Comparison of Oral Versus Normal and High-Dose Rectal Paracetamol in the Treatment of Fever in Children

Address for correspondence Dr. Ramchandra Bastola Consultant Paediatrician Department of Paediatrics, Pokhara Academy of Health Sciences (PAHS) Pokhara, Nepal Tel No; +977 061520066 E-mail: Dr_rc@yahoo.com 1Dr. Ramchandra Bastola, MBBS, MD, Consultant Paediatrician, Department of Paediatrcis, PAHS, 2Dr. Shree Krishna Shrestha, MBBS, MD, Chief Consultant Paediatrician, PAHS, 3Dr. Bhawana Sigdel Bastola, BDS, Dental Officer, PAHS, Pokhara, 4Dr. Dhruba Shrestha, MBBS, MD, Consultant Paediatrician, Siddhi Memorial Hospital, Bhaktapur, 5Dr. Yograj Sharma, MBBS, MD, Consultant Paediatrician, Rapti Zonal Hospital, Nepal. Abstract


Introduction
P eople often conceive fever as a disease that requires treatment, rather than being a symptom or a sign of an illness.In their anxious quest to treat fever, parents suff ering from "fever phobia" may end up unintentionally overdosing their children with diff erent antipyretics, or with diff erent preparations of the same antipyretics.Paracetamol is the most commonly used drug in paediatrics 1 .For routine clinical use, it is administered in oral and rectal forms, as a tablet, liquid, or suppository.The rectal route is especially useful in several specifi c circumstances like vomiting or unconsciousness.Rectal administration of liquid preparations is impractical and has very limited clinical applicability; thus, rectal suppositories occupy an important role in the treatment of fever and pain in children.
Parents, as well as physicians, use the standard dose (10-20 mg/kg) of oral and rectal Paracetamol preparations interchangeably to treat fever in children, assuming they have equal antipyretic eff ects.However, the evidence for rapid absorption (within 30-60 minutes) and the pharmacokinetics of a single oral dose is wellestablished 2,3 .The absorption of rectal paracetamol is erratic and prolonged, varying with the suppository size, composition of its base, rate of dissolution, position in the rectum, and the rectal contents 4 .Moreover, an increasing body of evidence indicates that the rectal Paracetamol dose of 10-15 mg/kg fails to achieve antipyretic serum levels of 10-20 μg/ml.Indeed, a rectal Paracetamol dose of 30-45 mg/kg is needed to achieve adequate serum levels 5,6 .The recommendation from the American Academy of Pediatrics 7 has discouraged the use of rectal Paracetamol by parents unless specifi c instructions are given by medical personnel, their rationale being that there is "potential for inadequate therapeutic eff ect from poor absorption as well as cumulative toxic eff ects from excessive or too frequent rectal doses." In America, the recommended dose for Paracetamol is 10 to 15 mg/kg/dose every 4 to 6 hours, regardless of the route of administration 8 .Although some investigators 2,3,6 both in Europe and in North America, have studied and recommended rectal doses as high as 60 mg/kg/dose, these higher doses have not been adopted as standard practice in America and Canada.In one study oral paracetamol proved superior to the rectal preparation 9 , two others 10,11 saw no diff erence in the antipyretic responses of oral and rectal paracetamol.However, Vernon's study was un-blinded and lacked placebo control, and compared the standard doses of 15-20 mg/kg of oral and rectal Paracetamol only.Scolnik's study, also lacking blinding and placebo control, was further limited by the fact that it assessed antipyretics during the fi rst three hours after drug administration, a time during which maximum antipyretic eff ect of rectal Paracetamol may not have occurred.
The objectives of this study were to compare the antipyretic eff ective of two diff erent rectal doses of Paracetamol: 15 mg/kg and 30 mg/kg to that of a standard oral dose of 15 mg/kg.The individualized doze was given three hours of observation to allow detection of late antipyretic eff ect that may occur with rectal Paracetamol.The results of this study could provide further evidence on the comparative antipyretic eff ects of diff erent doses of rectal Paracetamol versus the standard oral one.

Material and Methods
This was a prospective, interventional, randomized, controlled study done in Western Regional Hospital, Nepal.All febrile children aged six months to six years were included in the study from August 2015 to October 2015.A total of 192 children were included in this study.There were 63 patients in the oral normal dose paracetamol group (15mg/kg), 59 patients in the normal dose rectal paracetamol group (15mg/kg) and 70 patients in the high dose (30mg/kg) rectal paracetamol group.
Fever was defi ned as Temperature ≥38°C or 100.4 0 F. Normal dose oral paracetamol was defi ned as15mg/ kg/dose, Normal dose rectal paracetamol as 15mg/kg/ dose and High dose rectal paracetamol as 30mg/kg/ dose.
Patients were assigned to either of the three treatment groups by the use of a computer-generated random-number table.The three treatment groups were as follows: Group A-rectal paracetamol 15 mg/kg in suppository form; Group B-rectal paracetamol 30 mg/ kg in suppository form; and group C-oral paracetamol 15 mg/kg in suspension.The suppository was inserted beyond the internal sphincter after appropriate lubrication.
Inclusion criteria involved all children aged six months to six years with axillary temperature ≥38°C (≥100.4F), attending in emergency department or admitted patients with fever in paediatric department of Western Regional Hospital, Pokhara, Nepal.Exclusion Criteria comprised of all patient with known allergy to paracetamol, patients with febrile neutropenia, patients who were kept NPO, with the history of vomiting or diarrhoea in the previous four hours, failure of the parents to provide informed consent, patients receiving paracetamol in the previous four hours and the patients who vomited the oral preparation within 20 minutes.Informed written consent from the parents or care taker were taken in a well understood Nepali Language.
Temperatures were recorded before and after the administration of paracetamol at an interval of 30, 60, 120, and 180 minutes by using a digital thermometer (Dr.Morepen).Parents were advised to reduce the amount and thickness of clothing the child was wearing.Axilla was dried with a cloth and bulb of thermometer was placed snugly by tightly holding the arm against chest.Thermometer was placed in the axilla for two minutes.
The groups were compared using analysis of variance for change in temperature during three hours.Diff erences in the proportion in each group that experienced a drop of 1°C or 2°C were assessed by ANOVA with Bonferroni Post Hoc comparison, chi square test, chi square (exact) test using SPSS 16.
There were no signifi cant diff erences in age, weight, temperature at 0 min, heart rate and respiratory rate among the three groups as shown in Table-1.Mean of Vitals like heart rate and respiratory rate were also not signifi cant among those three groups and is shown in Table-1.
Duration of fever of diff erent patients from diff erent group were from one day to maximum 90 days (Figure 1).Among total patients 17.2% had history of fever for one day, 36.5% had history of fever for two days.Similarly 20.3% had a history of fever for three days, 4.2% had four days, 5.7% had fi ve days, 1.6% had six days, 5.7% had seven days, 2.6% had eight days, 0.5% had nine days, 2.1% had ten days, 1% had eleven days, 1.6 had thirty days, 0.5% had forty fi ve days and 0.5% had ninety days history of fever.
The maximum drop in temperature for each of the three groups is summarized in Table 2.There were no signifi cant decrease in temperature in all three groups at 30 minutes and 60 minutes but fever decreased signifi cantly at 120 minutes and 180 minutes (Table 2).
At 30 min in Group A mean temperature was 100.8 0 F, in Group B it was 100.8 0 F and in Group C it was 100.66 0 F.This decrement was statistically not signifi cant (p-0.569).
At 60 minutes in Group A temperature decreased to 99.9 0 F, in Group B temperature decreased to 99.7 0 F, and in Group C mean decrease in temperature was up to 99.7 0 F.This decrement was also not statistically signifi cant (p-0.261).
Since it is possible that temperatures dropped more rapidly in one particular patient or group and this would not be refl ected in the calculations described so far, the area under the curve for temperature versus time (Fig 2 ) was individually calculated for all patients in the three groups.This comparison reveals signifi cance among the three groups at 120 minutes and 180 minutes.

Discussion
In febrile children, brought to an emergency, OPD and indoor departments of Western Regional Hospital, the single-dose oral paracetamol was more eff ective than rectal paracetamol 15 mg/kg.But when we doubled the dose of rectal paracetamol, we found additional benefi t over both oral and rectal paracetamol 15mg/ kg.Moreover, the rectal route was as satisfactory to the parents as the oral route.
The use of high-dose rectal paracetamol has been studied extensively 3,9,10 .They suggest that higher doses of rectal paracetamol (30 mg/kg) was more eff ective in reducing fever than oral and rectal 15mg/kg paracetamol.The study done in Iran in 2010 A.D. by Karbasi et.al. 12 which was prospective parallel group designed study, 60 children who presented to the emergency department or outpatient paediatric clinic at a tertiary hospital and aged from six months to six years with rectal temperature over 39 °C were enrolled.Patients were randomly assigned to two equal-sized groups.Group 1 received 15 mg/kg acetaminophen rectally and group 2 received the same dose orally.Temperature was recorded at baseline and 1 and 3 hours after drug administration.The result showed Rectal and oral paracetamol preparations had equal antipyretic eff ects in children.The rectal route was proved to be as acceptable as the oral one for the parents.
Rumack 13 , in an unreferenced review, quoted that therapeutic level of paracetamol in serum was 10 to 20 mg/L.Walson et al 14 found that even concentrations of paracetamol as low as 6.8 mg/L reduce temperature to a signifi cantly greater extent than placebo.Others did not fi nd a correlation between maximal serum concentration and fall in temperature 15 .The weak correlation between serum concentrations and clinical outcome, and the availability of temperature as a reliable and objective outcome measures were the reasons why we choose to study the eff ect of diff erent doses and routes of paracetamol without assessing serum levels.This study was however limited as it could not assess the systemic absorption of the drug.Previous studies on the antipyretic eff ect of rectal paracetamol in children yielded confl icting results.Keinanen et al 16 showed that both oral and rectal paracetamol were eff ective in reducing temperature in febrile children: the maximal temperature decrement was signifi cantly greater in the oral group, and the eff ect was seen earlier.However, this study was not randomized.Moreover, a relatively low dose i.e. 10 mg/kg paracetamol was used in the study.
In a nonrandomized trial 14 , administering 15 mg/kg paracetamol to the same febrile patients either rectally on the fi rst day after cardiac surgery or via nasogastric tube the next day produced no diff erence in temperature reduction.
In a randomized study, Vernon et Al 17 showed no diff erence in the decrement in fever among 37 children who were treated with either oral or rectal acetaminophen in a dose of 15 to 20 mg/kg.However, the eff ect of highdose rectal paracetamol was not investigated.Treluyer JM et al 18 showed that 30 mg/kg oral paracetamol caused a swifter and greater decrement in fever than conventional doses of 15 mg/kg, with mean diff erence in temperature was 0.5°C.Our study also showed a similar fi nding on administrating 30mg/kg rectal paracetamol.
Parents were found satisfi ed equally with the rectal and oral routes of administration of paracetamol but the results would have been diffi cult if they had inserted the suppository themselves.Thus, rectal route is preferred especially in condition where oral route poses diffi culties, such as with the child who is vomiting or spitting up oral medications.

Conclusion
Rectal paracetamol in a dose of 30mg/kg is more eff ective than oral paracetamol in a dose of 15 mg/kg.However oral paracetamol given in a dose of 15 mg/ kg is more eff ective than rectal paracetamol in a same dose.Thus, rectal paracetamol in a dose of 30 mg/kg is superior to oral route both because of its rapidity of action in bringing down the temperature in a febrile child and of easy administration.

Limitations of Study:
This study has several limitations.It was randomized but not blinded or placebo controlled.This was because the primary outcome measure was an objective measure (body temperature), which was not subjected to observer bias and blinding was not considered necessary.

Fig 1 :
Fig 1: Showing durations of fever among all group patients Duration of fever in days

Fig 2 :
Fig 2: Showing average temperature in 0 F at each time point for the 3 groups

Table 1 :
Showing mean for diff erent variables among 3 groups and their p-value

Table 2 :
Showing decrease in temperature in diff erent interval following administration of paracetamol

Table 3 :
Showing decrease in temperature in diff erent intervals with mean and SD and their p-value