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  Paediatrica Indonesiana, Vol. 46, No. 11-12 ã November - December 2006 ã 271 Paediatrica Indonesiana VOLUME 46NUMBER 11-12November - December ã 2006 Original Article From the Department of Child Health, Medical School, University of Indonesia, Jakarta, Indonesia. Reprint request to:  Sri Lestari, MD, Department of Child Health, MedicalSchool, University of Indonesia, Cipto Mangunkusumo Hospital Jakarta, Jl. Salemba No. 6, Jakarta 10430, Indonesia. Email: sriaisha@yahoo.co.id Double blind clinical trial on a lactose-free anda lactose-containing formula in the treatment of acutediarrhea in children Sri Lestari, Agus Firmansyah, Zakiudin Munasir A BSTRACT Background   Lactose intolerance is a common complication ofdiarrhea in young children particularly that due to rotaviral infec-tion. A meta-analysis study evaluated the use of undiluted lactosecontaining formula or cow’s milk during an episode of diarrhea. Itwas concluded that routine dilution of milk and the use of lactose-free milk formula are not necessary. Objective   To evaluate the effect of lactose free formula comparedwith lactose-containing milk formula during acute diarrheal episodein outpatient setting.  Methods   A total of 56 children with acute diarrhea with mild-mod-erate or no dehydration attending to the outpatient clinic were ran-domly assigned to receive a lactose-free formula (Nestle Nan  ®   freelactose) or lactose-containing milk formula (Nestle Nan 2  ®   formula)after initial rehydration. Comparisons of stool frequency, durationof diarrhea and treatment failure rates were noted. Treatment fail-ure was defined as clinical requirement for intravenous infusionafter rehydration or prolonged diarrhea (>7 days). Results The duration of diarrhea was similar between the twogroups (P=0.195) in spite of two children who received lactosefree formula did not resolve from diarrhea within 7 days of treat-ment. The median of stool frequency was indifferent in the twogroups (P=0.199) in rotavirus gastroenteritis; there were no differ-ences in the duration of diarrhea or the stool frequency. Conclusion   Children without dehydration or with mild dehydra-tion tolerated to lactose-containing formula as well as lactose-freeformula for the treatment of acute diarrhea [Paediatr Indones2006;46:271-275] . Keywords : diarrhea, milk formula, lactose-free for- mula, lactose intolerance. A cute diarrheal disease is still a major publichealth problem in developing countries. 1 In Indonesia, the disease consistentlyranked among the top 5 causes of morbidity and mortality of children between the ageof 0-4 years. 2  Lactose intolerance is a commoncomplication of diarrhea in young children particularlythat due to rotaviral infection. 3,4 It occurred whenrotavirus destroyed the villus cells and diminisheddisaccharide, especially lactose absorption. 5,6  Thiscondition had been the reason to delay refeeding milk-based formula; when feeding is introduced, often beganwith low-lactose formula or lactose-free formula.Suharjono et al , 7  found that the incidence of lactoseintolerance was 52.8% in 838 patients with acutediarrhea and Hegar et al 8  found 23.1% lactoseintolerance of hospitalized patients. Since it causes ahigh incidence of lactose intolerance, we had been usinglow-lactose formula or dilution of milk in the treatmentof acute diarrhea in our practice, especially for childrenwith clinically presentation of lactose intolerance.  Paediatrica Indonesiana 272 ã Paediatrica Indonesiana, Vol. 46, No. 11-12 ã November - December 2006 Recently Brown et al 9  performed a meta-analy-sis study that evaluated the use of undiluted lactosecontaining formula or cow’s milk during an episodeof diarrhea. It was concluded that routine dilution of milk and the use of lactose-free milk formula are notnecessary. No controlled trial to compare lactose-freemilk formula with lactose-containing formula duringacute diarrhea in our outpatient’s case had been re-ported. At the same time, we need the data to changeour policy. The purpose of this study was to comparethe effect of lactose-free milk formula with lactose-containing formula during acute diarrhea in the out-patient clinic setting. Methods This study was a randomized, double blind controlledclinical trial conducted at the outpatient clinic of Cipto Mangunkusumo (CM) Hospital, Jakarta, from July to September 2005. The sample size was 28patients per treatment group according to standardstatistical methods. 10  The inclusion criteria werechildren aged 6-24 months who suffered from diarrhea(defined as the passage of unusually or watery stools,usually at least three times in a 24 hour period 11 ) forless than 7 days duration, who were not breast fed,with weight-for-age not less than 70% of median of National Center for Health Statistics Standards, andhad no intake of any antibiotics during the 7 dayspreceding enrollment. They were excluded if they hadsign of severe dehydration, failed to have their stoolspecimens taken on the same day of their visits to theclinic, presence of a major systemic illness likepneumonia and sepsis, bloody diarrhea, or if theirparents refused to join the study.The study was approved by The Committee forMedical Research Ethics, Medical School, Universityof Indonesia. Informed consent was obtained fromparents or caregivers of the children who served assubjects in the study. After informed consent was ob-tained, the parents or caregivers were interviewed toget detailed information, regarding clinical history of the illness. All subjects underwent physical examina-tion to assess clinical status and degree of dehydra-tion (based on the WHO standard 11 ). A stool speci-men was collected during enrollment. The specimenswere plated at the bedside on Cary Blair transportmedia and then plated on Mac Conkey agar to iden-tify Enteropathogenic E. coli  (EPEC) and on SS agarto identify Salmonella spp . Portions of each stool speci-men were also tested at the bedside for stool reducingsubstance using clinitest (Ames, Ltd ® ) and for mea-suring the pH using pH meter (special indicator,Merck) and the rest for rotavirus antigen using a com-mercial ELISA preparation (Quick Stripe ® , Savyon).Oral rehydration therapy was provided accordingto WHO guidelines (children with mild-moderate de-hydration received 75 ml/kg). 11  Rehydration was com-pleted within four hours by administering oral rehydra-tion solution (ORS) recommended by WHO. Afterinitial rehydration phase, children were randomly allo-cated to receive either a lactose-free or a lactose-con-taining formula. Children were fed with free lactosefood as appropriate to age and ORS 10 ml/kg after eachwatery stool. Milk formula was randomized in blocks of four (two lactose-free Nestle Nan FL ® and two lac-tose-containing formula Nestle Nan 2 ® ) and coded toensure sequential distribution. We educated the par-ents how to manage diarrhea at home before childrenwere discharged from hospital. The parents were askedto record the time, frequency and duration of diarrheain the research form. The parents were asked to cometo the hospital if their children fall into deeper dehy-dration and could not receive ORS. We monitored theprogress of illness by making phone call to the parentsor doing home visit everyday.The total duration of diarrhea was defined as theduration in hours from the time of the first diarrheato the last watery of loose stool or no stool in 24 hoursperiod. Treatment failure was defined as clinical re-quirement for intravenous infusion after rehydrationor prolonged diarrhea (>7 days). Frequency of diar-rhea was defined as number of stools in hour from thefirst diarrhea until diarrhea stops.The primary outcome measurement in this in-tervention was the duration of diarrhea and stool fre-quency. A therapeutic failure rate was the secondaryoutcome.Data collected from completed forms were pro-cessed using computer program SPSS 12.0. An inde-pendent t-test was performed if the data were con-tinuous variables with normal distribution and theMann-Whitney test was used when the distributionwas not normal. Probabilities (P) less than 0.05 wereconsidered statistically significant.  Paediatrica Indonesiana, Vol. 46, No. 11-12 ã November - December 2006  ã 273 Sri Lestari et al : Lactose-free and lactose-containing formula in acute diarrhea Results The characteristics of the 28 children on admissionare showed in Table 1 .None of the differences between the groups wasstatistically significant. Twenty five subjects had rotavirusin their stool. EPEC was only found in 1 subject. Mostsubjects were well-nourished. Twenty nine subjectsshowed clinical signs of mild-moderate dehydration. Table 2  shows the mean duration of diarrhea insubjects receiving lactose-free formula compared withthose receiving lactose-containing formula (116.8hours vs 106.5 hours; P=0.195). The duration of rotaviral diarrhea is also similar between the two group(P=0.288) (Table 3) . There were no significant dif-ferences between the two groups in stool frequency(4 times/day vs 3.4 times/day; P=0.199) (Table 4) .Two of the subjects receiving lactose-free formulawere considered to be treatment failure. These sub-jects had continuous diarrhea for more than sevendays (7 days 2 hours). Discussion In 2003, an estimated 1.87 million children below 5 years old in developing countries died from diarrhea.Eight out of 10 of these deaths occurred in the firsttwo years of life. 11 The incidence of diarrhea washigher in infant aged 6-11 months followed bychildren aged 12-24 months. 2  This is in accordancewith the findings of Ariani et al 12  and Tjitrasari etal 13  in their studies at CM Hospital that the incidencerate of acute diarrhea was higher among the 6-11months age group than that in the 12-24 monthsage group. Infants who are younger than 6 monthsare protected by transplacental antibody and breastfeeding, whereas 80-100% of older children are T ABLE  2.  D URATION   OF   DIARRHEA   ACCORDING   TO   MILK   FORMULA Mean (SD)Median (range)P(hours)(hours) Lactose-containingformula (n=28)106.5 (29.2)102.5 (55-160)0.195Lactose-freeformula (n=28)116.8 (29.1)120 (68-170) Unpaired t test  T ABLE  1.  C HARACTERISTICS   OF   SUBJECTS   AT   THE   TIME   OFADMISSION LactoseLactose containingfreeformulaformulaTotalnnAge (months) 6-1113112412-24151732 Sex Male211839Female71017 Nutritional status Well-nourished201838Undernourished81018 Degree of dehydration No dehydration161127Mild-moderate121729 Duration of symptomsbefore admission (hours) 24-7225244996-168347 Frequency of diarrhea(times/day) < 5138215-10121628 > 10347 Stool culture Negative282756 Positive-1- Rotavirus Negative171431Positive111425 Reducing substance Negative192039Positive9817 Stool pH < 6131225 ≥ 6151631 T ABLE  4.  S TOOL   FREQUENCY   ACCORDING   TO   MILK   FORMULA Mean (SD)Median (range)P(times/day)(times/day) Lactose-containingformula (n=28)4.0 (1.5)3.4 (3-10)0.199Lactose-freeformula (n=28)4.5 (1.9)4.0 (3-10.5) Mann-Whitney test  T ABLE  3.  D URATION   OF   ROTAVIRUS   DIARRHEA   ACCORDINGTO   MILK   FORMULA Mean (SD)Median (range)P(hours)(hours) Lactose-containingformula (n=11)110.3 (28.0)110 (55-154)0.288Lactose-freeformula (n=14)120.8 (20.5)120 (92-1154) Unpaired t test   Paediatrica Indonesiana 274 ã Paediatrica Indonesiana, Vol. 46, No. 11-12 ã November - December 2006 protected by antibody produced by previousinfection. 5,14  As the children begin to crawl,contamination of wearing food and poor domestichygiene give the chances to get diarrhea. 5  On theother hand, we found that the incidence rate of diarrhea was higher among the 12-24 months agegroup than that in the 6-11 months age group. Weexcluded breast-fed children mostly under 12 monthsof age, 15  because breast feeding exerts a beneficialeffect on the course and outcome of acute diarrheaby reducing the number and volume of diarrheastools. 16  In a case control study on Bangladeshichildren <3 years, discontinuation of breast feedingduring the illness was associated with a five-foldincrease in the incidence of dehydration. 17 Furthermore, Hafeehee et al 18  found that in rotaviralgastroenteritis, breast feeding significantly reduced theduration of acute diarrhea compared to cow’s milkformula feeding. We also excluded children whosuffered from severe malnutrition because of gastrointestinal mucosal atrophy will increase thepossibility of lactose malabsorption. Most of thepatients in our study were well-nourished.Lactose intolerance is a common complicationof some episodes of diarrhea. Increase rates of lactosemalabsorption have been demonstrated in acute di-arrhea, particularly in children with rotaviral infec-tion. Our study identified rotaviral infection in 25 pa-tients. This finding was still within the range withother findings i.e. Frühwirth et al 19  (Austria) andHegar et al 20  (Indonesia) who found the prevalenceof 34% and 61.1%, respectively.Recently Tjitrasari et al 13  identified 35.7%rotaviral infection in pediatric outpatient. We justidentified 1.7% EPEC as the causing factor of diar-rhea. This data is similar to other studies which showedthe rotavirus as the most common cause of acute di-arrhea. 5,12,20 The appropriate use of lactose-containing for-mula, non human milk for young children with acutediarrhea is still in debates. Whereas some cliniciansroutinely withdraw milk from the diets of childrenduring diarrhea, primarily to avoid the potential con-sequences of lactose malabsorption, others continueto offer milk without apparent evidence of increasedclinical complications. As mentioned above, a meta-analysis performed by Brown et al 9 , concluded thatroutine use of lactose-free milk formula during an epi-sode of diarrhea is not necessary.In contrast, Yasman et al 21  found that the dura-tion of diarrhea with lactose intolerance was shortenedby 17.5 hours after receiving lactose-free formula com-pared to that receiving lactose-containing formula. Thisstudy was done on hospitalized patients with variousdegree of dehydration. Children with severe dehydra-tion were included in this study. This is similar withthat found by Simakachorn et al. 22 Our study showed that there were no differencesin stool frequency or in the duration of diarrhea be-tween lactose-free formula and lactose-containingformula. It is likely that the degree of dehydration of our patient was in a level of no dehydration or mild-moderate dehydration. Besides, most of our patientswere well-nourished. Therefore, they could recoverbetter from diarrhea. When substantial absorptive func-tion is lost because of an inflammatory lesion, enteralnutrition is generally still well tolerated. This is assumedthat viral infection of gastrointestinal tract may notaffect all regions of the small bowel equally and theresidual function is sufficient for successful enteral nu-trition. 23 The mixed feeding of milk with other foodsresulted in a more absorption of lactose than when milkis given alone. 9,23  We used mixed diet in our study be-cause we believe that the lactose load may be decreasedby adding other food stuffs to the milk.The treatment failure rate in our study was verysmall (only 2 patients who received lactose-free for-mula). This is unlikely to be of clinical importancebecause the duration of diarrhea was only 7 days and2 hours. We succeeded to treat the diarrhea becausewe followed the WHO guidelines to use oral rehy-dration therapy for children with acute diarrhea. Inaddition, the new standard WHO-ORS reduces theincidences of vomiting by 30% and stool volume by20% and also reduces the requirement of intrave-nous rehydration therapy by 33%. 11 We concluded that routine use of lactose-freemilk formula in well-nourished children with diarrheawithout dehydration or with mild-moderate dehydra-tion does not influence the stool frequency and theduration of diarrhea.Considering many limitations within this study,there is a need to do further multicenter study to givea better result. Stool output, treatment failure rate,stool frequency and duration of diarrhea must be moreconsidered in the next study.
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