-tyrosine, L-tryptophan 11 4.0 40% MCT, 60% corn oil
100 10 100% Corn syrup solids
14 4.8 88% MCT, 12% corn oil, 2% lecithin 40
781 78 3.1 8 16 156 188 2.03 0.20 0.6 8 1.05 15.6 13.3 Trace 94 70 7.2 1.9 20 0.16 0.94 0.12 87 125 48 22 220
35
312 62.5 2.3 8 16 78 94 1.25 0.063 0.3 8 0.47 15.6 13,3 5 94 63 7.2 1.9 11 0.09 0.63 0.03 87 110 48 13 350
40 3.0 Soy isolate plus methionine 12 5.3 55% Coconut oil, 45% corn oil 48
300 63 3.1 8.1 15.66 78 94 1.25 0.063 0.31 7.8 0.47 15.6 7.8 4.7 94 74 10.2 1.88 10.9 0.094 0.78 0.025 83 122 36 200 200
MCT, Medium-chaintriglycerides. *Nanon is a cow milk formula producedby Nestle, Inc., Sao Paulo, Brazil. Portagen,Pregestimil,and Prosobeeare producedby the Mead Johnson & Co. Division of Bristol-Myers,Evansville,Ind. "~Cowmilk formula was diluted to provide67 kcal per 150 ml. All other formulas were fed at full strength and provided 100 kcal per 150 ml.
MATERIAL
AND METHODS
per day in the 24 hours preceding hospitalization and were
Fifty male infants less than 12 months of age who had severe diarrhea for less than 1 week were selected for this
at least 5% dehydrated at the time of admission to the hos-
study. Each had had at least four or more bowel movements
received prior antibiotic treatment. Breast-feeding had been
pital. They had no associated infections and had not
Volume 118 Number 4, Part 2
Refeeding o f infants with acute diarrhea
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T a b l e II. Clinical characteristics of infants in five formula groups No. of male infants
Age (mo) 0-2 2-6 6-12 Nutritional status? Normal I
Diluted cow milk*
Cow milk formula
Portagen
Pregestimil
Prosobee
4 4 2
1 7 2
2 4 4
3 3 4
3 3 4
3
3
2
3
3
4
1
3
4
4
5
3
3
4 4 2
4 6 0
4 3 3
II-III 3 6 Pathogens in stools Negative 3 3 E. coli')i 6 6 Othersw 1 1 *Dilutedto provide67 kcal per 150 ml. AII other formulasprovided 100 kcal per 150 ml. tGomez criteria. ~E. coli 0111 (18 patients),0152, 0127, 0167, or 055. w Shigella, Campylobacter, or rotavirus. discontinued in all patients for at least 1 month before hospital admission. The patients were weighed and were placed on metabolic beds. The use of urine bags assured the separate collection of stools and urine. Oral hydration and intravenous therapy were given to all patients. The amount of fluid given was calculated to replace the estimated hydration deficit and the continuing stool losses. The patients were rehydrated between 4 and 12 hours after admission to the hospital. As soon as they were rehydrated, refeeding was initiated and oral hydration or intravenous solutions or both were given in quantities equal to stool losses. Body weight, fluid intake, vomiting, and stool and urine output were carefully measured. Hydration status was monitored, and fluid reqjairements were calculated every 8 hours throughout the study. The refeeding protocol provided maintenance calories during the first day of treatment. Thereafter, oral intake was increased gradually, and patients were fed up to 120 kcal/kg per day during the second or third day of treatment. Feedings were given as desired every 3 hours. Ten infants in each group randomly received one of five types of feedings. Unless dehydration occurred, the patients continued to receive the selected formula for a minimum of 7 2 hours. The nutrient composition of the formulas is listed in Table I. Feedings included diluted (two-thirds strength) cow milk, a standard cow milk formula (Nanon, Nestle, Inc., S~o Paulo, Brazil), and the following proprietary formulas: Portagen, Pregestimil, or Prosobee (Mead Johnson & Co. Division, Evansville, Ind.). Only the cow milk was diluted; each of the formulas was fed at full strength. The first two types of feeding contain lactose as the carbohydrate source, whereas the other three formulas contain corn syrup solids. Portagen contains a small amount of su-
crose. Additionally, the selected formulas varied in content and composition of fat and protein. Portagen contains medium-chain triglycerides and casein; Pregestimil contains casein hydrolysate; and Prosobee contains soy protein isolate. There were also differences in osmolality (Table I). The Pregestimil used in this study was the previously marketed formulation that had a higher amount of carbohydrate, less total fat, a lower amount of medium-chain triglycerides, and a higher osmolality than the formula currently available in the United States. Diluted cow milk had the lowest osmolarity of the feedings used. All the formulas were isocaloric (100 kcal per 150 ml), except for diluted cow milk, which at two-thirds strength provided 67 kcal per 150 ml. Other minor differences in the formula composition concerned microelements, vitamins, and minerals. The formulas fed to the patients were selected by the Hospital Umberto I pharmacy. The dietary department personnel prepared and administered the formulas. The physicians in charge of the patients were unaware of the feeding selection given throughout the study because the formulas were identical in appearance and numbered sequentially according to a randomization chart coded by the pharmacy. The patient's age, nutritional status, and cause of diarrhea are shown in Table II. All five groups of patients who received different formulas had similar nutritional status according to Brazilian anthropometric standards. 1~ The differences in enteropathogens among groups in each feeding category were not significant. During the study, we observed a high frequency of stools infected with Escherichia coli 0111. This organism has been the most frequently isolated enteropathogen in patients with acute diarrhea in S~o
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The Journal of Pediatrics April 1991
150
150
~k
1O0
"~, 100
50
z
50 b-
Q~ 0
<3
3 DAYS ON FORMULA
3
<3 $
OAYS ON FORMULA
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3 DAYS ON FORMULA
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D Fig. I. Combined data of 50 patients studied in five formula groups. A, Oral intake (formula-fed); B, fecal losses. C, intravenous or oral rehydration fluids both given;D, sodium replacement. No differencesin the first 2 days of treatment were seen; therefore data were combined. Replacement included intravenous solutions and fluids given by the mother. (Data are expressed as mean _+ SD.)
Paulo during the last 25 years. 11 In a few instances, rotavirus, Shigella, or Salmonella were isolated from stool cultures. The criteria of formula failure were based on the induction of dehydration and the severity of the diarrhea. Dehydration that occurred during the time of refeeding was defined as a daily weight loss >5% of body weight that was not prevented by intravenous and oral rehydration fluids. Severe diarrhea was defined as liquid stool losses >40 gm/ kg of body weight per day up to the third day of treatment. If the formula failed, Pregestimil was offered. In patients fed initially with Pregestimil or for those in whom Pregestimil failed as the second formula, 3232A (a Pregestimillike formula without carbohydrate) was given for treatment. Carbohydrate intolerance, not considered a formula failure, was defined by the presence of acid stools or the excretion of carbohydrate in feces or both, and was measured by semiquantitative techniques.5 Recovery was defined as improvement in diarrhea with stools excreted during the third day of refeeding in amounts <30 gm/kg of body weight per day.
The differences in response to the various feedings were analyzed by the chi-squared test and by a two-way analysis of variance. Cumulative recovery rates and cumulative proportions for each of the variables were also reported. ~2 In all instances informed consent was signed by parents. The protocol was approved by the North Shore University Hospital Research and Publication Committee and by the research committee of the Escola Paulista de Medicina. RESULTS The combined purging rates of all 50 patients studied in the five formula groups are shown in Fig. 1. The mean stool output was approximately 80 gm/kg body weight per day during the first 2 days of dietary treatment. Improvement was noticed by day 3 when mean stool losses decreased to <40 gm/kg per day. Oral intake provided only 50 to 60 kcal/kg body weight per day during the first 48 hours of treatment. Although oral intake improved with time, at 72 hours only 70 to 80 kcal/kg of body weight per day were being ingested. None of the patients received a full caloric
Volume 118 Number 4, Part 2
Refeeding o f infants with acute diarrhea
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Fig. 2. C•mbineddata•f5•patientsstudiedin•vef•rmu•agr•ups•nDay••A••ra•intake(f•rmu•a-fed);B•feca•••sses. C, intravenous or oral rehydration fluids or both given; D, sodium replacement. DCM, Diluted cow milk; CMF, cow milk formula (NANON); PORT, Portagen; PRE, Pregestimil; PROS, Prosobee.
supply during the second or third day of treatment, as had been originally intended. The intravenous and oral rehydration fluids given and the amount of sodium replacements are also shown in Fig. 1. During the first 48 hours of dietary treatment, the patients required large quantities of intravenous fluids or oral hydration solutions, or both, because of the large quantities of stool losses. However, by the third day the fluid replacements were markedly decreased and sodium was being provided only in maintenance quantities. Patients fed Portagen excreted the least amount of stools, whereas stool output was about equal in the other groups (Fig. 2). Patients ingested about the same volume of all feedings during refeeding, even though diluted cow milk provided one third fewer calories than the other formulas. The quantities of intravenous fluids or oral hydration solutions given were also significantly lower in infants being fed Portagen or Prosobee than in those fed diluted cow milk, cow milk formula, or Pregestimil (Fig. 2). Patients fed Portagen or Prosobee also required the least amount of sodium to maintain balance. The treatment failures were also related to the type of
feeding given (Fig. 3). Most patients who started with Portagen (9/10) or with Pregestimil (8/10) were able to complete the 72-hour feeding trial, whereas in 8 of the 10 patients given diluted cow milk treatment failed. Similarly, half the patients given cow milk formula and more than half those given Prosobee had to be given a second formula choice because of dehydration. The cumulative proportions of patients who became dehydrated indicated that this complication was more frequently induced with diluted cow milk formula feedings than with other formula selections (Table III). Dehydration developed in only one of the patients fed Portagen during refeeding, but 50% of cow milk-fed patients became dehydrated. These differences were highly significant because they represented the most effective and the least effective feeding in regard to severe fluid losses. The differences in the rates of cumulative proportion of dehydration for the other three formulas were not significant. The cumulative proportions of patients whose high purging rates persisted during the first 3 days of refeeding also indicated that the severity of diarrhea was related to the formula choice (Table III). Among the group fed Portagen,
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The Journal of Pediatrics April 1991
TREATMENT FAILURES
5 ~D
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2 0
I
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36
48
60
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HOURS OF REFEEDING
Fig. 3. Number of patients in the five formula groups who failed to complete their 72-hour feeding trial. DCM, Diluted cow milk; CMF, cow milk formula (NANON); PORT, Portagen; PRE, Pregestimil; PROS, Prosobee.
T a b l e III. Proportions of infants with dehydration and severe diarrhea (>40 gm/kg body weight per day) in five formula groups Dehydration
Diluted cow milk Cow milk formula Portagen Pregestimil Prosobee
Severe diarrhea
Day I"
Day 2"
Day 3"
Cumulative proportions (%)
Day 1'
Day 2"
Day 3"
Cumulative proportions (%)
4/10 2/10 0/10 1/10 2/10
4/6 2/8 1/10 1/9 4/8
1/2 3/5 0/9 2/8 0/4
50t 30 3~ 14 27
8/10 7/10 4/10 9/10 9/10
4/6 6/8 4/10 7/9 5/8
1/2 3/5 2/9 4/8 0/4
72 69 34t 67 64
*Expressed as number of patients who met criteria/number of patients in the group on a given day. "~p <0.02 for severe diarrhea; p <0.03 for dehydration. Significant differences were derived by chi-squared analysis.
a significantly smaller number of patients had severe diarrhea at any one time during the 3 days of refeeding than observed among the other feeding groups. These differences were significant despite the formula failures in those who required a second formula choice before completing the 72hour trial. The differences in total cumulative recovery rates of the patients at 72 hours of treatment with various formulas were significantly higher for infants fed Portagen. Patients fed diluted cow milk were the least likely to improve. Eight of the ten patients fed Portagen had mild or no diarrhea by the third day of refeeding, whereas only one of ten infants fed diluted cow milk formula improved during this period. Differences in cumulative recovery rates at 72 hours among the other three formulas, including cow milk formula (4/10), Pregestimil (6/10), and Prosobee (4/10), were not significant.
All infants with formula failures who had a change to Pregestimil had improvement in diarrhea (Fig. 4). The four in the group initially treated with Pregestimil who had failures also improved after 3232A formula was introduced. By day 5 the diarrhea had resolved in all but one patient, including those who initially had a failure with cow milk. The presence of carbohydrate intolerance was also related to the feedings used (Table IV). Those patients fed Portagen were also those who had the lowest cumulative proportion of carbohydrate intolerance during the refeeding trial. In contrast, infants who received diluted cow milk had the highest proportion of carbohydrate intolerance. The differences in the cumulative proportions of carbohydrate intolerance were not significant for the cow milk formula, Pregestimil, or Prosobee. The presence of vomiting was also related to the formula used (Table IV). The infants fed Portagen or cow milk formula had the lowest frequency of
Volume 118 Number 4, Part 2
vomiting, Again, diluted cow milk was most closely associated with vomiting. The presence of specific pathogens in the stools, the patient's nutritional status, age, birth weight, and/or the acceptability of the formula by the infant were not related to timing of the patient's recovery or to the quantity of oral intake. The degree of purging and mean fecal losses and oral intake also did not differ among patients with respect to the presence or absence of any of these risk factors. Similarly, intravenous fluids and/or sodium replacement did not differ between patients who had these factors and those who did not. DISCUSSION These data show that diluted cow milk is poorly tolerated by infants with severe diarrhea during the initial stages of the disease. In contrast, Portagen, a hypotonic formula containing casein, a high proportion of medium-chain triglycerides, and corn syrup solids, was the most effective of all formulas tested. This formula was associated with a lesser degree of purging and a more benign evolution of the disease; recovery occurred in most patients at the end of the 72-h0ur feeding trial. Feedings with the other three form ulas yielded similar outcomes despite differences in carbohydrate, fat, and protein content. The clinical progress of the disease, purging rates, and complications did not differ among patients fed any of these formulas, but their clinical progress was intermediate between the superior performance of Portagen and the poorly tolerated diluted cow milk. Our data agree with those of other investigators who also evaluated the effects of different commercially available formulas in infants with acute diarrhea and who used stool weights as the dependent variable. 13 These authors showed that lactose-containing feedings adversely affected recovery as compared with lactose-free diets; however, as in our studies, treatment with an elemental diet or a soy-based formula did not add any advantage to treatment for patients with acute diarrhea 9 In contrast, in the treatment of chr0n!c p0stinfectious diarrhea, the use of a casein-hydrolyzed, semielemental diet (Pregestimil) may be advantageous: 14 The reasons for differences in the progress of patients in regard to the various formula feedings were not studied. Some of the risk factors that have been shown to influence the duration of diarrheal disease of infancy 15 did not appear to be important in our studies. Protein sensitization also did not influence the outcome of the patients. 16 The progress of diarrhea was similar in the three groups of patients fed either Pregestimil, Prosobee, or cow milk formula (Nanon). portagen seems to contain a combination and types of carbohydrate, fat, protein, and osmolality that were well suited for these infants with acute diarrhea. Carbohydrate
Refeeding of infants with acute diarrhea
S 105
70 I .-.. 60 o>, '13
9
l
) 50 40 ~, Itl
30
s
l
1
l
N 20
1 2 3 4 5 DAYS SINCETHE INITIATIONOF THE SECONDFORMULA Fig. 4. Improvement of diarrhea in patients in whom the first
feeding failed and who were then given Pregestimil. Patients in whom the Pregestimi! regimen failed received formula 3232A. All patients eventually improved.
intolerance is a frequent complication in young infants after infectious diarrhea, 5 particularly in those infected with rotavirus17, 18 and enteroinvasive Escherichia coli. 19 Glucose polymers are better absorbed and tolerated under these Conditions.20, 21 Additionally, there may be fat malabsorption in gastroenteritis,22 particularly when malnutrition is present; 23 improved fat absorption occurs with mediumchain triglycerides in infants with gastrointestinal disease.24, 25 Protein and nitrogen losses are also high during diarrheal illness, and the absorption of protein may be positively influenced by several dietary factors, including the protein source and its biologic value, 26 as well as the total energy intake and dilution Of the feedings. 27 Casein has a high biologic value, is easily digestible, and has a high performance rate for the treatment of malnourished infantsY Finally, the low osmolality of the formula (220 mOsm/kg) may also have exerted a beneficial effect; hypertonic feedings enhance intestinal water losses in diarrhea. 29 Other studies have compared different dietary approaches toward treatment of diarrheal disease in infancy. These include comparisons of lactose and lactose-free formulas with cow milk, 3~ comparisons of t'ormula and whey hydrolysate, 31 full-strength milk feeding regimens of three different formulas containing various sources of carbohydrate, protein, and fat, 32 and comparison s of human milk with cow milk and soy-based formulas. 33 In these studies the feeding of modified formulas to infants with acute diarrheal disease offered no advantage. However, these studies were based primarily on clinical data and duration of the illness, not on purging rates such as those measured in our metabolic study. Feedings with unprocessed diluted cow milk appear to
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The Journal of Pediatrics April 1991
T a b l e IV. Proportions of infants with carbohydrate intolerance and vomitus in five formula groups
Vomitus
Carbohydrate intolerance"
Diluted cow milk Cow milk formula Portagen Pregestimil Prosobee
Day t t
Day 2t
Day 3T
Cumulative proportions
Day t t
Day 2t
Day 3t
Cumulative proportions
4/10 3/10 0/10 2/10 4/10
4/6 3/8 1/10 1/9 2/8
0/2 1/5 1/9 1/8 0/4
44%:~ 30% 7% 15% 27%
5/10 2/10 1/10 7/10 5/10
2/6 0/8 1/10 2/9 2/8
2/2 0/5 1/9 0/8 0/4
50%w 9%:~ 10%w 33% 32%
Significant differences were derived by chi-squared analysis. *Defined as excretion of acid stools (pH <6.0) and feces containing >0.5% carbohydrates measured by semiquantitative techniques. "~Expressed as number of patients who met criteria/number of patients in the group on a given day.
,p <0.03. w <0.01 for vomitus.
pose a special risk for infants with severe diarrhea. Our observations revealed that their fecal output was greater than that with the other formulas, although it was less than that reported by Torres-Pinedo et al. 34, 35with full-strength milk feedings. Moreover, diluted cow milk feedings were associated with frequent dehydration despite administration of hydration solutions. Previous studies have also shown that milk feedings in infants with diarrhea were associated with dehydration and metabolic acidosis. 34, 35 Another frequent occurrence in acute enteric infections is lactose malabsorption/intolerance.6' 36-38This complication is associated with increased morbidity and complications if cow milk feedings are administered.39'4~ An improved clinical outcome after the elimination of lactose or lactose-containing milk from the diet has been demonstrated.14, 41, 42 However, the WHO continues to recommend feeding diluted cow milk to infants with diarrhea for the first 2 days of illness.9 These recommendations are based on reports of other investigators who have found no apparent benefit from reduction or withdrawal of lactose, cow milk, or cow milk formula in infantile diarrhea. 29, 43-50They are also based on cost considerations and the limited availability of proprietary formula throughout the developing world. In our studies there was a clear difference between the response to treatment with diluted cow milk and that observed with other formulas, including proprietary cow milk formula. These data suggest that there may be differences in regard to digestibility, absorption, and tolerance to lactose with different kinds of milk, the worst being unmodified cow milk. Human milk, which contains a relatively high lactose content, is well tolerated by infants with acute diarrhea. 1, 51 Others have found that soy protein formulas are better tolerated when they contain lactose instead of sucrose or dextromaltose. 52 In Europe, after more processed milk formulas were introduced, the prevalence
and severity of carbohydrate intolerance after gastroenteritis decreased. 53 In other areas of the world, where these milk formulas are not readily available, the current prevalence of lactose intolerance remains unabated 14,2i and is similar to that which we reported many years ago in studies of infants with diarrhea fed evaporated cow milk. 5 Thus differences in the processing of formulas or cow milk may account for the variations in lactose tolerance in infants with diarrhea that have been reported from different geographic locations and during distinct periods of time. RECOMMENDATIONS Recommendations to use special dietary formulas for non-breast-fed infants with acute severe diarrhea include a number of considerations. Our data show that most infants with severe diarrhea rapidly recover if hydration is preserved, regardless of the dietary treatment given. Independent of the feeding choice, diarrhea improves with appropriate fluid and electrolyte therapy. However, the data also show that additional improvement is possible with a proprietary formula such as Portagen, which contains the most appropriate combination of nutrients and osmolality for infants with acute diarrhea. Therefore, in severely ill infants, when proprietary formulas are readily available, the use ofa hyposmolar formula containing glucose polymers, medium-chain triglycerides, and casein may be the safest choice for refeeding. This approach may improve the outcome of these patients; data indicate that the outcome of infants with severe diarrhea is cause for concern.6, 14, 39, 40 Acute diarrhea in children may require hospitalization in 5% of cases. 54 In one recent study in the United States, diarrhea was given as the cause of death for an average of 500 children each year. In 50% of these cases death occurred after the child was receiving medical care. 55 The cost of special formulas has to be considered in re-
Volume 118 Number 4, Part 2
lation to the beneficial effect t h a t m a y be gained by retarding the progress of the disease. T h e r e c o m m e n d a t i o n to continue diluted cow milk feedings m a y be the only alternative when no other infant formula is available; starving the sick infant by delaying feedings may be more detrimental t h a n feedings of cow m i l k ) l, 43-47, 56, 57 U n d e r these circumstances, locally available cereal-based mixtures m a y provide safer alternatives t h a n diluted cow milk for refeeding the sick infant. 58 Medical personnel, h e a l t h authorities, and the patients' families are often less hesitant to incur expenses for diarrheal medications t h a t at best have no benefit59; however, appropriate nutritional rehabilitation m a y result in a milder course and more rapid recovery. Specially designed formulas for the t r e a t m e n t of severe dia r r h e a m a y reduce complications and prolonged hospitalization, a n d p r o m p t dietary t r e a t m e n t m a y reduce the n u m b e r of infants with chronic postinfectious diarrhea and m a l n u t r i t i o n with c o n c o m i t a n t high morbidity and mortality)4, 60
REFERENCES 1. Khin MU, Nyunt-Nyunt-Wai, Myo-Khin, Mu-Mu-Khin, TinU, Thane-Toe. Effect on clinical outcome of breast feeding during acute diarrhoea. Br Med J 1985;290:587-9. 2. Water with sugar and salt [Editorial]. Lancet 1978;2:300-1. 3. Hirschhorn N. The treatment of acute diarrhea in children: an historical and physiological perspective. Am J Clin Nutr 1980;33:637-63. 4. Molla AM, Molla A, Rohde J, Greenough WIII. Turning off the diarrhea: the role of food and ORS. J Pediatr Gastroenterol Nutr 1989;8:81-4. 5. Lifshitz F, Coello-Ramirez P, Gutierrez-Topete G, CornadoCornet MC. Carbohydrate intolerance in infants with diarrhea. J PEDIATR 1971;79:760-7. 6. Lifshitz F. Nutrition for special needs in infancy. In: Lifshitz F, ed. Nutrition for special needs in infancy: protein hydrolysates. New York: Marcel Dekker, 1985:1-10. 7. MacLean WD, De Romana CL, Massa E, Graham GG. Nutritional management of chronic diarrhea and malnutrition: primary reliance on oral feeding. J PEDIATR 1980;97:316-23. 8. Forbes GB, Woodruff CW. Pediatric nutrition handbook. 2nd ed. Elk Grove Village, II.: American Academy of Pediatrics, Committee on Nutrition, 1985:209-10, 277-9. 9. World Health Organization. A manual for the treatment of diarrhoea: Diarrhoeal diseases control programme. Programme Report. Geneva: World Health Organization, 1984 (WHO/CDD/80.2). 10. Ariza MJ. Metodo para la evaluacion del crecimiento de hombres y mujeres desde el nacimiento hasta los 20 anos, para uso a nivel nacional e internacional. Arch Latinoam Nutr 1972; 22:531-46. 1 l. Gomes AT, Blake P, Trabulsi LR. Prevalence ofE. coli strains with localized, diffuse and aggregative adherence to HeLa cells in infants with diarrhea and matched controls. J Clin Microbiol 1989;27:288-9. 12. Zar J. Biostatistical analysis. 2nd ed. Englewood Cliffs, N.J.: Prentice-Hall, 1984.
Refeeding o f infants with acute diarrhea
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13. Rajah R, Pettifor JM, Noormohamed M r et al. The effect of feeding four different formulae on stool weights in prolonged dehydrating infantile gastroenteritis. J Pediatr Gastroenterol Nutr 1988;7:203-7. 14. Lifshitz F, Fagundes-Neto U, Castro Ferreira V, Cordano A, da Costa Ribeiro H. The response to dietary treatment of patients with chronic post-infectious diarrhea and lactose intolerance. J Am Coil Nutr 1990;9:231-40. 15. Househam KC, Bowie DC, Mann MD, Bowie MD. Factors influencing the duration of acute diarrheal disease in infancy. J Pediatr Gastroenterol Nutr 1990;10:37-40. 16. Iyngkaran N. Intolerance to food proteins. In: Lifshitz F, ed. Pediatric nutrition. New York: Marcel Dekker, 1982:449-76. 17. Sack DA, Roads M, Molla M, Wahed A. Carbohydrate malabsorption in infants with rotavirus diarrhea. Am J Clin Nutr 1982;36:1112-8. 18. Manuel PD, Mukhtar DJL, Walker-Smith JA. Transient monosaccharide intolerance in infants with acute and protracted diarrhoea. J Pediatr Gastroenterol Nutr 1984;3:41-5. 19. Fagundes-Neto U, Patricio FR da S, Wheba J, Reis MHL, Gianotic OF, Trabulsi LR. An Escheriehia coli strain that causes diarrhea by invasion of the small intestinal mucosa induces monosaccharide intolerance. Arq Gastroent Sao Paulo 1979;16:205-8. 20. Lebenthal E, Rong-Bao L. Glucose polymers in diarrhea: high caloric density nutrients with low osmolality. J Pediatr Gastroenterol Nutr I990;11:1-6. 21. Fagundes-Neto U, Viaro T, Lifshitz F. Glucose polymer intolerance in infants with diarrhea and disaccharide intolerance. Am J Clin Nutr 1985;41:228-34. 22. Jones A, Avigad S, Diver-Harver AMS, Katznelson D. Disturbed fat absorption following infectious gastroenteritis in children. J PEDIATR 1979;95:362-6. 23. Mann MD, Hill ID, Peat GM, Bowie MD. Protein and fat absorption in prolonged diarrhea in infancy. Arch Dis Child 1982;57:268-73. 24. Galeano NF, Lepage G, Leroy C, et al. Comparison of two special infant formulas designed for the treatment of protracted diarrhea. J Pediatr Gastroenterol Nutr 1988;7:76-83. 25. Woolf GN, Kurian R, Jeejeebhoy KN. Diet for patients with a short bowel: high fat or high carbohydrate? Gastroenterology 1983;84:823-8. 26. MacLean WC Jr, Klein G, Lopez de Romana G, Massa E, Graham GG. Protein quality of conventionai and high protein rice and digestibility of glutinous and non-glutinous rice by preschool children. J Nutr 1978;108:1740-7. 27. Gastanabuy A, Cordano A, Graham G. Acceptability, tolerance and nutritional value of a rice-based infant formula. J Pediatr Gastroenterol Nutr 1990;t 1:240-6. 28. Graham G, Bartl JM, Cordano A, Morales E. Lactose free medium chain triglyceride formulas in severe malnutrition. Am J Res Child 1973;126:330-5. 29. Klish W J, Udall JN, Calvin RT, Nichols BL. The effect of intestinal solute load on water secretion in infants with acquired monosaccharide intolerance. Pediatr Res 1980;14:1343-6. 30. Bhan MK, Aroza NK, Khoshoo V, et al. Comparison of a lactose-free cereal-based formula and cow's milk in infants and children with acute gastroenteritis. J Pediatr Gastroenterol Nutr 1988;7:208-13. 31. Armitstead J, Kelly D, Walker-Smith J. Evaluation of infant feeding in acute gastroenteritis. J Pediatr Gastroenterol Nutr 1989;8:240-4.
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32. Conway SP, Ireson A. Acute gastroenteritis in well nourished infants: comparison of four feeding regimens. Arch Dis Child 1989;64:87-91. 33. Haffejee IE. Cow's milk-based formula, human milk, and soya feeds in acute infantile diarrhea: a therapeutic trial. J Pediatr Gastroenterol Nutr 1990; 10:193-8. 34. Torres-Pinedo R, Lavastida M, Rivera CL, Rodriquez H, Ortiz A. Studies in infant diarrhea. I. A comparison of the effects of milk feeding and intravenous therapy upon the composition and volume of the stool and urine. J Clin Invest 1966;45:46980. 35. Lugo-de-Rivera C, Rodriguez H, Torres-Pinedo R. Studies on the mechanism of sugar malabsorption in infantile infectious diarrhea. Am J Clin Nutr 1972;25:1248-53. 36. Brown KH, Black RE, Parry L. The effect of diarrhea on incidence of lactose malabsorption among Bangladeshi children. Am J Clin Nutr 1980;33:2226-7. 37. Hyams JS, Krause P J, Gleason PA. Lactose malabsorption following rotavirus infection in young children. J PEDIATR 1981;99:916-8. 38. Davidson GP, Goodwin D, Robb TA. Incidence and duration of lactose malabsorption in children hospitalized with acute enteritis:study in a well-nourished urban population. J PEDIATR 1984;105:587-90. 39. Lifshitz F. Perspectives of carbohydrate intolerance in infants with diarrhea. In: Lifshitz F, ed. Carbohydrate intolerance in infancy. New York: Marcel Dekker, 1982:3-20. 40. Lifshitz F. Nutrition in chronic diarrhea of infancy. In: Stern L, ed. Feeding the sick infant. New York: Raven, 1987:275-89. 41. Penny ME, Paredes P, Brown KH. Clinical and nutritional consequences of lactose feeding during persistent postenteritis diarrhea, Pediatrics 1989;84:835-44. 42. Dagan R, Gorodischer R, Moses SW. Dietary treatment of acute diarrhea: comparison Of cow's milk and a soy formula without disaceharides. J Trop Pediatr 1984;30:221-4. 43. Soeprapto, Soenarto Y, Nelwan, Moengihan PA, Ismangoen. Feeding children with diarrhea. J Trop Pediatr 1979;25:97100. 44. Rees L, Brook CGD. Gradual reintroduction of full-strength milk after acute gastroenteritis in children. Lancet 1979;1: 770-1. 45. Dugdale A, LovelI S, Gibbs V, Ball D. Refeeding after acute gastroenteritis: a controlled study. Arch Dis Child 1982;57: 76-8. 46. Haque KN, A1-Frayh A, El-Rifai R. Is it necessary to regrad-
The Journal of Pediatrics April 1991
47. 48.
49.
50.
51.
52. 53. 54.
55. 56.
57.
58.
59.
60.
uate milk after acute gastroenteritis in children? Trop Geogr Med 1983;35:369-73. Ransome O J, Roode H. Early introduction of milk feeds in acute infantile gastro-enteritis. S Afr Med J 1984;65:127-8. Isolauri E, Vesikari T, Saha P, Viander M. Milk versus no milk in rapid refeeding after acute gastroenteritis. J Pediatr Gastroenterol Nutr 1986;5:254-61. Groothuis JR, Berman S, Chapman J. Effect of carbohydrate ingested on outcome in infants with mild gastroenteritis. J PEDIATR 1986;108:903-6. Pichaipat V, Thanomsingh P, Assadamongkul R, Varavithya W. Effects of amount and concentration of a lactose-containing formula on outcome of infantile diarrhoea. J Med Assoc Thai 1986~,69:132-6. Okuni M, Okinaga K, Baba K. Studies on reducing sugars in stools Of acute infantile diarrhea, with special reference to differenceS between breast fed and artificially fed babies. Tohoku J Exp Med 1972;107:395-402. Donovan GK, Torres-Pinedo R. Chronic diarrhea and soy formulas. Am J Dis Child 1987;141:1069-71. What has happened to carbohydrate intolerance following gastroenteritis? [Editorial] Lancet 1987;1:23-4. Kotloff RL, Wasserman SS, Steciak JY, et al. Acute diarrhea in Baltimore children attending an outpatient clinic. Pediatr Infect Dis J 1988;7:753-9. Ho MS, Glass RI, Pinsky PF, et al. Diarrheal deaths in American children. Are they preventable? JAMA 1988;260:3281-5. Gazala E, Weitzman S, Weitzman Z, et al. Early versus late refeeding in acute infantile diarrhea. Isr J Med Sci 1988;24: 175-9. Karsten J, Paerregaard A, Petersen W, et al. Rapid versus gradual refeeding in acute gastroenteritis in childhood: energy intake and weight gain. J Pediatr Gastroenterol Nutr 1989; 8:75-8. Brown KH, Black RE, Lopez de Romana G, Creed de Kanashiro H. Infant-feeding practices and their relationship with diarrheal and other diseases in Huascar (Lima), Peru. Pediatrics 1989;83:31-40. Lerman S J, Shepard SD, Cash R. Treatment of diarrhoea in Indonesian children: what it costs and who pays for it. Lancet 1985;21:651-4. Lifshitz F, Coello-Ramirez P, Gutierrez-Topete G. Monosaccharide intolerance and hypoglycemia in infants with diarrhea. I. Clinical course of 23 cases. J PEDIATR 1970;77:595-603.
There is a general agreement that breast-feeding should continue during acute diarrhea, 1 Additionally, the use of oral rehydration solutions to replace the fluid and electrolyte losses is now considered essential during acute diarrheal episodes. 24, However, the choice of diet to be used for refeeding non-breast-fed infants who have acute diarrhea remains controversial. Lactose intolerance and prolongation of the diarrheal illness have been described in infants
Reprint requests: Fima Lifshitz, MD, Department of Pediatrics, North Shore University Hospital, Cornell University Medical College, Manhasset, NY 11030. 9/0/2"7126
who were fed cow milk. 57 For these reasons the American Academy of Pediatrics has recommended a lactose-free formula, s However, the World Health Organization (WHO) continues to recommend diluted cow milk or cow milk formula as the first choice for refeeding non-breast-fed infants who have acute diarrhea. 9 This prospective, randomized, single-blind study was designed to determine which of five formulas would be the most efficacious for refeeding infants during an acute episode of severe diarrhea. The response to formula feedings was measured by timing the recovery, evaluating the purging rates, and noting the complications during the refeeding trial. Complications measured included the development of dehydration, the presence of carbohydrate intolerance, and vomiting. $99
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The Journal of Pediatrics April 1991
Table I. N u t r i e n t composition of five formulas Formulos*
Cow milk'l"
Nanon
Calories Carbohydrate (gm) Type
100 7.7 Lactose
100 11.0 Lactose
Percent of calories Protein (gm) Type
30.8 5.5
44 2.5
Percent of calories Fat (gm) Type
22 5.5 Animal
Percent of calories Linoleate (gin) Linolenic (gm) Percent of calories Vitamin A (I.U.) Vitamin D (I.U.) Vitamin E (I.U.) Vitamin C (rag) Folic acid (#g) Thiamine (mg) Riboflavin (mg) Niacin (mg) Vitamin B6 (mg) Vitamin B12 (~g) Biotin (~g) Pantothenic acid (mg) Vitamin K (#g) Choline (mg) Inositol (rag) Calcium (mg) Phosphorus (mg) Iodine (#g) Ir0n (mg) Magnesium (mg) Copper (mg) Zinc (mg) Manganese (mg) Chloride (mg) Potassium (rag) Sodium (mg) Renal solute load Osmolality (mOsm/kg H20)
47.2 0.13 0.08 49.5 207 1.69 #g 0.06 mg 1.55 8.07 0.06 0.27 20.6 0.06 0.58 5.81 0.52 9.67 32.3 6.61 195 153 5.9 0.08 21 0.02 0.63 0.004 169 250 80.6
52 298 59 1.18 8.04 9.02 0.06 0.14 0.75 0.08 0.22 2.2 0.45 3.06 7.45 4.51 78.4 45.1 5.10 1.18 7.65 0.06 0.75 7.06 76.44 111.72 25.5
300
300
10.0 5.1 80% Milk fat, 20% corn oil 46 0.67
Portagen
Pregestimll
Prosobee
100 11.5 73% Corn syrup solids; 25% sucrose 46 3.5 Sodium caseinate
100 13.5 85% Corn syrup solids, 15% modified tapioca starch 54 2.8 Casein hydrolysate with added L-cysteine, cystein, L-tyrosine, L-tryptophan 11 4.0 40% MCT, 60% corn oil
100 10 100% Corn syrup solids
14 4.8 88% MCT, 12% corn oil, 2% lecithin 40
781 78 3.1 8 16 156 188 2.03 0.20 0.6 8 1.05 15.6 13.3 Trace 94 70 7.2 1.9 20 0.16 0.94 0.12 87 125 48 22 220
35
312 62.5 2.3 8 16 78 94 1.25 0.063 0.3 8 0.47 15.6 13,3 5 94 63 7.2 1.9 11 0.09 0.63 0.03 87 110 48 13 350
40 3.0 Soy isolate plus methionine 12 5.3 55% Coconut oil, 45% corn oil 48
300 63 3.1 8.1 15.66 78 94 1.25 0.063 0.31 7.8 0.47 15.6 7.8 4.7 94 74 10.2 1.88 10.9 0.094 0.78 0.025 83 122 36 200 200
MCT, Medium-chaintriglycerides. *Nanon is a cow milk formula producedby Nestle, Inc., Sao Paulo, Brazil. Portagen,Pregestimil,and Prosobeeare producedby the Mead Johnson & Co. Division of Bristol-Myers,Evansville,Ind. "~Cowmilk formula was diluted to provide67 kcal per 150 ml. All other formulas were fed at full strength and provided 100 kcal per 150 ml.
MATERIAL
AND METHODS
per day in the 24 hours preceding hospitalization and were
Fifty male infants less than 12 months of age who had severe diarrhea for less than 1 week were selected for this
at least 5% dehydrated at the time of admission to the hos-
study. Each had had at least four or more bowel movements
received prior antibiotic treatment. Breast-feeding had been
pital. They had no associated infections and had not
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Refeeding o f infants with acute diarrhea
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T a b l e II. Clinical characteristics of infants in five formula groups No. of male infants
Age (mo) 0-2 2-6 6-12 Nutritional status? Normal I
Diluted cow milk*
Cow milk formula
Portagen
Pregestimil
Prosobee
4 4 2
1 7 2
2 4 4
3 3 4
3 3 4
3
3
2
3
3
4
1
3
4
4
5
3
3
4 4 2
4 6 0
4 3 3
II-III 3 6 Pathogens in stools Negative 3 3 E. coli')i 6 6 Othersw 1 1 *Dilutedto provide67 kcal per 150 ml. AII other formulasprovided 100 kcal per 150 ml. tGomez criteria. ~E. coli 0111 (18 patients),0152, 0127, 0167, or 055. w Shigella, Campylobacter, or rotavirus. discontinued in all patients for at least 1 month before hospital admission. The patients were weighed and were placed on metabolic beds. The use of urine bags assured the separate collection of stools and urine. Oral hydration and intravenous therapy were given to all patients. The amount of fluid given was calculated to replace the estimated hydration deficit and the continuing stool losses. The patients were rehydrated between 4 and 12 hours after admission to the hospital. As soon as they were rehydrated, refeeding was initiated and oral hydration or intravenous solutions or both were given in quantities equal to stool losses. Body weight, fluid intake, vomiting, and stool and urine output were carefully measured. Hydration status was monitored, and fluid reqjairements were calculated every 8 hours throughout the study. The refeeding protocol provided maintenance calories during the first day of treatment. Thereafter, oral intake was increased gradually, and patients were fed up to 120 kcal/kg per day during the second or third day of treatment. Feedings were given as desired every 3 hours. Ten infants in each group randomly received one of five types of feedings. Unless dehydration occurred, the patients continued to receive the selected formula for a minimum of 7 2 hours. The nutrient composition of the formulas is listed in Table I. Feedings included diluted (two-thirds strength) cow milk, a standard cow milk formula (Nanon, Nestle, Inc., S~o Paulo, Brazil), and the following proprietary formulas: Portagen, Pregestimil, or Prosobee (Mead Johnson & Co. Division, Evansville, Ind.). Only the cow milk was diluted; each of the formulas was fed at full strength. The first two types of feeding contain lactose as the carbohydrate source, whereas the other three formulas contain corn syrup solids. Portagen contains a small amount of su-
crose. Additionally, the selected formulas varied in content and composition of fat and protein. Portagen contains medium-chain triglycerides and casein; Pregestimil contains casein hydrolysate; and Prosobee contains soy protein isolate. There were also differences in osmolality (Table I). The Pregestimil used in this study was the previously marketed formulation that had a higher amount of carbohydrate, less total fat, a lower amount of medium-chain triglycerides, and a higher osmolality than the formula currently available in the United States. Diluted cow milk had the lowest osmolarity of the feedings used. All the formulas were isocaloric (100 kcal per 150 ml), except for diluted cow milk, which at two-thirds strength provided 67 kcal per 150 ml. Other minor differences in the formula composition concerned microelements, vitamins, and minerals. The formulas fed to the patients were selected by the Hospital Umberto I pharmacy. The dietary department personnel prepared and administered the formulas. The physicians in charge of the patients were unaware of the feeding selection given throughout the study because the formulas were identical in appearance and numbered sequentially according to a randomization chart coded by the pharmacy. The patient's age, nutritional status, and cause of diarrhea are shown in Table II. All five groups of patients who received different formulas had similar nutritional status according to Brazilian anthropometric standards. 1~ The differences in enteropathogens among groups in each feeding category were not significant. During the study, we observed a high frequency of stools infected with Escherichia coli 0111. This organism has been the most frequently isolated enteropathogen in patients with acute diarrhea in S~o
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Lifshitz et al.
The Journal of Pediatrics April 1991
150
150
~k
1O0
"~, 100
50
z
50 b-
Q~ 0
<3
3 DAYS ON FORMULA
3
<3 $
OAYS ON FORMULA
P(O.05
A
m P(O.O01
C
10
150
100
v
==
50
I (3
3 DAYS ON FORMULA
B
3
(3 DAYS ON FORMULA
*** P(0.001
~ * P(O.001
D Fig. I. Combined data of 50 patients studied in five formula groups. A, Oral intake (formula-fed); B, fecal losses. C, intravenous or oral rehydration fluids both given;D, sodium replacement. No differencesin the first 2 days of treatment were seen; therefore data were combined. Replacement included intravenous solutions and fluids given by the mother. (Data are expressed as mean _+ SD.)
Paulo during the last 25 years. 11 In a few instances, rotavirus, Shigella, or Salmonella were isolated from stool cultures. The criteria of formula failure were based on the induction of dehydration and the severity of the diarrhea. Dehydration that occurred during the time of refeeding was defined as a daily weight loss >5% of body weight that was not prevented by intravenous and oral rehydration fluids. Severe diarrhea was defined as liquid stool losses >40 gm/ kg of body weight per day up to the third day of treatment. If the formula failed, Pregestimil was offered. In patients fed initially with Pregestimil or for those in whom Pregestimil failed as the second formula, 3232A (a Pregestimillike formula without carbohydrate) was given for treatment. Carbohydrate intolerance, not considered a formula failure, was defined by the presence of acid stools or the excretion of carbohydrate in feces or both, and was measured by semiquantitative techniques.5 Recovery was defined as improvement in diarrhea with stools excreted during the third day of refeeding in amounts <30 gm/kg of body weight per day.
The differences in response to the various feedings were analyzed by the chi-squared test and by a two-way analysis of variance. Cumulative recovery rates and cumulative proportions for each of the variables were also reported. ~2 In all instances informed consent was signed by parents. The protocol was approved by the North Shore University Hospital Research and Publication Committee and by the research committee of the Escola Paulista de Medicina. RESULTS The combined purging rates of all 50 patients studied in the five formula groups are shown in Fig. 1. The mean stool output was approximately 80 gm/kg body weight per day during the first 2 days of dietary treatment. Improvement was noticed by day 3 when mean stool losses decreased to <40 gm/kg per day. Oral intake provided only 50 to 60 kcal/kg body weight per day during the first 48 hours of treatment. Although oral intake improved with time, at 72 hours only 70 to 80 kcal/kg of body weight per day were being ingested. None of the patients received a full caloric
Volume 118 Number 4, Part 2
Refeeding o f infants with acute diarrhea
S 103
150 .
150
g lo0
i I ,
-
,oo.
[
T
T !
v
50
o_
50-
|
nO
OCM
CMF
'PORT
PRE
PROS
0
DCM
CMF
PRE
PORT
PROS
C
A
10
150
100
q
50
o
DCM
CMF
PORT
PRE
PROS
D
DCM
CMF
PORT "
PRE
PROS
P(0.05;
"* P(0.01
vm.
PORT
Fig. 2. C•mbineddata•f5•patientsstudiedin•vef•rmu•agr•ups•nDay••A••ra•intake(f•rmu•a-fed);B•feca•••sses. C, intravenous or oral rehydration fluids or both given; D, sodium replacement. DCM, Diluted cow milk; CMF, cow milk formula (NANON); PORT, Portagen; PRE, Pregestimil; PROS, Prosobee.
supply during the second or third day of treatment, as had been originally intended. The intravenous and oral rehydration fluids given and the amount of sodium replacements are also shown in Fig. 1. During the first 48 hours of dietary treatment, the patients required large quantities of intravenous fluids or oral hydration solutions, or both, because of the large quantities of stool losses. However, by the third day the fluid replacements were markedly decreased and sodium was being provided only in maintenance quantities. Patients fed Portagen excreted the least amount of stools, whereas stool output was about equal in the other groups (Fig. 2). Patients ingested about the same volume of all feedings during refeeding, even though diluted cow milk provided one third fewer calories than the other formulas. The quantities of intravenous fluids or oral hydration solutions given were also significantly lower in infants being fed Portagen or Prosobee than in those fed diluted cow milk, cow milk formula, or Pregestimil (Fig. 2). Patients fed Portagen or Prosobee also required the least amount of sodium to maintain balance. The treatment failures were also related to the type of
feeding given (Fig. 3). Most patients who started with Portagen (9/10) or with Pregestimil (8/10) were able to complete the 72-hour feeding trial, whereas in 8 of the 10 patients given diluted cow milk treatment failed. Similarly, half the patients given cow milk formula and more than half those given Prosobee had to be given a second formula choice because of dehydration. The cumulative proportions of patients who became dehydrated indicated that this complication was more frequently induced with diluted cow milk formula feedings than with other formula selections (Table III). Dehydration developed in only one of the patients fed Portagen during refeeding, but 50% of cow milk-fed patients became dehydrated. These differences were highly significant because they represented the most effective and the least effective feeding in regard to severe fluid losses. The differences in the rates of cumulative proportion of dehydration for the other three formulas were not significant. The cumulative proportions of patients whose high purging rates persisted during the first 3 days of refeeding also indicated that the severity of diarrhea was related to the formula choice (Table III). Among the group fed Portagen,
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Lifshitz et al.
The Journal of Pediatrics April 1991
TREATMENT FAILURES
5 ~D
10
rv-
,9
8
laJ
,,,
6
o
4
'1I,Z 0
e~e o---o &.-. & G--Q e- -~
Z Z
'.'
n,..
DCM CMF PORT PRE PROS
2 0
I
i
I
I
i
24
36
48
60
72
HOURS OF REFEEDING
Fig. 3. Number of patients in the five formula groups who failed to complete their 72-hour feeding trial. DCM, Diluted cow milk; CMF, cow milk formula (NANON); PORT, Portagen; PRE, Pregestimil; PROS, Prosobee.
T a b l e III. Proportions of infants with dehydration and severe diarrhea (>40 gm/kg body weight per day) in five formula groups Dehydration
Diluted cow milk Cow milk formula Portagen Pregestimil Prosobee
Severe diarrhea
Day I"
Day 2"
Day 3"
Cumulative proportions (%)
Day 1'
Day 2"
Day 3"
Cumulative proportions (%)
4/10 2/10 0/10 1/10 2/10
4/6 2/8 1/10 1/9 4/8
1/2 3/5 0/9 2/8 0/4
50t 30 3~ 14 27
8/10 7/10 4/10 9/10 9/10
4/6 6/8 4/10 7/9 5/8
1/2 3/5 2/9 4/8 0/4
72 69 34t 67 64
*Expressed as number of patients who met criteria/number of patients in the group on a given day. "~p <0.02 for severe diarrhea; p <0.03 for dehydration. Significant differences were derived by chi-squared analysis.
a significantly smaller number of patients had severe diarrhea at any one time during the 3 days of refeeding than observed among the other feeding groups. These differences were significant despite the formula failures in those who required a second formula choice before completing the 72hour trial. The differences in total cumulative recovery rates of the patients at 72 hours of treatment with various formulas were significantly higher for infants fed Portagen. Patients fed diluted cow milk were the least likely to improve. Eight of the ten patients fed Portagen had mild or no diarrhea by the third day of refeeding, whereas only one of ten infants fed diluted cow milk formula improved during this period. Differences in cumulative recovery rates at 72 hours among the other three formulas, including cow milk formula (4/10), Pregestimil (6/10), and Prosobee (4/10), were not significant.
All infants with formula failures who had a change to Pregestimil had improvement in diarrhea (Fig. 4). The four in the group initially treated with Pregestimil who had failures also improved after 3232A formula was introduced. By day 5 the diarrhea had resolved in all but one patient, including those who initially had a failure with cow milk. The presence of carbohydrate intolerance was also related to the feedings used (Table IV). Those patients fed Portagen were also those who had the lowest cumulative proportion of carbohydrate intolerance during the refeeding trial. In contrast, infants who received diluted cow milk had the highest proportion of carbohydrate intolerance. The differences in the cumulative proportions of carbohydrate intolerance were not significant for the cow milk formula, Pregestimil, or Prosobee. The presence of vomiting was also related to the formula used (Table IV). The infants fed Portagen or cow milk formula had the lowest frequency of
Volume 118 Number 4, Part 2
vomiting, Again, diluted cow milk was most closely associated with vomiting. The presence of specific pathogens in the stools, the patient's nutritional status, age, birth weight, and/or the acceptability of the formula by the infant were not related to timing of the patient's recovery or to the quantity of oral intake. The degree of purging and mean fecal losses and oral intake also did not differ among patients with respect to the presence or absence of any of these risk factors. Similarly, intravenous fluids and/or sodium replacement did not differ between patients who had these factors and those who did not. DISCUSSION These data show that diluted cow milk is poorly tolerated by infants with severe diarrhea during the initial stages of the disease. In contrast, Portagen, a hypotonic formula containing casein, a high proportion of medium-chain triglycerides, and corn syrup solids, was the most effective of all formulas tested. This formula was associated with a lesser degree of purging and a more benign evolution of the disease; recovery occurred in most patients at the end of the 72-h0ur feeding trial. Feedings with the other three form ulas yielded similar outcomes despite differences in carbohydrate, fat, and protein content. The clinical progress of the disease, purging rates, and complications did not differ among patients fed any of these formulas, but their clinical progress was intermediate between the superior performance of Portagen and the poorly tolerated diluted cow milk. Our data agree with those of other investigators who also evaluated the effects of different commercially available formulas in infants with acute diarrhea and who used stool weights as the dependent variable. 13 These authors showed that lactose-containing feedings adversely affected recovery as compared with lactose-free diets; however, as in our studies, treatment with an elemental diet or a soy-based formula did not add any advantage to treatment for patients with acute diarrhea 9 In contrast, in the treatment of chr0n!c p0stinfectious diarrhea, the use of a casein-hydrolyzed, semielemental diet (Pregestimil) may be advantageous: 14 The reasons for differences in the progress of patients in regard to the various formula feedings were not studied. Some of the risk factors that have been shown to influence the duration of diarrheal disease of infancy 15 did not appear to be important in our studies. Protein sensitization also did not influence the outcome of the patients. 16 The progress of diarrhea was similar in the three groups of patients fed either Pregestimil, Prosobee, or cow milk formula (Nanon). portagen seems to contain a combination and types of carbohydrate, fat, protein, and osmolality that were well suited for these infants with acute diarrhea. Carbohydrate
Refeeding of infants with acute diarrhea
S 105
70 I .-.. 60 o>, '13
9
l
) 50 40 ~, Itl
30
s
l
1
l
N 20
1 2 3 4 5 DAYS SINCETHE INITIATIONOF THE SECONDFORMULA Fig. 4. Improvement of diarrhea in patients in whom the first
feeding failed and who were then given Pregestimil. Patients in whom the Pregestimi! regimen failed received formula 3232A. All patients eventually improved.
intolerance is a frequent complication in young infants after infectious diarrhea, 5 particularly in those infected with rotavirus17, 18 and enteroinvasive Escherichia coli. 19 Glucose polymers are better absorbed and tolerated under these Conditions.20, 21 Additionally, there may be fat malabsorption in gastroenteritis,22 particularly when malnutrition is present; 23 improved fat absorption occurs with mediumchain triglycerides in infants with gastrointestinal disease.24, 25 Protein and nitrogen losses are also high during diarrheal illness, and the absorption of protein may be positively influenced by several dietary factors, including the protein source and its biologic value, 26 as well as the total energy intake and dilution Of the feedings. 27 Casein has a high biologic value, is easily digestible, and has a high performance rate for the treatment of malnourished infantsY Finally, the low osmolality of the formula (220 mOsm/kg) may also have exerted a beneficial effect; hypertonic feedings enhance intestinal water losses in diarrhea. 29 Other studies have compared different dietary approaches toward treatment of diarrheal disease in infancy. These include comparisons of lactose and lactose-free formulas with cow milk, 3~ comparisons of t'ormula and whey hydrolysate, 31 full-strength milk feeding regimens of three different formulas containing various sources of carbohydrate, protein, and fat, 32 and comparison s of human milk with cow milk and soy-based formulas. 33 In these studies the feeding of modified formulas to infants with acute diarrheal disease offered no advantage. However, these studies were based primarily on clinical data and duration of the illness, not on purging rates such as those measured in our metabolic study. Feedings with unprocessed diluted cow milk appear to
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Lifshitz et al.
The Journal of Pediatrics April 1991
T a b l e IV. Proportions of infants with carbohydrate intolerance and vomitus in five formula groups
Vomitus
Carbohydrate intolerance"
Diluted cow milk Cow milk formula Portagen Pregestimil Prosobee
Day t t
Day 2t
Day 3T
Cumulative proportions
Day t t
Day 2t
Day 3t
Cumulative proportions
4/10 3/10 0/10 2/10 4/10
4/6 3/8 1/10 1/9 2/8
0/2 1/5 1/9 1/8 0/4
44%:~ 30% 7% 15% 27%
5/10 2/10 1/10 7/10 5/10
2/6 0/8 1/10 2/9 2/8
2/2 0/5 1/9 0/8 0/4
50%w 9%:~ 10%w 33% 32%
Significant differences were derived by chi-squared analysis. *Defined as excretion of acid stools (pH <6.0) and feces containing >0.5% carbohydrates measured by semiquantitative techniques. "~Expressed as number of patients who met criteria/number of patients in the group on a given day.
,p <0.03. w <0.01 for vomitus.
pose a special risk for infants with severe diarrhea. Our observations revealed that their fecal output was greater than that with the other formulas, although it was less than that reported by Torres-Pinedo et al. 34, 35with full-strength milk feedings. Moreover, diluted cow milk feedings were associated with frequent dehydration despite administration of hydration solutions. Previous studies have also shown that milk feedings in infants with diarrhea were associated with dehydration and metabolic acidosis. 34, 35 Another frequent occurrence in acute enteric infections is lactose malabsorption/intolerance.6' 36-38This complication is associated with increased morbidity and complications if cow milk feedings are administered.39'4~ An improved clinical outcome after the elimination of lactose or lactose-containing milk from the diet has been demonstrated.14, 41, 42 However, the WHO continues to recommend feeding diluted cow milk to infants with diarrhea for the first 2 days of illness.9 These recommendations are based on reports of other investigators who have found no apparent benefit from reduction or withdrawal of lactose, cow milk, or cow milk formula in infantile diarrhea. 29, 43-50They are also based on cost considerations and the limited availability of proprietary formula throughout the developing world. In our studies there was a clear difference between the response to treatment with diluted cow milk and that observed with other formulas, including proprietary cow milk formula. These data suggest that there may be differences in regard to digestibility, absorption, and tolerance to lactose with different kinds of milk, the worst being unmodified cow milk. Human milk, which contains a relatively high lactose content, is well tolerated by infants with acute diarrhea. 1, 51 Others have found that soy protein formulas are better tolerated when they contain lactose instead of sucrose or dextromaltose. 52 In Europe, after more processed milk formulas were introduced, the prevalence
and severity of carbohydrate intolerance after gastroenteritis decreased. 53 In other areas of the world, where these milk formulas are not readily available, the current prevalence of lactose intolerance remains unabated 14,2i and is similar to that which we reported many years ago in studies of infants with diarrhea fed evaporated cow milk. 5 Thus differences in the processing of formulas or cow milk may account for the variations in lactose tolerance in infants with diarrhea that have been reported from different geographic locations and during distinct periods of time. RECOMMENDATIONS Recommendations to use special dietary formulas for non-breast-fed infants with acute severe diarrhea include a number of considerations. Our data show that most infants with severe diarrhea rapidly recover if hydration is preserved, regardless of the dietary treatment given. Independent of the feeding choice, diarrhea improves with appropriate fluid and electrolyte therapy. However, the data also show that additional improvement is possible with a proprietary formula such as Portagen, which contains the most appropriate combination of nutrients and osmolality for infants with acute diarrhea. Therefore, in severely ill infants, when proprietary formulas are readily available, the use ofa hyposmolar formula containing glucose polymers, medium-chain triglycerides, and casein may be the safest choice for refeeding. This approach may improve the outcome of these patients; data indicate that the outcome of infants with severe diarrhea is cause for concern.6, 14, 39, 40 Acute diarrhea in children may require hospitalization in 5% of cases. 54 In one recent study in the United States, diarrhea was given as the cause of death for an average of 500 children each year. In 50% of these cases death occurred after the child was receiving medical care. 55 The cost of special formulas has to be considered in re-
Volume 118 Number 4, Part 2
lation to the beneficial effect t h a t m a y be gained by retarding the progress of the disease. T h e r e c o m m e n d a t i o n to continue diluted cow milk feedings m a y be the only alternative when no other infant formula is available; starving the sick infant by delaying feedings may be more detrimental t h a n feedings of cow m i l k ) l, 43-47, 56, 57 U n d e r these circumstances, locally available cereal-based mixtures m a y provide safer alternatives t h a n diluted cow milk for refeeding the sick infant. 58 Medical personnel, h e a l t h authorities, and the patients' families are often less hesitant to incur expenses for diarrheal medications t h a t at best have no benefit59; however, appropriate nutritional rehabilitation m a y result in a milder course and more rapid recovery. Specially designed formulas for the t r e a t m e n t of severe dia r r h e a m a y reduce complications and prolonged hospitalization, a n d p r o m p t dietary t r e a t m e n t m a y reduce the n u m b e r of infants with chronic postinfectious diarrhea and m a l n u t r i t i o n with c o n c o m i t a n t high morbidity and mortality)4, 60
REFERENCES 1. Khin MU, Nyunt-Nyunt-Wai, Myo-Khin, Mu-Mu-Khin, TinU, Thane-Toe. Effect on clinical outcome of breast feeding during acute diarrhoea. Br Med J 1985;290:587-9. 2. Water with sugar and salt [Editorial]. Lancet 1978;2:300-1. 3. Hirschhorn N. The treatment of acute diarrhea in children: an historical and physiological perspective. Am J Clin Nutr 1980;33:637-63. 4. Molla AM, Molla A, Rohde J, Greenough WIII. Turning off the diarrhea: the role of food and ORS. J Pediatr Gastroenterol Nutr 1989;8:81-4. 5. Lifshitz F, Coello-Ramirez P, Gutierrez-Topete G, CornadoCornet MC. Carbohydrate intolerance in infants with diarrhea. J PEDIATR 1971;79:760-7. 6. Lifshitz F. Nutrition for special needs in infancy. In: Lifshitz F, ed. Nutrition for special needs in infancy: protein hydrolysates. New York: Marcel Dekker, 1985:1-10. 7. MacLean WD, De Romana CL, Massa E, Graham GG. Nutritional management of chronic diarrhea and malnutrition: primary reliance on oral feeding. J PEDIATR 1980;97:316-23. 8. Forbes GB, Woodruff CW. Pediatric nutrition handbook. 2nd ed. Elk Grove Village, II.: American Academy of Pediatrics, Committee on Nutrition, 1985:209-10, 277-9. 9. World Health Organization. A manual for the treatment of diarrhoea: Diarrhoeal diseases control programme. Programme Report. Geneva: World Health Organization, 1984 (WHO/CDD/80.2). 10. Ariza MJ. Metodo para la evaluacion del crecimiento de hombres y mujeres desde el nacimiento hasta los 20 anos, para uso a nivel nacional e internacional. Arch Latinoam Nutr 1972; 22:531-46. 1 l. Gomes AT, Blake P, Trabulsi LR. Prevalence ofE. coli strains with localized, diffuse and aggregative adherence to HeLa cells in infants with diarrhea and matched controls. J Clin Microbiol 1989;27:288-9. 12. Zar J. Biostatistical analysis. 2nd ed. Englewood Cliffs, N.J.: Prentice-Hall, 1984.
Refeeding o f infants with acute diarrhea
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13. Rajah R, Pettifor JM, Noormohamed M r et al. The effect of feeding four different formulae on stool weights in prolonged dehydrating infantile gastroenteritis. J Pediatr Gastroenterol Nutr 1988;7:203-7. 14. Lifshitz F, Fagundes-Neto U, Castro Ferreira V, Cordano A, da Costa Ribeiro H. The response to dietary treatment of patients with chronic post-infectious diarrhea and lactose intolerance. J Am Coil Nutr 1990;9:231-40. 15. Househam KC, Bowie DC, Mann MD, Bowie MD. Factors influencing the duration of acute diarrheal disease in infancy. J Pediatr Gastroenterol Nutr 1990;10:37-40. 16. Iyngkaran N. Intolerance to food proteins. In: Lifshitz F, ed. Pediatric nutrition. New York: Marcel Dekker, 1982:449-76. 17. Sack DA, Roads M, Molla M, Wahed A. Carbohydrate malabsorption in infants with rotavirus diarrhea. Am J Clin Nutr 1982;36:1112-8. 18. Manuel PD, Mukhtar DJL, Walker-Smith JA. Transient monosaccharide intolerance in infants with acute and protracted diarrhoea. J Pediatr Gastroenterol Nutr 1984;3:41-5. 19. Fagundes-Neto U, Patricio FR da S, Wheba J, Reis MHL, Gianotic OF, Trabulsi LR. An Escheriehia coli strain that causes diarrhea by invasion of the small intestinal mucosa induces monosaccharide intolerance. Arq Gastroent Sao Paulo 1979;16:205-8. 20. Lebenthal E, Rong-Bao L. Glucose polymers in diarrhea: high caloric density nutrients with low osmolality. J Pediatr Gastroenterol Nutr I990;11:1-6. 21. Fagundes-Neto U, Viaro T, Lifshitz F. Glucose polymer intolerance in infants with diarrhea and disaccharide intolerance. Am J Clin Nutr 1985;41:228-34. 22. Jones A, Avigad S, Diver-Harver AMS, Katznelson D. Disturbed fat absorption following infectious gastroenteritis in children. J PEDIATR 1979;95:362-6. 23. Mann MD, Hill ID, Peat GM, Bowie MD. Protein and fat absorption in prolonged diarrhea in infancy. Arch Dis Child 1982;57:268-73. 24. Galeano NF, Lepage G, Leroy C, et al. Comparison of two special infant formulas designed for the treatment of protracted diarrhea. J Pediatr Gastroenterol Nutr 1988;7:76-83. 25. Woolf GN, Kurian R, Jeejeebhoy KN. Diet for patients with a short bowel: high fat or high carbohydrate? Gastroenterology 1983;84:823-8. 26. MacLean WC Jr, Klein G, Lopez de Romana G, Massa E, Graham GG. Protein quality of conventionai and high protein rice and digestibility of glutinous and non-glutinous rice by preschool children. J Nutr 1978;108:1740-7. 27. Gastanabuy A, Cordano A, Graham G. Acceptability, tolerance and nutritional value of a rice-based infant formula. J Pediatr Gastroenterol Nutr 1990;t 1:240-6. 28. Graham G, Bartl JM, Cordano A, Morales E. Lactose free medium chain triglyceride formulas in severe malnutrition. Am J Res Child 1973;126:330-5. 29. Klish W J, Udall JN, Calvin RT, Nichols BL. The effect of intestinal solute load on water secretion in infants with acquired monosaccharide intolerance. Pediatr Res 1980;14:1343-6. 30. Bhan MK, Aroza NK, Khoshoo V, et al. Comparison of a lactose-free cereal-based formula and cow's milk in infants and children with acute gastroenteritis. J Pediatr Gastroenterol Nutr 1988;7:208-13. 31. Armitstead J, Kelly D, Walker-Smith J. Evaluation of infant feeding in acute gastroenteritis. J Pediatr Gastroenterol Nutr 1989;8:240-4.
S 10 8
Lifshitz et al
32. Conway SP, Ireson A. Acute gastroenteritis in well nourished infants: comparison of four feeding regimens. Arch Dis Child 1989;64:87-91. 33. Haffejee IE. Cow's milk-based formula, human milk, and soya feeds in acute infantile diarrhea: a therapeutic trial. J Pediatr Gastroenterol Nutr 1990; 10:193-8. 34. Torres-Pinedo R, Lavastida M, Rivera CL, Rodriquez H, Ortiz A. Studies in infant diarrhea. I. A comparison of the effects of milk feeding and intravenous therapy upon the composition and volume of the stool and urine. J Clin Invest 1966;45:46980. 35. Lugo-de-Rivera C, Rodriguez H, Torres-Pinedo R. Studies on the mechanism of sugar malabsorption in infantile infectious diarrhea. Am J Clin Nutr 1972;25:1248-53. 36. Brown KH, Black RE, Parry L. The effect of diarrhea on incidence of lactose malabsorption among Bangladeshi children. Am J Clin Nutr 1980;33:2226-7. 37. Hyams JS, Krause P J, Gleason PA. Lactose malabsorption following rotavirus infection in young children. J PEDIATR 1981;99:916-8. 38. Davidson GP, Goodwin D, Robb TA. Incidence and duration of lactose malabsorption in children hospitalized with acute enteritis:study in a well-nourished urban population. J PEDIATR 1984;105:587-90. 39. Lifshitz F. Perspectives of carbohydrate intolerance in infants with diarrhea. In: Lifshitz F, ed. Carbohydrate intolerance in infancy. New York: Marcel Dekker, 1982:3-20. 40. Lifshitz F. Nutrition in chronic diarrhea of infancy. In: Stern L, ed. Feeding the sick infant. New York: Raven, 1987:275-89. 41. Penny ME, Paredes P, Brown KH. Clinical and nutritional consequences of lactose feeding during persistent postenteritis diarrhea, Pediatrics 1989;84:835-44. 42. Dagan R, Gorodischer R, Moses SW. Dietary treatment of acute diarrhea: comparison Of cow's milk and a soy formula without disaceharides. J Trop Pediatr 1984;30:221-4. 43. Soeprapto, Soenarto Y, Nelwan, Moengihan PA, Ismangoen. Feeding children with diarrhea. J Trop Pediatr 1979;25:97100. 44. Rees L, Brook CGD. Gradual reintroduction of full-strength milk after acute gastroenteritis in children. Lancet 1979;1: 770-1. 45. Dugdale A, LovelI S, Gibbs V, Ball D. Refeeding after acute gastroenteritis: a controlled study. Arch Dis Child 1982;57: 76-8. 46. Haque KN, A1-Frayh A, El-Rifai R. Is it necessary to regrad-
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47. 48.
49.
50.
51.
52. 53. 54.
55. 56.
57.
58.
59.
60.
uate milk after acute gastroenteritis in children? Trop Geogr Med 1983;35:369-73. Ransome O J, Roode H. Early introduction of milk feeds in acute infantile gastro-enteritis. S Afr Med J 1984;65:127-8. Isolauri E, Vesikari T, Saha P, Viander M. Milk versus no milk in rapid refeeding after acute gastroenteritis. J Pediatr Gastroenterol Nutr 1986;5:254-61. Groothuis JR, Berman S, Chapman J. Effect of carbohydrate ingested on outcome in infants with mild gastroenteritis. J PEDIATR 1986;108:903-6. Pichaipat V, Thanomsingh P, Assadamongkul R, Varavithya W. Effects of amount and concentration of a lactose-containing formula on outcome of infantile diarrhoea. J Med Assoc Thai 1986~,69:132-6. Okuni M, Okinaga K, Baba K. Studies on reducing sugars in stools Of acute infantile diarrhea, with special reference to differenceS between breast fed and artificially fed babies. Tohoku J Exp Med 1972;107:395-402. Donovan GK, Torres-Pinedo R. Chronic diarrhea and soy formulas. Am J Dis Child 1987;141:1069-71. What has happened to carbohydrate intolerance following gastroenteritis? [Editorial] Lancet 1987;1:23-4. Kotloff RL, Wasserman SS, Steciak JY, et al. Acute diarrhea in Baltimore children attending an outpatient clinic. Pediatr Infect Dis J 1988;7:753-9. Ho MS, Glass RI, Pinsky PF, et al. Diarrheal deaths in American children. Are they preventable? JAMA 1988;260:3281-5. Gazala E, Weitzman S, Weitzman Z, et al. Early versus late refeeding in acute infantile diarrhea. Isr J Med Sci 1988;24: 175-9. Karsten J, Paerregaard A, Petersen W, et al. Rapid versus gradual refeeding in acute gastroenteritis in childhood: energy intake and weight gain. J Pediatr Gastroenterol Nutr 1989; 8:75-8. Brown KH, Black RE, Lopez de Romana G, Creed de Kanashiro H. Infant-feeding practices and their relationship with diarrheal and other diseases in Huascar (Lima), Peru. Pediatrics 1989;83:31-40. Lerman S J, Shepard SD, Cash R. Treatment of diarrhoea in Indonesian children: what it costs and who pays for it. Lancet 1985;21:651-4. Lifshitz F, Coello-Ramirez P, Gutierrez-Topete G. Monosaccharide intolerance and hypoglycemia in infants with diarrhea. I. Clinical course of 23 cases. J PEDIATR 1970;77:595-603.