No abstract

Gastroenteritis accounts for nearly 500,000 deaths in children younger than 5 years annually. Although probiotics have been touted as having the potential to expedite diarrhea resolution, recent clinical trials question their effectiveness. A potential explanation is a shift in pathogens following the introduction of a rotavirus vaccine. Here, we report the results of a multi-center, double-blind trial of 816 children with acute gastroenteritis who completed follow-up and provided multiple stool specimens. Participants were randomized to receive a probiotic containing Lactobacillus rhamnosus and Lactobacillushelveticus or placebo. We report no virus-specific beneficial effects attributable to the probiotic, either in reducing clinical symptoms or viral nucleic acid clearance from stool specimens collected up to 28 days following enrollment. We provide pathophysiological and microbiologic evidence to support the clinical findings and conclude that our data do not support routine probiotic administration to children with acute gastroenteritis, regardless of the infecting virus.

BackgroundThe burden of acute gastroenteritis on children and their families continues to be enormous. Probiotics, defined as viable microbial preparations that have a beneficial effect on the health of the host, represent a rapidly expanding field. Although clinical trials in children with gastroenteritis have been performed, most have significant flaws, and guidelines do not consistently endorse their use.Methods/DesignPROGUT is a randomized, placebo-controlled, double-blind, five-center, Canadian, emergency department trial. Children aged 3 months to 48 months who present between November 2013 and June 2017 with <72 hours of gastroenteritis symptoms will be assessed for eligibility. A total of 886 children will be randomized (1:1 allocation via an internet based, third party, randomization service) to receive 5 days of a combination probiotic agent (Lactobacillus rhamnosus and L. helveticus) or placebo. All participants, caregivers, and outcome assessors will be blinded to group assignment. The study includes three key outcomes: 1) clinical - the development of moderate to severe disease following an emergency department (ED) evaluation that employs a validated clinical score (Modified Vesikari Scale); 2) safety - side effect; and 3) mechanism - fecal secretory immunoglobulin A levels.DiscussionDefinitive data are lacking to guide the clinical use of probiotics in children with acute gastroenteritis. Hence, probiotics are rarely prescribed by North American physicians. However, the following current trends obligate an urgent assessment: 1) probiotics are sold as food supplements, and manufacturers can encourage their use while their relevance has yet to be established; 2) North American and European government agencies remain concerned about their value and safety; 3) some institutions are now recommending the routine use of probiotics; and 4) parents of affected children are often providing probiotics. With probiotic consumption increasing in the absence of solid evidence, there is a need to conduct this definitive trial to overcome the limitations of prior work in this field.Trial registrationClinicalTrials.gov: NCT01853124; first registered 9 May 2013.

Study objective We determine whether single-dose oral ondansetron administration to children with vomiting as a result of acute gastroenteritis without dehydration reduces administration of intravenous fluid rehydration. Methods In this 2-hospital, double-blind, placebo-controlled, emergency department–based, randomized trial conducted in Karachi Pakistan, we recruited children aged 0.5 to 5.0 years, without dehydration, who had diarrhea and greater than or equal to 1 episode of vomiting within 4 hours of arrival. Patients were randomly assigned (1:1), through an Internet-based randomization service using a stratified variable-block randomization scheme, to single-dose oral ondansetron or placebo. The primary endpoint was intravenous rehydration (administration of ≥20 mL/kg of an isotonic fluid during 4 hours) within 72 hours of randomization. Results Participant median age was 15 months (interquartile range 10 to 26) and 59.4% (372/626) were male patients. Intravenous rehydration use was 12.1% (38/314) and 11.9% (37/312) in the placebo and ondansetron groups, respectively (odds ratio 0.98; 95% confidence interval [CI] 0.60 to 1.61; difference 0.2%; 95% CI of the difference –4.9% to 5.4%). Bolus fluid administration occurred within 72 hours of randomization in 10.8% (34/314) and 10.3% (27/312) of children administered placebo and ondansetron, respectively (odds ratio 0.95; 95% CI 0.56 to 1.59). A multivariable regression model fitted with treatment group and adjusted for antiemetic administration, antibiotics, zinc prerandomization, and vomiting frequency prerandomization yielded similar results (odds ratio 0.91; 95% CI 0.55 to 1.53). There was no interaction between treatment group and age, greater than or equal to 3 stools in the preceding 24 hours, or greater than or equal to 3 vomiting episodes in the preceding 24 hours. Conclusion Oral administration of a single dose of ondansetron did not result in a reduction in intravenous rehydration use. In children without dehydration, ondansetron does not improve clinical outcomes.

Background/aims Despite evidence that preferential use of balanced/buffered fluids may improve outcomes compared with chloride-rich 0.9% saline, saline remains the most commonly used fluid for children with septic shock. We aim to determine if resuscitation with balanced/buffered fluids as part of usual care will improve outcomes, in part through reduced kidney injury and without an increase in adverse effects, compared to 0.9% saline for children with septic shock. Methods The Pragmatic Pediatric Trial of Balanced versus Normal Saline Fluid in Sepsis (PRoMPT BOLUS) study is an international, open-label pragmatic interventional trial being conducted at > 40 sites in the USA, Canada, and Australia/New Zealand starting on August 25, 2020, and continuing for 5 years. Children > 6 months to < 18 years treated for suspected septic shock with abnormal perfusion in an emergency department will be randomized to receive either balanced/buffered crystalloids (intervention) or 0.9% saline (control) for initial resuscitation and maintenance fluids for up to 48 h. Eligible patients are enrolled and randomized using serially numbered, opaque envelopes concurrent with clinical care. Given the life-threatening nature of septic shock and narrow therapeutic window to start fluid resuscitation, patients may be enrolled under “exception from informed consent” in the USA or “deferred consent” in Canada and Australia/New Zealand. Other than fluid type, all decisions about timing, volume, and rate of fluid administration remain at the discretion of the treating clinicians. For pragmatic reasons, clinicians will not be blinded to study fluid type. Anticipated enrollment is 8800 patients. The primary outcome will be major adverse kidney events within 30 days (MAKE30), a composite of death, renal replacement therapy, and persistent kidney dysfunction. Additional effectiveness, safety, and biologic outcomes will also be analyzed. Discussion PRoMPT BOLUS will provide high-quality evidence for the comparative effectiveness of buffered/balanced crystalloids versus 0.9% saline for the initial fluid management of children with suspected septic shock in emergency settings. Trial registration PRoMPT BOLUS was first registered at ClinicalTrials.gov (NCT04102371) on September 25, 2019. Enrollment started on August 25, 2020.

BACKGROUND:Ondansetron is an effective antiemetic employed to prevent vomiting in children with gastroenteritis in high-income countries; data from low-and middle-income countries are sparse. METHODS:We conducted a randomized, double-blind, placebo-controlled superiority trial in 2 pediatric emergency departments in Pakistan. Dehydrated children aged 6 to 60 months with $1 diarrheal (ie, loose or liquid) stool and $1 vomiting episode within the preceding 4 hours were eligible to participate. Participants received a single weight-based dose of oral ondansetron (8-15 kg: 2 mg; .15 kg: 4 mg) or identical placebo. The primary outcome was intravenous administration of $20 mL/kg over 4 hours of an isotonic fluid within 72 hours of random assignment.RESULTS: All 918 (100%) randomly assigned children completed follow-up. Intravenous rehydration was administered to 14.7% (68 of 462) and 19.5% (89 of 456) of those administered ondansetron and placebo, respectively (difference: 24.8%; 95% confidence interval [CI], 29.7% to 0.0%). In multivariable logistic regression analysis adjusted for other antiemetic agents, antibiotics, zinc, and the number of vomiting episodes in the preceding 24 hours, children administered ondansetron had lower odds of the primary outcome (odds ratio: 0.70; 95% CI, 0.49 to 1.00). Fewer children in the ondansetron, relative to the placebo group vomited during the observation period (difference: 212.9%; 95% CI, 218.0% to 27.8%). The median number of vomiting episodes (P , .001) was lower in the ondansetron group.CONCLUSIONS: Among children with gastroenteritis-associated vomiting and dehydration, oral ondansetron administration reduced vomiting and intravenous rehydration use. Ondansetron use may be considered to promote oral rehydration therapy success among dehydrated children in low-and middle-income countries.WHAT'S KNOWN ON THIS SUBJECT: Ondansetron administration to dehydrated children with gastroenteritis-associated vomiting in emergency departments in high-income countries reduces vomiting and intravenous rehydration. Although it is ineffective among well-hydrated children, evidence of efficacy in dehydrated children in low-and middle-income countries is lacking.WHAT THIS STUDY ADDS: Emergency department oral ondansetron administration to dehydrated children with gastroenteritis-associated vomiting in Pakistan safely reduces intravenous rehydration fluid administration and vomiting, and it should be considered to promote oral rehydration therapy in this population.

Background We previously conducted the Probiotic Regimen for Outpatient Gastroenteritis Utility of Treatment (PROGUT) study, which identified no improvements in children with acute gastroenteritis (AGE) administered a probiotic. However, the aforementioned study did not evaluate immunomodulatory benefits. Objectives The object of this study was to determine if stool secretory immunoglobulin A (sIgA) concentrations in children with AGE increase more among participants administered a Lactobacillus rhamnosus / helveticus probiotic compared with those administered placebo. Methods This a priori planned multicenter, randomized, double-blinded, placebo-controlled ancillary study enrolled children presenting for emergency care who received a 5-d probiotic or placebo course. Participants submitted stool specimens on days 0, 5, and 28. The primary endpoint was the change in stool sIgA concentrations on day 5 compared with baseline. Results A total of 133 ( n = 66 probiotic, 67 placebo) of 886 PROGUT participants (15.0%) provided all 3 specimens. Median stool sIgA concentrations did not differ between the probiotic and placebo groups at any of the study time points: day 0 median (IQR): 1999 (768, 4071) compared with 2198 (702, 5278) ( P = 0.27, Cohen's d = 0.17); day 5: 2505 (1111, 5310) compared with 3207 (982, 7080) ( P = 0.19, Cohen's d = 0.16); and day 28: 1377 (697, 2248) compared with 1779 (660, 3977) ( P = 0.27, Cohen's d = 0.19), respectively. When comparing measured sIgA concentrations between days 0 and 5, we found no treatment allocation effects [β: −0.24 (−0.65, 0.18); P = 0.26] or interaction between treatment and specimen collection day [β: −0.003 (−0.09, 0.09); P = 0.95]. Although stool sIgA decreased between day 5 and day 28 within both groups ( P < 0.001), there were no differences between the probiotic and placebo groups in the median changes in sIgA concentrations when comparing day 0 to day 5 median (IQR) [500 (−1135, 2362) compared with 362 (−1122, 4256); P = 0.77, Cohen's d = 0.075] and day 5 to day 28 [−1035 (−3130, 499) compared with −1260 (−4437, 843); P = 0.70, Cohen's d = 0.067], respectively. Conclusions We found no effect of an L. rhamnosus / helveticus probiotic, relative to placebo, on stool IgA concentrations. This trial was registered at clinicaltrials.gov as NCT01853124.

Compositional analysis of the intestinal microbiome in pre-schoolers is understudied. Effects of probiotics on the gut microbiota were evaluated in children under 4-years-old presenting to an emergency department with acute gastroenteritis. Included were 70 study participants (n=32 placebo, n=38 probiotics) with stool specimens at baseline (day 0), day 5, and after a washout period (day 28). Microbiota composition and deduced functions were profiled using 16S ribosomal RNA sequencing and predictive metagenomics, respectively. Probiotics were detected at day 5 of administration but otherwise had no discernable effects, whereas detection of bacterial infection (P&lt;0.001) and participant age (P&lt;0.001) had the largest effects on microbiota composition, microbial diversity, and deduced bacterial functions. Participants under 1 year had lower bacterial diversity than older aged pre-schoolers; compositional changes of individual bacterial taxa were associated with maturation of the gut microbiota. Advances in age were associated with differences in gut microbiota composition and deduced microbial functions, which have the potential to impact health later in life.Clinical Trial Registrationwww.ClinicalTrials.gov, identifier: NCT01853124.