Pediatrics
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Acute gastroenteritis is known to result in significant morbidity in developed countries. Furthermore, it is responsible for millions of deaths in developing nations. Oral rehydration therapy (ORT) is successful for many patients, however the persistence of vomiting greatly hinders the effects of ORT. While the American Academy of Pediatrics does not typically favor the use of antiemetic agents, most emergency physicians feel that it is in the best interest of the child to administer these medications in order to facilitate care and help the patient to symptomatically feel better. Antiemetic medications that are currently available include ondansetron, granisetron, tropisetron, dolasetron, ramosetron, promethazine, dimenhydrinate, metoclopramide, domperidone, droperidol, prochlorperazine, and trimethobenzamide. This journal club will review several articles that show the effectiveness of ondansetron in patients with acute gastroenteritis. 
 
Study #1: In subjects with acute gastritis/acute gastroenteritis and mild to moderate dehydration who failed initial oral rehydration therapy, the proportion of children who received intravenous hydration was smaller in the ondansetron group than in the placebo group.
 
Citation
Roslund G, Hepps TS, McQuillen KK. The Role of Oral Ondansetron in Children With Vomiting as a Result of Acute Gastritis/Gastroenteritis Who Have Failed Oral Rehydration Therapy: A Randomized Controlled Trial. Annals of Emergency MedicineVol 52, Issue 1, Pages 22-29, e6 (July 2008)


Methodology & Results
This double-blind, placebo-controlled, prospective, randomized trial enrolled a convenience sample of subjects 1 to 10 years old, with acute gastritis or acute gastroenteritis, who failed oral rehydration therapy in the emergency department (ED). Subjects received a weight-based dose of ondansetron (0.15 mg/kg of the orally dissolving tablet) or placebo, and oral rehydration therapy was reattempted 30 minutes later. If a subject vomited or refused to drink, he or she was considered a failed oral rehydration therapy and received acute gastroenteritis. If a subject tolerated adequate oral rehydration therapy, he or she was discharged. Parents completed symptom diaries and were contacted by telephone for follow-up. 106 subjects were enrolled: 51 received ondansetron and 55 received placebo. Eleven of 51 (21.6%; 95% confidence interval [CI] 11.3% to 35.3%) of subjects who received ondansetron required intravenous hydration and 30 of 55 (54.5%; 95% CI 40.6% to 68%) of placebo subjects required intravenous hydration (p <0.001) for a difference of 32.9% (95% CI 14.54% to 48.37%). Admission rates were 5.9% (3/51) with ondansetron and 12.7% (7/55) with placebo.

Study #2: In children with gastroenteritis and dehydration, a single dose of oral ondansetron reduces vomiting and facilitates oral rehydration and may thus be well suited for use in the emergency department.
 
Citation
Freedman SB, Adler M, Seshadri R, Powell EC. Oral ondansetron for gastroenteritis in a pediatric emergency department. N Engl J Med 2006 Apr 20;354(16):1698-705.

Methodology & Results
Vomiting limits the success of oral rehydration in children with gastroenteritis. We conducted a double-blind trial to determine whether a single oral dose of ondansetron, an antiemetic, would improve outcomes in children with gastroenteritis.

We enrolled 215 children 6 months through 10 years of age who were treated in a pediatric emergency department for gastroenteritis and dehydration. After being randomly assigned to treatment with orally disintegrating ondansetron tablets or placebo, the children received oral-rehydration therapy according to a standardized protocol. The primary outcome was the proportion who vomited while receiving oral rehydration. The secondary outcomes were the number of episodes of vomiting and the proportions who were treated with intravenous rehydration or hospitalized.

As compared with children who received placebo, children who received ondansetron were less likely to vomit (14 percent vs. 35 percent; relative risk, 0.40; 95 percent confidence interval, 0.26 to 0.61), vomited less often (mean number of episodes per child, 0.18 vs. 0.65; P<0.001), had greater oral intake (239 ml vs. 196 ml, P=0.001), and were less likely to be treated by intravenous rehydration (14 percent vs. 31 percent; relative risk, 0.46; 95 percent confidence interval, 0.26 to 0.79). Although the mean length of stay in the emergency department was reduced by 12 percent in the ondansetron group, as compared with the placebo group (P=0.02), the rates of hospitalization (4 percent and 5 percent, respectively; P=1.00) and of return visits to the emergency department (19 percent and 22 percent, P=0.73) did not differ significantly between groups.

Study #3: Intravenous ondansetron decreases vomiting in children with gastroenteritis. In addition, ondansetron reduces the need for admission in those who are treated at an initial visit to the emergency department and have a measured serum carbon dioxide > or =15 mEq/L. The safety and low cost of this therapy suggests that ondansetron can be valuable in treating gastroenteritis in children.
 
Citation
Reeves JJ, Shannon MW, Fleisher GR. Ondansetron decreases vomiting associated with acute gastroenteritis: a randomized, controlled trial. Pediatrics. 2002 Apr;109(4):e62.

Methodology & Results
Relatively little research has examined the role of antiemetic agents in the treatment of acute gastroenteritis. The use of the selective 5-HT3 receptor antagonists (eg, ondansetron) offers a potentially valuable treatment option. The objective of this study was to evaluate the efficacy of ondansetron for the treatment of vomiting associated with acute gastroenteritis in children.

A randomized, double blind, placebo-controlled trial was conducted in the emergency department of a tertiary-care children’s hospital. Eligible patients were 1 month to 22 years old and required intravenous fluids for gastroenteritis. Of 172 patients approached, 107 were enrolled (54 to intravenous ondansetron, 53 to placebo). The mean age was 5.3 years, and 53% of the patients were male. The frequency of vomiting, admission rate, and occurrence of complications were measured.

After drug administration, 38 (70%) of the 54 patients in the ondansetron group had complete cessation of vomiting compared with 27 (51%) of the 53 patients in the placebo group. Sixteen (30%) of the 53 patients in the placebo group required admission compared with 14 (26%) of the 54 in the ondansetron group. An analysis of previously untreated patients with a measured serum carbon dioxide > or =15 mEq/L showed that 11 (23%) of the 47 who received placebo were admitted compared with 3 (7%) of the 43 who received ondansetron. No significant complications were detected.

Study #4: Ondansetron was effective in reducing the emesis from gastroenteritis during the ED phase of oral rehydration and in lowering the rates of intravenous fluid administration and hospital admission.

Citation
Ramsook C, Sahagun-Carreon I, Kozinetz CA, Moro-Sutherland D. A randomized clinical trial comparingoral ondansetron with placebo in children with vomiting from acute gastroenteritis. Ann Emerg Med 2002 Apr;39(4):397-403

Methodology & Results
Vomiting in children suffering from acute gastroenteritis interferes with the oral rehydration process and equally frustrates parents and health care providers. Adjuncts such as promethazine and metoclopramide are less than optimally effective and are associated with side effects. Ondansetron, a 5-HT3 receptor antagonist marketed as Zofran, is a safe and effective antiemetic used extensively in oncology and postoperative patients. We evaluate the effect of the antiemetic ondansetron versus placebo on the clinical outcome of patients with vomiting from gastroenteritis in a pediatric emergency department.

This was a randomized, prospective, double-blind clinical trial in a university-affiliated children’s hospital ED. Children between the ages of 6 months and 12 years who had vomited at least 5 times during the preceding 24 hours were randomized to receive either oral ondansetron or a taste- and color-matched placebo. Oral rehydration was commenced 15 minutes later at 5 mL/min per standard oral rehydration protocols. Patients were discharged after they voided and continued standard oral rehydration at home with the introduction of a bananas, rice, applesauce, and toast (BRAT) diet after the first 24 hours. Any patient requiring admission was considered a treatment failure, and no further doses were given. Discharged patients were given 5 additional doses to be used every 8 hours, and they were contacted by telephone 24 and 48 hours after discharge to record the number of episodes of vomiting and diarrhea. The parents were also required to complete a diary of the same information, which was mailed to the investigators for confirmation of the telephone data. One hundred forty-five patients were enrolled, of whom 51% (n=74) were randomized to ondansetron. At baseline, age distribution, sex, and severity of illness did not differ between the ondansetron and placebo groups. During the observation period in the ED, the median number of episodes of vomiting was 0 in both groups, but the rank sum of vomiting episodes was significantly lower in the ondansetron group (P =.001). The number of episodes of emesis in the ED after enrollment ranged from 0 to 7 in the placebo group and 0 to 2 in the ondansetron group. During the 48 hours of follow-up, the median number of episodes of vomiting remained 0, with no statistically significant difference between the groups. There was no statistically significant difference in the rank sum of episodes of diarrhea in the ED between the groups (P =.622); however, during the next 48 hours, the patients in the ondansetron group had significantly more diarrhea than the placebo group. A lower proportion of patients receiving ondansetron compared with placebo required intravenous fluid therapy (P =.015). The admission rate was also lower in patients receiving ondansetron (P =.007). The revisit rate was higher in the ondansetron group compared with the placebo group (P =.047).


Final Analysis:
Ondansetron is very effective for patients who present with complaints of vomiting. As always, the cause of the underlying complaint should be sought after. I would also discourage the prescribing of more than 2-3 additional doses of an anti-emetic agent as this can mask underlying disease and we want the patient to follow up. Some physicians feel that antiemetic agents should not be used as acute gastroenteritis is a self-limiting disease, antiemetic agents have serious adverse effects and vomiting can help “ rid the body of toxic substances. However, several studies have shown that anti-emetic medications are commonly prescribed in the treatment of pediatric gastroenteritis and that adverse events are uncommon. The randomized clinical trials that I have referenced show that ondansetron is efficacious for the treatment of gastroenteritis-related vomiting. The dose of ondansetron is 0.15mg/kg, however, I do like the easy scheme used in the Freedman article of: 2mg for 8-15kg, 4mg/kg for 15-30kg and 8mg for >30kg.
Judicious use of ondansetron will significantly increase the success of ORT and reduce health care costs by decreasing the necessity of intravenous fluid therapy hospitalization. While it is practical to give a dose of ondansetron in the triage area and start ORT, it is imperative that the underlying cause of the vomiting be sought after and this be the priority when a patient presents with vomiting. Please also remember that phenergan has a block box FDA warning against it’s use in children less than 2 years of age.
As a reminder, patients with vomiting alone should never be given the diagnosis of “gastroenteritis.” Causes of vomiting include:

Infections-UTI, Meningitis, Otitis media
Head Injury-non accidental trauma should also be excluded
Inborn errors of metabolism
Endocrine- ie diabetes, adrenal insufficiency
GI causes- intussusception, appendicitis, malrotation with volvulus, pyloric stenosis
GU-torsion, hernia

Ghazala Q. Sharieff, MD, is the medical director and associate clinical professor at Rady Children’s Hospital and Health Center in San Diego, Cal. Dr. Sharieff is also the director of pediatric emergency medicine for the Palomar-Pomerado Health System
 

Comments   

# Pharm.D.Bill Murray 2008-10-26 00:08
Ghazala, note typo (4mg/kg for 15-30kg) in your comments. Should be 4 mg, not per kg.
:-)
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