INDICATIONS TO LABORATORY AND MICROBIOLOGICAL INVESTIGATIONS
AGE does not usually require stool microbiological investigations. Most children have a viral cause and in addition bacterial or protozoal agents generally do not require antimicrobial treatment. Stool cultures should be considered in case of persistent diarrhea, when antimicrobial treatment is considered (e.g. in immune-compromised children, in septic or toxic children or children with dysentery), in case of an outbreak or if the child has recently been abroad.
Electrolyte abnormalities may develop, although usually they are not severe. Hypernatremia and hyponatremia may occur, although isonatremic dehydration is the most common form. Selected children may have hypoglycemia and some may present metabolic acidosis, but their incidence is low. Furthermore, the accuracy of available tests in detecting severity of dehydration is not established. The laboratory test that best correlates with dehydration is serum bicarbonate . Blood tests are not routinely needed, but serum potassium, sodium, urea and creatinine, and serum bicarbonate should be considered for children severely dehydrated or in whom i.v. rehydration is required. However, in the absence of risk-benefit indications, ordering laboratory tests based on clinical judgment may be superior to routine screening [6▪▪]. Despite this, a recent survey showed that 40–60% of enrolled physicians require laboratory tests in moderately dehydrated patients [11▪].
Rehydration may be provided through oral, enteral (through nasogastric tube; NGT), and i.v. route according to the severity of dehydration and the conditions of the child. In the hospital setting, the last two options are typically considered.
Rehydration through nasogastric tube
A Cochrane review compared the efficacy of IVT in 17 trials with oral or nasogastric rehydration . In eight of 17 trials, rehydration was given through NGT alone or in combination with ORT. There were no differences in the rehydration failure, incidence of hyponatremia, hypernatremia, mean duration of diarrhea, weight gain, or total fluid intake in children on ORT or IVT. Children on ORT had a significantly shorter stay in hospital and a lower risk of phlebitis . A meta-analysis showed that NGT rehydration is associated with reduced risk of electrolyte imbalances, cerebral edema, phlebitis compared with i.v. rehydration. Rehydration through NGT is a valid alternative to IVT with equal efficacy, less adverse events and reduces the length of hospital stay .
Current guidelines concluded that rehydration should be provided through NGT if children are unable to drink it or if they have persistent vomit. The American Academy of Pediatrics recommends rapid (over 4 h) NGT rehydration for treatment of children with moderate dehydration. This regimen offers several benefits including a shorter stay in the hospital and less disruption of the family routine compared with the standard regimen. A prospective, randomized, clinical trial compared two different regimens of nasogastric rehydration: the standard nasogastric regimen (SNR) (replace fluids over 24 h) and the rapid nasogastric regimen (RNR) (100 ml/kg of rehydration solution administered over 4 h) [13▪]. The results showed no significant difference in the primary treatment failure defined as an additional loss of more than 2% of weight at any time during the rehydration period. Furthermore, no differences in the secondary treatment failures defined as inability to tolerate NGT, persistent vomiting, need of i.v. rehydration, persistent signs of moderate dehydration, need of nasogastric fluids beyond 24 h, were observed between the two groups at 4–6 h after beginning of rehydration therapy. At 24 h and 7 days after the admission, a higher proportion of secondary treatment failures in the RNR group compared with the SNR group was observed.
Despite the evidence of safety and efficacy, NGT rehydration regimen continues to be poorly applied in clinical practice, perhaps because placing a NGT is considered more invasive than IVT. These concerns need to be balanced against the i.v. complications such as phlebitis or cellulitis.
The indications to IVT generally overlap the indications to hospital admission. Guidelines recommend i.v. rehydration in case of severe dehydration and/or in case of oral rehydration failure. The recent evidence-based guidelines from Cincinnati Children's Hospital [6▪▪] recommend i.v. therapy, if there is a severe dehydration or if it is impossible to replace the estimated deficit fluids using oral solution alone.
Intravenous rehydration consists in the administration of an isotonic crystalloid solution without dextrose as an i.v. bolus of 20 ml/kg followed by a continuous infusion of dextrose – containing crystalloid solution if prolonged hydration is required. Intravenous rehydration should be started with isotonic fluid (normal saline) because this is more effective in reducing the risk of hyponatremia than hypotonic fluids (half normal saline with 5% dextrose) . Isotonic Ringer lactate is associated with a better outcome from shock compared with hypotonic fluids in children with severe malnutrition and hypovolemia . The Cincinnati Children's Hospital guidelines [6▪▪] recommend to start IVT with a bolus of 20 ml/kg of normal saline over 30–60 min followed by a maintenance volume of half normal saline with 5% dextrose to replace losses and maintain hydration. Despite the lack of evidence of efficacy, in the last years a rapid rehydration scheme (40–60 ml/kg normal saline bolus over 60 min) has been gradually incorporated into clinical practice with the aim to obtain a reduction of symptoms, an improvement of appetite, and a reduction of hospital stay and of global costs of AGE. A survey of North American physicians, specialized in pediatric emergency, found that several regimens are used [16▪▪]. In a recent clinical trial comparing two different i.v. schemes, the tolerance to the administration of 50 ml/kg in 1 h was similar to that of 50 ml/kg in 3 h, but it was associated to earlier discharge from emergency department (ED) . A recent trial comparing the effect of boluses of 20–40 ml/kg of 5% albumin solution or 0.9% saline solution or no bolus in critically ill African children, showed that both bolus-fluid resuscitation, compared with no bolus regimen, increased the absolute risk of death at 48 h by 3.3%. These data, although obtained in clinical conditions other than AGE, suggest that there may be severe risks associated to rapid rehydration regimens [18▪▪]. In order to evaluate the efficacy of rapid rehydration for AGE-induced dehydration, a randomized blinded comparative trial was conducted in children in whom oral rehydration failed and i.v. rehydration was required [19▪▪]. Children randomly received a 20 ml/kg (standard) or 60 ml/kg (rapid) of 0.9% saline infusion over 60 min followed by 5% dextrose in 0.9% saline at maintenance rate. Clinical dehydration scores, vital signs, and adverse events were recorded every 30 min for a total of 4 h. No difference in the percentage of children rehydrated after 2 h was observed between the two groups (36% in rapid rehydration group vs. 29% in standard rehydration group). There was no difference in the rates of prolonged treatment, mean dehydration scores, repeat visits to emergency, adequate oral intake. However, the median time to discharge was significantly longer in the rapid compared with the standard group (6.3 vs. 5.0 h; P = 0.03) and children receiving rapid i.v. rehydration were more commonly admitted to the hospital. The authors concluded that none of the outcomes support the use of rapid i.v. rehydration and that there was a trend toward worse outcomes in these children. This data strongly indicate that the routine use of i.v. rapid rehydration should be prescribed cautiously.
Only few of the many drugs proposed for AGE have proof of efficacy in preventing complications and in reducing hospital admission, duration of symptoms and the length of stay in hospital setting (Table 2).
Vomiting is probably the main indirect cause of hospital admission. However, the therapy for vomiting remains controversial. None of the currently available guidelines suggests a routine use of antiemetics in children with AGE [3–5,6▪▪,7,8▪], but emerging evidence indicates that selected antiemetics may help in oral rehydration delivery, and reduce i.v. rehydration and hospital admissions.
The use of ondansetron, a selective (5-HT3) serotonin antagonist, is progressively increasing [20▪] to the point that American Pediatric Emergency Medicine Physicians indicated ondansetron as the drug of choice in vomiting patients with AGE [16▪▪].
A recent systematic review, including seven trials and more than 1000 patients, provided evidence in support of ondansetron as adjunct therapy in case of mild-moderate dehydration [21▪▪].
A single oral dose (0.15–0.3 mg/kg) of ondansetron controlled vomiting and reduced hospitalization rates [risk ratio (RR) 0.40, 95% CI 0.19–0.83, P = 0.01] and i.v. fluids need (RR 0.57, 95% CI 0.42–0.76, P = 0.0002, NNT = 6) when administered in EDs [21▪▪]. This intervention may be highly cost-effective .
In a 5-year retrospective study, the increased use of ondansetron (from 1 to 18%) was associated with a reduction of i.v. rehydration (from 26 to 14%, P < 0.001), length of stay in ED (8.6 ± 3.4 to 5.9 ± 2.8 h, P = 0.03) and return visits (18–13% P = 0.008) [20▪].
Major concerns on antiemetics prescription have been historically related to the potential side effects. A Cochrane review only reported few cases of increased diarrhea secondary to ondansetron administration [21▪▪]. Nevertheless, in September 2011, the US Food and Drug Administration (FDA) released a warning on the use of ondansetron in patients with underlying heart conditions, such as congenital long QT syndrome, heart failure, and bradyarrhythmias . This was based on case reports of QT prolongation after ondansetron administration in adults  and children . However, in addition to heart conditions, the FDA extended the warning to patients predisposed to hypokalemia and hypomagnesemia, or taking medications that may lead to QT prolongation. Abnormalities in electrolyte serum levels may be frequent in AGE, which opens a burning question on a routine use of ondansetron to prevent the need of i.v. rehydration and hospitalization in the light of some (low) risk of (potentially severe) side effects.
Antiemetic drugs alternative to ondansetron are limited; domperidone is a widely used drug with little evidence of efficacy . A randomized controlled trial assessing the efficacy of ondansetron and domperidone compared with placebo in children admitted to EDs for AGE is currently ongoing in Italy [27▪].
A recent trial in Qatar showed no difference between ondansetron and metoclopramide in cessation of vomiting, length of stay, and side effects [28▪]. On the basis of these results, it was suggested that metoclopramide could represent an effective and cost-sparing alternative to ondansetron for persistent vomiting in poor countries. Considering the severe side effects reported for metoclopramide, this proposal raises concerns in terms of safety, mainly in developing areas where surveillance and accurate follow-up are limited.
Indications are, therefore, strongly needed on the use of antiemetics in AGE.
The simple replacement of lost fluids does not shorten the course of diarrhea and different approaches have been proposed to reduce duration and severity of diarrhea in hospitalized children, such as antimotility/antiperistaltic drugs, antesecretory, absorbents, and antimicrobial treatments.
These are recognized as first-line therapy for AGE in adjunct to rehydration , based on a demonstrated effect in reducing the duration of diarrhea by about 24 h, the risk of diarrhea lasting at least 4 days and the stool frequency on day 2 [30▪]. An analysis on hospitalized children also showed a significant effect of probiotics on duration of diarrhea (mean difference −20.90 h 95% CI −31.44 to −10.35) [30▪].
As the beneficial effects of probiotics are strain related, pooling data on different strains is inappropriate.
Lactobacillus rhamnosus GG [LGG] and Saccharomyces boulardii are the two strains, with consistent evidence of efficacy. LGG is the recommended treatment in evidence-based guidelines [3,6▪▪]. It also reduced the duration of hospitalization in previous meta-analysis .
Two recent double-blind RCTs, were conducted on S. boulardii in children hospitalized in low-income areas.
The first was carried out in two Brazilian hospitals and showed a reduction of diarrhea duration within 72 h from its onset. This reduction was significant in children with rotavirus infection (RR 0.45, 95% CI 0.28–0.74), but not in nonrotaviral diarrheal episodes [32▪].
The second study, performed on a small Bolivian population with rotaviral infection, compared the effect of S. boulardii and a mix of probiotics containing lactobacilli, bifidobacteria and S. boulardii with placebo. The authors reported a modest but significant effect of S. boulardii on the duration of diarrhea that was not observed with the combined probiotic product [33▪]. A new strain (DSM 17938) of Lactobacillus reuteri was tested in 70 children hospitalized with mild-to-moderate diarrhea [34,35▪]. L. reuteri reduced the duration of diarrhea (2.1 ± 1.7 vs. 3.3 ± 2.1 days, P < 0.03) and the prevalence of children with diarrheal stools at day 2 (55 vs. 81%, P < 0.02) and day 3 (46 vs. 73%, P < 0.03).
Guidelines produced in developing countries do not recommend probiotics in children with AGE  and their administration is currently considered as a common violation to recommendations [37▪].
This discrepancy between different geographic settings is essentially due to the limited evidence of efficacy available in developing areas wherein cause of diarrhea, availability of fluids/water and probably alimentary habits may limit probiotic efficacy.
Racecadotril, an enkephalinase inhibitor, is not approved by US FDA and data comes from European countries and developing areas [38▪▪]. In a recent meta-analysis including nine RCTs and more than 1300 inpatients and outpatients, racecadotril was effective in reducing diarrhea duration and stool output. The effect was independent from dehydration, rotavirus positivity and country [39▪▪].
A deterministic and probabilistic sensitivity analysis on the economic impact of racecadotril showed a reduction in the hospital expenses related to AGE event by about £380 due to primary care reconsultation and secondary referral [40▪].
Other antidiarrheal drugs
Zinc supplementation is recommended as universal treatment for acute diarrhea in childhood , based on several clinical trials and meta-analysis [41–43]. Efficacy is unclear in nonmalnourished children [44▪,45], but a clear efficacy has been shown in children severely malnourished .
Zinc-enriched ORS did not show similar efficacy in a recent trial in Indian inpatients [46▪]. A randomized placebo-controlled trial assessing the efficacy of a 14-days oral zinc supplementation in US inpatients and outpatients children is currently ongoing at the Boston Children's Hospital. The length of stay is the main outcome measure (clinicaltrials.gov NCT01198587).
Smectite is a natural clay with effects on permeability, cytokine production and electrolyte secretion, able to reduce duration of diarrhea and stool volumes.
A controlled trial, involving about 100 Indian children, showed a significant reduction of diarrhea duration of about 18 h [47▪].
A further option to be considered in severe and/or immunocompromised patients or in severe AGE episodes is oral administration of immunoglobulins [48,49]. This approach seems highly indicated for children in severe conditions with viral diarrhea. Oral administration of a hyperimmune immunoglobulin preparation produced from hens immunized against human rotavirus (anti HRV IgY, 500 mg × 4 per day) showed a significant effect on rotavirus excretion (P = 0.05), duration of diarrhea (P = 0.01), duration of i.v. rehydration (P = 0.03) and ORS needed (P = 0.004) [50▪]. As almost all the patients (92%) in the trial had, together with the rotavirus infection, a second enteric noncholera pathogen, the authors speculated that the product may improve the clinical outcomes also in patients with mixed enteric infections.
Florescu et al.[51▪] proposed the oral administration human immunoglobulins, for norovirus enteritis in a small population of patients that underwent bone marrow or solid organ transplantation or chemotherapy. A trend toward resolution of diarrhea and stool output was observed after 7 days from the onset of symptoms, although no benefits were found on the length of stay and hospital costs.
Antibiotics are not routinely recommended in pediatric AGE  and they may increase costs, prolong diarrheal episodes, and contribute to spreading antibiotic resistance . A quality care improvement approach with a multifaceted intervention led to a weak reduction of inappropriate antibiotic prescription in children with AGE in Kenya [53▪].
In developing areas where antibiotics are largely used to manage AGE, antibiotic resistance is becoming a common problem [54,55▪,56] and new molecules are being tested.
Vinh et al.[57▪] recently tested the efficacy of a 3-day course of gatifloxacin compared with the WHO standard treatment with ciprofloxacin for shigellosis in hospitalized children with no significant difference between the two antibiotics in terms of treatment failure (about 10%) and resolution of symptoms.
Several guidelines on the management of AGE in children are available, of good quality and similar in their indications [58▪▪]. Their application should limit the high number of inappropriate interventions that are common in hospital settings and could significantly reduce hospital costs . Children admitted to ED with mild-to-moderate dehydration often receive i.v. fluids and unnecessary laboratory tests. However, protocols to rehydrate children with AGE are needed. The rapid/ultrarapid rehydration schemes may be loaded with electrolyte imbalances and have no clear advantages compared with standard rehydration. The main advantage is an early discharge with the reduction of the ED overcrowding, however, children treated with rapid i.v. rehydration are often readmitted to the ED. Several studies support the use of antiemetics in ED to prevent hospitalization, but recently the FDA released a warning on the use of ondansetron in patients with underlying heart conditions and electrolyte disorders. Finally, although AGE is a self-limiting disease, several efforts are ongoing to find the ‘ideal drug’ for treatment of acute diarrhea.
Conflicts of interest
The authors have no conflict of interest to be declared.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
- ▪ of special interest
- ▪▪ of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 93–94).
1. Parashar UD, Burton A, Lanata C, et al. Global mortality associated rotavirus disease among children in 2004. J Infect Dis 2009; 200:s9–s15.
2. Hartling L, Bellemare S, Wiebe N. Oral versus intravenous rehydration for treating dehydration due to gastroenteritis in children. Cochrane Database Sys Rev 2006:CD004390.
3. Guarino A, Albano F, Ashkenazi S, et al. ESPGHAN/ESPID evidence-based Guidelines for the management of acute gastroenteritis in children in Europe Expert Working GroupEuropean society of gastroenterology, epatology and nutrition/European society for pediatric infectious diseases evidence-based guidelines for the management of acute gastroenteritis in children in Europe. J Pediatr Gastroenterol Nutr 2008; 46:s81–s184.
5. NICE Guidelines-Diarrhea and vomiting caused by gastroenteritis: diagnosis, assessment and management in children younger than 5 years. National Collaborating Centre for women's and children's Health. April 2009. http://http://www.nice.org.uk
6▪▪. Acute gastroenteritis guidelines Team, Cincinnati Children's Hospital Medical Center: evidence –based care guidelines for prevention and management of acute gastroenteritis in children aged 2 months to 18 years, http//http://www.cincinnatichildrens.org
/service/j/Anderson-center/evidence–based-care/gastroenteritis/Guideline 5, pages I-20. [Accessed 21 December 2011].
A very useful document with practical indications on the management of AGE in children.
7. Harris C, Wilkinson F, Mazza D, et al. Evidence based guidelines for the management of diarrhea with or without vomiting in children. Aust Fam Physician 2008; 37:22–29.
8▪. Wittenberg DF. Management guidelines for acute infective diarrhea/gastroenteritis in infants. S Afr Med J 2012; 102:104–107.
A recent position paper produced by a single author and focused on the management of South African children with acute diarrhea.
9▪▪. Desai R, Curns AT, Steiner CA, et al. All-cause gastroenteritis and rotavirus-coded hospitalizations among US children, 2000–2009. Clin Infect Dis 2012; 55:e28–e34.
A recent retrospective study reporting the decreases in rotavirus-coded hospitalization rates in 2008 and 2009 compared with rates in prevaccine years in United States. Implementation of rotavirus immunization program significantly reduced diarrhea hospitalizations and related hospital charges in US children.
10. Steiner MJ, DeWalt DA, Byerley JS. Is this child dehydrated? JAMA 2004; 291:2746–2754.
11▪. Nunez J, Liu DR, Nager AL. Dehydration treatment practices among pediatrics-trained and nonpediatrics trained emergency physicians. Pediatr Emer Care 2012; 28:322–328.
This is a survey comparing the management strategies for AGE of pediatric-trained and nonpediatric-trained emergency medicine physicians. It demonstrates that a large number of physicians frequently violate available guidelines. Although the article has several limitations due to the fact that the survey is not validated and is based on a ‘vignette’, its results are in keeping with other reports and the anonymous responses truly reflect what happens in clinical practice.
12. Fonseca BK, Holdgate A, Craig JC. Enteral vs intravenous rehydration therapy for children with gastroenteritis: a meta-analysis of randomized controlled trials. Arch Pediatr Adolesc Med 2004; 158:483–490.
13▪. Powell CVE, Priestley SJ, Young S, Heine RG. Randomized clinical trial of rapid versus 24-h rehydration for children with acute gastroenteritis. Pediatrics 2011; 218:e771.
This randomized clinical trial showed no significant difference in rehydration efficacy between a rapid regimen (100 ml/kg over 4 h) and the standard regimen of nasogastric rehydration (replacement of fluids over 24 h). Interestingly, a significantly higher proportion of secondary treatment failures in the rapid rehydration group were observed. The study has several limitations. It is not a double blind study, the sample size has not been reached.
14. Hanna M, Saberi MS. Incidence of hyponatremia in children with gastroenteritis treated with hypotonic intravenous fluids. Pediatr Nephrol 2010; 25:1471–1475.
15. Akech SO, Karisa J, Nakamya P, et al. Phase II trial of isotonic fluid resuscitation in Kenyan children with severe malnutrition and hypovolaemia. BBMC Pediatr 2010; 10:71–80.
16▪▪. Freedman SB, Sivabalsundaram V, Bohn V, et al. The treatment of pediatric gastroenteritis: a comparative analysis of pediatric emergency physicians’ practice patterns. Acad Emerg Med 2011; 18:38–45.
This survey aims to evaluate the current treatment practices in the treatment of AGE comparing practice patterns between Canadian and US physicians. Significant differences were observed between the two groups regarding the use of antiemetics, the choice of i.v. rehydration regimens, and the use of laboratory tests.
17. Nager AL, Wang VJ. Comparison of ultrarapid intravenous rehydration in pediatric patients with dehydration. Am J Emerg Med 2010; 28:123–129.
18▪▪. Maitland K, Kiguli S, Opoka RO, et al. Mortality after fluid bolus in African children with severe infection. N Engl J Med 2011; 364:2483–2495.
This trial performed on about 3000 children with shock and life-threatening infections who live in resource-limited areas, studied the role and effects of three different fluid resuscitation schemes including (5% albumin-bolus or 0.9% saline-bolus) or not (controls) administration of bolus. Authors demonstrated that fluid boluses significantly increased 48-h mortality in critically ill children with impaired perfusion. Children with AGE were excluded, but the results reported in that trial could have a significant impact on clinical management of severely dehydrated children, mainly in low-income countries.
19▪▪. Freedman SB, Parkin PC, Willan AR, Schuh S. Rapid versus standard intravenous rehydration in paediatric gastroenteritis: pragmatic blinded randomized clinical trial. BMJ 2011; 343:d6976.
This is a well conducted, extremely rigorous, randomized, blinded clinical trial demonstrating that rapid i.v. rehydration is not superior to standard regimen in rehydrating children with AGE. The main limitation is that the enrolled children are only moderately dehydrated, although this reflects what happen in developed countries.
20▪. Freedman SB, Tung C, Cho D, et al. Time-series analysis of ondansetron use in pediatric gastroenteritis. J Pediatr Gastroenterol Nutr 2012; 54:381–386.
A recent retrospective cohort study addressing the utility of ondansetron in ED settings in reducing i.v. rehydration therapy, length of stay and return visits by analyzing indirectly the consequences of its introduction on those outcomes during a 5 years time frame.
21▪▪. Fedorowicz Z, Jagannath VA, Carter B. Antiemetics for reducing vomiting related to acute gastroenteritis in children and adolescents. Cochrane Database of Systematic Reviews 2011:CD005506. doi:0.1002/14651858.CD005506.pub5.
A recent Cochrane systematic review on the use of antiemetics in pediatric population with gastroenteritis addressing the value of ondansetron as drug of choice in this population. Evidence shows an effective cessation of vomiting and reduced number of intravenous rehydration and hospital admissions.
22. Freedman SB, Steiner MJ, Chan KJ. Oral ondansetron administered in emergency departments to children with gastroenteritis: an economic analysis. PLoS Med 2010; 7:1000350.
24. Hafermann MJ, Namdar R, Seibold GE, Page RL 2nd. Effect of intravenous ondansetron on QT interval prolongation in patients with cardiovascular disease and additional risk factors for torsades: a prospective, observational study. Drug Healthc Patient Saf 2011; 3:53–58.
25. McKechnie K, Froese A. Ventricular tachycardia after ondansetron administration in a child with undiagnosed long QT syndrome. Can J Anaesth 2010; 57:453–457.
26. Albano F, Bruzzese E, Spagnuolo MI, et al. Antiemetics for children with gastroenteritis: off-label but still on in clinical practice. J Pediatr Gastroenterol Nutr 2006; 43:402–404.
27▪. Marchetti F, Maestro A, Rovere F, et al. Oral ondansetron versus domperidone for symptomatic treatment of vomiting during acute gastroenteritis in children: multicentre randomized controlled trial. BMC Pediatr 2011; 11:15–23.
This article presents an ongoing trial comparing the efficacy of ondansetron and domperidone in more than 500 children admitted to EDs for AGE. The main objective of the trial is to assess the efficacy of domperidone, a widely used antiemetic in selected countries.
28▪. Al-Ansari K, Alomary S, Abdulateef H, et al. Metoclopramide versus ondansetron for the treatment of vomiting in children with acute gastroenteritis. J Ped Gastroenterol Nutr 2011; 53:156–160.
A recent double-blinded nonrandomized trial comparing the efficacy of ondansetron and metoclopramide in 167 children with AGE and suggesting a role of metoclopramide as cost-effective alternative to ondansetron in developing areas and other poor settings.
29. Guarino A, Lo Vecchio A, Canani RB. Probiotics as prevention and treatment for diarrhea. Curr Opin Gastroenterol 2009; 25:18–23.
30▪. Allen SJ, Martinez EG, Gregorio GV, Dans LF. Probiotics for treating acute infectious diarrhoea. Cochrane Database of Systematic Reviews 2010:CD003048.
A Cochrane meta-analysis on the use of probiotics as treatment for acute gastroenteritis. The authors report a significant effect of probiotics in reducing duration and frequency of diarrhea and the risk of persistent diarrhea. However, the lack of subgroup analysis makes those results difficult to be applied in the pediatric hospital setting.
31. Szajewska H, Skorka A, Ruszczynski M, et al. Meta-analysis: Lactobacillus GG for treating acute diarrhoea in children. Aliment Pharmacol Ther 2007; 25:871–881.
32▪. Correa N, Penna FJ, Lime FMLS, et al. Treatment of acute diarrhea with Saccharomyces boulardii in infants. J Pediatr Gastroenterol Nutr 2011; 53:497–501.
An intention-to-treat and per-protocol analysis reported significant results of the intervention on duration of diarrhea, but when data were analyzed according to the presence of rotavirus, it was clear that a cumulative effect size was responsible for the efficacy of S. boulardii on viral rotavirus infection.
33▪. Grandy G, Medina M, Soria R, et al. Probiotics in the treatment of acute rotavirus diarrhea. A randomized, double-blind, controlled trial using two different probiotic preparation in Bolivian children. BMC Infect Dis 2010; 10:253–259.
This trial provides evidence in support of S. boulardii obtained in rotavirus diarrhea.
34. Rosander A, Connoly E, Roos S. Removal of antibiotic resistance gene carrying plasmids from Lactobacillus reuteri ATCC 55730 and characterization of the resulting daughter strain, L reuteri DSM 17938. Appl Environ Microbiol 2008; 74:6032–6040.
35▪. Francavilla R, Lionetti E, Castellaneta S, et al. Randomized clinical trial: Lactobacillus reuteri DSM 17938 vs placebo in children with acute diarrhea – a double blind study. Aliment Pharmacol Ther 2012; 36:363–369.
This RCT was performed on a small population of inpatients and demonstrated the efficacy of the new L. reuteri daughter strain in reducing duration and relapse of diarrhea. No efficacy has been found for the length of stay.
36. Bhatnagar S, Lodha R, Choudhury P, et al. IAP guidelines 2006 on management of acute diarrhea. Indian Pediatr 2007; 44:380–389.
37▪. Pathak D, Pathak A, Marrone G, et al. Adherence to treatment guidelines for acute diarrhea in children up to 12 years in Ujjain, India: a cross-sectional prescription analysis. BMC Infectious Diseases 2011; 11:32–40.
A cross-sectional study assessing the prescription for acute gastroenteritis in major hospitals and pharmacies in a big Indian city. Any prescription but ORS and zinc, was considered to be inappropriate according to referral guidelines. Only a minority of prescriptions were made in compliance with recommendations.
38▪▪. Guarino A, Dupont C, Gorelov AV, et al. The management of acute diarrhea in children in developed and developing areas. From evidence base to clinical practice. Expert Opin Pharmacother 2012; 13:17–26.
A critical evaluation of therapeutic interventions with a worldwide perspective.
39▪▪. Lehert P, Cheron G, Calatayud GA, et al. Racecadotril for childhood gastroenteritis: an individual patient data meta-analysis. Dig Liver Dis 2011; 43:707–713.
This is the first meta-analysis assessing the effect of racecadotril for acute diarrhea. The authors included published and not-published data, and performed an individual patient analysis introducing as outcome measure the percentage of patients with diarrhea shorter than 2 days. Although there was no sub-group analysis for hospitalized patients, the stool output, a reliable outcome measure considered only in hospitalized patients, showed a significant reduction. Some methodological issues related to the subgroup analysis, outcome measures and study selection, may limit these conclusions.
40▪. Rautenberg TA, Zerwes U, Foerster D, Aultman R. Evaluating the cost utility of racecadotril for the treatment of acute watery diarrhea in children: the RAWD model. Clinicoecon Outcomes Res 2012; 4:109–116.
A recent cost-effectiveness analysis on the use of racecadotril in children with AGE. According to the authors racecadotril seems to be cost-effective from a UK payer perspective, as it reduces costs by £380.
41. Patro B, Golicki D, Szajewska H. Meta-analysis: zinc supplementation for acute gastroenteritis in children. Aliment Pharmacol Ther 2008; 28:713–723.
42. Lazzerini M, Ronfani L. Oral zinc for treating diarrhoea in children. Cochrane Database Syst Rev 2008:CD005436.
43. Lukacik M, Thomas RL, Aranda JV. A meta-analysis of the effects of oral zinc in the treatment of acute and persistent diarrhea. Pediatrics 2008; 121:326–336.
44▪. Passariello A, Terrin G, De Marco G, et al. Efficacy of a new hypotonic oral rehydration solution containing zinc and prebiotics in the treatment of childhood acute diarrhea: a randomized controlled trial. J Pediatr 2011; 158:228–292.
A recent single blind placebo-controlled trial on the use of a zinc-enriched ORS in Italian children with AGE showing an effect of intervention in reducing diarrhea duration.
45. Patro B, Szymański H, Szajewska H. Oral zinc for the treatment of acute gastroenteritis in Polish children: a randomized, double-blind, placebo-controlled trial. J Pediatr 2010; 157:984–988.
46▪. Wadhwa N, Natchu UC, Sommerfelt H, et al. ORS containing zinc does not reduce duration or stool volume of acute diarrhea in hospitalized children. J Pediatr Gastroenterol Nutr 2011; 53:161–167.
This controlled trial on 500 Indian children randomized to ORS or Zinc-ORS, does not support the use of enriched oral solution and this setting.
47▪. Mujawar QM, Naganoor R, Ali MD, et al. Efficacy of dioctahedral smectite in acute watery diarrhea in Indian children: a randomized clinical trial. J Trop Pediatr 2012; 58:63–67.
A recent randomized open-labeled controlled trial on 117 Indian children with acute watery diarrhea. Smectite was associated with a reduction of diarrheal duration and prevention of protracted course of diarrhea without any relevant side effect nor difficulty in drug administration.
48. Guarino A, Canani RB, Russo S, et al. Oral immunoglobulins for treatment of acute rotaviral gastroenteritis. Pediatrics 1994; 93:12–16.
49. De Marco G, Bracale I, Buccigrossi V, et al. Rotavirus induces a biphasic enterotoxic and cytotoxic response in human-derived intestinal enterocytes, which is inhibited by human immunoglobulins. J Infect Dis 2009; 200:813–819.
50▪. Rahman S, Higo-Moriguchi K, Htun KW, et al. Randomized placebo-controlled clinical trial of immunoglobulin Y as adjunct to standard supportive therapy for rotavirus-associated diarrhea among pediatric patients. Vaccine 2012; 30:4661–4669.
In this article the authors reported the effects of hyperimmune immunoglobulin against a broad range of rotavirus serotypes on diarrheal outcomes in mice and in a population of children aged 3–14 months with acute rotavirus-positive diarrhea. The results demonstrate a potential role of oral immunoglobulin as therapy of acute intestinal infection in pediatric patients.
51▪. Florescu DF, Hermsen ED, Kwon JY, et al. Is there a role for oral human immunoglobulin in the treatment for norovirus enteritis in immunocompromised patients? Pediatr Transpl 2011; 15:718–721.
A matched case–control study on a small and heterogeneous population (24 patients) of adults and children (mean age 2 years) mainly the recipients of bone marrow or solid organ transplantation treated with a total dose of 200 mg/kg of human immunoglobulins administration through oral route eight times in 2 days.
52. Kohanski MA, DePristo MA, Collins JJ. Sublethal antibiotic treatment leads to multidrug resistance via radical-induced mutagenesis. Mol Cell 2010; 37:311–320.
53▪. Opondo C, Ayieko P, Ntoburi S, et al. Effect of a multifaceted quality improvement intervention on inappropriate antibiotic use in children with nonbloody diarrhoea admitted to district hospitals in Kenya. BMC Pediatr 2011; 11:109.
A randomized quality improvement intervention multicenter study carried out in Kenya to reduce the inappropriate use of antibiotics in children hospitalized for AGE. The authors reported a ‘substantial’ effect on antibiotic prescription also if the efficacy of the multifaceted intervention is not clearly shown.
54. Vinh H, Nhu NT, Nga TV, et al. A changing picture of shigellosis in southern Vietnam: shifting species dominance, antimicrobial susceptibility and clinical presentation. BMC Infect Dis 2009; 9:204.
55▪. Meng CY, Smith BL, Bodhidatta L, et al. Etiology of diarrhea in young children and patterns of antibiotic resistance in Cambodia. Pediatr Infect Dis J 2011; 30:331–335.
A recent controlled study analyzing the cause and resistance pattern of 600 cases of diarrhea in a developing country. The authors reported a high prevalence of antibiotic resistance for the most frequent isolated pathogens.
56. Suman Nandy, Utpala Mitra, K. Rajendran, et al.
Subtype prevalence, plasmid profiles and growing fluoroquinolone resistance in Shigella from Kolkata, India (2001–2007): a hospital-based study. Trop Med Int Health 2010; 15:1499–1507.
57▪. Vinh H, Anh VTC, Anh ND, et al. A multi-center randomized trial to assess the efficacy of gatifloxacin versus ciprofloxacin for the treatment of shigellosis in Vietnamese children. PLoS Negl Trop Dis 2011; 5:e1264.
A randomized controlled open-label trial comparing the effects of a new generation fluoroquinolone (gatifloxacin) vs. the standard treatment with ciprofloxacin in Vietman, a Shigella endemic area with a high prevalence of antibiotic resistant bacterial strains.
58▪▪. Lo Vecchio A, Giannattasio A, Duggan C, et al. Evaluation of the quality guidelines for acute gastroenteritis in children with the AGREE instruement. J Pediatr Gastroenterol Nutr 2011; 52:183–189.
A methodological evaluation of quality of guidelines on AGE in children performed through the Appraisal of Guidelines for Research and Evaluation instrument. The assessment highlights the main strengths and limitations of single documents and shows an overall solid quality level with some limitation in stakeholder involvement and editorial independence.
59. Tieder JS, Robertson A, Garrison MM. Pediatric hospital adherence to the standard of care for acute gastroenteritis. Pediatrics 2009; 124:e1081–e1087.
Keywords:© 2013 Lippincott Williams & Wilkins, Inc.
acute diarrhea; acute gastroenteritis; hospital; rehydration