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Date: April 16th, 2019

Reference: Schnadower et al. Lactobacillus rhamnosus GG versus placebo for acute gastroenteritis in children. NEJM 2018

Guest Skeptic: Dr. Anthony G. Crocco is a Pediatric Emergency Physician and is the Medical Director & Division Head of the Division of Pediatric Emergency at McMaster’s Children’s Hospital. He is an Associate Professor at McMaster University. Anthony is known for his online RANThonys and website SketchyEBM.

Case: A two-year-old girl presents with two days of non-bloody watery stools and one episode of vomiting.  She is otherwise well appearing and has normal vitals and examines normally.  After you explain the diagnosis of gastroenteritis to the parents, and the importance of hand washing at home, they ask you whether they should give probiotics to help shorten the course of her illness.

Background: We have covered many pediatric topics with you on the SGEM. One of them included a RANThony on getting x-rays for constipation. This time we are talking about stuff coming out too much rather than not enough. 

Viral gastroenteritis is rivalled by bronchiolitis for one of the most common Pediatric presentations to the emergency department.  The discomfort this illness imbues, the time away from daycare required, and the time away from parental work necessitated can be quite disruptive.  Even small changes to the course of this illness, due to its prevalence, could have huge comfort and economic benefit.

We looked at a trial by Freedman et al using half-strength apple juice or fluids of choice to treat mild gastroenteritis in children who were minimally dehydrated (SGEM#158). The bottom line from that episode was that this strategy was a better choice compared to electrolyte solutions.

We have also reviewed a couple of papers that looked at using ondansetron in pediatric gastroenteritis (SGEM#12 and SGEM#122).

There are some guidelines on managing gastroenteritis:

  • TREKK– Gastroenteritis
  • AAP– Managing Acute Gastroenteritis Among Children
  • NICE– Diarrhoea and vomiting caused by gastroenteritis in under 5s: diagnosis and management
  • AAFP– Gastroenteritis in Children
  • Sick Kids– Acute Gastroenteritis

In this episode we are going to be looking at using probiotics to treat pediatric gastroenteritis. The theory of using probiotics to replenish the normal gut flora to minimize disease is neither new nor unstudied.  Previous work in this area has been described as being “underpowered or had methodology problems related to the trial design and choice of appropriate end points.”

Clinical Question: Does prescribing probiotics to children with gastroenteritis, specifically giving L. rhamnosus, improve the course of the illness?

Reference: Schnadower et al.  Lactobacillus rhamnosus GG versus placebo for acute gastroenteritis in children. NEJM 2018

  • Population: Children three months to four years of age presenting to the emergency department with a diagnosis of acute gastroenteritis. This was defined as “three or more episodes of watery stools per day, with or without vomiting, for fewer than 7 days.”
    • Exclusions: There were 18 exclusion criteria and these can be found at ClinicalTrials NCT 01773967.
  • Intervention: L. rhamnosus GG twice a day for five days
  • Comparison: Placebo twice a day for five days
  • Outcome:
    • Primary Outcome: Moderate-to-severe gastroenteritis. This was defined as an illness episode with a modified Vesikari scale greater than 8 during the 14-day follow-up period. The modified Vesikari Scale helps establish severity of gastro symptoms using a 7-item scale that ranges from 0-20 overall points.  Although I have never used this scale clinically, its utility is in being able to quantify symptom improvement in research.

  • Secondary Outcomes:
    • Frequency and duration of diarrhea and vomiting, the incidence of unscheduled health care visits for symptoms of gastroenteritis within two weeks after the index visit, the number of days of day care missed by participants, the number of hours of work missed by caregivers, and the rate of household transmission.
    • Safety outcomes included extra intestinal infection by L. rhamnosus GG (e.g., bacteremia), side effects and adverse events

Authors’ Conclusions: “Among preschool children with acute gastroenteritis, those who received a 5-day course of L. rhamnosus GG did not have better outcomes than those who received placebo.”

 Quality Checklist for Randomized Clinical Trials:

  1. The study population included or focused on those in the emergency department. Yes
  2. The patients were adequately randomized. Yes
  3. The randomization process was concealed. Yes
  4. The patients were analyzed in the groups to which they were randomized. Yes/No
  5. The study patients were recruited consecutively (i.e. no selection bias). Yes
  6. The patients in both groups were similar with respect to prognostic factors. No
  7. All participants (patients, clinicians, outcome assessors) were unaware of group allocation. Yes
  8. All groups were treated equally except for the intervention. Yes
  9. Follow-up was complete (i.e. at least 80% for both groups). Yes
  10. All patient-important outcomes were considered. Yes
  11. The treatment effect was large enough and precise enough to be clinically significant. No

Key Results: They included 971 children in this trial with a median age of 1.4 years. The median number of diarrhea stools in 24 hours was six and the median number of vomiting episodes in 24 hours was three. Intravenous fluids were given to 13% of children and 5% were admitted to hospital.

No identified significant difference between the probiotic group and the placebo group. 

  •  Primary Outcome: Modified Vesikari scale score RR 0.96 (95% CI 0.68 to 1.35; P=0.83)

  • Secondary Outcomes: No significant differences were noted in the secondary outcomes when the data was adjusted for multiple comparisons.

1) It’s OK to Be Negative: Although this is a negative study, in that they could not show a significant improvement with the use of probiotics, it should be seen as useful.  Studies like these help us understand when we should consider the value of therapeutic choices we’re making.

2) Not All Probiotics are the Same:  Much like antibiotics, we have to be careful not to lump all probiotics together.  We wouldn’t do a study on cephalosporins for enterococcus infections (which are resistant) and conclude that no antibiotics work for enterococcus.  This means we cannot conclude that probiotics do not work but rather that the probiotics used in this study have not been demonstrated to have a net benefit. However, the burden of proof is on the probiotic advocates to prove their claim of efficacy. Until that burden of proof has been met, probiotics for the treatment of pediatric gastroenteritis cannot be recommended.

3) Freedman et al 2018: There is a companion study in this same NEJM edition with a similar design, population and outcomes who reached the same conclusions.  They did use a combination treatment of L. rhamnosus and L. helveticus. Once again, I am reminded of the quality and relevance of Freedman’s work – X-rays for constipation?  Freedman. Ondansetron use for gastro? Freedman.  Juice for gastro?  Freedman. See a research paper by Stephen Freedman?  My advice: Read it.

4) NEJM: I have said before on the SGEM that the NEJM is not my favorite journal. It is good to see them publish a negative study that does not promote a commercial interest and they deserve credit.

5) Unbalanced at Baseline: One minor concern with more visible minorities in the treatment arm could have created bias in that group.

Comment on Authors’ Conclusion Compared to SGEM Conclusion: We agree with the authors’ conclusions.  It appears that given the results of this trial, and its companion trial by Freedman et al, we should not be prescribing L. rhamnosus to children with acute gastroenteritis.  Further work is required to clarify if there is a role for other probiotics in this patient population.

SGEM Bottom Line: Prescribing L. rhamnosus to children with acute gastroenteritis cannot be recommended at this time.

Case Resolution: Welcoming the parents’ enlightened question, you answer that we have not been able to find any improvement in children like theirs if given L. rhamnosus.  We are unsure whether we can recommend other forms of probiotics, but we are currently skeptical.  We used to suggest the BRAT (Bananas, rice, applesauce and toast) diet but this has gone out of favor.  Although easily digested, the BRAT diet has very low nutritional value and is no longer recommended.  My approach is to ensure adequate fluid intake, whatever the child will tolerate – not necessarily an electrolyte solution, then advance to an age-appropriate diet as tolerated.

Dr. Anthony Crocco

Clinical Application: In children with acute gastroenteritis we should not prescribe L rhamnosus. Of interest, a Cochrane SR by Goldenberg et al in 2015 looking at probiotics for antibiotic associated diarrhea found that “moderate quality evidence suggests a protective effect of probiotics in preventing antibiotic associated diarrhea” but that “probiotic use should be avoided in children at risk for side effects.”

What Do I Tell the Patient/Parents?  Do not use L. rhamnosus or any other probiotic for your child with acute gastroenteritis. However, if you child is put on antibiotics in the future you may want to consider probiotics at that time.

Keener Kontest: Last weeks’ winner was Sam Steeves. He knew it was 1976 when orthopedic surgeon James Styner crashed his small plane crash into a corn field in rural Nebraska? It was this tragic event that lead to the creation of the Advanced Trauma Life Support (ATLS) course. 

Listen to the podcast to hear this weeks’ trivia question. If you know the answer, send an email to TheSGEM@gmail.com with “keener” in the subject line. The first correct answer will receive a cool skeptical prize.

Other FOAMed:

  • PEM Blog: Should we prescribe probiotics for gastroenteritis?

Remember to be skeptical of anything you learn, even if you heard it on the Skeptics’ Guide to Emergency Medicine.