Constipation, defined as infrequent, painful bowel movements sometimes in combination with the involuntary loss of feces in the underwear is a common problem in children (1). The current treatment advice in cases of simple constipation consists of toilet training and a high-fiber diet, whereas chronic childhood constipation is treated with oral and sometimes rectal laxatives for an extended time (1). Two large randomized controlled trials in pediatric patients have been published, evaluating the effect of laxative treatment (lactulose, polyethylene glycol solution) (2,3). These studies showed that polyethylene glycol was superior to lactulose in the treatment of constipation.
Despite intense debate on its efficacy, no large controlled trials studying the effect of dietary fiber in children with constipation have been performed to our knowledge (4–6). Two small randomized controlled trials showed a beneficial effect of glucomannan, a nonabsorbable fiber gel polysaccharide, on defecation frequency and stool consistency in children with constipation (7,8).
Dietary fibers have water-retaining capacity and stimulate gastrointestinal motility by increasing feces volume, bacterial growth, and bacterial degradation products (9–11). This promotes colonic propulsion, reduces transit time, and facilitates defecation. (7,8,12–14).
In previous studies, only single types of fiber were used. A more effective approach may be the use of a combination of different types of fiber: short- and long-chain fibers. In this way degradation products can be expected to be produced throughout the colon, in contrast to lactulose, which has its effect mainly in the proximal colon (15–18). The aim of the present study was to assess the clinical efficacy and safety of a dietary fiber mixture and compare it with lactulose in the treatment of childhood constipation.
PATIENTS AND METHODS
Constipated children, referred by general practitioners and public health physicians to the outpatient pediatric clinic of the Hospital Rijnstate, Arnhem, the Netherlands, were eligible for this study. All of the children had to fulfill at least 2 of 4 criteria for constipation: stool frequency less than 3 times per week, fecal incontinence 2 or more times per week, periodic passage of large amounts of stool at least once every 7 to 30 days, or a palpable abdominal or rectal mass (19). Children ages 1 to 13 years were included. Children with organic causes of defecation disorders, including Hirschsprung disease, spina bifida, hypothyroidism or other metabolic or renal abnormalities, and mental retardation; children using drugs influencing gastrointestinal function other than laxatives; and children having used lactulose or other laxatives, prebiotics or probiotics, or antibiotics in the previous 4 weeks before the first visit were excluded from the study. Written informed consent was obtained before the start of the study. The study protocol was approved by the medical ethics committee of the hospital.
Patients received either a yogurt drink with mixed dietary fibers (10 g/125 mL) or a yogurt drink containing lactulose (10 g/125 mL) (Duphalac Lactulose, Solvay, the Netherlands). The fiber mixture yogurt contained 3.0 g transgalacto-oligosaccharides (Vivinal GOS Elixor Sirup, Friesland Foods Domo, Zwolle, the Netherlands), 3.0 g inulin (Frutafit TEX, Cosun, Roosendaal, the Netherlands), 1.6 g soy fiber (Fibrim 2000, J. Rettenmaier & Sohne, Ellwangen, Germany), and 0.33 g resistant starch 3 (Novelose 330, National Starch & Chemical GmbH, Neustadt, Germany) per 100 mL.
Bottles with yogurt were prepared and packed by Numico Research (Wageningen, the Netherlands), transported to the hospital, and stored at room temperature. Storage and delivery were supervised by the local hospital pharmacist. The treatment products could not be distinguished from each other with respect to color, taste, or consistency.
The amount of fiber and fluid intake depended on body weight. Patients with a weight <15 kg received 1 bottle (125 mL, 10 g fibers) daily, those with a weight between 15 kg and 20 kg received 2 bottles (250 mL, 20 g) daily, and those with a weight above 20 kg received 3 bottles (375 mL, 30 g) daily. The study product was taken at breakfast and, in the case of 2 or more bottles, also at lunch.
Study Design and Study Outline
The study had a randomized double-blind parallel-group design. Randomization was performed by use of sequential numbers allocated to the patients at study entry and coordinated by the logistics manager of Numico Research using a block design. The study period consisted of 3 phases: a 1-week baseline period, an 8-week intervention period, and a 4-week weaning period (Table 1).
Patients were screened during their first visit to the hospital. A detailed medical history using a standard questionnaire was taken, and a complete physical examination, including abdominal and rectal examination, was performed. In case of rectal impaction, an enema was given during the first visit.
During the baseline period, defecation frequency, frequency of fecal incontinence, consistency of stool, abdominal pain, and flatulence were recorded. During the treatment period, patients were seen at the outpatient clinic 3 and 8 weeks after inclusion. In addition, data were recorded daily in the bowel diary by the parents or patient. Finally, parents of patients were contacted by a research nurse by telephone 1 and 4 weeks after inclusion. If clinical parameters compared with baseline did not improve 3 weeks after the start of the intervention period, then step-up medication (macrogol 3350) was given per protocol. During the weaning period, the patients' study medication was lowered. If persistent diarrhea was reported, the original dose was reduced by 50%. After 4 and 8 weeks of treatment, patients who were able to write and read filled in a questionnaire themselves to evaluate the drink with a figure between 0 and 10. During the baseline period and after 3 weeks, fecal samples were collected for determination of dry weight.
Finally, all adverse events encountered during the study were recorded. An adverse event was defined as any adverse change from baseline (pretreatment) condition, which occurred during the course of the study after treatment had started, whether it was considered to be related to treatment.
The primary outcome parameter was defecation frequency per week; defecation was noted on a daily basis during the treatment period. Secondary outcome parameters were fecal incontinence each day (yes or no), stool consistency according to the Bristol Stool Form Scale (20) (stools are rated based on water content of the feces, with 1 meaning hard stools to 7 meaning liquid stools), abdominal pain (0 = not at all, 1 = sometimes, 2 = often, and 3=continuous), flatulence (0 = not at all, 1 = sometimes, 2 = often, and 3 = continuous), use of step-up medication (yes or no), taste (1–10), dry weight of feces at week 0 and 3, and adverse effects.
The sample size for the study was based on the primary outcome variable defecation frequency. It was calculated that a random allocation of 150 children would allow for the detection of a mean difference in defecation of 1.0/week between the 2 treatment groups with a power of 80% and α = 0.05 (21). Comparisons between the 2 treatment groups at specific different time points were performed by use of the Student t t est or the nonparametric Mann-Whitney U test depending on the distribution of values. Frequencies in Table 2 are given as minimum and maximum; distribution was skewed, so median is given instead of mean. Statistical analysis was performed by use of SPSS-PC version 13.0 (SPSS Inc, Chicago, IL) software. P < 0.05 was considered statistically significant.
Between September 2001 and April 2004, 147 patients were eligible (Fig. 1). Twelve patients and their parents received information but chose not to participate. During the treatment period, 33 patients dropped out: 22 in the fiber group after 1 to 56 days (median 7) and 11 in the lactulose group after 1 to 51 days (median 8) (P = 0.020). Those patients refused to continue to drink the yogurt. Therefore, the final data set consisted of a total of 97 patients (42 in the fiber mix group and 55 in the lactulose group). No significant differences were found in baseline characteristics between the 2 groups (Table 2). Defecation frequency per week showed no difference between groups after 8 weeks of treatment (7 times per week in the fiber group vs 6 in the lactulose group; P = 0.481).
No significant difference between the fiber mix and lactulose group was found with respect to the number of patients with 1 or more fecal incontinence episodes per week (9/42 vs 5/55 patients; P = 0.084), nor were statistically significant reductions found between baseline and the end of the intervention period within each group: in the fiber mix group 8 versus 9 patients (P = 0.664) and in the lactulose group 7 versus 5 patients (P = 0.423).
Improvement in consistency of stools was observed within both groups. In the fiber mix group, a trend toward statistically significant softer stools was observed after 3 weeks of treatment, and significantly softer stools were observed at the end of the intervention period (P = 0.07 and P = 0.036, respectively). The consistency of stools in the lactulose group significantly changed to softer stools after 3 and 8 weeks of therapy (P < 0.001 and P < 0.001, respectively). The presence of abdominal pain and flatulence scores did not differ between groups (Table 3).
Step-up medication was given to a significantly greater number of fiber-treated patients after 3 weeks (P = 0.028). However, this difference disappeared after 8 weeks (P = 0.356) and 12 weeks (P = 0.793) (Table 4). Taste score at 4 weeks in the fiber-treated group was 8 (median), with a range from 1 to 10, and in the lactulose group 7 (range 1–10) (P = 0.516) and at 8 weeks 8 (1–10) and 7 (1–10) (P = 0.712). The percentage dry weight of feces decreased significantly from week 0 to week 3 in the lactulose group (30.4% vs 25.3%; P = 0.006) but not in the fiber-treated group (28.1% vs 26.7%; P = 0.124).
During the 8-week study period, no serious or significant adverse effects were recorded in the 2 study groups. In 3 cases (1 in the fiber mixture group and 2 in the lactulose group), the study yogurt intake was decreased because of persistent diarrhea.
This trial shows that both a fluid fiber mixture and lactulose are effective in the treatment of childhood constipation. In our study population, a defecation frequency of 2 or fewer times per week was observed in 44% of the patients, lower than that observed in previous studies showing percentages of 60% (2,22,23). Moreover, only 32% of the patients in this study had fecal incontinence. This is in contrast with others, who have reported 60% to 80% of constipated patients with fecal incontinence (2,8). Most likely these differences occurred because our group of patients consisted of children referred by general practitioners and public health physicians. In the above-mentioned studies, patients were referred to tertiary centers, suggesting more severe constipation. Inasmuch as the results of this study probably apply to children with more mild to moderate complaints of constipation, it may have been more difficult to observe clinically relevant improvements in stool characteristics in an 8-week intervention period.
Subjective measurement of consistency of stools according to the 7-point Bristol stool form scale showed an improvement within both groups, with (trends toward) significantly softer stools after 3 and 8 weeks of intervention in both groups. A statistically significant softer consistency of stools was observed in the lactulose group in comparison with the fiber group after 3 and 8 weeks of treatment. In the fiber group, improvement in consistency was steady and slow compared with that in the lactulose group. Notably, stools in the lactulose group at 8 weeks became harder again. Lactulose can be considered as a semisynthetic undigestible carbohydrate, reaching the cecum intact and broken down by bacteria into short-chain fatty acids. Subsequently, the intraluminal pH value decreases causing an increase of peristaltic movements. The short-chain fatty acids are absorbed together with water and electrolytes, tending to reduction of fecal water content. Fermentation, however, stimulates bacterial growth, which contributes to increased stool weight and volume, and bowel wall dilatation, which then triggers the reflex action of the bowel peristalsis. The fate of the dietary fibers in our mixture is comparable to that of lactulose except for the difference in fermentation site and rate. Different strains of bacteria and their inducible enzymes are involved and probably may take more time to efficiently degrade fibers consisting of multiple units, in comparison with lactulose consisting of only 2 units (24–26). This could explain the more prolonged softening of stool seen in the fiber group. Stool softness caused by lactulose may reach a maximum earlier in the treatment, but the effect may be short-lived. The higher need for step-up medication in the fiber mix group after 3 weeks of treatment, which disappeared at week 8, underlines this hypothesis.
To avoid taste problems, we developed a palatable yogurt drink containing a high dose of dietary fiber or containing an equal dose in grams of lactulose. However, 33 patients were not able to continue to drink this yogurt for a period of 12 weeks. Patients complained about taste, the large volume to drink every day, and/or the lack of choice in taste. None of the children stopped because of worsening of complaints connected to constipation. The larger number of dropouts in the fiber group, although overall taste was rated as 8 in this group versus 7 in the lactulose group, cannot be explained by increased side effects, which were comparable in both groups. In comparison with other studies in childhood constipation (2,3), however, the number of dropouts was considerable. In 1 study that compared polyethylene glycols without electrolytes (28 patients) and milk of magnesia (21 patients), none of the patients taking polyethylene glycols refused the medication, in contrast to 33% of the patients refusing milk of magnesia (27). Our taste questionnaire showed large disagreement among the patients about the taste of the yogurt drinks (scores ranging from 1 to 10), and this did not correlate with age.
Decrease in the percentage of dry weight of feces between weeks 0 and 3 was larger in the lactulose group than in the fiber mixture group. Lactulose can be expected to be fermented almost completely, in contrast to the fiber mixture. Therefore, the percentage dry weight of children in the lactulose group can be expected to be lower because of the lower amount of undigested fibers. The percentage dry weight of feces still containing a certain amount of fiber can be expected to be relatively higher. By contrast, other factors, like the osmotic effect of lactulose (resulting in a higher water content) and the effect of the growth of bacterial mass (resulting in a higher water content), also determine the percentage dry weight of stools. In this study, which used not only a qualitative measurement (Bristol stool form scale) but also a quantitative measurement (dry weight of feces), lactulose gave more a favorable result than the fiber mixture with respect to softer and more wet feces.
High fiber intake has been advocated as a treatment option for chronic childhood constipation. Early reports showed a positive relation between low fiber intake and the risk of constipation (28–31). Other reports from the Netherlands and Brazil did not confirm this relation (32,33). Table 5 shows that patients in our study already received 77% to more than 100% of the recommended fiber intake per day according to age, just by drinking the yogurt. Possibly adding more fiber to the diet than the advised daily allowance is not accompanied by additional effects on stool frequency and consistency (34). This may be an important observation, inasmuch it has been shown that starting and maintaining high-fiber diets in pediatric patients is difficult (35).
In conclusion, the results of this study show that a fluid fiber mixture in the treatment of childhood constipation is feasible and has overall results comparable with those of treatment with lactulose.
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