The reslult suggest that frequency and consistency of defecation, as well as clinical symptoms were improved significantly when using lactulose with 2 ml/ kg/day. The mean weekly stool frequency improved from 1.9 ± 0.8 times to 4.9 ± 1.8 times after 1 month and to 5.9 ± 1.4 times after 3 months of treatment (p < 0.01).
JOURNAL OF MEDICAL RESEARCH THE EFFECT OF LACTULOSE IN THE TREATMENT OF CHRONIC FUNCTIONAL CONSTIPATION IN CHILDREN Do Thi Minh Phuong, Nguyen Thi Viet Ha Department of Pediatrics, Hanoi Medical University Constipation is a common gastrointestinal problem in children The aim of the present study was to evaluate the beneficial effects of lactulose in the management of functional constipation in children An open clinical trial was conducted in 140 children aged – years at the National Children Hospital, Hanoi, Vietnam with a diagnosis of functional constipation The reslult suggest that frequency and consistency of defecation, as well as clinical symptoms were improved significantly when using lactulose with ml/ kg/day The mean weekly stool frequency improved from 1.9 ± 0.8 times to 4.9 ± 1.8 times after month and to 5.9 ± 1.4 times after months of treatment (p < 0.01) The rate of effective treatment (the weekly stool frequency ≥ times and fecal incontinence ≤ time every two weeks) was 68% after month and increased to 72.8% after and months of treatment In addition to using laxatives, fiber and fluid intake per day > 80% standard recommendation improve the effect in the treatment In conclusion, lactulose is a safe, effective and well-tolerated long-term treatment for constipation Regular supplement of fiber and fluid in children with constipation is important to improve the effect in the treatment of constipation Keywords: chronic functional constipation, lactulose, children, Rome III I INTRODUCTION Constipation is one of the mast common constipation digestive complaints in children, and has recently grown into a disproportionate public health problem A recent systematic review of pediatric patents of the sample reported constipation in 0.7% to 29.6% of the sample [1] Functional constipation was recognized as a separate clinical entity by combining features of functional Corresponding author: Do Thi Minh Phuong, Department of Pediatrics, Hanoi Medical University Email: dominhphuong@hmu.edu.vn Received: 13 August 2017 Accepted: 16 November 2017 JMR 111 E2 (2) - 2018 fecal retention and functional constipation The North American Society for Pediatric Gastroenterology, Hepatology and Nutrition define constipation as a delay or difficulty in defecation, present for or more week [2] The occurrence of chronic functional constipation in children can lead to significant abdominal pain, anal fissure, loss of appetite, faecal incontinence and social isolation The aim of constipation management is to produce soft, painless stools and to prevent the re-accumulation of feces, which can be achieved through dietary modification, behavioral interventions, fecal disimpaction and the use of laxatives, or a combination thereof [6] Lactulose is considered 61 JOURNAL OF MEDICAL RESEARCH to be safe and recommended for all ages in the management of constipation by NASPGHAN and ESPGHAN [3] Many studies have demonstrated that lactulose improved frequency and consistency of defecation and clinical symptoms [4; 5; 7; 8] To our knowledge, however, no large studies evaluat the effect of lactulose in childhood constipation have been published in Vietnam The primary objective of the present study was to evaluate the beneficial effects of lactulose in the treatment of chronic functional constipation in children II MATERIALS AND METHODS Subjects 140 children aged - years recruited from the sample consisted of the National Children Hospital, Hanoi, Vietnam with a diagnosis of functional constipation Study design The treatment trial was performed in Hanoi, Vietnam from 1/10/2013 to 31/11/2014 The Rome III guideline was used to diagnose patients with chronic functional constipation [9] According to the guideline, in the absence of organic pathology, patients must meet two or more of the following criteria: 1) Two or fewer defecations in the toilet per week 2) At least one episode of fecal incontinence per week after the acquisition of toileting skills 3) History of retentive posturing or excessive volitional stool retention 4) History of painful or hard bowel movements 5) Presence of a large fecal mass in the rectum 6) The history of large diameter stools which may obstruct the toilet Infants up to years have to fulfill ≥ of the crite- 62 ria for at least month, whereas those > years need to fulfill ≥ of the criteria for at least months and have insufficient criteria for irritable bowel syndrome A total of 140 children from ages - years old presenting with constipation based on a modification of the Rome III criteria were eligible for the trial Evaluation of treatment outcome All patients were examined, advised to change dietary, adherence to daily toilet training, used lactulose with ml/kg/day If patients have diarrhea, the dose of lactulose will decrease ml/kg/day After week of treatment, patients still defecate hard stool < times per week, lactulose will increase ml//kg/day Parents received fiber chart of common foods; the Bristol stool chart; and a stool diary to record the frequency of daily bowel movements, fecal soiling, stool consistency, as well as any symptoms they considered important The children were evaluated clinically at study entry and at 4, and 12 weeks after enrollment Treatment responses were assessed by evaluation of the daily stool diary Treatment compliance was assessed by direct interview with the patient, checking the diary cards (on which the number of daily capsules taken was recorded), and counting the capsules returned by the patient at each visit Statistical analysis Statistical analysis was performed using the computer software SPSS 16.0 Student’s t test was used to compare means of continuous variables approximating a normal distribution The x² test or Fisher’s exact test was used, as appropriate, to compare percentages A p-value < 0.05 was JMR 111 E2 (2) - 2018 JOURNAL OF MEDICAL RESEARCH considered statistically significant III RESULTS Ethics Baseline characteristics of study groups From 1/10/2013 to 31/11/2014, 140 children presenting with constipation were enrolled in the study This study was approved by the Science Council of Hanoi Medical University A written informed consent was signed by children’s parents/ caretakers before participating in the present study Table Baseline characteristics Age (months) 35,9 ± 17,4 Gender Boys (%) 51.8 Girls (%) 43.2 Disease duration (months) 11 ± 9.7 Mean weekly stool frequency 1,9 ± 0,8 Stool consistency (%) Type 77.9 Type 22.2 Patients with painful bowel movements (%) 80.7 Patients with anal fissure (%) 54.3 Patients with a fecal mass in the rectum (%) 66,4 The beneficial effects of lactulose with ml/kg/day in the treatment of chronic functional constipationin children Figure shows the mean stool frequency increased from 1.9 ± 0.8 stools/ week at baseline to 4.9 ± 1.8 at weeks and 5.9 ± 1.4 at the end of the study (p < 0.01) Fingure Change in the weekly stool frequency JMR 111 E2 (2) - 2018 63 JOURNAL OF MEDICAL RESEARCH The successful treatment rate (defined as weekly stool frequency ≥ times and fecal incontinence ≤ time every weeks) was 68% after weeks and increased to 72.8% after and 12 weeks of treatment Table Change in stool consistency during treatment Stool consistency (%) Type Type Type Type Baseline 78.6 21.4 0 weeks 9.7 49.5 40.8 weeks 2.9 30.1 67 12 weeks 0 14.6 85.4 p-value < 0.01 < 0.01 Stool consistency : Type – Separate hard lumps, like nuts; Type – Sausage – shaped, but lumpy; Type – Like a sausage but with cracks on its surface; Type – Like a sausage or snake, smooth and soft The percentage of patients used 2ml of lactulose/ kg/ day after weeks of treatment was 87.4% This rate decreased to 80.6% (after weeks) and 75.5% after 12 weeks (Table 2) Table Change in dose of lactulose from baseline to after 12 weeks At weeks At weeks At 12 weeks Dose n % n % n % ml/kg/day 11 10.7 14 13.6 17 16.5 ml/kg/day 90 87.4 83 80.6 78 75.7 ml/kg/day 1.9 5.8 6.8 Time Amount of water and fiber/ day affect to treatment Table shows a difference in the mean weekly stool frequency between fiber intake per day > 80% and ≤ 80% standard recommended after weeks, weeks and 12 weeks of treatment with p value.Children with fiber intake per day ≤ 80% standard recommendation had increased risk for hard stools (type - 3) compared to > 80% group at weeks and weeks (p < 0.05) Table 4: Amount of fiber/day affect to mean weekly stool frequency Time At weeks 64 Amount of fiber n (%) X ± SD ≤ 80% 49 (47.6) 4.4 ± 1.8 > 80% 54 (52.4) 5.2 ± 1.8 p value 0.03 JMR 111 E2 (2) - 2018 JOURNAL OF MEDICAL RESEARCH At weeks At 12 weeks ≤ 80% 35 (34) 4.7 ± 1.7 > 80% 68 (66) 5.5 ± 1.5 ≤ 80% 11 (10.7) 5.5 ± 1.9 > 80% 92 (89.3) ± 1.3 0.02 0.30 IV DISCUSSION Based on recommendations from NASPGHAN and ESPGHAN, we chose a daily intake of mean dose of lactulose (2 ml/kg/ day) in this study The results showed that the frequency and consistency of defecation and other clinical symptoms as painful bowel movements, anal fissure, fecal incontinence, blood in stool improved significantly (p < 0.05) In this study, we used different doses of lactulose to evaluate the effects of lactulose in the treatment of functional constipation The effective dose of lactulose was changeable based on factors such as diet, adherence to treatment, duration of constipation and any previous used medications Banaszkiewicz’ trial used lactulose with ml/ kg/day, which showed that the mean weekly stool frequency improved, as did our study [4] According to Sadeghzadeh's study, the frequency of defecation per week increased from 0.8 ± 0.8 to 1.5 ± 0.98 times (in the lactulose group) and from 1.7 ± 0.8 to 2.1 ± 0.7 times (in the lactulose plus protease group) after weeks of treatment [5] The improvement of frequency of defecation in this study was slower than our results In one study conducted by Wang, 111 patients over years of age received lactulose with 15 ml/kg, the median stool frequency following week of treatment inJMR 111 E2 (2) - 2018 creased to from to times per week, and following weeks of treatment increased to times per week Prior to treatment, the stool consistencies of all enrolled patients ranged from type to on the Bristol Stool Scale Lactulose treatment also improved the stool consistency to 3.64 ± 1.33 following week of treatment and 3.63 ± 1.33 following weeks [7] In our study, almost 70% of children with constipation were successfully treated after weeks of treatment This rate increased up to 72.8% after weeks The lactulose dose of ml/kg/day is appropriate for children with constipation After weeks of treatment, almost all patients maintained the dose of ml/kg/day; only 10.7% of them reduced the dose (1 ml/kg/day) due to diarrhea, and a few had to be increased due to unresponsive treatment (1.9%) The success rate in our study was higher than Voskuijl’s study after weeks of treatment (29%) In Voskuijl’s study, the mean lactulose dose associated with improvement were 11.52 (4.56) g/day (1.9 sachets) and 13.86 (6.66) g/day (2.3 sachets) at and weeks The optimal dose of lactulose in clinically successful patients < years and ≥ years was 0.96 (0.45) g/kg/day and 0.45 (0.27) g/kg/day, respectively [8] According to Wang, the effective rate of treatment was 65 JOURNAL OF MEDICAL RESEARCH 39.64% after week and increased 41.44% after weeks of treatment [7] Limited water and fiber intake per day as risk factors for constipation have been shown in many studies The results of our study showed that fiber intake per day ≤ 80% standard recommendation affected the effect of lactulose in improving the frequency and consistency of defecation and clinical symptoms Dietary fiber is good for treating constipation, but the role of additional fiber in improving the effect of constipation treatment is not yet approved In Kokke, and Loening-Baucke's clinical trials, there was no significant improvement in bowel movements after fiber therapy compared with placebo and traditional treatments such as lactulose (Duphalac) [10; 11] The strength of our study lies in the large sample size for a pediatric trial, a compliance rate of 73,6%, and a follow-up A weakness of the study was the difficulty of conducting a randomized double-blind trial over a wide weight range, as would be unethical having control groups allowing more optimal dosing V CONCLUSION Lactulose is a safe, effective and well-tolerated long-term treatment for constipation Regular supplement of fiber and fluid over 80%, according to standard recommendation for constipated children is important to improve the effect in the treatment of constipation Acknowledgments We would like to thank the doctors and staff at the Gastrointestinal department at 66 the National Children Hospital in Hanoi, Vietnam for their assistance We also wish to thank all children and their parents who participated in the study for their precious collaborative spirit REFERENCES Van den Berg MM, Benninga MA, Di Lorenzo C (2006) Epidemiology of childhood constipation: a systematic review American Journal of Gastroenterology, 101, 2401 - 2409 Vandenplas Y, De Greef E, Devreker T et al (2013).Probiotics and prebiotics in infants and children Current Infectious Disease Reports, 15(3), 251 - 262 Tabbers MM, DiLorenzo C, Berger MY, et al (2014) Evaluation and treatment of functional constipation in infants and children: evidence-based recommendations from ESPGHAN and NASPGHAN Journal of Pediatric Gastroenterology and Nutrition, 58, 258 - 274 Banaszkiewicz A, Szajewska H (2005) Ineffectiveness of Lactobacillus GG as an adjunct to lactulose for the treatment of constipation in children: a double - blind, placebo – controlled randomized trial The Journal of Pediatrics, 146(3), 364 - 369 Sadeghzadeh M, Rabieefar A, Khoshnevisasl P, et al (2014) The effect of probiotics on childhood constipation: randomized controlled double blind clinical trial International Journal Pediatric, 937212 Rowan-Legg A (2011) Managing functional constipation in children Paediatric Child Health, 16(10), 661 – 670 Wang Y, Wang B, Jiang X et al (2012) Polyethylene glycol 4000 treatment JMR 111 E2 (2) - 2018 JOURNAL OF MEDICAL RESEARCH for children with constipation: A randomized comparative multicenter study Experimental and Therapeutic Medicine, 3(5), 853 856 Voskuijl W, de Lorijn F, Verwijs W, et al (2004) PEG 3350 (Transipeg) versus lactulose in the treatment of childhood functional constipation: a double blind, randomized, controlled, multicenter trial Gut 53(11), 1590 - 1594 Rome Foundation (2006) Guidelines Rome III Diagnostic Criteria for Functional Gastrointestinal Disorders Journal of JMR 111 E2 (2) - 2018 Gastrointestinal and Liver Disease, 15(3), 307 - 312 10 Loening-Baucke V (2007) Prevalence rates for constipation and faecal and urinary incontinence Archives of Disease in Childhood, 92(6), 486 - 489 11 Kokke FT, Scholtens PA, Alles MS, et al (2009) A dietary fiber mixture versus lactulose in the treatment of childhood constipation: a double blind randomized controlled trial Journal of Pediatric Gastroenterology and Nutrition, 47(5), 592 - 597 67 ... objective of the present study was to evaluate the beneficial effects of lactulose in the treatment of chronic functional constipation in children II MATERIALS AND METHODS Subjects 140 children. .. fecal incontinence, blood in stool improved significantly (p < 0.05) In this study, we used different doses of lactulose to evaluate the effects of lactulose in the treatment of functional constipation. .. weeks The lactulose dose of ml/kg/day is appropriate for children with constipation After weeks of treatment, almost all patients maintained the dose of ml/kg/day; only 10.7% of them reduced the