Efficacy and safety of switching from intravenous to oral antibiotics (amoxicillin-clavulanic acid) versus a full course of intravenous antibiotics in neonates with probable bacterial infection (RAIN): a multicentre, randomised, open-label, non-inferiority trial.

BACKGROUND: Switching from intravenous antibiotic therapy to oral antibiotic therapy among neonates is not yet practised in high-income settings due to uncertainties about exposure and safety. We aimed to assess the efficacy and safety of early intravenous-to-oral antibiotic switch therapy compared with a full course of intravenous antibiotics among neonates with probable bacterial infection. METHODS: In this multicentre, randomised, open-label, non-inferiority trial, patients were recruited at 17 hospitals in the Netherlands. Neonates (postmenstrual age ≥35 weeks, postnatal age 0-28 days, bodyweight ≥2 kg) in whom prolonged antibiotic treatment was indicated because of a probable bacterial infection, were randomly assigned (1:1) to switch to an oral suspension of amoxicillin 75 mg/kg plus clavulanic acid 18·75 mg/kg (in a 4:1 dosing ratio, given daily in three doses) or continue on intravenous antibiotics (according to the local protocol). Both groups were treated for 7 days. The primary outcome was cumulative bacterial reinfection rate 28 days after treatment completion. A margin of 3% was deemed to indicate non-inferiority, thus if the reinfection rate in the oral amoxicillin-clavulanic acid group was less than 3% higher than that in the intravenous antibiotic group the null hypothesis would be rejected. The primary outcome was assessed in the intention-to-treat population (ie, all patients who were randomly assigned and completed the final follow-up visit on day 35) and the per protocol population. Safety was analysed in all patients who received at least one administration of the allocated treatment and who completed at least one follow-up visit. Secondary outcomes included clinical deterioration and duration of hospitalisation. This trial was registered with ClinicalTrials.gov, NCT03247920, and EudraCT, 2016-004447-36. FINDINGS: Between Feb 8, 2018 and May 12, 2021, 510 neonates were randomly assigned (n=255 oral amoxicillin-clavulanic group; n=255 intravenous antibiotic group). After excluding those who withdrew consent (n=4), did not fulfil inclusion criteria (n=1), and lost to follow-up (n=1), 252 neonates in each group were included in the intention-to-treat population. The cumulative reinfection rate at day 28 was similar between groups (one [<1%] of 252 neonates in the amoxicillin-clavulanic acid group vs one [<1%] of 252 neonates in the intravenous antibiotics group; between-group difference 0 [95% CI -1·9 to 1·9]; pnon-inferiority<0·0001). No statistically significant differences were observed in reported adverse events (127 [50%] vs 113 [45%]; p=0·247). In the intention-to-treat population, median duration of hospitalisation was significantly shorter in the amoxicillin-clavulanic acid group than the intravenous antibiotics group (3·4 days [95% CI 3·0-4·1] vs 6·8 days [6·5-7·0]; p<0·0001). INTERPRETATION: An early intravenous-to-oral antibiotic switch with amoxicillin-clavulanic acid is non-inferior to a full course of intravenous antibiotics in neonates with probable bacterial infection and is not associated with an increased incidence of adverse events. FUNDING: The Netherlands Organization for Health Research and Development, Innovatiefonds Zorgverzekeraars, and the Sophia Foundation for Scientific Research.

Gut-directed hypnotherapy versus standard medical treatment for nausea in children with functional nausea or functional dyspepsia: protocol of a multicentre randomised trial.

INTRODUCTION: The treatment of chronic functional nausea or nausea due to functional dyspepsia in children is generally symptomatic. Moreover, these disorders pose a risk for worse psychosocial and health outcomes in children. Hypnotherapy (HT), by its ability to positively influence gastrointestinal and psychosocial functioning, may be an effective treatment for chronic nausea. METHODS AND ANALYSIS: To test efficacy, this multicentre, parallel, randomised controlled, open label trial evaluates whether gut-directed HT is superior to standard medical treatment (SMT) for reducing nausea. The study will be conducted at eleven academic and non-academic hospitals across the Netherlands. A total of 100 children (8-18 years), fulfilling the Rome IV criteria for chronic idiopathic nausea or functional dyspepsia with prominent nausea, will be randomly allocated (1:1) to receive HT or SMT. Children allocated to the HT group will receive six sessions of HT during 3 months, while children allocated to the SMT group will receive six sessions of SMT+supportive therapy during the same period. The primary outcome will be the difference in the proportion of children with at least 50% reduction of nausea, compared with baseline at 12 months' follow-up. Secondary outcomes include the changes in abdominal pain, dyspeptic symptoms, quality of life, anxiety, depression, school absences, parental absence of work, healthcare costs and adequate relief of symptoms, measured directly after treatment, 6 and 12 months' follow-up. If HT proves effective for reducing nausea, it may become a new treatment strategy to treat children with chronic functional nausea or functional dyspepsia with prominent nausea. ETHICS AND DISSEMINATION: Results of the study will be publicly disclosed to the public, without any restrictions, in peer-reviewed journal and international conferences. The study is approved by the Medical Research Ethics Committees United (MEC-U) in the Netherlands. TRIAL REGISTRATION NUMBER: NTR5814.

Prevalence of functional constipation among Palestinian preschool children and the relation to stressful life events.

AIM: Increasing evidence exists with respect to the relation between stressful life events and functional constipation (FC). We aimed to investigate the prevalence of FC in Palestinian refugee preschool children and to determine if stress and trauma exposure are risk factors of FC in these children. METHODS: From November 2013 until May 2014, a cross-sectional survey was conducted in West Bank, Gaza and Jordan. Mothers of 862 Palestinian refugee children aged 7-48 months were interviewed on defecation pattern, socio-economic factors and the child's exposure to traumatic events. RESULTS: Twelve percent of the Palestinian refugee children fulfilled the criteria for FC. The prevalence of constipation was significantly lower in Gaza compared to Jordan (2% vs. 17%, p <0,001). Living in Gaza was associated with lower odds of FC (OR 0,08, 95% CI 0,03-0,20). Trauma exposure was associated with higher odds of FC (OR 1,19, 95% CI 1,06-1,35), however only a small number of children had been exposed to traumatic events. CONCLUSION: The overall prevalence of FC in Palestinian preschool children is comparable to prevalence rates among older children worldwide. In this age group stressful life events and trauma exposure seem not to play an important role in the development of FC.

Stalled decline in infant mortality among Palestine refugees in the Gaza Strip since 2006.

BACKGROUND: The United Nations Relief and Works Agency for Palestine refugees in the Near East (UNRWA) has periodically estimated infant mortality rates (IMR) among Palestine refugees in the Gaza Strip (Gaza). These surveys have recorded a decline from 127 per 1000 live births in 1960 to 20.2 in 2006. Thereafter, a survey revealed an IMR of 22.4 in 2011. Alerted by these findings, a follow up survey was conducted in 2015 to further assess the trend of IMR. METHODS: We used the same preceding-birth technique as in previous surveys to estimate IMR and neonatal mortality rate (NMR) per 1000 live births. All multiparous mothers who came to the 22 UNRWA health centers to register their last-born child for immunization were asked if their preceding child was alive or dead. We based our target sample size on the previous IMR of 22.4 and we interviewed 3126 mothers from September to November 2015. FINDINGS: The third survey estimated mortality rates in 2013. The IMR was 22.7 (95% CI 17.2-28.1) per 1000 live births. IMR did not decline since the estimated IMR of 20.2 (15.3-25.1) per 1000 live births in 2006 and 22.4 (16.4-28.3) per 1000 live births in 2011. NMR was 16.1 (11.6-20.7) per 1000 live births, which was not statistically significantly different from 2006 (12.1 (8.7-16.4)), and was lower than in 2011 (20.3 (15.3-26.2)). CONCLUSION: The estimated mortality rate in infants of Palestine refugees in Gaza has not declined since 2006. The stagnation of infant mortality rates indicates that further efforts are needed to investigate causes for this stagnation and ways of addressing the potentially preventable causes among Palestine refugee children in Gaza.

Increasing Neonatal Mortality among Palestine Refugees in the Gaza Strip.

BACKGROUND: The United Nations Relief and Works Agency for Palestine refugees in the Near East (UNRWA) has periodically estimated infant mortality rates among Palestine refugees in Gaza. These surveys have recorded a decline from 127 per 1000 live births in 1960 to 20.2 in 2008. METHODS: We used the same preceding-birth technique as in previous surveys. All multiparous mothers who came to the 22 UNRWA health centres to register their last-born child for immunization were asked if their preceding child was alive or dead. We based our target sample size on the infant mortality rate in 2008 and included 3128 mothers from August until October 2013. We used multiple logistic regression analyses to identify predictors of infant mortality. FINDINGS: Infant mortality in 2013 was 22.4 per 1000 live births compared with 20.2 in 2008 (p = 0.61), and this change reflected a statistically significant increase in neonatal mortality (from 12.0 to 20.3 per 1000 live births, p = 0.01). The main causes of the 65 infant deaths were preterm birth (n = 25, 39%), congenital anomalies (n = 19, 29%), and infections (n = 12, 19%). Risk factors for infant death were preterm birth (OR 9.88, 3.98-24.85), consanguinity (2.41, 1.35-4.30) and high-risk pregnancies (3.09, 1.46-6.53). CONCLUSION: For the first time in five decades, mortality rates have increased among Palestine refugee newborns in Gaza. The possible causes of this trend may include inadequate neonatal care. We will estimate infant and neonatal mortality rates again in 2015 to see if this trend continues and, if so, to assess how it can be reversed.

No role for increased rectal compliance in pediatric functional constipation.

BACKGROUND & AIMS: Increased rectal compliance has been proposed to contribute to pediatric functional constipation (FC). We evaluated the clinical relevance of increased rectal compliance and assessed whether regular use of enemas improves rectal compliance in children with FC. METHODS: A prospective longitudinal study was conducted on children (8-18 years old) with FC. Pressure-controlled rectal distensions were performed at baseline and at 1 year. Rectal compliance was categorized into 3 groups: normal, moderately increased, or severely increased. Patients were randomly assigned to groups given conventional therapy or rectal enemas and conventional therapy. Clinical success was defined as >or=3 spontaneous defecations per week and fecal incontinence <1 per week. RESULTS: Baseline measurements were performed in 101 children (11.0 +/- 2.1 years); rectal compliance was normal in 36%, moderately increased in 40%, and severely increased in 24%. Patients with severely increased rectal compliance had lower defecation frequency (P = .03), more fecal incontinence (P = .04), and more rectal fecal impaction (P < .001). After 1 year, success values were similar between groups: 42% normal, 41% moderately increased, and 40% with severely increased compliance. Barostat studies performed after 1 year in 80 children (37 conventional therapy and 43 rectal enemas in addition to conventional therapy) revealed that rectal compliance had not changed in either group and had not improved in successfully treated patients. CONCLUSIONS: Constipated children with severely increased rectal compliance have severe symptoms. However, increased rectal compliance is not related to treatment failure. Regular use of enemas to avoid rectal fecal impaction does not improve rectal compliance in pediatric FC.

A randomized controlled trial of enemas in combination with oral laxative therapy for children with chronic constipation.

BACKGROUND & AIMS: After 5 years of intensive oral laxative use, up to 30% of constipated children still have an unsuccessful outcome. Children refractory to oral laxatives might benefit from regular rectal evacuation by enemas. This randomized controlled trial compared the effects of additional treatment with rectal enemas (intervention) with conventional treatment alone (oral laxatives, control) in severely constipated children. METHODS: In a tertiary hospital in the Netherlands, 100 children, aged 8-18 years, with functional constipation for at least 2 years were randomly assigned to intervention or control groups. The control group received education, behavioral strategies, and oral laxatives. The intervention group was also given 3 rectal enemas/week, reduced by 1 enema/week every 3 months. Outcome measures were defecation and fecal incontinence frequency and overall success at 12, 26, 39, and 52 weeks. Overall success was defined as 3 or more defecations/week and less than 1 fecal incontinence episode/week, irrespective of laxative use. RESULTS: Defecation frequency normalized in both groups but was significantly higher in the intervention group compared with controls at 26 and 52 weeks (5.6 vs 3.9/week, P = .02, and 5.3 vs 3.9/week, P = .02, respectively). There were no significant differences between groups in reduction of fecal incontinence episodes (P = .49) and overall success rates (P = .67). After 1 year of treatment, the overall success rate was 47.1% in the intervention group versus 36.1% in the control group. CONCLUSIONS: There is no additional effect of enemas compared with oral laxatives alone as maintenance therapy for severely constipated children.

The role of a probiotics mixture in the treatment of childhood constipation: a pilot study.

BACKGROUND: Inconsistent data exist about the efficacy of probiotics in the treatment of constipation. Several studies in adults with constipation showed positive effects of probiotics on constipation. Inconsistent data exist regarding the effect of a single probiotic strain in constipated children. The aim of this pilot study was to determine the effect of a mixture of probiotics containing bifidobacteria and lactobacilli in the treatment of childhood constipation. METHODS: Children aged 4-16 years with constipation as defined by the Rome III criteria were eligible for the study. During a 4 week period, children received a daily mix of 4 x 109 colony forming units of a probiotic mixture (Ecologic(R)Relief) containing Bifidobacteria (B.) bifidum, B. infantis, B. longum, Lactobacilli (L.) casei, L. plantarum and L. rhamnosus. Primary outcome measures were frequency of bowel movements (BMs) per week and stool consistency. Secondary outcome measures were number of faecal incontinence episodes per week, abdominal pain and side effects. RESULTS: Twenty children, 50% male, median age 8 (range 4-16) were included. The frequency of BMs per week increased from 2.0 (1.0-5.0) to 4.2 (0.0-16.0) in week 2 (p = 0.10) and 3.8 (2.1-7.0) in week 4 (p = 0.13). In 12 children presenting with <3 BMs/week, BMs per week increased significantly from 1.0 (0.0-2.0) to 3.0 (0.0-7.0) in week 2 (p = 0.01) and 3.0 (0.0-10.0) in week 4 (p = 0.01). The stool consistency was reported as hard in 7 children at baseline, in 4 children at week 2 (p = 0.23) and in 6 children after 4 weeks of treatment (p = 1.00). A significant decrease in number of faecal incontinence episodes per week was found in the entire group: 4.0 (0.0-35.0) to 1.5 (0.0-14.0) in week 2 (p = 0.01) and 0.3 (0.0-7.0) in week 4 (p = 0.001). The presence of abdominal pain decreased significantly from 45% to 25% in week 2 (p = 0.04) and 20% at week 4 (p = 0.006). No side effects were reported. CONCLUSION: This pilot study shows that a mixture of probiotics, has positive effects on symptoms of constipation. To confirm these findings, a large randomised placebo controlled trial is required.

Epidemiology of childhood constipation: a systematic review.

OBJECTIVE: A systematic review of the published literature was performed to assess the prevalence, incidence, natural history, and comorbid conditions of functional constipation in children. METHODS: Articles were identified through electronic searches in Medline, Embase, Cochrane Central Library, Cinhal and PsychInfo databases. Study selection criteria included: (1) epidemiology studies of general population, (2) on the prevalence of constipation without obvious organic etiology, (3) in children from 0 to 18 yr old, and (4) published in English and full manuscript form. RESULTS: Eighteen studies met our inclusion criteria. The prevalence of childhood constipation in the general population ranged from 0.7% to 29.6% (median 8.9; inter quartile range 5.3-17.4). The prevalence of constipation defined as defecation frequency of < 3/wk varied from 0.7% to 29.6% (median 10.4; inter quartile range 1.3-21.3). Identified studies originated from North America (N = 4), South America (N = 2), Europe (N = 9), the Middle-East (N = 1), and Asia (N = 2). Variance of gender specific prevalence was reported in seven studies and five of seven studies reported no significant difference between boys and girls. The age group in which constipation is most common could not be assessed with certainty. Socioeconomic factors were not found to be associated with constipation. CONCLUSION: Childhood constipation is a common problem worldwide. Most studies report similar prevalence rates for boys and girls. Large epidemiologic studies with the use of generally accepted diagnostic criteria are needed to define the precise prevalence of constipation.

Barostat testing in children with functional gastrointestinal disorders.

Children and adolescents with chronic defecation disorders and chronic abdominal pain without obvious organic etiology form a challenging group of patients for pediatric health-care professionals. The pathophysiologic mechanisms underlying such functional gastroenterology disorders are poorly understood. Research studies on the use of the barostat have been aimed to increase our knowledge in this area. Barostat testing allows defining visceral hyper- or hyposensitivity, contractility, and compliance of the gut. This review focuses on rectal barostat studies performed in children with abdominal pain, constipation, and fecal incontinence.

Colonic manometry as predictor of cecostomy success in children with defecation disorders.

PURPOSE: The aim of this study was to define the predictive value of colonic manometry and contrast enema before cecostomy placement in children with defecation disorders. METHODS: Medical records, contrast enema, and colonic manometry studies were reviewed for 32 children with defecation disorders who underwent cecostomy placement between 1999 and 2004. Diagnoses included idiopathic constipation (n = 13), Hirschsprung's disease (n = 2), cerebral palsy (n = 1), imperforate anus (n = 6), spinal abnormality (n = 6), and anal with spinal abnormality (n = 4). Contrast enemas were evaluated for the presence of anatomic abnormalities and the degree of colonic dilatation. Colonic manometry was considered normal when high-amplitude propagating contractions (HAPC) occurred from proximal to distal colon. Clinical success was defined as normal defecation frequency with no or occasional fecal incontinence. RESULTS: Colonic manometry was done on 32 and contrast enema on 24 patients before cecostomy. At follow-up, 25 patients (78%) fulfilled the success criteria. Absence of HAPC throughout the colon was related to unsuccessful outcome (P = .03). Colonic response with normal HAPC after bisacodyl administration was predictive of success (P = .03). Presence of colonic dilatation was not associated with colonic dysmotility. CONCLUSION: Colonic manometry is helpful in predicting the outcome after cecostomy. Patients with generalized colonic dysmotility are less likely to benefit from use of antegrade enemas via cecostomy. Normal colonic response to bisacodyl predicts favorable outcome.

Cecostomy in children with defecation disorders.

Administration of antegrade enemas through a cecostomy is a therapeutic option for children with severe defecation disorders. The purpose of this study is to report our 4-year experience with the cecostomy procedure in 31 children with functional constipation (n = 9), Hirschsprung's disease (n = 2), imperforate anus (n = 5), spinal abnormalities (n = 8), and imperforate anus in combination with tethered spinal cord (n = 7). Data regarding complications, antegrade enemas used, symptoms, and quality of life were retrospectively obtained. Placement of cecostomy tubes was successful in 30 of 31 patients. Soiling episodes decreased significantly in children with functional constipation (P = 0.01), imperforate anus (P < 0.01), and spinal abnormalities (P = 0.04). Quality of life improved in patients with functional constipation and imperforate anus. No difference in complications was found between percutaneous and surgical placement. Use of antegrade enemas via cecostomy improved symptoms and quality of life in children with a variety of defecation disorders.