Alimentary Pharmacology & Therapeutics

Clinical trial: oral ondansetron for reducing vomiting secondary to acute gastroenteritis in children a double-blind randomized study
H. L. YILMAZ*, R. D. YILDIZDAS & Y. SERTDEMIR

*Department of Pediatric Emergency Medicine, Medical School of Cukurova University, Adana, Turkey; Department of Pediatric Intensive Care Medicine, Medical School of Cukurova University, Adana, Turkey; Department of Biostatistics, Medical School of Cukurova University, Adana, Turkey Correspondence to: Dr H. Levent Yilmaz, Yenibaraj M. 68001 S. Gulek Plaza A Blok 6 9 01150 Seyhan, Adana, Turkey. E-mail: hyilmaz@cu.edu.tr

SUMMARY Background Vomiting as a consequence of gastroenteritis frequently occurs in children. It is still debatable whether vomiting should be treated with antiemetic drugs. Aim To investigate potential benecial effects of ondansetron in treating vomiting during acute gastroenteritis. Methods A randomized, double blind, placebo-controlled trial was performed in our emergency departments. Children, aged 5 months to 8 years, were randomized to receive either ondansetron 0.2 mg kg or placebo at 8h intervals. The primary outcome measure was the frequency of emesis during an 8-h-period after enrolment. Results A hundred and nine patients were enrolled; 54 received placebo and 55 received ondansetron. As compared with the children who received placebo, children who received ondansetron were less likely to vomit both during the rst 8-h follow-up in the emergency department [relative risk (RR): 0.33, 95% CI: 0.190.56, NNT: 2, 95% CI: 1.63.5], and during the next 24-h follow-up (RR: 0.15, 95% CI: 0.070.33, NNT: 2, 95% CI: 1.32.1). Conclusion Ondansetron may be an effective and efcient treatment that reduces the incidence of vomiting from gastroenteritis during both the rst 8 h and the next 24 h, and is probably a useful adjunct to oral rehydration.
Aliment Pharmacol Ther 31, 8291

Publication data Submitted 17 July 2009 First decision 31 July 2009 Resubmitted 12 September 2009 Accepted 13 September 2009 Epub Accepted Article 16 September 2009

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2010 Blackwell Publishing Ltd doi:10.1111/j.1365-2036.2009.04145.x

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INTRODUCTION
Acute gastroenteritis is a common cause of mortality and morbidity in children and is an important health problem worldwide.14 Current recommendations for the treatment of acute gastroenteritis focus primarily on the correction of dehydration and electrolyte abnormalities.1, 5 Oral rehydration is recommended for the treatment of mild-to-moderate dehydration caused by acute gastroenteritis1, 6 and it has been shown to be safe and cost-effective.3 However, it remains widely underused.79 Indeed, paediatric emergency physicians are more likely to choose intravenous over oral rehydration when the child vomits repeatedly.8, 9 According to estimations, oral rehydration is used in under 30% of the cases of diarrhoea in the US8, 9 and some physicians prescribe antiemetics such as promethazine, prochlorperazine, trimethobenzamide and metoclopramide for the treatment of vomiting in children with acute gastroenteritis.10, 11 However, these drugs are not recommended because of their side effects such as somnolence, nervousness, irritability, dystonic reactions and other extrapyramidal symptoms.1, 6, 11, 12 On the other hand, new antiemetics such as ondansetron and granisetron, which have far fewer side effects, are being used successfully in children receiving chemotherapy and post-operative patients.13 There have been a limited number of studies evaluating the role of ondansetron in the treatment of acute gastroenteritis complicated by vomiting.2, 3, 5, 7, 14, 15 Enough data have not been collected yet to make a nal judgment on the possibility of using ondansetron to support oral rehydration treatment (ORT) in acute gastroenteritis.4, 16 Therefore, we conducted a study to investigate potential benecial effects of oral ondansetron vs. placebo in treating vomiting during acute gastroenteritis in children.

METHODS
A randomized, double blind, placebo-controlled trial was performed in the emergency departments of one university hospital and one government hospital between August 2003 and September 2004. The study protocol was approved by our institutional review board and informed consent was granted by all patients or their guardians. All patients with symptoms consistent with acute gastroenteritis were examined by a paediatrician (HLY), and the patients who had nonbillious, nonbloody vomit at least 4 times in the last 6 h, who could not tolerate
Aliment Pharmacol Ther 31, 8291 2010 Blackwell Publishing Ltd

oral feeding, who had at least four episodes of diarrhoea in the previous 24 h, and who had mild-to-moderate dehydration were included in the study. Aetiology of acute gastroenteritis (viral, bacterial or amebic) was not taken into account in the patients included in the study. As an 8-h hospital observation had been planned, only the patients presenting between 7 AM and 9 AM on the weekdays were included in the study. Those presenting on Saturdays and Sundays were excluded. Exclusion criteria were a history of liver disease, ondansetron allergy or presence of any disease (such as congenital heart disease, immune deciency, malignancy, malnutrition, cystic brosis, sickle cell anaemia, diabetes mellitus), prior abdominal operation, ndings indicating a disease other than gastroenteritis on physical examination (such as focal neurologic signs, abdominal distention, peritoneal signs, abdominal tenderness, shock, pneumonia), severe dehydration, antiemetics use within the last 72 h, administration of oral or inhaled corticosteroids within the last week and chronic drug use (other than vitamins). According to the study protocol, treatment, observation and discharge decisions about the patients were carried out by two paediatricians (Dr. Ilhan Kavas and Dr. Adnan l), not by the investigators of the study. Karacabag The computerized randomization codes of the patients were produced in blocks of six randomizations by a statistician, who was not one of the investigators of this study, from the Department of Medical Biostatistics in our hospital and the pharmacies of the hospitals were given these codes. Every morning at the pharmacies of the hospitals, orally disintegrating ondansetron tablets were dissolved in 0.9% saline solution of 4 mL and drawn into 5 mL injectors, and identical looking placebo liquid of 4 mL was also drawn into 5 mL injectors by a pharmacist who was not one of the investigators of this study. Code numbers were written on the injectors in accordance with the randomization and they were placed in the refrigerator. We planned to administer a total of three doses of oral ondansetron 0.2 mg kg (0.2 mL kg) at 8 h intervals. Therefore, the study uid of 0.2 mL kg was administered by a nurse orally from injectors containing ondansetron or injectors containing placebo according to the randomization order. The subjects, parents, study personnel and other medical staff were blinded to which study drug was given. Thirty minutes after the drug was administered, the standard ORT protocol used in both hospitals and prepared upon the basis of WHO recommendations17 was started.

84 H . L . Y I L M A Z et al.

Administration of 75 mL kg ORT solution (Ge-oral, Kansuk, Turkey), containing 3.5 g sodium chloride, 2.9 g trisodium citrate, 1.5 g potassium chloride and 20 g glucose anhydride in each package, to patients with observed dehydration at the rate of 0.5 mL kg every 2 min with a spoon, glass or syringe was ordered. During and 4 h after ORT, the success of ORT and oral uid tolerance were evaluated. Oral uid tolerance was considered good when oral uid intake was 50 mL kg or over in the rst 4 h, it was considered insufcient when oral uid intake was between 20 and 49 mL kg, and it was considered lacking when oral uid intake was 19 mL kg or less. All patients were re-examined by the paediatrician at the eighth hour of ORT. However, when the patients developed additional complaints, or when they refused ORT, they were re-evaluated by the paediatrician without delays. During each examination, the patients were evaluated for fever, weight, hydration level, number of vomiting, number of stools, oral intake tolerance, sufciency of oral intake, if possible, IV rehydration necessity and hospitalization necessity. Decisions about the patients observed throughout ORT were made as in the following (Figure 1): (i) At the end of the initial 8 h, the patients who could tolerate oral intake with no vomiting were discharged. Before discharge, they were given the second dose (0.2 mL kg) of ondansetron or placebo. The study uid was given to the caregivers in an injector. They were instructed the method of application and the time of administration. (ii) When the patients vomited more than 4 times in the rst 8 h, or 2 or more times in 1 h (except for the rst hour), intravenous uid treatment was started and the study protocol was discontinued. (iii) When the patients received insufcient oral uids, showed no weight gain and vomited 34 times and the severity of dehydration was not moderate severe at the end of the rst 8 h, they were admitted to the paediatric emergency department (ED) observation unit and the study protocol was continued. a. When the patients admitted to the paediatric ED observation unit vomited three or more times and oral intake was insufcient or none, they were admitted to the ward, intravenous uid treatment was started and the study protocol was discontinued. (iv) When the uid intake was insufcient, there was no weight gain and vomiting occurred three or more times, and when the severity of dehydration was

moderate at the end of the rst 8 h, the children were admitted to the paediatric ED observation unit, intravenous uid treatment was started and the study protocol was discontinued. (v) When the patients refused oral uid intake three times consecutively, intravenous uid treatment was started and the study protocol was discontinued. (vi) As a result of an evaluation carried out 8 h later, the patients for whom intravenous uid treatment had to be started, who had completed their hydration and who could tolerate oral intake without vomiting were discharged. (vii) When abnormal ndings (such as distension of the abdomen, bloody bilious vomit, acute abdominal ndings, seizures, etc.) were detected during observation, when there was no oral intake in spite of IV uid treatment, when dehydration was not better, the patients were admitted to the ward. In all these instances, the study protocol was discontinued. (viii) When the patients showed weight loss at the end of the rst 8 h, they were admitted to the ward and the study protocol was discontinued. The caregivers of the patients discharged at the end of the rst 8 h were told that they would be contacted by telephone in 16 h, and asked for information about the patients. They were informed that they would be asked about the general condition of the patients at home, number of stools, number of vomiting, nourishment, administration time of the study medication, side effects of the drug and whether they had to take the children to another doctor or hospital. The telephone calls were made by a paediatrician (RDY) blinded to the patients. The doctor was given a list of the names and telephone numbers of the patients to be called at the end of each study day by the nurse observing the patients. When discharged patients vomited three or more times or when they did not have oral intake or when their oral intake was insufcient, they were asked back to the hospital for re-evaluation. When a patient was asked back to the hospital, Dr. RDY informed a paediatrician (Dr. Ilhan Kavas) not involved in the study. Re-evaluations were carried out by this paediatrician. Records of the patients were given to the study nurse the next day, and placed in the study le. The primary outcome measure was the frequency of emesis during an 8-h period after enrolment. The secondary outcomes were the rates of intravenous uid administration or admission to hospital, toleration of ORT, weight gain and frequency of diarrhoea. Intravenous uid administration or hospitalization (except
Aliment Pharmacol Ther 31, 8291 2010 Blackwell Publishing Ltd

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125 patients conformed to study criteria 11 patients refused to enroll the study

FIRST 8 HOURS

109 patients asked to enroll the study

109 patients were randomized

Ondansetron 55

Placebo 54

Discharged 54

24-hour observation 1

IV fluid treatment 2

Discharged 42

24-hour observation 10

THE NEXT 24 HOURS

Revisit 7

Discharged 1

Admission 2

Revisit 6

Discharged Admission 6 3

IV fluid treatment 1

Discharged 4

IV fluid treatment 1

Admission 2

IV fluid treatment 1

Discharged 5

Admission 1

Discharged 1 FINAL DECISION

Admission 1

ONDANSETRON

PLACEBO

ORT successful 52

ORT Unsuccessful 3

ORT successful 44

ORT unsuccessful 10

Figure 1. Patient progress throughout the trial.

observation in the paediatric ED observation unit) was considered as treatment failure. All patients were examined for possible side effects of ondansetron (such as diarrhoea, headache, constipation, dizziness, malaise, abdominal pain, xerostomia and weakness etc.).
Aliment Pharmacol Ther 31, 8291 2010 Blackwell Publishing Ltd

Data analysis
The study sample size was determined as in the following. The sample size was considered as 51 persons in each group assuming that in the 8th hour after treatment, the rate of vomiting in the control group

86 H . L . Y I L M A Z et al.

was 50%, and that there would be a 30% decrease in the rate of vomiting in the ondansetron group, and that the study would have a statistical power of 85% and a = 0.05. SPSS v16 (SPSS, Inc, Chicago, IL, USA) was used for statistical analysis. The study was a double-blind, placebo-controlled clinical trial. T-test was used to compare continuous variables like age, weight and body temperature between the groups. MannWhitney U test was used to compare number of diarrhoea episodes between the groups. Chi-square test was used to compare categorical variables like the degree of dehydration and emesis (vomiting) at initial presentation and 8 and 24 h after medication between the placebo and ondansetron groups.

RESULTS
Children presenting between 7 AM and 9 AM on weekdays from August 2003 to September 2004 were included in the study. One hundred and twenty-ve patients presenting during the above mentioned period fullled the study criteria. Of 125 patients, 11 did not agree to participate. The remaining 109 patients were enrolled in the study. Ondansetron was administered to 55 patients and placebo to 54 patients (Figure 1). Baseline characteristics of the two groups were not signicantly different as shown in Table 1.

from 0 to 5 in the placebo group and from 0 to 3 in the ondansetron group. The mean number of episodes of vomiting was signicantly lower among the children who received ondansetron than among those who received placebo (0.36 vs. 1.33, P < 0.001). In the paediatric ED, during the rst 8 h of observation, the proportion of still vomiting patients was 21.8% in the ondansetron group, and 66.7% in the placebo group (Figure 2, and Table 2) and the difference between the two groups was statistically signicant [Relative risk (RR) = 0.33; 95% condence interval (CI) = 0.19 to 0.56, P < 0.001]. In the ondansetron group, the absolute risk reduction (ARR) for vomiting was 44.9% and the number needed to treat (NNT) was 2 (95% CI = 1.63 to 3.55). At 24 h (Table 3), the frequency of emesis ranged from 0 to 5 in the placebo group and from 0 to 4 in the ondansetron group. The mean number of vomiting episodes was signicantly lower among the children who received ondansetron than among those who received placebo (0.2 vs. 1.66, P < 0.001). At the end of twenty-four hours, the proportion of still vomiting patients was 10.9% in the ondansetron group, and 72.2% in the placebo group (Figure 3) and the difference between the two groups was statistically signicant (RR = 0.15; 95% CI = 0.07 to 0.33, P < 0.001). In the ondansetron group, the absolute risk reduction (ARR) for vomiting was 61.3% and the NNT was 2 (95% CI = 1.3 to 2.1).

Vomiting in the paediatric ED and during the study follow-up

At 8 h (Table 2), the frequency of emesis during observation in the paediatric ED after enrollment ranged
Table 1. Demographic characteristics of the study population Characteristics Gender no. (% male) Age months s.d. (median) Age range months Weight kg s.d. Dehydration status at start, no. (%) Normal hydration Mild dehydration Moderate dehydration Vomiting no. of episodes in the previous 24 h (mean s.d.) Diarrhoea no. of episodes in the previous 24 h (mean s.d.)

Toleration of ORT, weight gain and dehydration status

At 8 h (Table 2), the proportion of the subjects in the ondansetron group able to tolerate oral hydration was

Ondansetron group (n = 55) 39 (55.7) 20.4 21.5 (12) 586 9.7 3.9 0 30 (54) 25 6,8 2.7 median (range): 6 (420) 6.8 2.2 median (range): 6 (415)

Placebo group (n = 54) 31 (44.3) 20.9 22.3 (12) 694 10.4 3.6 0 32 (59) 22 7.3 2.1 median (range): 7 (415) 7.2 1,7 median (range): 7 (412)

P value 0.141 0.863 0.979 0.451

0.108 0.134

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Table 2. Comparison of Groups at 8 h Outcome at rst 8 h Ondansetron group (n = 55) Placebo group (n = 54) Relative risk (95% CI) 1.17 (0.991.38) 0.33 (0.190.56) NNT P value (95% CI) 0.06 <0.001 <0.001 NS 2 (1.633.55)

Oral hydration 50 (90.9) 42 (77.8) accepted* no. (%) Vomiting during oral 12 (21.8) 36 (66.7) hydration no. (%) Mean no. of vomiting 0.36 0.75 median 1.33 1.31 median (Mean s.d.) (range): 0 (03) (range): 1 (05) Vomiting episodes per patient no. (%) 0 43 (78.2) 18 (33.3) 12 11 (20) 23 (42.6) 3 1 (1.8) 13 (24.1) Mean no. of diarrhoea 2.14 1.18 median 2.0 0.97 median (Mean s.d.) (range): 2 (06) (range): 2 (04) Dehydration status (%) Normal hydration 35 (63.6) 26 (48.1) Mild dehydration 20 (36.4) 28 (51.9)(1 case moderate dehydration) Weight difference (%) Up to 2% 30 (54.5) 44 (81.5) 2% and over 25 (45.5) 10 (18.5) First decision no. (%) Discharged 54 (98.2) 42 (77.8) Not discharged 1 (1.8) 12 (22.2) 24 h observation 1 (1.8) 10 (18.5) Intravenous rehydration 2 (3.7) * Those who took more than 49 mL kg oral rehydration uid. Five patients could only take between 20 and 49 mL kg uid. Twelve patients could only take between 20 and 49 mL kg uid.

<0.001

0.619

1.32 (0.941.86)

0.11

NS

2.5 (1.314.61)

0.005

4 (2.39.8)

0.08 (0.010.61)

0.014

5 (3.111.4)

signicantly higher than that in the placebo group (RR = 1.17; 95% CI = 0.99 to 1.38, P = 0.06). There were no signicant differences between these two groups in their dehydration status (ARR = 13.1%,
8 hours after study medication 80 70
Percent (%)

78 Ondansetron 43 33 20 2 0 12 Vomiting episodes 3+ 24 Placebo P < 0.001

60 50 40 30 20 10 0

RR = 1.32; 95% CI = 0.94 to 1.86, P = 0.11). Weight gain in the ondansetron group was signicantly higher than in the placebo group (ARR = 27%, RR = 2.5, 95% CI; 1.31 to 4.61, p: 0.005). At 24 h (Table 3), the proportion of the subjects in the ondansetron group able to tolerate oral hydration was not signicantly higher than that of the placebo group (ARR = 5.8%, RR = 1.07; 95% CI = 0.31 to 1.26, P = 0.41).

Treatment failure (intravenous uid administration and or hospital admission)

The proportion of the patients who were not discharged at the end of the rst 8 h was 1.8% in the ondansetron group and 22.2% in the placebo group, and the difference between the two groups was statistically signicant (RR = 0.08; 95% CI = 0.01 to 0.61, P = 0.014). As a result, the absolute risk reduction for

Figure 2. Comparison of vomiting episodes at 8 h.

Aliment Pharmacol Ther 31, 8291 2010 Blackwell Publishing Ltd

88 H . L . Y I L M A Z et al. Table 3. Comparison of Groups at 24 h Outcome at sequential 24 h Oral hydration accepted* no. (%) Vomiting during oral hydration no.(%) Mean no. of vomiting (Mean s.d.) Ondansetron group (n = 55) 48 (87.3) 6 (10.9) 0.2 0.7 median (range): 0 (04) Placebo group (n = 54) Relative risk (95% CI) NNT P Value (95% CI) NS 2 (1.32.1)

44 (81.5) 1.07 (0.911.26) 0.41 39 (72.2) 0.15 (0.070.33) <0.001 <0.001 1.66 1.53 median (range): 1 (05) 15 (27.8) <0.001 24 (44.4) 15 (27.8) 0.04 4.3 1.47 median (range): 4 (210) 6 (14.3) 0.91 (0.332.5) 0.85

Vomiting episodes per patient no. (%) 0 12 3 Mean no. of diarrhoea (Mean s.d.)

49 (89.1) 4 (7.3) 2 (3.6) 5.04 2.45 median (range): 5 (010) 7 (13.0)

Return visit to emergency department no. (%) The placebo group included 42 and the ondansetron group 54 patients Final decision no. (%) Discharged Not discharged Hospitalization Intravenous rehydration

52 (94.6) 3 2 (3.6) 1 (1.8)

44 (81.5) 10 9 (16.7) 1 (1.9)

0.29 (0.861.01)

0.04

8 (491.7)

* Those who took more than 49 mL kg oral rehydration uid. Seven patients could only take between 20 and 49 mL kg uid. Three patients could only take between 20 and 49 mL kg uid. Seven patients could only take less than 20 mL kg uid. These patients were discharged after the administration of 20 mL 30 min uid.

24 hours after study medication 100 80 Percent (%) 60 40 20 0 0 12 Vomiting episodes 3+ 28 7 4 89 Ondansetron Placebo P < 0.001 44 28

of the patients hospitalized and or subjected to intravenous rehydration was 5.4% in the ondansetron group and 18.6% in the placebo group (RR = 0.29; 95% CI = 0.086 to 1.01, P = 0.04) (Table 3). At the end of the study, we found that the absolute risk reduction and the number needed to treat were 13.2% and 8 (95% CI = 4.0 to 91.7) respectively in terms of ondansetron use, hospitalization and or intravenous rehydration treatment.

Adverse events
There were no cardiovascular, respiratory and dermatological side effects. However, one patient receiving ondansetron was re-evaluated for a distended abdomen and inability of oral intake and was hospitalized. At 8 h, there was no statistically signicant difference in diarrhoea episodes between the two groups (Table 2). However, the children who received ondansetron had more episodes of diarrhoea while undergoing oral rehydration than those who received placebo at 24 h (P = 0.04) (Table 3).
Aliment Pharmacol Ther 31, 8291 2010 Blackwell Publishing Ltd

Figure 3. Comparison of vomiting episodes at 24 h.

failure to discharge patients on ondansetron at the end of the rst 8 h would be 20.4% and the NNT was 5 (95% CI = 3.1 to 11.4). At 24 h, the rates of return visits to the emergency department did not differ signicantly between the groups (ARR = 1.3%, RR = 0.91; 95% CI = 0.33 to 2.50, P = 0.85). At the end of the study, the proportion

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DISCUSSION
Children frequently present with gastroenteritis and vomiting to hospitals worldwide. However, there have been relatively few studies on vomiting, which prevents the successful execution of ORT, recommended for gastroenteritis. The most important reason for this is that treatment of vomiting in gastroenteritis, especially use of antiemetic drugs is still debatable and that the American Academy of Pediatrics objects to the use of antiemetics.1 This prospective, randomized, double blind, placebo controlled study has shown that the rate of vomiting decreased and the success rate of oral uid treatment increased in patients receiving oral ondansetron. The results we obtained in this study are discussed in detail under the sub-headings below:

72nd hours in a study by Stork et al.15 However, 10 patients from the ondansetron group and 15 patients from the placebo group could not be reached at the 24th hour in the study by Ramsook et al.3 and there was a large amount of missing data about the subjects in the study by Stork et al.,15 and exclusion of the data about these patients from the statistical evaluation may have contributed to the results conicting with those from the present study.

Toleration of ORT and weight gain

In the study by Roslund et al.,14 30 min after the study medication was administered, 32.9% of the patients in the ondansetron group could tolerate ORT (RR: 1.73; 95% CI: 1.25 to 2.38, NNT: 3). In the present study, there was a slightly signicant decrease in the proportion of intolerance of ORT in the ondansetron group within the rst 8 h (ARR: 13.1, RR: 1.17; 95% CI: 0.99 to 1.38, P = 0.06). The conicting results of these two studies might have been caused by their different criteria for tolerance of oral intake. Unlike the study by Roslund et al.,14 we used the criteria refusing oral intake and amount of ORT intake. These criteria were not dened clearly in the study by Roslund et al.14 In the study by Stork et al.,15 ORT toleration status was evaluated 2 h and 4 h after the study medication was administered. At 2 h, the proportion of the subjects in the ondansetron group able to tolerate oral hydration was signicantly larger than that of the placebo group and the absolute risk reduction (ARR) was 18.8%, with a NNT of 5 (95% CI 3 to 20). At 4 h, the proportion of the patients receiving ondansetron and able to tolerate oral hydration remained higher than that of the placebo group; however, the difference was not signicant (RR: 1.12; 95% CI: 0.66 to 1.92). The results of their study obtained at the 4th hour are compatible with the results of this study. In the present study, a weight gain of 2% or more during ORT increased by 2.5 folds in the ondansetron group compared with the placebo group (ARR: 27%, RR: 2.45; 95% CI 1.31 to 4.61, NNT: 4; 95% CI, 2.3 to 9.8). A comparison with previous studies was not possible as those studies had not evaluated weight gain.

Vomiting in the paediatric ED and during the study follow-up

There have been ve studies3, 5, 7, 14, 15 on whether patients continued to have emesis in the emergency departments (ER) after administration of the study drug. The data obtained from a total of 659 participants included in these ve studies were evaluated with a meta-analysis conducted by DeCamp et al.,18 and it turned out that the patients who received ondansetron were two and half times more likely to stop vomiting in the ER (RR: 0.45, 95% CI: 0.330.62). DeCamp et al.18 estimated that ve children would need to be treated with ondansetron to prevent one child from vomiting in the ED (95% CI, 47). Consistent with the prior studies, the present study showed that the rate of vomiting decreased by three folds at the end of the rst 8 h after a single dose of ondansetron. Accordingly, two children would need to receive ondansetron to prevent vomiting in one child (95% CI, 1.63 to 3.55). In the present study, the rate of vomiting in children administered a total of 3 doses of ondansetron decreased by six times between the 8th24th hours of the study. It means that two children would need to receive ondansetron to prevent vomiting in one child (95% CI, 1.3 to 2.1). Consistent with the results of this study, Cubeddu et al.2 reported that the patients treated with a single dose of ondansetron (58%) were three times more likely to stop vomiting within 24 h than the patients receiving placebo (17%). However, no difference was found in the vomiting frequency between the ondansetron and placebo groups at the 24th hour in a study by Ramsook et al.,3 and at the 24th and
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Dehydration status
In the study by Stork et al.,15 the only study performed so far to evaluate dehydration status, no statistically signicant difference was determined in dehydration

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status at 2 and 4 h after the administration of the study medication between the ondansetron, dexametazone and placebo groups, which is consistent with the results of the present study.

Failure of treatment (hospital admission and or intravenous uid administration)

Five studies3, 5, 7, 14, 15 of ondansetron were conducted in the ED and included hospital admission as an outcome. The data obtained from 662 participants in these studies were evaluated by a meta-analysis18 carried out by DeCamp et al. The relative risk (RR) of admission after receiving ondansetron compared to placebo during the initial ED visit was 0.52 (95% CI, 0.270.95; ARR, 7.1%). The calculated NNT showed that 14 children would need to be treated with ondansetron to prevent 1 child from being admitted to hospital (95% CI, 944), which is consistent with the ndings obtained during 8-h and twenty-four-hour observations in the present study.

Adverse events
During the study, abdominal distention was observed in one patient on ondansetron and no additional side effects were determined. Consistent with the previous studies,2, 3, 7 the frequency of diarrhoea in children on ondansetron was higher in the present study (P = 0.04). There are several potential limitations of this study. First, we only included the children presenting from 07.00 AM to 09.00 AM on weekdays, which led to exclusion of many cases of acute gastroenteritis. However, the doctors and nurses responsible for treatment of gastroenteritis and education of parents about the issue work in the government hospital where the study was conducted between 07.00 AM and 05.00 PM. To conduct the study protocol properly, an 8-h-observation had to be completed until 05.00 PM and therefore, only the children presenting between 07.00 AM and 09.00 AM were included in the study. We aimed to dis-

charge all the patients before the night shift began, when the emergency department was the most crowded. This allowed conducting the rst 8-h period of the study by a team knowledgeable about the study protocol. The patients who could not be discharged till 05.00 PM were those who did not respond to treatment or those who had a poor response to treatment. As there were only few patients in the emergency department, this did not cause any risk during the night shift. Second, the telephone follow-up had the risk of providing unreliable data. Last, culture of specimens for bacterial or viral causes is not routinely performed in children with gastroenteritis in our hospitals. If we had made evaluations in terms of the aetiology of acute gastroenteritis and had assigned the patients into the groups based on the aetiology of gastroenteritis or if we had included only the patients with gastroenteritis because of a single aetiological factor, we could have evaluated the results of the study more easily. In addition, we could have avoided the possible effects of the cause of gastroenteritis on the obtained results. However, this is a double-blind, randomized controlled trial, which helped to minimize this possible negative effect on the results. It can be concluded that administration of orally disintegrated tablets in children with acute gastroenteritis who are vomiting and unable to tolerate oral intake and have mild-to-moderate dehydration decreases vomiting and the ratio of hospitalization. It can be suggested that administration of ondansetron would be benecial in such patients, as it has no serious side effects other than increased diarrhoea frequency and it decreases the need for IV uid treatment and the rate of hospitalization.

ACKNOWLEDGEMENTS
_ Declaration of personal interests: We thank Ilhan Kavas, MD; Adnan Karacabagli, MD, the physician and staff at Adana State Hospital for their assistance throughout the study. Declaration of funding interests: None.

REFERENCES
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