A Randomized, Prospective, Comparison Study of Polyethylene Glycol 3350 Without Electrolytes and Milk of Magnesia for Children With Constipation and Fecal Incontinence

Patients

All new children (≥1 per week) who were referred to the Children’s Hospital of Iowa (Iowa City, IA) for treatment of functional constipation with fecal incontinence, in August 2001 to September 2004, were eligible for the study. Children and their families were recruited by the 2 authors. Inclusion criteria were age of ≥4 years and presence of functional constipation with fecal incontinence. Functional constipation was defined by a duration of ≥8 weeks and ≥2 of the following characteristics: frequency of bowel movements of <3 stools per week, >1 episode of fecal incontinence per week, large stools noted in the rectum or felt during abdominal examination, passing of stools so large that they obstructed the toilet, and retentive posturing (withholding behavior). These criteria are similar to the recently proposed Paris Consensus on Childhood Constipation Terminology criteria²⁰ and the new Rome criteria.²¹ The previous Rome criteria²² were too restrictive and excluded many children who had functional constipation.^23,24 Children with stool toileting refusal, children with fecal incontinence but no constipation, children who had refused previously 1 of the study medications, children who came from far away for a second opinion, and children with Hirschsprung’s disease, chronic intestinal pseudo-obstruction, or previous surgery involving the colon or anus were not recruited.

The study was approved by the institutional review board of the University of Iowa. Children ≥7 years of age gave written assent, and all parents gave written informed consent.

Randomization, Treatment, and Follow-up Monitoring

Before the first appointment, parents were mailed a detailed questionnaire developed by Levine and Bakow,^25,26 which included questions on stooling habits and fecal incontinence. This questionnaire was reviewed with the parents. All children were assessed by 1 of the authors. A short evaluation form that has been used for many years in our clinics was completed by the physician during the interview and after the examination. This form included questions about age at the time of development of constipation, whether the child was ever toilet trained for stool and at what age, presence of retentive behavior, frequency of fecal incontinence per week (smear, small bowel movement, or large bowel movement in underpants), frequency, size, and consistency of stools defecated into the toilet, passage of bowel movements that obstructed the toilet, presence of abdominal pain, urinary incontinence during the day or night, previous treatments, and presence of an abdominal fecal mass and/or rectal mass.

Randomization was performed by children drawing a sealed envelope with an enclosed assignment. The investigators, the children, and their parents were aware of the study group assignment. Children received initially either 0.7 g/kg body weight PEG daily¹¹ or 2 mL/kg body weight MOM daily. Large dosages could be divided into 2 doses. A capful of PEG (17 g) was mixed in 8 oz of a beverage (such as juice, Kool-Aid, Crystal Light, or water), making a solution of ∼2 g/30 mL. Plain MOM could be mixed into applesauce or milkshakes, or chocolate and other flavorings could be added. Children were disimpacted with 1 or 2 phosphate enemas in the clinic on the day of the visit, if necessary, and started laxative therapy that evening. Parents were provided with written instructions regarding how to adjust the dosage of medication and children were treated with the minimal effective dosage of PEG or MOM, allowing for a daily stool and preventing abdominal pain and fecal incontinence. The written instructions said that we aim for 1 or 2 stools of milkshake consistency each day. Parents were asked to increase the dosage if the stools were too hard or not frequent enough and to decrease the dosage if the stools were watery or too numerous. Small changes, such as 2 oz of PEG or 0.5 tbsp of MOM every 3 days, were recommended. Regular stool sittings for 5 minutes after each meal were required initially. Toilet sitting frequency was reduced after the children recognized the urge to defecate and initiated toilet use themselves. Parents were instructed to keep a stool diary for the duration of the study, recording each bowel movement’s amount and consistency, episodes of fecal incontinence, abdominal pain, and medication use. Stool diaries were obtained rarely from patients who did not come for a follow-up visit. Data from parents’ verbal reports were accepted.

Return clinic visits were planned at 1, 3, 6, and 12 months after enrollment. A follow-up call was made at 9 months. At each visit, the interim history was assessed, stool diaries were reviewed and discussed, and a physical examination, including a rectal examination, was performed. Clinical progress, compliance with the treatment program, stool frequency, frequency of fecal incontinence episodes, occurrence of abdominal pain, and medication compliance were assessed from the stool diaries and history. A predesigned script, which had been approved by the institutional review board, was used during each visit or telephone call. The laxative dosage was adjusted as necessary, an enema was given if the child was impacted, and the stimulant laxative senna was added to the treatment program if the child was retaining liquid stools. If a child did not return for a planned follow-up visit, then the follow-up data were obtained through a telephone call by the authors, who gave advice regarding dose adjustment, toilet sitting, and a reward system and encouraged the parent to come for a follow-up visit if the child had not already recovered. If the family could not be reached by telephone, then a questionnaire was mailed to the last known address.

Safety Profiles

During each visit, patients and their parents were questioned with respect to diarrhea, ease of passage of stools, cramps, flatus, or any other adverse effects. Laboratory tests were optional, but children were encouraged to have blood drawn for measurement of serum sodium, potassium, chloride, blood urea nitrogen, creatinine, alkaline phosphatase, aspartate aminotransferase (AST), alanine aminotransferase (ALT), hemoglobin, and hematocrit levels, platelet count, red blood cell count, and white blood cell count during the initial, 3-month, 6-month, and 12-month visits.

Primary Outcomes

Improvement was defined as ≥3 bowel movements per week, ≤2 episodes of fecal incontinence per month, and no abdominal pain, with or without laxative therapy.^5–7,11,24 Recovery was defined as ≥3 bowel movements per week, ≤2 episodes of fecal incontinence per month, and no abdominal pain, with no laxative treatment for ≥1 month.^5–7,11,24 Children were counted as not improved and not recovered from the time of the refusal if they refused their study medication consistently and needed to be switched to a different laxative, if they discontinued participation in the study, if they were lost to follow-up monitoring, or if they were allergic to the study medication. Children who received additional senna treatment were counted as not improved and not recovered during the time they were receiving senna treatment.

Secondary Outcomes

Other outcomes studied were (1) improvement in stool frequency per week, improvement in episodes of fecal incontinence per week, and resolution of abdominal pain; (2) safety profile; and (3) patient’s acceptance and compliance.

Statistical Analyses

We hypothesized that PEG would be as successful as MOM in treating chronic constipation and fecal incontinence. Our previous study showed that 33% of children refused to take MOM during the first 12 months of treatment.¹¹ We estimated that 38 subjects were required in each group to be able to detect a difference in failure rates between the 2 groups of 30% in 12 months (40% vs 10%), at the .05 significance level with .80 power.

Data were entered into Excel (Microsoft, Redmond, WA), and analyzed. Efficacy analyses (improved and recovered) were performed with the intent-to-treat population, defined as all children assigned randomly. Bowel movement frequency, frequency of fecal incontinence episodes, and presence/absence of abdominal pain were calculated from the available follow-up data. Comparisons were made between the initial data and the follow-up data, between the 1-, 3-, 6-, and 12-month follow-up data, and within groups. Statistical analyses included determination of means and SDs, t test, χ² test, and Fisher’s exact test, with significance accepted at the 5% level. Results are expressed as mean ± SD or percentage.

Initial Patient Characteristics

A total of 137 children and their families were asked to participate in our study. Seventy-nine children (65 boys and 14 girls; age range: 4–16.2 years; mean ± SD: 8.1 ± 3.0 years; median: 7.4 years) and their families agreed to participate and were enrolled in the study. A detailed flow diagram of the children’s progress through the study is presented in Fig 1. Thirty-nine children (31 boys and 8 girls) were assigned randomly to receive PEG 3350 without electrolytes. Forty children (34 boys and 6 girls) were assigned randomly to receive MOM. Initial patient characteristics of the children who received PEG and MOM are shown in Table 1. The baseline characteristics of the 2 groups were not statistically different (P > .07), with respect to demographic features and various parameters of constipation and incontinence. The frequency of bowel movements per week was higher than expected in both groups, but many children came to our clinic because of chronic continuous problems with constipation and fecal incontinence, often while receiving some form of treatment.

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FIGURE 1

Trial profile. The numbers of children who returned for the follow-up visits are given in parentheses.

One-Month Follow-up Findings

In the PEG group, 33 children returned for the 1-month follow-up visit and 5 families were contacted by telephone. One child discontinued participation in the study because of an allergic skin rash, which reoccurred after rechallenge with PEG. In the MOM group, 27 children came for the 1-month follow-up visit and 10 families were contacted by telephone. Three children refused to take the MOM after a few days. Results of the 1-month follow-up visit are shown in Fig 2 and Table 2. Improvement was seen for 49% of children in the PEG group and 55% of children in the MOM group (P > .6) (Fig 2). In both groups, bowel movement frequency increased and fecal incontinence frequency and abdominal pain decreased significantly from baseline (Table 2).

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FIGURE 2

Improvement and recovery rates. Initial and follow-up data on the percentages of children in the PEG and MOM groups with improvement or recovery are shown. Improvement was defined as ≥3 bowel movements per week, ≤2 episodes of fecal incontinence per month, and no abdominal pain, with or without laxative therapy. Recovery was defined as ≥3 bowel movements per week, ≤2 episodes of fecal incontinence per month, and no abdominal pain, with no laxative treatment for ≥1 month. There were no significant differences in improvement and recovery rates between the 2 treatment groups at any time points.

Three-Month Follow-up Findings

In the PEG group, 29 children came for the 3-month follow-up visit and 9 families were contacted by telephone. In the MOM group, 26 children returned for the 3-month follow-up visit, 10 families were contacted by telephone, and 1 child was lost to follow-up monitoring. Four additional children refused to take the MOM, and 1 child experienced relapse and was switched to PEG by his primary practitioner. The rates of improvement and recovery were similar for the 2 groups (Fig 2). Improvement in the constipation parameters was significant for both groups, compared with baseline (P < .001) (Table 2).

Six-Month Follow-up Findings

In the PEG group, 21 children returned for the 6-month follow-up visit, 16 families were contacted by telephone, and 1 child was lost to follow-up monitoring. One child had refused PEG permanently, and 3 children needed senna. In the MOM group, 16 children came for the 6-month follow-up visit and 15 families were contacted by telephone. Three additional children had refused MOM, and 2 children had discontinued participation in the study. By 6 months, a total of 10 children (25%) had refused MOM. The 6-month outcome data (Fig 2 and Table 2) were not significantly different between the 2 treatment groups, remained significantly improved, compared with the initial data (P < .001), and were similar to the 1- and 3-month data (P > .1).

Twelve-Month Follow-up Findings

In the PEG group, 16 children returned for the 12-month follow-up visit, 19 families were contacted by telephone, and 1 child was lost to follow-up monitoring. Two of the 3 children who were receiving senna at the 6-month follow-up visit were still receiving daily senna. One child had refused PEG. After 12 months, a total of 2 children were lost to follow-up monitoring, 2 children (5%) had refused PEG, 1 child was allergic to PEG, and 2 children were receiving senna. These 7 children were counted as not improved and not recovered. In the MOM group, 8 children came for the follow-up visit, 17 families were contacted by telephone, and 1 child was lost to follow-up monitoring. Four additional children had refused to continue with MOM. By 12 months, 2 children were lost to follow-up monitoring, 3 children had discontinued study participation, 14 children (35%) had refused to take MOM, and 1 child was receiving senna.

The percentages of children who experienced improvement were similar in the PEG group (62%) and the MOM group (43%; P < .086) (Fig 2). The recovery rates were similar for children in the PEG group (33%) and the MOM group (23%; P = .283) (Fig 2). The 12-month data for frequency of bowel movements, frequency of episodes of fecal incontinence, and percentage of children with abdominal pain were not significantly different between the PEG and MOM groups (Table 2).

Treatment Doses

The mean PEG treatment dose at the 1-month follow-up evaluation was 0.7 ± 0.2 g/kg body weight daily and that at the 3-month follow-up evaluation was 0.6 ± 0.3 g/kg body weight daily. The mean PEG doses were similar for children who had and had not experienced improvement.

The mean MOM treatment dose at the 1-month follow-up evaluation was 1.2 ± 0.7 mL/kg body weight daily and that at the 3-month follow-up evaluation was 1.2 ± 0.8 mL/kg body weight daily. The mean MOM doses were similar for children who had and had not experienced improvement. There were 3 children who received the stimulant laxative senna in addition to PEG and 1 child who received it in addition to MOM at some point during the study (P > .29).

Safety Profiles

One child was allergic to PEG. No other significant clinical adverse effects were reported with either PEG or MOM except for transient diarrhea, which disappeared with dose reduction. There were no complaints of increased flatus, abdominal distention, or new onset of abdominal pain. The children in both groups who came for follow-up evaluations continued to grow in weight and height, along their growth curves, during the 12 months. There were no new abnormal physical findings on examination.

Most laboratory test results were within normal limits for the 30 children who had their blood evaluated before starting PEG treatment. Four children had elevated platelet counts (402000–492000 platelets per mm³; normal: <400000 platelets per mm³), and 2 had elevated AST levels (46 and 56 U/L; normal: ≤40 U/L) with elevated ALT levels (77 and 32 U/L; normal: ≤30 U/L). Twenty-seven children had 41 follow-up blood tests while receiving PEG; 17 children had 3-month follow-up blood tests, 15 had 6-month tests, and 9 had 12-month tests; 11 had 1 follow-up blood test, 9 had 2 tests, and 7 had 3 tests. Only 1 of the 4 children with elevated platelet counts showed an elevated platelet count; 1 blood test showed a decreased sodium level (133 mEq/L; normal: 135–145 mEq/L) at the 6-month follow-up evaluation, but the level was normal at 12 months. All children had normal ALT and AST values at follow-up evaluations.

Of 25 children who underwent laboratory testing before starting MOM, 1 had an elevated platelet count (453000 platelets per mm³) and 2 had mildly decreased serum potassium levels (3.3 mEq/L; normal: 3.5–5 mEq/L). Twenty children had 30 follow-up blood tests while receiving MOM, 15 children at 3 months, 10 at 6 months, and 5 at 12 months; 12 children had 1 follow-up blood test, 6 had 2 tests, and 2 had 3 tests. One child had a high platelet count (563000 platelets per mm³), 1 child had a low serum sodium level (134 mEq/L), 1 child had an elevated AST level (43 U/L), and 1 child had an elevated ALT level (48 U/L).

Patient Acceptance

Several children complained about the taste of PEG and MOM. Only 2 children (5%) continued to refuse PEG, whereas 14 children (35%) continued to refuse MOM during the 12 months of the study (P < .001) (Fig 1).