REVIEW URRENT C OPINION
Ondansetron and probiotics in the management of pediatric acute gastroenteritis in developed countries David Schnadower a, Yaron Finkelstein b, and Stephen B. Freedman c
Purpose of review Acute gastroenteritis (AGE) is a common and impactful disease, typically managed with supportive care. There is considerable interest in the role of adjunctive therapies, particularly ondansetron and probiotics in improving AGE outcomes. The purpose of this review is to present the latest evidence regarding the use of these agents in children with AGE in developed countries. Recent findings Single-dose oral ondansetron is effective and safe in reducing hospital admissions and the use of intravenous rehydration in children with AGE in emergency-department-based trials. Ondansetron use has increased significantly; however, ‘real-world’ studies of effectiveness have documented less impressive clinical impacts. Similarly, probiotic consumption is growing rapidly. Although several strains appear to reduce the duration of diarrhea in hospitalized children, current data are insufficient to support the routine use of probiotics in outpatient pediatric AGE. Summary Ondansetron and probiotics may improve patient outcomes in pediatric AGE. Appropriate strategies are needed to optimally integrate oral ondansetron into clinical practice to maximize its potential benefits. Although probiotics remain a promising option, there are challenges in generalizing the data available to patients presenting for outpatient care. Large randomized controlled trials are needed to definitively guide the clinical use of probiotics in outpatients in developed countries. Keywords acute gastroenteritis, children, ondansetron, outpatient, probiotics
INTRODUCTION Globally, acute gastroenteritis (AGE) is the second leading cause of death in children younger than 5 years [1,2]. It is responsible for approximately 800 000 deaths annually (10% of childhood deaths), most of them occurring in Africa and South Asia [3,4]. In North America AGE is rarely fatal; each year 1 in 6 Americans experiences AGE (48 million persons/year) and approximately 128 000 are hospitalized [5], causing significant economic burden [6]. Although there has been a significant decline in the burden of rotavirus disease in the United States since the introduction of a rotavirus vaccine in 2006 [7], the number of pediatric emergency department (ED) visits for AGE remains high [8 ]. In fact, norovirus is now recognized as the leading cause of medically attended gastroenteritis in United States children with close to 1 million healthcare visits annually [9 ,10]. &
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The mainstay of therapy for children experiencing vomiting and/or diarrhea from AGE is supportive care aimed at preventing and treating dehydration [11]. Although dehydration assessment a Division of Pediatric Emergency Medicine, St. Louis Children’s Hospital, Washington University School of Medicine, St. Louis, Missouri, USA, b Divisions of Emergency Medicine and Clinical Pharmacology and Toxicology, The Hospital for Sick Children, University of Toronto, Toronto, Ontario and cSections of Pediatric Emergency Medicine and Gastroenterology, Department of Pediatrics, Alberta Children’s Hospital, Alberta Children’s Hospital Research Institute, University of Calgary, Calgary, Alberta, Canada
Correspondence to David Schnadower, MD, MPH, Associate Professor of Pediatrics, Fellowship Director, Division of Pediatric Emergency Medicine, Washington University School of Medicine, 660 S Euclid Avenue, Campus Box 8116, St. Louis, MO 63110, USA. Tel: +1 314 747 5604; fax: +1 314 454 4345; e-mail: [email protected] Curr Opin Gastroenterol 2015, 31:1–6 DOI:10.1097/MOG.0000000000000132
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KEY POINTS Ondansetron and probiotics are increasingly used in the treatment of AGE. Single-dose oral ondansetron is well tolerated and effective in reducing hospital admissions and the use of intravenous rehydration in children with AGE in ED-based trials. Appropriate strategies are needed to optimally integrate oral ondansetron into clinical practice to maximize its potential benefits. Probiotics, particularly the strains Lactobacillus GG and Saccharomyces boulardii, appear to reduce diarrhea duration in hospitalized children with AGE. Large RCTs are needed to definitively guide the clinical use of probiotics in outpatients in developed countries.
is challenging [12], therapy should be primarily directed by its severity [13]. Guidelines from the American Academy of Pediatrics [14], the Canadian Paediatric Society [15] and the European Society for Gastroenterology, Hepatology and Nutrition [16 ], recommend the use of oral rehydration therapy in children with mild-to-moderate dehydration. There is however, poor implementation and adherence to guidelines and significant practice variation [17–19]. Adjunctive therapies have been evaluated to improve patient outcomes and reduce costs. In this review, we present the latest evidence and recommendations regarding the use of two of the most controversial, yet potentially significant, innovations in the care of children with AGE in developed countries: ondansetron and probiotics. &
ONDANSETRON Antiemetic agents are frequently used to facilitate rehydration therapy in children with vomiting associated with AGE. In a recent survey, over 80% of physicians routinely administer antiemetics to children who fail oral fluid challenge, regardless of training (pediatric vs. nonpediatric) or setting (community vs. academic center) [20]. Use appears to be maximal (87%) among physicians working in pediatric EDs with ondansetron being the antiemetic of choice identified by 99% of pediatricians [20]. A 2013 overview [11] identified four studies that evaluated the efficacy of oral ondansetron compared to placebo in children with gastroenteritis presenting for medical care in developed countries. Oral ondansetron administration resulted in reductions in the hospital admission and intravenous rehydration 2
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rates [relative risk (RR) ¼ 0.40, 95% confidence interval (CI) 0.19, 0.83; number needed to treat (NNT) ¼ 17, 95% CI 13, 60 and RR ¼ 0.41, 95% CI 0.29, 0.59; NNT ¼ 5, 95% CI 4, 8, respectively]. Following discharge, ED revisit rates were similar between the ondansetron and placebo groups. Among the subgroup of children who did revisit an ED, those administered ondansetron at the index visit were less likely to receive intravenous rehydration at the revisit. An additional open-label clinical trial published in 2013 evaluated the efficacy of oral ondansetron, compared with domperidone, in 73 children presenting with gastroenteritis [21]. The study was powered to detect a reduction in the proportion of children who vomited in the 24 h following randomization from 50% (domperidone) to 14% (ondansetron). Despite reporting a clinically relevant reduction of vomiting from 56 to 38% (32% relative risk reduction), this did not achieve statistical significance (P ¼ 0.16). Notwithstanding the benefits observed in clinical trials, recent database studies have reported less dramatic benefits associated with ondansetron administration. A cross-sectional analysis of over 160 000 ED visits for AGE at 21 pediatric institutions between July 2009 and June 2011 documented ondansetron administration in 52% of the visits [18]. However, there was no significant correlation between oral ondansetron administration and the administration of intravenous rehydration (P ¼ 0.39). In a follow-up study [8 ] employing the same database, the authors looked at 804 000 AGE visits between 2002 and 2011. Hospital-level analyses were performed to assess the associations between ondansetron administration and rates of intravenous rehydration, hospitalization, and ED revisits within 3 days from discharge. Although ondansetron administration increased from a median rate of less than 1 to 42%, intravenous rehydration rates only declined from 19 to 18% during the same period. Although there was no change in hospitalization rates, 3-day ED revisits modestly declined (adjusted percentage change ¼ 0.31%; 95% CI, 0.49, 0.13%). The latter study was accompanied by an editorial [22] that explored the potential reasons behind the ‘failed implementation’ of ondansetron into clinical care. Possibilities include: first, the medicine is not being provided to the best candidate patients. This is evidenced by the administration of oral ondansetron to only 14% of the children receiving intravenous rehydration; second, ondansetron administration has not adequately been incorporated into bundled care pathways;third,thetiming ofdeliverymay beoptimizedin relation to medical evaluation and decision making. &
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Ondansetron and probiotics Schnadower et al.
A secondary analysis of a prospective clinical trial explored predictors of ED revisits in children administered intravenous rehydration at the index visit [23]. In this analysis, three independent predictors were identified – absence of a primary care provider [odds ratio (OR) 7.8; 95% CI 1.2, 51.0], ondansetron administration (OR 2.4; 95% CI 1.0, 5.5) and a higher baseline serum bicarbonate value (OR 1.1; 95% CI 1.0, 1.3). This study highlights the challenges of interpreting data from nonrandomized trials involving ondansetron. As the medication is usually administered to children with significant vomiting, a group more likely to receive intravenous rehydration and to revisit an ED [24,25], the use of ondansetron is by itself a surrogate marker of disease severity which reinforces the importance of randomized clinical trials when assessing the efficacy of a therapeutic intervention. This interpretation is supported by an Irish study [26] that assessed the efficacy of ondansetron for decreasing the need for intravenous dehydration in children with gastroenteritis who failed oral rehydration. The authors compared data collected over a 6-week period in 2009 (ondansetron period) with a similar period in the preceding year (no antiemetic) and noted that the proportion of children with gastroenteritis who received intravenous rehydration was reduced from 41 to 22% [26]. The aforementioned data should be considered in the context of ondansetron’s safety profile, which has come under close scrutiny as the Food and Drug Administration issued a warning regarding its potential association with the development of cardiac arrhythmias [27]. However, concerns regarding the use of single-dose ondansetron in children with AGE have been allayed by a recent postmarketing analysis of global pharmacovigilance registries [World Health Organization (Vigibase), FDA Adverse Events Reporting System, the manufacturer] and systematic review of the medical literature conducted to identify all cases of arrhythmias occurring within 24 h of ondansetron administration [28]. The research team did not identify any report describing an arrhythmia occurring in a patient (child or adult) in association with the administration of a single oral dose of ondansetron. They did identify 60 temporally associated arrhythmia reports that described other situations – most commonly (80%) intravenous ondansetron administration, typically in high-risk patients. Most arrhythmia incidents were attributed to other associated factors by the original authors, such as the presence of a significant medical history (67%) and concomitant use of additional QT-prolonging medications (67%). Approximately, one third of events occurred in patients receiving chemotherapeutic
agents and an additional third involved administration to prevent postoperative nausea and vomiting. The authors concluded that administration of a single oral dose of ondansetron to prevent nausea and vomiting in a patient with AGE with no known risk factors is safe, and does not require electrocardiogram or electrolyte screening [28].
PROBIOTICS Probiotics are defined as viable microbial preparations with beneficial health effects in the host [29]. There is considerable interest in the role of probiotics in health maintenance, in the treatment of diseases, and in their interactions with the intestinal microflora [30,31]. In-vitro and animal models have shown that probiotics compete with pathogenic bacteria for nutrients and adhesion binding sites, produce antimicrobial substances, provide nutrients to colonocytes and reduce intestinal permeability [32,33]. Additional potential mechanisms of action in children with AGE include altering epithelial gene expression, enhancing phagocyte and natural killer cell activity, and increasing fecal, salivary and systemic immunoglobulin A levels [32,33]. Until recently, probiotics were rarely prescribed by North American physicians [19,34,35]; however, their consumption is increasing significantly. The variety of probiotic containing foods on supermarket shelves has expanded, and probiotic dietary supplements are being aggressively marketed in retail stores and on the Internet [36 ]. In 2012, the market for probiotic products was over $26 billion, with a projected compound annual growth rate of 6% between 2014 and 2019 [37]. We are increasingly seeing the caregivers of patients with AGE administering probiotics to their children without guidance from medical professionals [34]. Several meta-analyses have investigated the effect of probiotics in children with AGE [38–44]. The latest Cochrane review [38] (2010) evaluated 63 randomized controlled trials (RCTs) of which 56 were carried out in infants and young children. The authors reported reductions in the mean duration of diarrhea (25 h, 95% CI: 16, 34 h), proportions with diarrhea lasting 4 days or more (RR 0.41, 95% CI: 0.32, 0.53) and mean stool frequency on day 2 (mean difference 0.8, 95% CI: 1.14, 0.45). A recent meta-analysis (15 RCTs) focusing on Lactobacillus GG showed comparable results [39]. There was a reduction in the mean duration of diarrhea by 1.05 days (95% CI 1.7, 0.4 days) with the effect being most pronounced at higher doses (1010 colony forming units/dose) and in European countries [39]. Two additional meta-analyses of Saccharomyces
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boulardii (22 RCTs) [42] and Lactobacillus reuteri (five RCTs) [44] reported similar reductions in the mean duration of diarrhea in the treatment groups. Finally, a small meta-analysis (four RCTs) of Lactobacillus acidophilus B for hospitalized patients with AGE failed to show any differences between the treatment and placebo groups [43]. In the only ED-based clinical trial conducted in the United States [45], 129 children 6 months to 18 years were randomized to Lactobacillus GG or placebo. There were no statistically significant differences between groups in the median time to normal stool or in the median number of diarrheal stools; however, among children who presented with more than 2 days of diarrhea, the LGG group returned to normal stool earlier [Lactobacillus GG 51 h (32,78) vs. placebo 74 h (45,120), P ¼ 0.02] and had fewer episodes of diarrheal stools [Lactobacillus GG 3.5 (1.0,7.5) vs. placebo 7 (3.0,16.3) P ¼ 0.02] than children in the placebo group [45]. Since the review dates of the aforementioned meta-analyses, three additional randomized trials have been published. Huang et al. [46] conducted an open-label trial of BIO-THREE (a combination of Bacillus mesentericus, Clostridium butyricum and Enterococcus faecalis) in 159 patients 3 months to 14 years of age hospitalized with AGE in Taiwan. The authors reported a decrease in the duration of diarrhea in the intervention group (1.8 1.6 days vs. 2.9 1.4 days, P < 0.001); however, there were no statistically significant differences in the overall clinical severity scores or length of hospitalization [46]. Dinleyici et al. [47] published a single-blinded study of L. reuteri in 209 hospitalized children 3–60 months of age in Turkey. They reported decreases in the duration of diarrhea (77.9 30.5 h vs. 114.6 37.4 h, P < 0.0001) and length of stay (4.94 1.7 days vs. 5.77 1.97 days, P ¼ 0.002) among children administered the probiotic agent [47]. Finally, Sindhu et al. [48] explored the role of a 4-week course of Lactobacillus GG in 124 hospitalized Indian children with acute rotavirus or crytptosporidium diarrhea. They found that LGG was useful in decreasing recurrences of diarrhea in children with rotavirus, and found higher immunoglobulin G levels in children with rotavirus as well as improved permeability (reduced lactulose to mannitol ratios) in children with crytptosporidium following treatment with Lactobacillus GG. The authors did not report, however, whether the clinical course of patients differed between the groups [48]. These meta-analyses and several subsequent studies appear to show that probiotics have a positive effect in children with AGE. This has prompted recommendations for the use of select probiotic organisms [49], and some institutions 4
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have promoted the rapid implementation of routine probiotic use in hospitalized children [50]. Many experts, however, question whether there is sufficient evidence to support widespread use, particularly among outpatients [38,51 ]. Few studies [8 ,38] have included large numbers of outpatient children, a group that actually represents over 95% of individuals affected by AGE in the United States and other high-income countries. The methodological quality of studies varies considerably: only 10 of 63 studies in the Cochrane review [38], one of 22 studies in Feizizadeh’s meta-analysis of S. boulardii [42], and none of 24 studies in Szajewska’s metaanalyses of Lactobacillus GG [39], L. reuteri [44], and L. acidophilus B [43] meet all four methodological quality assessment parameters (generation of the allocation sequence, concealment of allocation, blinding and loss to follow-up). Few studies have incorporated all aspects of the disease (e.g. diarrhea, vomiting, fever, health resource utilization, etc.) such as can be achieved through the use of gastroenteritis severity scores [52,53]. Furthermore, the widespread implementation of rotavirus vaccination programs in many developed countries has altered the epidemiology of disease [7]. This is important, as the greatest benefit associated with probiotic use appears to be among inpatients with rotavirus AGE; little is known about its effectiveness in relation to other specific, yet common pathogens (for example, norovirus). Finally, few studies have independently verified probiotic viability and standardized colony counts or monitored sideeffects and adverse events systematically [38,54]. We remain cautious in our interpretation of meta-analyses results. Even when methodologically sound, their results depend on the quality of the studies they include. A third of meta-analyses do not predict the results of subsequent well designed large RCTs [55,56]. An illustrative example of this issue is a multicenter RCT of a combination probiotic for the prevention of antibiotic associated diarrhea and Clostridium difficile infection in almost 3000 hospitalized older adults [57]. Contrary to meta-analyses, which included smaller studies [58–60], this large trial found no evidence that this multistrain preparation is effective [57]. In summary, although promising, the current data are insufficient to support a broad, generalizable recommendation to endorse routine probiotic use in children with AGE in developed countries. There continues to exist a need for definitive, non-industry funded RCTs, evaluating specific probiotic regimens employing standardized definitions and relevant patient-centered outcomes [61]. The studies need to employ agents that have undergone verification of viability and standardized &
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colony forming units concentrations and product stability and determine probiotics efficacy and safety in relation to specific pathogens [38,51 ,62]. &
CONCLUSION ED-based trials provide evidence that a single dose of oral ondansetron is effective and well tolerated in reducing hospital admissions and the use of intravenous rehydration in children with AGE. Failures of implementation have limited ondansetron’s overall impact and resulted in excessive use in populations of children who are less likely to derive benefits. Future research directions include assessing the impact of varying knowledge translation strategies designed to optimize the uptake of ondansetron use in EDs, its effectiveness in primary care settings and perhaps use in developing countries. Probiotics, and particularly Lactobacillus GG and S. boulardii, appear to reduce diarrhea duration in children with AGE; however, widespread use should not be routinely endorsed given the challenges that exist in generalizing the data available to patients presenting for outpatient care in developed countries. Large RCTs are needed to provide a robust evidence-base to inform AGE treatment guidelines. Acknowledgements None. Conflicts of interest Both D.S. and S.F. are currently conducting NIH and CIHR sponsored studies in the United States and Canada to evaluate the effectiveness of Lactobacillus GG (NIH RO1HD071915) and Lactobacillus helveticus and Lactobacillus rhamnosus (CIHR #126175) in children with gastroenteritis. Both have received study drug and placebo in kind to conduct these studies. S.F. has received drug and placebo for past ondansetron studies. No money has been paid to them or to their institutions from the drug producers to conduct any of these studies. Yaron Finkelstein is a site investigator in the CIHR study.
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47. Dinleyici EC, Group PS, Vandenplas Y. Lactobacillus reuteri DSM 17938 effectively reduces the duration of acute diarrhoea in hospitalised children. Acta Paediatr 2014; 103:e300–e305. 48. Sindhu KN, Sowmyanarayanan TV, Paul A, et al. Immune response and intestinal permeability in children with acute gastroenteritis treated with Lactobacillus rhamnosus GG: a randomized, double-blind, placebo-controlled trial. Clin Infect Dis 2014; 58:1107–1115. 49. Szajewska H, Guarino A, Hojsak I, et al. Use of probiotics for management of acute gastroenteritis: a position paper by the ESPGHAN working group for probiotics and prebiotics. J Pediatr Gastroenterol Nutr 2014; 58:531– 539. 50. Parker MW, Schaffzin JK, Lo Vecchio A, et al. Rapid adoption of Lactobacillus rhamnosus GG for acute gastroenteritis. Pediatrics 2013; 131:S96–S102. 51. Freedman SB, Williamson-Urquhart S, Schuh S, et al. Impact of emergency & department probiotic treatment of pediatric gastroenteritis: study protocol for the PROGUT (Probiotic Regimen for Outpatient Gastroenteritis Utility of Treatment) randomized controlled trial. Trials 2014; 15:170. This article highlights ideal methods required to conduct definitive trials for probiotics in AGE in developed countries. 52. Freedman SB, Eltorky M, Gorelick M; Pediatric Emergency Research Canada Gastroenteritis Study Group. Evaluation of a gastroenteritis severity score for use in outpatient settings. Pediatrics 2010; 125:e1278–e1285. 53. Schnadower D, Tarr PI, Gorelick MH, et al. Validation of the modified Vesikari score in children with gastroenteritis in 5 US emergency departments. J Pediatr Gastroenterol Nutr 2013; 57:514–519. 54. Floch MH. Probiotic safety and risk factors. J Clin Gastroenterol 2013; 47:375–376. 55. LeLorier J, Gregoire G, Benhaddad A, et al. Discrepancies between metaanalyses and subsequent large randomized, controlled trials. N Engl J Med 1997; 337:536–542. 56. Villar J, Carroli G, Belizan JM. Predictive ability of meta-analyses of randomised controlled trials. Lancet 1995; 345:772–776. 57. Allen SJ, Wareham K, Wang D, et al. Lactobacilli and bifidobacteria in the prevention of antibiotic-associated diarrhoea and Clostridium difficile diarrhoea in older inpatients (PLACIDE): a randomised, double-blind, placebocontrolled, multicentre trial. Lancet 2013; 382:1249–1257. 58. Hempel S, Newberry SJ, Maher AR, et al. Probiotics for the prevention and treatment of antibiotic-associated diarrhea: a systematic review and metaanalysis. JAMA 2012; 307:1959–1969. 59. Johnston BC, Ma SS, Goldenberg JZ, et al. Probiotics for the prevention of Clostridium difficile-associated diarrhea: a systematic review and metaanalysis. Ann Intern Med 2012; 157:878–888. 60. Goldenberg JZ, Ma SS, Saxton JD, et al. Probiotics for the prevention of Clostridium difficile-associated diarrhea in adults and children. Cochrane Database Syst Rev 2013; 5:CD006095. 61. Washington AE, Lipstein SH. The Patient-Centered Outcomes Research Institute: promoting better information, decisions, and health. N Engl J Med 2011; 365:e31. 62. ClinicalTrials.gov. Impact of Emergency Department Probiotic (LGG) Treatment of Pediatric Gastroenteritis 2014 [cited 1 June 2014]. http://clinical trials.gov/ct2/show/NCT01773967.
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Ondansetron and probiotics in the management of pediatric acute gastroenteritis in developed countries David Schnadower a, Yaron Finkelstein b, and Stephen B. Freedman c
Purpose of review Acute gastroenteritis (AGE) is a common and impactful disease, typically managed with supportive care. There is considerable interest in the role of adjunctive therapies, particularly ondansetron and probiotics in improving AGE outcomes. The purpose of this review is to present the latest evidence regarding the use of these agents in children with AGE in developed countries. Recent findings Single-dose oral ondansetron is effective and safe in reducing hospital admissions and the use of intravenous rehydration in children with AGE in emergency-department-based trials. Ondansetron use has increased significantly; however, ‘real-world’ studies of effectiveness have documented less impressive clinical impacts. Similarly, probiotic consumption is growing rapidly. Although several strains appear to reduce the duration of diarrhea in hospitalized children, current data are insufficient to support the routine use of probiotics in outpatient pediatric AGE. Summary Ondansetron and probiotics may improve patient outcomes in pediatric AGE. Appropriate strategies are needed to optimally integrate oral ondansetron into clinical practice to maximize its potential benefits. Although probiotics remain a promising option, there are challenges in generalizing the data available to patients presenting for outpatient care. Large randomized controlled trials are needed to definitively guide the clinical use of probiotics in outpatients in developed countries. Keywords acute gastroenteritis, children, ondansetron, outpatient, probiotics
INTRODUCTION Globally, acute gastroenteritis (AGE) is the second leading cause of death in children younger than 5 years [1,2]. It is responsible for approximately 800 000 deaths annually (10% of childhood deaths), most of them occurring in Africa and South Asia [3,4]. In North America AGE is rarely fatal; each year 1 in 6 Americans experiences AGE (48 million persons/year) and approximately 128 000 are hospitalized [5], causing significant economic burden [6]. Although there has been a significant decline in the burden of rotavirus disease in the United States since the introduction of a rotavirus vaccine in 2006 [7], the number of pediatric emergency department (ED) visits for AGE remains high [8 ]. In fact, norovirus is now recognized as the leading cause of medically attended gastroenteritis in United States children with close to 1 million healthcare visits annually [9 ,10]. &
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The mainstay of therapy for children experiencing vomiting and/or diarrhea from AGE is supportive care aimed at preventing and treating dehydration [11]. Although dehydration assessment a Division of Pediatric Emergency Medicine, St. Louis Children’s Hospital, Washington University School of Medicine, St. Louis, Missouri, USA, b Divisions of Emergency Medicine and Clinical Pharmacology and Toxicology, The Hospital for Sick Children, University of Toronto, Toronto, Ontario and cSections of Pediatric Emergency Medicine and Gastroenterology, Department of Pediatrics, Alberta Children’s Hospital, Alberta Children’s Hospital Research Institute, University of Calgary, Calgary, Alberta, Canada
Correspondence to David Schnadower, MD, MPH, Associate Professor of Pediatrics, Fellowship Director, Division of Pediatric Emergency Medicine, Washington University School of Medicine, 660 S Euclid Avenue, Campus Box 8116, St. Louis, MO 63110, USA. Tel: +1 314 747 5604; fax: +1 314 454 4345; e-mail: [email protected] Curr Opin Gastroenterol 2015, 31:1–6 DOI:10.1097/MOG.0000000000000132
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KEY POINTS Ondansetron and probiotics are increasingly used in the treatment of AGE. Single-dose oral ondansetron is well tolerated and effective in reducing hospital admissions and the use of intravenous rehydration in children with AGE in ED-based trials. Appropriate strategies are needed to optimally integrate oral ondansetron into clinical practice to maximize its potential benefits. Probiotics, particularly the strains Lactobacillus GG and Saccharomyces boulardii, appear to reduce diarrhea duration in hospitalized children with AGE. Large RCTs are needed to definitively guide the clinical use of probiotics in outpatients in developed countries.
is challenging [12], therapy should be primarily directed by its severity [13]. Guidelines from the American Academy of Pediatrics [14], the Canadian Paediatric Society [15] and the European Society for Gastroenterology, Hepatology and Nutrition [16 ], recommend the use of oral rehydration therapy in children with mild-to-moderate dehydration. There is however, poor implementation and adherence to guidelines and significant practice variation [17–19]. Adjunctive therapies have been evaluated to improve patient outcomes and reduce costs. In this review, we present the latest evidence and recommendations regarding the use of two of the most controversial, yet potentially significant, innovations in the care of children with AGE in developed countries: ondansetron and probiotics. &
ONDANSETRON Antiemetic agents are frequently used to facilitate rehydration therapy in children with vomiting associated with AGE. In a recent survey, over 80% of physicians routinely administer antiemetics to children who fail oral fluid challenge, regardless of training (pediatric vs. nonpediatric) or setting (community vs. academic center) [20]. Use appears to be maximal (87%) among physicians working in pediatric EDs with ondansetron being the antiemetic of choice identified by 99% of pediatricians [20]. A 2013 overview [11] identified four studies that evaluated the efficacy of oral ondansetron compared to placebo in children with gastroenteritis presenting for medical care in developed countries. Oral ondansetron administration resulted in reductions in the hospital admission and intravenous rehydration 2
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rates [relative risk (RR) ¼ 0.40, 95% confidence interval (CI) 0.19, 0.83; number needed to treat (NNT) ¼ 17, 95% CI 13, 60 and RR ¼ 0.41, 95% CI 0.29, 0.59; NNT ¼ 5, 95% CI 4, 8, respectively]. Following discharge, ED revisit rates were similar between the ondansetron and placebo groups. Among the subgroup of children who did revisit an ED, those administered ondansetron at the index visit were less likely to receive intravenous rehydration at the revisit. An additional open-label clinical trial published in 2013 evaluated the efficacy of oral ondansetron, compared with domperidone, in 73 children presenting with gastroenteritis [21]. The study was powered to detect a reduction in the proportion of children who vomited in the 24 h following randomization from 50% (domperidone) to 14% (ondansetron). Despite reporting a clinically relevant reduction of vomiting from 56 to 38% (32% relative risk reduction), this did not achieve statistical significance (P ¼ 0.16). Notwithstanding the benefits observed in clinical trials, recent database studies have reported less dramatic benefits associated with ondansetron administration. A cross-sectional analysis of over 160 000 ED visits for AGE at 21 pediatric institutions between July 2009 and June 2011 documented ondansetron administration in 52% of the visits [18]. However, there was no significant correlation between oral ondansetron administration and the administration of intravenous rehydration (P ¼ 0.39). In a follow-up study [8 ] employing the same database, the authors looked at 804 000 AGE visits between 2002 and 2011. Hospital-level analyses were performed to assess the associations between ondansetron administration and rates of intravenous rehydration, hospitalization, and ED revisits within 3 days from discharge. Although ondansetron administration increased from a median rate of less than 1 to 42%, intravenous rehydration rates only declined from 19 to 18% during the same period. Although there was no change in hospitalization rates, 3-day ED revisits modestly declined (adjusted percentage change ¼ 0.31%; 95% CI, 0.49, 0.13%). The latter study was accompanied by an editorial [22] that explored the potential reasons behind the ‘failed implementation’ of ondansetron into clinical care. Possibilities include: first, the medicine is not being provided to the best candidate patients. This is evidenced by the administration of oral ondansetron to only 14% of the children receiving intravenous rehydration; second, ondansetron administration has not adequately been incorporated into bundled care pathways;third,thetiming ofdeliverymay beoptimizedin relation to medical evaluation and decision making. &
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Ondansetron and probiotics Schnadower et al.
A secondary analysis of a prospective clinical trial explored predictors of ED revisits in children administered intravenous rehydration at the index visit [23]. In this analysis, three independent predictors were identified – absence of a primary care provider [odds ratio (OR) 7.8; 95% CI 1.2, 51.0], ondansetron administration (OR 2.4; 95% CI 1.0, 5.5) and a higher baseline serum bicarbonate value (OR 1.1; 95% CI 1.0, 1.3). This study highlights the challenges of interpreting data from nonrandomized trials involving ondansetron. As the medication is usually administered to children with significant vomiting, a group more likely to receive intravenous rehydration and to revisit an ED [24,25], the use of ondansetron is by itself a surrogate marker of disease severity which reinforces the importance of randomized clinical trials when assessing the efficacy of a therapeutic intervention. This interpretation is supported by an Irish study [26] that assessed the efficacy of ondansetron for decreasing the need for intravenous dehydration in children with gastroenteritis who failed oral rehydration. The authors compared data collected over a 6-week period in 2009 (ondansetron period) with a similar period in the preceding year (no antiemetic) and noted that the proportion of children with gastroenteritis who received intravenous rehydration was reduced from 41 to 22% [26]. The aforementioned data should be considered in the context of ondansetron’s safety profile, which has come under close scrutiny as the Food and Drug Administration issued a warning regarding its potential association with the development of cardiac arrhythmias [27]. However, concerns regarding the use of single-dose ondansetron in children with AGE have been allayed by a recent postmarketing analysis of global pharmacovigilance registries [World Health Organization (Vigibase), FDA Adverse Events Reporting System, the manufacturer] and systematic review of the medical literature conducted to identify all cases of arrhythmias occurring within 24 h of ondansetron administration [28]. The research team did not identify any report describing an arrhythmia occurring in a patient (child or adult) in association with the administration of a single oral dose of ondansetron. They did identify 60 temporally associated arrhythmia reports that described other situations – most commonly (80%) intravenous ondansetron administration, typically in high-risk patients. Most arrhythmia incidents were attributed to other associated factors by the original authors, such as the presence of a significant medical history (67%) and concomitant use of additional QT-prolonging medications (67%). Approximately, one third of events occurred in patients receiving chemotherapeutic
agents and an additional third involved administration to prevent postoperative nausea and vomiting. The authors concluded that administration of a single oral dose of ondansetron to prevent nausea and vomiting in a patient with AGE with no known risk factors is safe, and does not require electrocardiogram or electrolyte screening [28].
PROBIOTICS Probiotics are defined as viable microbial preparations with beneficial health effects in the host [29]. There is considerable interest in the role of probiotics in health maintenance, in the treatment of diseases, and in their interactions with the intestinal microflora [30,31]. In-vitro and animal models have shown that probiotics compete with pathogenic bacteria for nutrients and adhesion binding sites, produce antimicrobial substances, provide nutrients to colonocytes and reduce intestinal permeability [32,33]. Additional potential mechanisms of action in children with AGE include altering epithelial gene expression, enhancing phagocyte and natural killer cell activity, and increasing fecal, salivary and systemic immunoglobulin A levels [32,33]. Until recently, probiotics were rarely prescribed by North American physicians [19,34,35]; however, their consumption is increasing significantly. The variety of probiotic containing foods on supermarket shelves has expanded, and probiotic dietary supplements are being aggressively marketed in retail stores and on the Internet [36 ]. In 2012, the market for probiotic products was over $26 billion, with a projected compound annual growth rate of 6% between 2014 and 2019 [37]. We are increasingly seeing the caregivers of patients with AGE administering probiotics to their children without guidance from medical professionals [34]. Several meta-analyses have investigated the effect of probiotics in children with AGE [38–44]. The latest Cochrane review [38] (2010) evaluated 63 randomized controlled trials (RCTs) of which 56 were carried out in infants and young children. The authors reported reductions in the mean duration of diarrhea (25 h, 95% CI: 16, 34 h), proportions with diarrhea lasting 4 days or more (RR 0.41, 95% CI: 0.32, 0.53) and mean stool frequency on day 2 (mean difference 0.8, 95% CI: 1.14, 0.45). A recent meta-analysis (15 RCTs) focusing on Lactobacillus GG showed comparable results [39]. There was a reduction in the mean duration of diarrhea by 1.05 days (95% CI 1.7, 0.4 days) with the effect being most pronounced at higher doses (1010 colony forming units/dose) and in European countries [39]. Two additional meta-analyses of Saccharomyces
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boulardii (22 RCTs) [42] and Lactobacillus reuteri (five RCTs) [44] reported similar reductions in the mean duration of diarrhea in the treatment groups. Finally, a small meta-analysis (four RCTs) of Lactobacillus acidophilus B for hospitalized patients with AGE failed to show any differences between the treatment and placebo groups [43]. In the only ED-based clinical trial conducted in the United States [45], 129 children 6 months to 18 years were randomized to Lactobacillus GG or placebo. There were no statistically significant differences between groups in the median time to normal stool or in the median number of diarrheal stools; however, among children who presented with more than 2 days of diarrhea, the LGG group returned to normal stool earlier [Lactobacillus GG 51 h (32,78) vs. placebo 74 h (45,120), P ¼ 0.02] and had fewer episodes of diarrheal stools [Lactobacillus GG 3.5 (1.0,7.5) vs. placebo 7 (3.0,16.3) P ¼ 0.02] than children in the placebo group [45]. Since the review dates of the aforementioned meta-analyses, three additional randomized trials have been published. Huang et al. [46] conducted an open-label trial of BIO-THREE (a combination of Bacillus mesentericus, Clostridium butyricum and Enterococcus faecalis) in 159 patients 3 months to 14 years of age hospitalized with AGE in Taiwan. The authors reported a decrease in the duration of diarrhea in the intervention group (1.8 1.6 days vs. 2.9 1.4 days, P < 0.001); however, there were no statistically significant differences in the overall clinical severity scores or length of hospitalization [46]. Dinleyici et al. [47] published a single-blinded study of L. reuteri in 209 hospitalized children 3–60 months of age in Turkey. They reported decreases in the duration of diarrhea (77.9 30.5 h vs. 114.6 37.4 h, P < 0.0001) and length of stay (4.94 1.7 days vs. 5.77 1.97 days, P ¼ 0.002) among children administered the probiotic agent [47]. Finally, Sindhu et al. [48] explored the role of a 4-week course of Lactobacillus GG in 124 hospitalized Indian children with acute rotavirus or crytptosporidium diarrhea. They found that LGG was useful in decreasing recurrences of diarrhea in children with rotavirus, and found higher immunoglobulin G levels in children with rotavirus as well as improved permeability (reduced lactulose to mannitol ratios) in children with crytptosporidium following treatment with Lactobacillus GG. The authors did not report, however, whether the clinical course of patients differed between the groups [48]. These meta-analyses and several subsequent studies appear to show that probiotics have a positive effect in children with AGE. This has prompted recommendations for the use of select probiotic organisms [49], and some institutions 4
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have promoted the rapid implementation of routine probiotic use in hospitalized children [50]. Many experts, however, question whether there is sufficient evidence to support widespread use, particularly among outpatients [38,51 ]. Few studies [8 ,38] have included large numbers of outpatient children, a group that actually represents over 95% of individuals affected by AGE in the United States and other high-income countries. The methodological quality of studies varies considerably: only 10 of 63 studies in the Cochrane review [38], one of 22 studies in Feizizadeh’s meta-analysis of S. boulardii [42], and none of 24 studies in Szajewska’s metaanalyses of Lactobacillus GG [39], L. reuteri [44], and L. acidophilus B [43] meet all four methodological quality assessment parameters (generation of the allocation sequence, concealment of allocation, blinding and loss to follow-up). Few studies have incorporated all aspects of the disease (e.g. diarrhea, vomiting, fever, health resource utilization, etc.) such as can be achieved through the use of gastroenteritis severity scores [52,53]. Furthermore, the widespread implementation of rotavirus vaccination programs in many developed countries has altered the epidemiology of disease [7]. This is important, as the greatest benefit associated with probiotic use appears to be among inpatients with rotavirus AGE; little is known about its effectiveness in relation to other specific, yet common pathogens (for example, norovirus). Finally, few studies have independently verified probiotic viability and standardized colony counts or monitored sideeffects and adverse events systematically [38,54]. We remain cautious in our interpretation of meta-analyses results. Even when methodologically sound, their results depend on the quality of the studies they include. A third of meta-analyses do not predict the results of subsequent well designed large RCTs [55,56]. An illustrative example of this issue is a multicenter RCT of a combination probiotic for the prevention of antibiotic associated diarrhea and Clostridium difficile infection in almost 3000 hospitalized older adults [57]. Contrary to meta-analyses, which included smaller studies [58–60], this large trial found no evidence that this multistrain preparation is effective [57]. In summary, although promising, the current data are insufficient to support a broad, generalizable recommendation to endorse routine probiotic use in children with AGE in developed countries. There continues to exist a need for definitive, non-industry funded RCTs, evaluating specific probiotic regimens employing standardized definitions and relevant patient-centered outcomes [61]. The studies need to employ agents that have undergone verification of viability and standardized &
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colony forming units concentrations and product stability and determine probiotics efficacy and safety in relation to specific pathogens [38,51 ,62]. &
CONCLUSION ED-based trials provide evidence that a single dose of oral ondansetron is effective and well tolerated in reducing hospital admissions and the use of intravenous rehydration in children with AGE. Failures of implementation have limited ondansetron’s overall impact and resulted in excessive use in populations of children who are less likely to derive benefits. Future research directions include assessing the impact of varying knowledge translation strategies designed to optimize the uptake of ondansetron use in EDs, its effectiveness in primary care settings and perhaps use in developing countries. Probiotics, and particularly Lactobacillus GG and S. boulardii, appear to reduce diarrhea duration in children with AGE; however, widespread use should not be routinely endorsed given the challenges that exist in generalizing the data available to patients presenting for outpatient care in developed countries. Large RCTs are needed to provide a robust evidence-base to inform AGE treatment guidelines. Acknowledgements None. Conflicts of interest Both D.S. and S.F. are currently conducting NIH and CIHR sponsored studies in the United States and Canada to evaluate the effectiveness of Lactobacillus GG (NIH RO1HD071915) and Lactobacillus helveticus and Lactobacillus rhamnosus (CIHR #126175) in children with gastroenteritis. Both have received study drug and placebo in kind to conduct these studies. S.F. has received drug and placebo for past ondansetron studies. No money has been paid to them or to their institutions from the drug producers to conduct any of these studies. Yaron Finkelstein is a site investigator in the CIHR study.
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Volume 31 Number 1 January 2015
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