What Is Known/What Is New
What Is Known
- Polyethylene glycol is routinely used for the long-term treatment of chronic constipation in adults.
- Polyethylene glycol has been demonstrated to be an effective treatment for childhood functional constipation.
- Both the safety and efficacy of polyethylene glycol have been reviewed extensively in adults; however, there are limited data in children younger than 24 months.
What Is New
- This systematic review provides promising results surrounding safety of polyethylene glycol with a lack of reported side effects for children younger than 24 months.
- There is currently insufficient evidence to establish appropriate dosage regimens of polyethylene glycol in children younger than 24 months.
Constipation is defined as significantly decreased movement of the bowel, which persists for 2 weeks or more. It may lead to the hardening of the stool, difficulties with defecation, and abdominal pain (1). Functional constipation is constipation with no known cause and a common digestive problem across all ages (2). It is estimated in the United States that 30% of children will suffer from functional constipation at one point in their lives, resulting in 2.5 million visits to physicians annually, costing hundreds of million dollars.
Polyethylene glycol (PEG) is routinely used for the long-term treatment of chronic constipation in adults, and has been demonstrated to be an effective treatment for childhood functional constipation (3–5). Both the safety and efficacy of PEG have been reviewed extensively in adults; however, there is limited information available in children younger than 24 months (5,6).
The main action of PEG lies in its ability to increase the osmotic pressure of the intestinal lumen, resulting in increased passage of water into the lumen (7). It is an osmotic agent available in various formulations (PEG 3350 and PEG 4000) with or without electrolytes. PEG 3350 has a lower molecular weight (3350 g/mol) than PEG 4000 (4000 g/mol) and therefore has a greater hygroscopic ability. Despite the lack of evidence supporting clear safety benefits, some PEG formulations contain the addition of electrolytes to help reduce plasma electrolyte loss (8).
This systematic review focused upon the use of PEG in the management of functional constipation in children younger than 24 months.
The review aligns with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) (9). The methodology was also published on PROSPERO (registration number: CRD42018104593). A primary search of studies was carried out in PubMed, EMBASE, MEDLINE Ovid, and the Cochrane Library in November 2017 (Supplemental Digital Content 1, https://links.lww.com/MPG/B840). Secondary searches of the same databases were carried out in September 2018 and February 2019. The following restrictions were applied: publication date from January 1, 2000 to February 1, 2019, human studies, and English language.
After removing duplicates, 2 authors (H.R. and A.F.G.) independently reviewed all records for eligibility. Case studies, cohort studies, controlled clinical trials, and longitudinal studies were reviewed. Meta-analyses, systematic reviews, cross-sectional studies, animal studies, and in vitro studies were excluded from further screening.
Inclusion criteria for abstract screening included: PEG therapy for children with functional constipation (excluding dysfunction of organic cause), children younger than 24 months, English language, and PEG dosage, safety, or efficacy. Additional criteria for full-text screening included a placebo or comparison group. Discrepancies between authors were discussed with a third author (S.K.K.) until consensus was reached. The following search terms were used, with a combination of keywords: “constipation,” “polyethylene glycol(s),” “polyoxyethylene,” “glycol(s),” “baby,” “babies,” “infant,” “infants,” “infancy,” “child(ren),” “girl(s),” “boy(s),” “toddlers,” and “children.”
For each eligible study, the following data were extracted: patient demographics; study methods; PEG administration, dose, and preparation; and as the comparators, different doses of PEG, placebo, or other treatments.
Supplemental content was reviewed to obtain additional information. No authors were successfully contacted.
The methodological quality of randomized controlled trials was assessed using the 11-item PEDro scale (10). All randomized controlled trials were evaluated using the Cochrane risk of bias tool (11). Retrospective chart reviews were rated against criteria from the Newcastle-Ottawa Scale (12).
The search retrieved a total of 282 studies (PubMed, n = 54; MEDLINE Ovid, n = 112; EMBASE, n = 51; Cochrane Library for Clinical Trials, n = 65) (Fig. 1). An additional study was obtained through manual searching. After duplicates (n = 129) were removed, there were 154 articles for title and abstract screening. In total, 19 articles were short listed. These articles underwent detailed full text analysis. With further exclusions, 5 papers were selected for review, comprising a pooled total of 459 patients, with 2 studies being clinical trials and 3 studies retrospective chart reviews. Supplemental Digital Content 2 (https://links.lww.com/MPG/B840) provides a summary of included studies.
The studies by Bekkali et al (7) and Dupont et al (13) were assessed using the PEDro scale (Supplemental Digital Content 3, https://links.lww.com/MPG/B840). Both studies obtained a score of 10, representing excellent quality. They also had a low risk of bias, according to the Cochrane risk of bias tool (Supplemental Digital Content 4, https://links.lww.com/MPG/B840). Studies by Michail et al (6), Loening-Baucke et al (14), and Loening-Baucke (15) were classified as poor quality, with respect to the Newcastle-Ottawa Scale, due to not meeting criteria in the “outcome” category (Supplemental Digital Content 5, https://links.lww.com/MPG/B840).
Dosage Recommendations and Safety of PEG3350 Plus Electrolytes Versus PEG4000
The participants in Bekkali et al (7) were grouped into 4 age groups: 6 to 24 months, 2 to 4 years, 4 to 8 years, and 8 to 16 years. For participants younger than 24 months, 5 constipation symptoms were recorded in a clinical diary: crying due to abdominal pain; diarrhea; flatulence; crying while having a bowel movement; and redness due to straining while having a bowel movement. These symptoms were scored using a 3-point scale, where more frequent symptoms contributed to a higher score. The points were accumulated into a total sum score, ranging from 0 to 15 points. Although constipation symptoms improved at the end of the study in both PEG3350+E and PEG4000 treatments for the entire cohort (mean reduction: −3.81 and −3.74, respectively), the study did not include mean reduction in total sum score, specifically for the 6 to 24 months age group (7).
The dose range for patients younger than 24 months of age was similar for those who used PEG3350+E versus PEG4000 (0.4–2.3 sachets per day vs 0.9–2.1 sachets per day, respectively) (7). The mean daily number of sachets used by the entire cohort was not statistically different during the whole study period (P = 0.67). In children younger than 24 months of age, the mean daily dose of PEG relative to body weight was, however, considerably lower for PEG3350+E (0.45 g/kg) versus PEG4000 (0.65 g/kg) (P < 0.001) (7).
The study concluded that none of the serious adverse events, including dehydration, upper respiratory tract infection, and metabolic acidosis were considered to be drug related. No significant differences with respect to efficacy and safety, rates of adverse events, or drug-related side effects were found between PEG formulations (7).
Dosage Recommendations and Safety of PEG4000
Dupont et al (13) undertook the first large-scale study to determine the effective dosage of PEG4000 for the treatment of childhood constipation. For children aged 6 to 12 months, the median effective dose was 0.48 g · kg−1 · day−1 (range: 0.30–0.59). This was lower than the mean dose of PEG4000 reported by Bekkali et al (7) for children aged 6 to 24 months (0.65 g · kg−1 · day−1). Moreover, significant improvement was observed in increased number of stools per week (P < 0.0001) and reduced hardness of stools (P = 0.0003) (13).
Based upon the studies of Bekkali et al (7) and Dupont et al (13), the PEG4000 dosage evaluated by the 2 studies is considered efficient and effective in children. The adverse effects described in Bekkali et al (7) were seen in few participants: abdominal pain (n = 1), diarrhea (n = 1), vomiting (n = 1), nasopharyngitis (n = 1), and headache (n = 1). The most common adverse events reported in Dupont et al (13) were similar to Bekkali et al, where diarrhea was reported in 32 of 96 (33%) participants and abdominal pain with immediate resolution was found in 18 of 96 (19%) participants.
Dosage Recommendations and Safety of PEG3350
Michail et al (6) focused on the determination of mean initial and maintenance dose of PEG3350 resulting in the most effective outcome, which was measured by improvements in stool frequency and pain. A mean initial dose of 0.88 g · kg−1 · day−1 was effective in 86% of patients. A mean maintenance dose of 0.78 g · kg−1 · day−1 was reported as effective in 96% of patients. Further analysis revealed a higher effective initial dose was correlated with a higher effective maintenance dose.
Loening-Baucke et al (14) evaluated the mean effective short-term (0–4 months) and long-term (≥6 months) dosage by reviewing the duration and symptoms of constipation at each patient visit. The authors found enough significant improvements in constipation symptoms, compared with the pre-PEG period, to conclude that a short-term dosage of 1.1 g · kg−1 · day−1 and long-term dosage of 0.8 g · kg−1 · day−1 would have the most effective outcome (14). In another review, Loening-Baucke (15) compared patient outcomes across 2 treatment modalities—dietary modification versus laxative therapy (milk of magnesia or PEG3350). At follow-up, 92% of children had significantly improved with daily laxative therapy. Only 25% of children, however, had improved after dietary modification.
A small proportion of patients experienced side effects on PEG3350. These included runny stools, watery stools, transient diarrhea, increased passage of gas, and excessive straining and discomfort (6,14,15). No serious adverse effects of PEG3350 were reported across all studies, including neurological or neuropsychiatric events (6,14,15).
There are few available studies investigating the use of PEG in treating functional constipation in children younger than 24 months. In the 5 studies selected, PEG formulations included PEG3350 without electrolytes, PEG3350 with electrolytes, and PEG4000 without electrolytes. Each study appeared to have different dosage categories. The dosage described by the studies were in terms of mean daily dose, mean effective short-term dose, mean long-term dose, mean initial dose, median daily effective dose, and mean effective maintenance dose. Despite variability across studies, the findings suggest the value of using a conservative initial dose to minimize adverse events and adjusting the dose if required. This method may reduce undesirable effects from initial high doses and increase the likelihood of treatment adherence, which is integral to sustained improvement.
Michail et al (6), Bekkali et al (7), Loening-Baucke et al (14), and Loening-Baucke (15) had different findings in terms of the specification of the dosage (6). Although Bekkali et al (7) and Loening-Baucke (15) concentrated on the mean daily dose used and found differing results (0.45 vs 1.0 ± 0.6 g/kg), the other studies focused on the mean effective dose (6,14). Bekkali et al (7) specified that subjects were only eligible for inclusion in the study if they had a baseline of younger than 3 spontaneous bowel motions per week at the time they were allocated to treatment. In contrast, Loening-Baucke (15) failed to record the baseline gastrointestinal symptoms of subjects at the commencement of treatment. This lack of data regarding the baseline symptoms of subjects in the Loening-Baucke (15) study questions how comparable the outcomes of these 2 studies are.
Michail et al (6) and Loening-Baucke (15) had similar findings for the mean effective long-term and mean effective maintenance dose (0.78 and 0.8 g · kg−1 · day−1, respectively). They also found that the short-term improvement of stool frequency and stool consistency were similar in both studies (P < 0.001 and P < 0.01, respectively) (6,15).
Multiple studies with participants greater than 24 months of age have indicated various dosage recommendations, ranging from 0.3 to 1.5 g · kg−1 · day−1(16–22). In their study of older children, Nurko et al (16) demonstrated 0.8 g/kg was associated with the highest improvement of bowel movement frequency and defecation symptoms, as well as increased adverse effects (abdominal cramping and more watery stools).
The most common adverse event recorded was diarrhea, which resolved after the dosage was adjusted (6,7,14,15). This finding is confirmed by numerous studies that have identified diarrhea as the main side effect of PEG3350 in older participants (20,21,23,24). An evidence-based appraisal also reported that the use of a higher dose would result in a higher rate of diarrhea and bloating (25). Therefore, this adverse effect is mainly the result of using a higher dose than needed. To successfully eliminate these adverse effects, some participants may or may not need dose adjustment. Despite the fact that diarrhea is often observed, no patients stopped treatment due to experiencing this side effect (6,7,14,15).
A recent article discussed consumer concerns regarding neurological and neuropsychiatric effects of PEG (26). The authors highlighted the impact that consumer voice in the public forum has upon medical decision making. Despite no published literature of significant neurological or neuropsychiatric effects from PEG, consumer concerns continue. In 2018 a small study explored levels of organic polymers (ethylene glycol; diethylene glycol; and triethylene glycol) in blood for children who used PEG versus a control group (27). Their findings suggest children are exposed to measurable amounts of these compounds regardless of PEG use. Reassuringly, the levels detected in children who used PEG was well below the 0.2% cutoff recommended by the Food and Drug Administration for pharmaceuticals and unlikely to reach levels that cause acute toxicity. Yet, the potential for adverse effects from continued exposure to these compounds is unknown and requires targeted research to address consumer concerns. For these reasons, a low initial dose of PEG may be a better alternative to a high dose to limit the possibility of adverse effects.
Studies by Bekkali et al (7) and Dupont et al (13) both investigated the most effective daily dose of PEG4000 and found different results (mean daily dose of 0.65 g/kg for children ≤24 months old, and median daily dose of 0.48 g/kg, range 0.30–0.59 g/kg for children aged 6–12 months old, respectively). The contrasting findings, however, could not be compared directly because of differences in age groups. Based on findings from Dupont et al (13), an initial treatment dose of 2 sachets was less likely to require adjustment to achieve the most effective dose. Accordingly, the maintenance dose was found to be influenced by the initial dose and body weight, rather than patient age. These findings also suggest the possibility that a low initial dose may be more suitable than a higher dose with a lower chance of adjustment.
A recent study comparing a low-dose and high-dose of PEG4000 (0.3 and 0.7 g/kg, respectively) in children aged 1 to 18 years revealed conflicting findings (22). Despite no significant differences in effectiveness, the study proved that the use of the higher-dose PEG4000 had a higher chance of treatment success compared with the low dose. Among the other findings, a lower dose of PEG4000 also required more dose adjustment, had a higher chance of painful defecation, and a decreased frequency of stools per week (22).
Despite reported adverse effects for both cohorts, these were relatively minor as shown in Bekkali et al's (7) supplemental table. Dupont et al's (13) safety findings also suggested minor effects, but would have benefited from a similar table as supporting evidence (13). Moreover, while Dupont et al (13) demonstrated 100% (15/15) normalization of bowel habits after 12 weeks in children aged 6 to 12 months, Bekkali et al (7) reported a 45% treatment success rate after 1 year among all subjects, without specific data for children younger than 24 months of age.
PEG 3350 With Electrolytes Versus PEG4000
Bekkali et al's (7) findings reporting a lower mean daily dose for PEG3350+E than PEG4000 may be attributed to differences in the chemical composition of each agent. The lower molecular weight of PEG3350 increases its hygroscopic action and, in turn, makes it more potent than PEG4000 based on the per gram aspect (28–30).
Bekkali et al (7) also reported that older children used significantly reduced PEG doses. Similarly, one study supported this finding by emphasizing that school-aged children used a lower effective dose after a 12-month period of follow-up (0.4 g/kg compared with 0.8 g · kg−1 · day−1 for infants and toddlers) (31). A previous study conducted in adults has also indicated that a low dose of PEG may be more effective because it has less adverse effects (particularly diarrhea) and starts with an initial dosage of 1 sachet (32). Although the age of participants was different, these findings suggest that PEG is recommended in a lower dose for children.
Based on limited studies, this systematic review has demonstrated a lack of reported side effects from PEG for treatment of pediatric functional constipation in children younger than 24 months. The authors were, however, not able to determine the optimal dose of PEG due to variability in dosage categories across studies. Acknowledging the reported side effects and effectiveness of PEG treatment for this cohort of children, the review suggests there is sufficient evidence to support a dose range that may be titrated to achieve an optimal outcome rather than a precise dose.
The authors would like to thank Poh Chua for her assistance with the systematic literature search; Krithika Sundaram and Anita J Horvath for their guidance during data synthesis; and The Royal Children's Hospital Foundation for their support of the project team.
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