Sahar M.A.Hassanein·Shaymaa M.Deifallah·Hend A.Bastawy

Abstract Background Constipation is a common problem in children with spastic cerebral palsy (sCP) with a prevalence that reaches 75%.We hypothesized that treating constipation in those children will improve their health and shorten time spent in daily care.Our aim was to evaluate the efficacy and safety of oral magnesium sulfate for treating chronic constipation in children with sCP.Methods A prospective,double-blinded randomized control trial was carried out involving 100 children aged 2—12 years with sCP (level III—V of the Gross Motor Functional Classification system) and chronic constipation.They were followed up in the Pediatric neurology clinic,Children’s hospital,Ain Shams University,May 2017-January 2019.The intervention group (O—Mg) received oral magnesium sulfate 1 mL/kg/day daily for 1 month compared to the placebo.Outcome measures were constipation improvement and decrease in bowel evacuation time after 1 month.Results Initially,weekly bowel movements,constipation scores and stool consistency were comparable in both groups.After 1 month of regular administration of oral magnesium sulfate,the constipation score,stool frequency and consistency improved compared to the placebo group (P ＜ 0.001).Effective safe treatment was achieved in 31 (68%) and 4 (9.5%) patients in the O—Mg and placebo groups,respectively (RR,2.95;95% CI 2.0—4.5) (P ＜ 0.001).Painful bowel evacuation attempts spent by mothers decreased from 25 (55.6%) of the cases initially to 10 (22%) cases after one month in the O—Mg group(P =0.001).In contrast,in the placebo group,the decrease went from 21 (50%) cases initially to 18 (42.9%) after 1 month and was not significant (P =0.5).Conclusions Oral magnesium sulfate seems effective in alleviating chronic constipation and pain experience in children with sCP.Consequently,saving maternal time spent in daily bowel evacuation attempts.

Keywords Bristol stool consistency scale·Constipation scale·Gross Motor Functional Classification system·Magnesium sulfate·Painful bowel evacuation·Spasticity

Introduction

Cerebral palsy (CP) is one of the most common causes of motor disability in children.Developing countries have a higher prevalence of CP and a different clinical profile regarding its severity and associated disability [1,2].There are no known treatments for CP,and few neuro-regenerative trials have been reported [3].54% of children with CP have more than one associated disability [4].Up to 75% of children with CP have constipation [5].Constipation commonly occurs in children with CP as a disease process or as a treatment complication,especially in children with multiple severe disabilities [6].Constipation can be caused by reduced mobility,feeding difficulties,or nutritional problems,and it also is a side effect of muscle-relaxing drugs.What adds to the problem is that those children’s fiber and water intake is usually below the required standards and although high doses of laxatives are used yet,they are frequently inadequate to prevent symptoms [5].Constipation is strongly associated with the degree of spasticity in children with CP [7].Constipation has long been considered a symptom,rather than a disease [8].Constipation can be defined as less than three bowel motions per week or as difficulty in passing stools [9].It has been reported that physical therapy,standing and stretching exercises can significantly improve spasticity and constipation in those children [10].

Oral magnesium therapy has been reported to significantly improve spasticity and lower limb range of motion[11].In animal studies,magnesium increased the availability of glucose in the peripheral and central nervous systems and increased the clearance of muscle lactate during exercise[12].Magnesium sulfate has been proven to promote cognitive abilities in humans [13].It reduces the need for intraoperative neuromuscular blocking agents and postoperative analgesia in children with CP [14].Magnesium is accepted as a standard treatment for constipation,but there are few studies to prove its effectiveness in children [15].

We hypothesized that treating constipation will save caregiver’s time spent in child daily care and will increase family time together.Our aim was to evaluate the efficacy and safety of oral magnesium sulfate for treating chronic constipation in children with spastic cerebral palsy (sCP).We also aimed to evaluate the effect of this treatment on decreasing time spent in bowel evacuation attempts.

Methods

Design

Participants

A randomized,placebo-controlled,double-blinded intervention was designed.The study was performed in children with sCP in the Pediatrics Neurology Outpatient Clinic,Faculty of Medicine,Ain Shams University from May 2017 to January 2019.

Children aged 2—12 years with sCP (level III—V of the Gross Motor Functional Classification system) [16],and meeting constipation criteria in neurologically disabled children were included in the study.Children with known organic etiology of constipation,congenital gastrointestinal malformations,inflammatory bowel disease,inborn errors of metabolism,impaired renal function and non-compliant were excluded.The diagnosis of constipation was based on“criteria for diagnosing constipation in neurologically disabled children”[5].Presence of hard stools for at least 2 months:either (A) hard stools in over a half of defecations;or (B) hard stools in over a quarter of defecations plus one of the following:(1) a defecation frequency of less than three times per week;(2) a large fecal mass palpable on abdominal examination;(3) laxative use or manual disimpaction of feces [5,15].Bristol Stool Consistency Scale(BSS) was used to assess stool forms.BSS (types 1—2,hard stools;types 3—5,normal stool form;types 6—7,loose/liquid).Parents were asked to choose the BSS stool type that best represented their children’s stools on a picture chart that was provided to them.Fecal impaction was defined as a hard-palpable lower abdomen mass,a large amount of stool on rectal examination,or excessive stool in the distal colon on abdominal radiography [17].

The mothers were asked to record stool frequency,consistency and the time spent on bowel care each day in a 2-week bowel diary provided to them.If they spent more than 2 hours per day on stool evacuation attempts (inserting suppositories,performing abdominal massage,positioning the child on the toilet,etc.),these were considered to be painful procedures to the child and a burden on the caregiver/family.Assessments were recorded for all children at baseline and after one month.

Interventions

One hundred children with sCP were randomly assigned to either the intervention group [oral magnesium sulfate(O—Mg) group;n=50]or the placebo group (control;n=50).The intervention group received oral magnesium sulfate solution 4% (4 mg elemental magnesium per milliliter solution).A daily morning dose of 1 mL/kg/day given for 1 month.The calculated dose did not exceed magnesium upper intake limits (65 mg/day for normal infants and children aged 1—3 years,110 mg/day for children 3—8 years and 350 mg/day for children above 9 years) [18].An equivalent saline solution in similar container was given to the placebo group.The included children kept their regular treatment protocol,which included regular physiotherapy sessions,muscle relaxants and anticonvulsants when needed.

Improvement was considered if the weekly number of defecations reached ≥ 3 and if softening in the stool consistency (BSS ≥ 3 and ＜ 6 score) occurred after one month.A decrease in frequency of stool evacuation attempts (more than 2 hours per day) also was considered as evidence of improvement.

Outcome measures

The primary outcome measure was improvement in defecation frequency and stool consistency after one month.The secondary outcome was a decrease in time spent by the mother in bowel evacuation attempts (more than 2 hours per day).

Sample size calculation

The sample size was calculated to include 41 children in each group,with expected treatment success rates after one month of 45% and 75% in the placebo and O—Mg intervention groups,respectively (alpha 0.05,power 0.80).Fifty children were included in each group to compensate for the expected 10% non-compliance or dropout by the patients.

Randomization and blinding

After fulfilling the inclusion criteria checked for by the concerned neurologist and nurse,all the eligible patients’ file numbers were entered in a computer program to randomly choose the calculated number of patients to participate in the study (100 patients).Study investigators,treating clinicians,nurses and patients were masked to treatment assignment.Participants were randomly allocated (1:1) to sequentially numbered identical containers prepared by the pharmacist filled with either magnesium sulfate solution or placebo by the use of a computer-generated random software.

Ethical considerations

All the study steps followed the ethical standards of the Declaration of Helsinki 1975.The study was explained in detail to the participating caregivers and to children when applicable.A written consent for participation and permission to publish the results was signed by all the included caregivers.The study was approved by the Ethics Committee of Faculty of Medicine,Ain Shams University (IRB:FMASU MS 5/2015).Furthermore,it was registered in Clinical Trial of the National Institutes of Health with ClinicalTrials.gov identifier number:NCT02510222.

Fig.1 Flow diagram of the study design

Statistical analysis

Data analysis was conducted using SPSS (version 18.0,IBM Corporation,Armonk,NY,USA).A two-samplettest and a pairedttest were each used to compare quantitatively measured parameters,whereas a chi-squared test was used to compare qualitatively parameters.Multinomial logistic regression was used to measure the effect of intervention on change of patient outcomes after one month.Odds ratios and their (95% CI),and relative risk (RR) of constipation after intervention were presented.The threshold for statistical significance was set atP＜ 0.05.

Results

The O—Mg group initially included 50 sCP children.Two children were non-compliant,and three were lost to followup.The placebo group also initially included 50 sCP children;four were lost to follow-up,and four were excluded due to poor compliance.Therefore,87 out of 100 children completed the study,which comprised the O—Mg group (n=45)and the placebo group (n=42) (Fig.1).The children in both groups were comparable in ages (P=0.35),sexes (P=0.91),and weights (P=0.48) (Table 1).

Initially,there was no difference in the constipation score between treatment groups:(O—Mg,25 (55.6%) scale A,20 (44.4%) scale B versus placebo 23 (54.8%) scale A,19 (45.2%) scale B (P=0.94) (Fig.2).Weekly stool frequency was 26 (57.8%) once/week,17 (37.8%) twice/week,2 (4.4%) thrice/week in the O—Mg group compared to 23 (54.8%),16 (38.1%),and 3 (7.1%) in the placebo group(P=0.86).The mean numbers of weekly bowel movements also were comparable initially (mean ± SD=1.47 ± 0.59 per week) for the O—Mg group,and (mean ± SD=1.52 ± 0.63 per week) for the placebo (P=0.33).Bristol stool consistency score 35 (34.14%) children were BSS-1,8 (8.79%)BSS-2,2 (2.07%) BSS-3 for the O—Mg group compared to 31 (31.86%) BSS-1,9 (8.21%) BSS-2,2 (1.93%) BSS-3 for the placebo group (P=0.91) (Tables 1 and 2).

After 1 month,there was significant improvement in the constipation score,in the O—Mg group where 8 (17.8%)of children were scale A,6 (13.3%) were scale B,and 31 (68.9%) experienced no constipation.In contrast,in the placebo group,20 (47.6%) of the children were scale A,18 (42.9%) were scale B,and 4 (9.5%) experienced no constipation (P＜ 0.001).Treatment was more effective for 31/45(68.9%) of the sCP children receiving O—Mg and that for 4/42 (9.5%) of the children in the placebo group (RR,2.95;95% CI 2.0—4.5) (P＜ 0.001) (Fig.2).

The number of weekly bowel movements increased to(mean ± SD,4.04 ± 1.69) in the O—Mg group compared to the placebo group (mean ± SD,2.29 ± 0.67) after 1 month(P＜ 0.001).Weekly bowel movements increased after 1 month compared to initial data in the O—Mg therapy(P＜ 0.001) and in the placebo group (P=0.001).After 1 month,a weekly stool frequency ≤ 2 was observed in 11 (24.4%) children and a frequency ≥ 3 was observed in 34 (75.6%) children in the O—Mg group.By comparison,a stool frequency ≤ 2 was observed in 33 (78.6%) children and a frequency ≥ 3 was observed in 9 (21.4%) children in the placebo group (P＜ 0.001).After 1 month,BSS ≤ 2 was observed in 4 (8.9%) children and BSS ≥ 3 was observed in 41 (91.1%) children in the O—Mg group.By comparison,BSS ≤ 2 was observed in 28 (66.6%) children and BSS ≥ 3 was observed in 14 (33.4%) children in the placebo group(P＜ 0.001).Odds ratios in multinomial logistic regression were significantly lower than one for all outcomes.These ratios implied that the placebo group was less likely than the intervention group to achieve improvement in outcome measures,in bowel frequency,in constipation scores and in Bristol scores after 1 month (P＜ 0.001,Table 3).

Initially,25 (55.6%) of mothers spent more than 2-hour per day on painful bowel evacuation attempts in the O—Mg group,whereas 21 (50%) of mothers in the placebo group did so (P=0.6).However,after 1 month,the proportion decreased to 10 (22%) of mothers in the O—Mg group and to 18 (42.9%)of mothers in the placebo group (P=0.03,Table 2).Major adverse effects were not reported in this study.

Discussion

In the present study,oral magnesium sulfate resulted in a significant improvement in constipation score,stool consistency and frequency after 1 month.The effectiveness of oral magnesium in treating constipation was reported.In adult women with functional constipation,the daily consumption of 1 l of natural mineral waterrich in magnesium reduced constipation and reduced hard or lumpy stools [19].Oral magnesium therapy improved health-related quality of life in children and in adults with chronic FC [22].Magnesium significantly increased duodeno-caecal transit time and fecal fat and weight [23].Although hypermagnesemia is the most important side effect of oral magnesium therapy [20],we did not report any major side effects related to magnesium therapy as all patients included had normal renal functions.Studies in children with functional constipation (FC) confirmed the safety and efficacy of oral magnesium for treating constipation,and reported no side effects due to hypermagnesemia [21].

In the present study,the use of a single effective medication,oral magnesium sulfate,to treat chronic constipation and to alleviate painful evacuations ensuresadherence to treatment.Studies in healthy children with FC reported low adherence rates to drug treatment [24].Parents reported low adherence rates in their children with FC due to treatment inconvenience and to dissatisfaction with treatment [25].Chronic constipation in CP children is difficult to treat.Multiple drugs were needed to have a therapeutic effect for chronic constipation among CP children.In these cases,treatments combined polyethylene glycol 0.5 g/kg/dose and domperidone 0.2 mg/kg/dose,three times daily,for 2 weeks to achieve effective treatment [26].

Table 1 Demographic characteristics and initial clinical data of the two groups

In the present study,painful experience of manual bowel evacuation attempts caused physical and psychological stress for children with CP and for their families.Alleviating constipation,decreasing pain and time in bowel evacuation positively affected the life of the whole family.Constipation relief improved quality-of-life aspects,such as sleep,appetite,and irritability,and significantly decreased rectal bleeding,anal fissure,crying,and painful defecation [27].A study related maternal psychological problems to mothers spent an average of 6.0 hours per day on weekdays and 8.3 hours per day on weekends caring for their children with CP [28].

In children with multiple disabilities,the impact of chronic constipation on HRQoL is higher.

Fig.2 Constipation scores for the O—Mg and placebo groups before and 1 month after intervention.*Mg-sulfate treatment was effective (RR,2.95;95% CI 2.0—4.5) (P ＜ 0.001)

Table 2 Comparison between intervention and placebo groups for stool frequency and consistency

Therefore,relief of constipation,pain and saving of time will positively affect the life of the whole family.

The study has several limitations.Firstly,the sample size is samll.However,because this is a pilot study,our results should be evaluated for larger populations to be generalized.Secondly,safety data after prolonged treatment for one year were not studied.

In conclusion,this study may show that oral magnesium sulfate was effective in the treatment of chronic constipation in children with sCP.It decreased pain experienced by children and decreased time spent by mothers in bowel evacuation attempts.

Table 3 Multinomial regression analysis comparing the O—Mg and placebo groups,initial and after onemonth for change in frequency of defecation per week,change in constipation score,and change in Bristol score

AcknowledgementsThe authors are grateful to the clinical pharmacology team who performed the blinding and prepared the oral solution.

Author contributionsAll the authors have finally reviewed the manuscript and agreed to its being submitted for publication.All individuals listed as authors meet the appropriate authorship criteria;nobody who qualifies for authorship has been omitted from the list.SMAH:research idea,patient follow-up,data collection,and writing the manuscript;SMD:clinical follow-up,data collection and writing;HB:data collection,and statistical analysis.

FundingThe authors received no financial support.

Compliance with ethical standards

Ethical approvalThe study was approved by the Ethics Committee of Faculty of Medicine,Ain Shams University (IRB:FMASU MS 5/2015),Furthermore,it was registered in Clinical Trial of the National Institutes of Health with ClinicalTrials.gov identifier number:NCT02510222.

Conflict of interestThe authors declare no financial or nonfinancial benefits have been received or will be received from any party related directly or indirectly to the subject of this article.