Introduction

Diarrheas are caused by various infectious agents such as viruses, bacteria and fungi, or  nutritional or psychological étiologies^1-11.The acute febrile diarrheal illnesses are usually caused by viruses and or toxin producing bacteria^{1, 2}. The consequences of diarrhea are fluid and electrolyte losses resulting in various degrees of dehydration 5, 6; Mild stages of dehydration are usually managed by giving plenty of liquids by mouth for twenty four hours 6 and later advancing to BRAT (Banana, rice, apple sauce and toast of bread) diet (Duro Deborah and Dugaan Christoper, 2007). Patients with moderate to severe dehydration are usually admitted into the hospital for intravenous hydration. Prostaglandins (PG) and cyclic AMP stimulate intestinal secretions¹². PGE and PGF facilitate movements of water and electrolytes into the intestinal lumen. Diarrheal diseases are associated with increased production of PGE and PGF¹³. Enteric pathogens increase secretion of fluid by increased stimulation of prostaglandin synthesis¹⁴. Aspirin and other non-steroidal anti-inflammatory drugs (NSAIDS) such as indomethacin and ibuprofen cause inhibition of adenylate cyclase, which decreases cyclic AMP resulting in reduction of secretions and increase in absorption of fluids^13,15. We hypothesized that Ibuprofen, when compared to acetaminophen in the treatment of febrile diarrhea, will be more efficacious in reducing the number of loose stools and preventing or reducing dehydration.

This prospective randomized double blind study was conducted to determine the efficacy of Ibuprofen in patients with febrile diarrheas as compared to Acetaminophen as evidenced by the decrease in the number of loose stools as the criterion.

Materials and Methods

Study Design

This is a prospective randomized double blind clinical study, approved by the NYMC Institution Review Board and also by the NYCHHC Research committee. IRB # L6370)

Study Setting and Population:

 Inclusion criteria:

1. Patients between the ages of 4 months to 6 years of age who present for febrile gastroenteritis with 3 or more loose stools in 24 hours.

2. Patients whose parents signed the informed consent.

3. Patients with mild dehydration (5% or less dehydration).

4. Patients with a temperature of 101*F (rectal) and above.

Exclusion Criteria:

1. Patients under the age of 4 months and above the age of 6 years.

2. Patients whose parents refused to sign the informed consent.

3. Patients with moderate to severe dehydration.

4. Patients currently receiving antibiotics for whatever reason

5. past medical history of allergy to either acetaminophen or NSAIDS.

6. Urine specific gravity >1030.

The study was conducted in the Metropolitan Hospital Center Pediatric Emergency department, which is inner City University Teaching hospital with an emergency medicine and pediatric residency program. The ED had a census of 75,000 patient visits per year with a pediatric patient visits roughly amounting to 25,000 per year. Data collection occurred over a period of one year in the year of 2002.

Study protocol:

 All pediatric patients presenting to our pediatric emergency department with febrile gastroenteritis between the ages of four months to six years were evaluated by clinical signs, urine specific gravity. Only those patients who met the inclusion criteria were enrolled in the study after obtaining informed consent from their parents.  Patients who were either on antibiotics or who had previously known NSAIDs allergy were excluded from the study as well as patients with moderate to severe dehydration.

Gastroenteritis is defined as the occurrence of 3 or more loose bowel movements in 24 hours.

The following table lists the various signs & symptoms of Dehydration.

(214 Textbook of Pediatric Emergency Medicine ■ Section II: Signs and Symptoms)

Table 1

FIGURE 18.1 Diagnostic approach to the immunocompetent child with diarrhea.

Patients with mild dehydration who do not need admission were enrolled and treated as our study patients. All the patients were given acetaminophen at 15mg/kg/dose q 6h, or ibuprofen 10mg/kg/dose q6h for 24 hours. It is double blinded to the parent/patient and the prescriber. The suspensions were prepared by the pharmacist as ibuprofen 100mg/5cc or acetaminophen150mg/5cc and the doses were dispensed as 0.5cc/kg/dose given at 6 hour intervals. The randomization was done by the pharmacist. Randomization was unblinded. Parents were counselled not to administer any antibiotics, over the counter medications, alternative medications or other antipyretics during the study period.  Patients were also advised to feed only pedialyte for 24 hours. As stated before, all the patients were reexamined 24 hours later and reassessed for the state of hydration by clinical signs, urine specific gravity and the number of loose stools since last visit. Information was also obtained of any side effects in the past 24 hours.

Measures:

Primary objective of study is decrease in the number of loose stools 24 hours later, as compared to the initial day visit (on day1) was taken as the primary outcome measure for the study.

Secondary observations are assessment of dehydration, urine specific gravity and change in temperature.

Data analysis:

Graph Pad Software version 4 was used for statistical analysis: Unpaired t test was used to calculate the p value and 95% confidence interval. 

Results

A total of 84 patients were enrolled into the study. Both drug categories had 42 (50%) enrollees. Two patients were lost to follow up in each group.

Table 2

Depicting age groups of patients

Table 3

Male to female ratio

The average number of stools on day 1 (initial visit) in group A (acetaminophen) was 5.12 and the average number of stools in group B (ibuprofen) was 5.25. 24 hours later the average number of stools in group A was 3.45 and the average number of stools in group B was 1.9 (Table 4).

Table 4

A table representing the number of loose stools on initial visit (day one) and 24 hours follow up visit (day two) as well as the decrease in number of stool in both groups (group A and group B)

The average decrease in the number of stools in Ibuprofen group was 3.35 and the average decrease in the number of stools in Acetaminophen group was 1.67 (Figure 1 and 2).

Graph 1

Average number of stools in both Acetaminophen and Ibuprofen groups on Day 1 and Day 2 A bar graph representing the number of stools at presentation and 24 hours later with standard Error of the Means (SEM) A. Number of stools at presentation in Group A B. Number of stools 24 hours later in Group A C. Number of stools at presentation in Group B D. Number of stools 24 hours later in Group B

Graph 2

Decrease the number of stools in Ibuprofen group and acetaminophen group on day 2

Graph Pad Software version 4 was used for statistical analysis. Unpaired t test was used to calculate the p value and 95% confidence interval. The two tailed P value for the decrease in the number of stools on day two compared to day one between the two groups is <0.0001 with confidence interval at 95% (1.44 -2.6)

Table 5

Depicting summary column for means values with ranges/standard deviations

Data on temperature: (For data see the attached table)

Average Temp: Tylenol group:

Day (1)--101.99, Day (2)--98.8

Average Temp: Ibuprofen Group

Day (1) ==102.035, Day (2) ==98.88

2x2 Chi-square test: Pearson two tailed p-value is 0.09608.

The groups are not different in terms of reduction of temperature.

Urine Specific Gravity

 A reflectometer designed to measure urine specific gravity was used. Patients with concentrated urine >1030 were excluded from the study. Urine specific gravity of enrolled patients ranged from 1010 to 1025 on both the days, with an average of 1018. Dehydration was assessed, based on clinical signs as mentioned above. At the follow up visit, none of the patients in either group, required rehydration or hospitalization.

Dehydration was assessed, based on clinical signs as mentioned above. At initial visit patients in both groups had 5% dehydration or less and on follow up visit, none of the patients in either group, required intravenous rehydration or hospitalization.

Results of weight difference from the initial visit and 24 hours later, comparing usage of acetaminophen and ibuprofen, the unpaired t test result show:

Unpaired t test result for the weight changes:

p-value and statistical significance:

 The two-tailed P value equals 0.6773
By conventional criteria, this difference is considered to be not statistically significant.

Confidence interval:
The mean of Group One minus Group Two equals 0.03138
95% confidence interval of this difference: From -0.11817 to 0.18092

Table 6

Data on temperature

Table 7a

Group A patients- depicting weight of infants of children on day 1 & 2 and difference in change of wt from initial visit (day 1) to 24 hrs follow up visit (day 2)

Table 7b

Group B depicting weight of infants of children on day 1 & 2 and difference in change of wt from day 1(initial visit) to (24 hrs follow up visit) day 2.

Discussion

Diarrheas are caused by various causes e.g., viruses, bacteria, fungi, nutritional or Psychological causes. The acute febrile diarrheal illnesses are usually caused by viruses and or toxin producing bacteria. The consequences of diarrhea are fluid and electrolyte losses resulting in various degrees of dehydration. Mild dehydration is usually managed by giving plenty of liquids by mouth for twenty-four hours and later advancing to BRAT (banana, rice, apple sauce, a toast of bread) diet. Patients with moderate to severe dehydration are usually admitted into the hospital for intravenous hydration. Acute febrile episode in pediatric population is usually managed with either Acetaminophen or Ibuprofen. Our study is to determine whether ibuprofen will be more beneficial compared to acetaminophen in febrile diarrheal illnesses regardless of the etiology. Prostaglandins and cyclic AMP stimulate intestinal secretions¹². PGE and PGF stimulate movements of water and electrolytes into the intestinal lumen. Diarrheal diseases are associated with increased production of PGE and PGF ^{12, 13, 15}. Enteric pathogens stimulate secretion of fluid by increasing prostaglandin synthesis ¹⁴.

Aspirin and other non-steroidal anti-inflammatory drugs (NSAIDS) such as indomethacin and ibuprofen cause inhibition of adenylate cyclase, which decreases cyclic AMP, reducing secretions and facilitating absorption of fluids ^{12, 13, 15}. In one original study Aspirin was successfully used to treat diarrheal illness associated vibrio cholera ¹⁵. However, it is well known that usage of Aspirin during viral illnesses was associated with Reye ’s syndrome. Hence it is not recommended for febrile illnesses caused by viruses ^16-18 No cases of Reye’s syndrome were reported after 1992. The primary author (Dr. K. Nibhanipudi) had the opportunity of presenting a case of Reyes syndrome as one of 3 diagnostic challenge cases@ National AAEM Annual Scientific assembly Feb, 2014 in New York City. This case in which mother gave 2 doses of aspirin during a course of viral illness occurred in 2005¹⁹.

Reye's syndrome exhibits a stereotypical biphasic course. It usually occurs in a previously healthy child. There is an etiologic link between Reye’s syndrome and the usage of aspirin and viral infections. An upper respiratory tract infection or chicken pox is followed by an interval in which the child has seemingly recovered. Then sudden onset of vomiting starts within 5 to 7 days of the viral illness. Delirium, followed by combative behavior, rapidly progresses to seizures, coma and death. There are usually associated abnormalities of the liver functions with slight to moderate liver enlargement. Jaundice is not present at the onset. Focal neurological signs are usually absent. CSF is normal except for elevated pressure.

Ibuprofen has not been associated with Reye’s syndrome and like aspirin it causes prostaglandin inhibition, which decreases cyclic AMP and causes reduction in the number of loose stools ¹³. Secretory diarrheal illnesses are associated with increased production of cyclic adenosine monophosphate (cAMP) known to stimulate intestinal secretions. Enteric pathogens are also known to stimulate intestinal secretions via the same mechanism 10. Non-steroidal anti-inflammatory drugs such as aspirin and ibuprofen decrease cAMP and Prostaglandin production. The usage of Ibuprofen in febrile diarrhea is expected to reduce the volume of fluid loss when compared to acetaminophen and decrease the degree of dehydration ^12-15.

In summary, our study showed statistically significant beneficial effect of Ibuprofen (group B) compared to Acetaminophen (group A) in the treatment of febrile diarrhea. Reduction in the number of loose stools by the history indicates that Ibuprofen group benefited from the medication when compared to the Acetaminophen group.

Conclusions

This prospective randomized double blind clinical study showed significant benefit from using Ibuprofen over Acetaminophen in treating febrile diarrheas as demonstrated by a decrease in the number of loose stools, 24 hours following the initial treatment.