The effect of lactulose in the treatment of chronic functional constipation in children

JOURNAL OF MEDICAL RESEARCH<br /> <br /> THE EFFECT OF LACTULOSE IN THE TREATMENT OF<br /> CHRONIC FUNCTIONAL CONSTIPATION IN CHILDREN<br /> Do Thi Minh Phuong, Nguyen Thi Viet Ha<br /> Department of Pediatrics, Hanoi Medical University<br /> Constipation is a common gastrointestinal problem in children. The aim of the present study was to<br /> evaluate the beneficial effects of lactulose in the management of functional constipation in children. An<br /> open clinical trial was conducted in 140 children aged 1 – 5 years at the National Children Hospital, Hanoi,<br /> Vietnam with a diagnosis of functional constipation. The reslult suggest that frequency and consistency<br /> of defecation, as well as clinical symptoms were improved significantly when using lactulose with 2 ml/<br /> kg/day. The mean weekly stool frequency improved from 1.9 ± 0.8 times to 4.9 ± 1.8 times after 1 month<br /> and to 5.9 ± 1.4 times after 3 months of treatment (p < 0.01). The rate of effective treatment (the weekly<br /> stool frequency ≥ 3 times and fecal incontinence ≤ 1 time every two weeks) was 68% after 1 month and<br /> increased to 72.8% after 2 and 3 months of treatment. In addition to using laxatives, fiber and fluid intake<br /> per day > 80% standard recommendation improve the effect in the treatment. In conclusion, lactulose<br /> is a safe, effective and well-tolerated long-term treatment for constipation. Regular supplement of fiber<br /> and fluid in children with constipation is important to improve the effect in the treatment of constipation.<br /> <br /> Keywords: chronic functional constipation, lactulose, children, Rome III<br /> <br /> I. INTRODUCTION<br /> Constipation is one of the mast common<br /> constipation digestive complaints in children, and has recently grown into a disproportionate public health problem. A recent<br /> systematic review of pediatric patents of<br /> the sample reported constipation in 0.7% to<br /> 29.6% of the sample [1]. Functional constipation was recognized as a separate clinical<br /> entity by combining features of functional<br /> Corresponding author: Do Thi Minh Phuong, Department of Pediatrics, Hanoi Medical University<br /> Email: dominhphuong@hmu.edu.vn<br /> Received: 13 August 2017<br /> Accepted: 16 November 2017<br /> <br /> JMR 111 E2 (2) - 2018<br /> <br /> fecal retention and functional constipation.<br /> The North American Society for Pediatric<br /> Gastroenterology, Hepatology and Nutrition<br /> define constipation as a delay or difficulty in<br /> defecation, present for 2 or more week [2].<br /> The occurrence of chronic functional constipation in children can lead to significant abdominal pain, anal fissure, loss of appetite,<br /> faecal incontinence and social isolation.<br /> The aim of constipation management is<br /> to produce soft, painless stools and to prevent the re-accumulation of feces, which<br /> can be achieved through dietary modification, behavioral interventions, fecal disimpaction and the use of laxatives, or a combination thereof [6]. Lactulose is considered<br /> 61<br /> <br /> JOURNAL OF MEDICAL RESEARCH<br /> to be safe and recommended for all ages in<br /> the management of constipation by NASPGHAN and ESPGHAN [3]. Many studies<br /> have demonstrated that lactulose improved<br /> frequency and consistency of defecation<br /> and clinical symptoms [4; 5; 7; 8]. To our<br /> knowledge, however, no large studies evaluat the effect of lactulose in childhood constipation have been published in Vietnam.<br /> The primary objective of the present study<br /> was to evaluate the beneficial effects of lactulose in the treatment of chronic functional<br /> constipation in children.<br /> <br /> II. MATERIALS AND METHODS<br /> 1. Subjects<br /> 140 children aged 1 - 5 years recruited<br /> from the sample consisted of the National<br /> Children Hospital, Hanoi, Vietnam with a diagnosis of functional constipation<br /> Study design<br /> The treatment trial was performed in Hanoi, Vietnam from 1/10/2013 to 31/11/2014.<br /> The Rome III guideline was used to diagnose patients with chronic functional constipation [9]. According to the guideline, in<br /> the absence of organic pathology, patients<br /> 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<br /> incontinence per week after the acquisition<br /> of toileting skills. 3) History of retentive posturing or excessive volitional stool retention.<br /> 4) History of painful or hard bowel movements. 5) Presence of a large fecal mass in<br /> the rectum. 6) The history of large diameter<br /> stools which may obstruct the toilet. Infants<br /> up to 4 years have to fulfill ≥ 2 of the crite-<br /> <br /> 62<br /> <br /> ria for at least 1 month, whereas those > 4<br /> years need to fulfill ≥ 2 of the criteria for at<br /> least 2 months and have insufficient criteria<br /> for irritable bowel syndrome. A total of 140<br /> children from ages 1 - 5 years old presenting with constipation based on a modification of the Rome III criteria were eligible for<br /> the trial.<br /> Evaluation of treatment outcome<br /> All patients were examined, advised to<br /> change dietary, adherence to daily toilet<br /> training, used lactulose with 2 ml/kg/day. If<br /> patients have diarrhea, the dose of lactulose<br /> will decrease 1 ml/kg/day. After 1 week of<br /> treatment, patients still defecate hard stool<br /> < 3 times per week, lactulose will increase<br /> 3 ml//kg/day. Parents received fiber chart<br /> of common foods; the Bristol stool chart;<br /> and a stool diary to record the frequency of<br /> daily bowel movements, fecal soiling, stool<br /> consistency, as well as any symptoms they<br /> considered important. The children were<br /> evaluated clinically at study entry and at 4,<br /> 8 and 12 weeks after enrollment. Treatment<br /> responses were assessed by evaluation of<br /> the daily stool diary. Treatment compliance<br /> was assessed by direct interview with the<br /> patient, checking the diary cards (on which<br /> the number of daily capsules taken was<br /> recorded), and counting the capsules returned by the patient at each visit.<br /> Statistical analysis<br /> Statistical analysis was performed using the computer software SPSS 16.0. Student’s t test was used to compare means<br /> of continuous variables approximating a<br /> normal distribution. The x² test or Fisher’s<br /> exact test was used, as appropriate, to<br /> compare percentages. A p-value < 0.05 was<br /> JMR 111 E2 (2) - 2018<br /> <br /> JOURNAL OF MEDICAL RESEARCH<br /> considered statistically significant.<br /> <br /> III. RESULTS<br /> <br /> 2. Ethics <br /> <br /> Baseline characteristics of study<br /> groups<br /> From 1/10/2013 to 31/11/2014, 140 children presenting with constipation were enrolled in the study.<br /> <br /> This study was approved by the Science Council of Hanoi Medical University.<br /> A written informed consent was signed by<br /> children’s parents/ caretakers before participating in the present study.<br /> <br /> Table 1. Baseline characteristics<br /> Age (months)<br /> <br /> 35,9 ± 17,4<br /> <br /> Gender<br /> <br /> Boys (%)<br /> <br /> 51.8<br /> <br /> Girls (%)<br /> <br /> 43.2<br /> <br /> Disease duration (months)<br /> <br /> 11 ± 9.7<br /> <br /> Mean weekly stool frequency<br /> <br /> 1,9 ± 0,8<br /> <br /> Stool consistency (%)<br /> <br /> Type 1<br /> <br /> 77.9<br /> <br /> Type 2<br /> <br /> 22.2<br /> <br /> Patients with painful bowel movements (%)<br /> <br /> 80.7<br /> <br /> Patients with anal fissure (%)<br /> <br /> 54.3<br /> <br /> Patients with a fecal mass in the rectum (%)<br /> <br /> 66,4<br /> <br /> The beneficial effects of lactulose with 2 ml/kg/day in the treatment of chronic functional constipationin children.<br /> Figure 1 shows the mean stool frequency increased from 1.9 ± 0.8 stools/ week at baseline to 4.9 ± 1.8 at weeks 4 and 5.9 ± 1.4 at the end of the study (p < 0.01).<br /> <br /> Fingure 1. Change in the weekly stool frequency<br /> <br /> JMR 111 E2 (2) - 2018<br /> <br /> 63<br /> <br /> JOURNAL OF MEDICAL RESEARCH<br /> The successful treatment rate (defined as weekly stool frequency ≥ 3 times and fecal incontinence ≤ 1 time every 2 weeks) was 68% after 4 weeks and increased to 72.8% after 8<br /> and 12 weeks of treatment.<br /> Table 2. Change in stool consistency during treatment<br /> Stool consistency (%)<br /> <br /> Type 1<br /> <br /> Type 2<br /> <br /> Type 3<br /> <br /> Type 4<br /> <br /> Baseline<br /> <br /> 78.6<br /> <br /> 21.4<br /> <br /> 0<br /> <br /> 0<br /> <br /> 4 weeks<br /> <br /> 0<br /> <br /> 9.7<br /> <br /> 49.5<br /> <br /> 40.8<br /> <br /> 8 weeks<br /> <br /> 0<br /> <br /> 2.9<br /> <br /> 30.1<br /> <br /> 67<br /> <br /> 12 weeks<br /> <br /> 0<br /> <br /> 0<br /> <br /> 14.6<br /> <br /> 85.4<br /> <br /> p-value<br /> < 0.01<br /> < 0.01<br /> <br /> Stool consistency : Type 1 – Separate hard lumps, like nuts; Type 2 – Sausage – shaped,<br /> but lumpy; Type 3 – Like a sausage but with cracks on its surface; Type 4 – Like a sausage<br /> or snake, smooth and soft.<br /> The percentage of patients used 2ml of lactulose/ kg/ day after 4 weeks of treatment was<br /> 87.4%. This rate decreased to 80.6% (after 8 weeks) and 75.5% after 12 weeks (Table 2).<br /> Table 3. Change in dose of lactulose from baseline to after 12 weeks<br /> At 4 weeks<br /> <br /> At 8 weeks<br /> <br /> At 12 weeks<br /> <br /> Dose<br /> <br /> n<br /> <br /> %<br /> <br /> n<br /> <br /> %<br /> <br /> n<br /> <br /> %<br /> <br /> 1 ml/kg/day<br /> <br /> 11<br /> <br /> 10.7<br /> <br /> 14<br /> <br /> 13.6<br /> <br /> 17<br /> <br /> 16.5<br /> <br /> 2 ml/kg/day<br /> <br /> 90<br /> <br /> 87.4<br /> <br /> 83<br /> <br /> 80.6<br /> <br /> 78<br /> <br /> 75.7<br /> <br /> 3 ml/kg/day<br /> <br /> 2<br /> <br /> 1.9<br /> <br /> 6<br /> <br /> 5.8<br /> <br /> 7<br /> <br /> 6.8<br /> <br /> Time<br /> <br /> Amount of water and fiber/ day affect to treatment<br /> <br /> Table 3 shows a difference in the mean weekly stool frequency between fiber intake<br /> per day > 80% and ≤ 80% standard recommended after 4 weeks, 8 weeks and 12 weeks of<br /> treatment with p value.Children with fiber intake per day ≤ 80% standard recommendation<br /> had increased risk for hard stools (type 2 - 3) compared to > 80% group at 4 weeks and 8<br /> weeks (p < 0.05).<br /> Table 4: Amount of fiber/day affect to mean weekly stool frequency<br /> Time<br /> At 4 weeks<br /> <br /> 64<br /> <br /> Amount of fiber<br /> <br /> n (%)<br /> <br /> X ± SD<br /> <br /> ≤ 80%<br /> <br /> 49 (47.6)<br /> <br /> 4.4 ± 1.8<br /> <br /> > 80%<br /> <br /> 54 (52.4)<br /> <br /> 5.2 ± 1.8<br /> <br /> p value<br /> 0.03<br /> <br /> JMR 111 E2 (2) - 2018<br /> <br /> JOURNAL OF MEDICAL RESEARCH<br /> <br /> At 8 weeks<br /> At 12 weeks<br /> <br /> ≤ 80%<br /> <br /> 35 (34)<br /> <br /> 4.7 ± 1.7<br /> <br /> > 80%<br /> <br /> 68 (66)<br /> <br /> 5.5 ± 1.5<br /> <br /> ≤ 80%<br /> <br /> 11 (10.7)<br /> <br /> 5.5 ± 1.9<br /> <br /> > 80%<br /> <br /> 92 (89.3)<br /> <br /> 6 ± 1.3<br /> <br /> 0.02<br /> 0.30<br /> <br /> IV. DISCUSSION<br /> Based on recommendations from NASPGHAN and ESPGHAN, we chose a daily<br /> intake of mean dose of lactulose (2 ml/kg/<br /> day) in this study. The results showed that<br /> the frequency and consistency of defecation and other clinical symptoms as painful<br /> bowel movements, anal fissure, fecal incontinence, blood in stool improved significantly (p < 0.05).<br /> In this study, we used different doses of<br /> lactulose to evaluate the effects of lactulose<br /> in the treatment of functional constipation.<br /> The effective dose of lactulose was changeable based on factors such as diet, adherence to treatment, duration of constipation<br /> and any previous used medications. Banaszkiewicz’ trial used lactulose with 1 ml/<br /> kg/day, which showed that the mean weekly<br /> stool frequency improved, as did our study<br /> [4]. According to Sadeghzadeh's study, the<br /> frequency of defecation per week increased<br /> from 0.8 ± 0.8 to 1.5 ± 0.98 times (in the<br /> lactulose group) and from 1.7 ± 0.8 to 2.1<br /> ± 0.7 times (in the lactulose plus protease<br /> group) after 4 weeks of treatment [5]. The<br /> improvement of frequency of defecation in<br /> this study was slower than our results.<br /> In one study conducted by Wang, 111<br /> patients over 8 years of age received lactulose with 15 ml/kg, the median stool frequency following 1 week of treatment inJMR 111 E2 (2) - 2018<br /> <br /> creased to from 2 to 5 times per week, and<br /> following 2 weeks of treatment increased<br /> to 6 times per week. Prior to treatment, the<br /> stool consistencies of all enrolled patients<br /> ranged from type 1 to 3 on the Bristol Stool<br /> Scale. Lactulose treatment also improved<br /> the stool consistency to 3.64 ± 1.33 following 1 week of treatment and 3.63 ± 1.33 following 2 weeks [7].<br /> In our study, almost 70% of children with<br /> constipation were successfully treated after<br /> 4 weeks of treatment. This rate increased<br /> up to 72.8% after 8 weeks. The lactulose<br /> dose of 2 ml/kg/day is appropriate for children with constipation. After 4 weeks of<br /> treatment, almost all patients maintained<br /> the dose of 2 ml/kg/day; only 10.7% of<br /> them reduced the dose (1 ml/kg/day) due<br /> to diarrhea, and a few had to be increased<br /> due to unresponsive treatment (1.9%). The<br /> success rate in our study was higher than<br /> Voskuijl’s study after 8 weeks of treatment<br /> (29%). In Voskuijl’s study, the mean lactulose dose associated with improvement<br /> were 11.52 (4.56) g/day (1.9 sachets) and<br /> 13.86 (6.66) g/day (2.3 sachets) at 4 and<br /> 8 weeks. The optimal dose of lactulose in<br /> clinically successful patients < 6 years and<br /> ≥ 6 years was 0.96 (0.45) g/kg/day and 0.45<br /> (0.27) g/kg/day, respectively [8]. According<br /> to Wang, the effective rate of treatment was<br /> 65<br /> <br />