1. DO ANTIPYRETIC DRUGS PREVENT FEBRILE CONVULSIONS
GILLIAN HAGGERTY
PAC 1
DECEMBER 2009

2. Introduction
FEVER
Increase in temperature caused by pyrogens acting on hypothalamus, ↑ temp set point → ↑ body temp
Normal physiological response to infection
(NICE 2007)
FEBRILE SEIZURE
Childhood seizure associated with fever
3 – 5 % children 6/12 – 6yrs
% will have another
No long-term consequences
(Moreno 2009)

3. SIMPLE - <15mins, does not reoccur during illness.
COMPLEX - >15mins, and/or several seizures during illness.
RISK OF RECURRANCE
Young age at time of 1st seizure
Family history
Number of febrile episodes
Time lapse <6/12 since last seizure
(Stuijvenberg et al 1998, Strengell et al 2009)

4. Current Practice
A recent influx of children to the ward following febrile convulsion has led to a review of our advice sheets, which in turn led to the question – are we offering the most up to date advice for parents?
Current advice is to give regular antipyretic medication (paracetamol or ibuprofen) during febrile episodes to reduce the child's temperature and therefore lowering the risk of febrile convulsion recurrence.
An opinion often expressed by both medical and nursing staff. However as APNPs it is important that we are providing our patients & carers with evidence based information.

5. The question P
Children under 6yrs who have had a febrile convulsion I
Antipyretic drugs – paracetamol & ibuprofen C
Placebo or no treatment O
Prevention of further febrile seizure
In children under 6yrs who have had a febrile convulsion does administration of paracetamol or ibuprofen compared to placebo prevent febrile seizure recurrence?

6. Search Strategy
Via Scottish eLibrary (accessed 23/11/09)
Search Terms
Child* or paediatric or pediatric
Febrile or fever or pyrexia*
Convulsion or seizure or fit
Antipyretic or paracetamol or ibuprofen
Cochrane Library - 18 reviews & 17 clinical trials
Medline – 26
Embase – 27
NICE guidance management of feverish illness in <5yrs.

7. Inclusion/Exclusion Criteria
Included
Antipyretic drugs – paracetamol, ibuprofen
Randomised controlled trials
Children under 6 years who have had febrile convulsion
1998 – present
Excluded
Epilepsy
Anticonvulsant drugs
CNS infection, meningitis
From the search 2 articles fitted the criteria.

8. CRITICAL APPRAISAL TOOL
Critical Appraisal Skills Programme (Casp) - 10 questions to help you make sense of randomised controlled trials from the Public Health Resource Unit (2006).

9. WAS A CLEARLY FOCUSED QUESTION ASKED?
Strengell et al (2009)
To assess the efficacy of different antipyretic drugs for preventing febrile convulsion recurrence.
231 children aged from 4 months to 4 years who had experienced a first febrile convulsion were randomised to receive first diclofenac or placebo then into 3 treatment groups - paracetamol or ibuprofen or placebo. The main outcome was the recurrence of febrile convulsions. (5 hospitals in Finland.)
Stuijvenberg et al (1998)
To assess the efficacy of ibuprofen in preventing febrile convulsion recurrence in children considered to be at increased risk.
230 children aged between 1 & 4yrs who had had a febrile convulsion in the past 6 months, with at least one risk factor for recurrent seizures, were randomised to receive either ibuprofen or placebo. The main outcome was 1st febrile convulsion recurrence during subsequent episode of fever.

10. WAS THIS A RANDOMISED CONTROL TRIAL?
Yes – randomised, placebo-controlled, double blind trial.
Ethical approval granted.
Informed parental consent given.
Informed parental consent.

11. WERE THE PARTICIPANTS APPROPRIATELY ALLOCATED TO THE GROUPS?
231 randomised first into 2 groups to receive pr. Diclofenac (117) or placebo (114) – used random-number tables, numerical codes in permuted blocks of 4.
Children then randomised into 3 groups to receive oral placebo (78) or paracetamol (77) or ibuprofen (76) – blocks of 6.
First randomisation generated by 2 of the study authors. Randomisation for oral medication by pharmaceutical company providing drugs.
Baseline characteristics of each group well balanced.
Computer generated randomisation,111 assigned ibuprofen , 119 placebo.
Baseline characteristics well balanced.

12. WERE PARTICIPANTS, STAFF & STUDY PERSONNEL BLIND?
Medications labelled with randomisation numbers – parents and staff administering them were blinded.
No mention of study personnel.
2 of study authors responsible for 1st randomisation – could introduce bias but don’t think it’s important in this study as they had no part in the 2nd randomisation.
Biostatistician & hospital pharmacists were only ones aware of treatment allocation.
Placebo matched oral ibuprofen liquid.

13. WERE ALL THE PARTICIPANTS WHO ENTERED THE TRIAL ACCOUNTED FOR AT ITS CONCLUSION?
181completed 2 year follow-up. Patients who dropped out were included in the intention to treat analysis. Numbers lost to follow-up, those who dropped out or were excluded are included in a clear diagram of the trial profile.
Two analyses performed: intention to treat – all 1st recurrent febrile seizures, regardless of compliance; and as per protocol – limited to febrile convulsion recurrence in patients who were compliant.
Reasons for dropping out or termination of follow-up given in a table.

14. WERE THE PARTICIPANTS IN ALL GROUPS FOLLOWED UP & DATA COLLECTED IN THE SAME WAY?
Parents instructed to administer trial medication if temp>38°C. If T≥40°C extra dose of paracetamol allowed.
Parents recorded all episodes on sheet covering symptoms, duration & medications used. Study nurses contacted families once a month.
Participants reviewed for 2 yrs.
At end of follow-up all patients had EEG & neuro exam, physician was blinded.
Parents administered study medication if temp≥38.5°C. No other medication was to be given. All used same type thermometer.
Parents recorded timing of medication & temperature.
Parents contacted investigator once a day during febrile episodes, investigator contacted parents every 3 months to ensure continued participation until study terminated.

15. DID THE STUDY HAVE ENOUGH PARTICIPANTS TO MINIMISE THE PLAY OF CHANCE?
Considered decrease of 20% in rate of recurrent seizures to be important, calculated that total of 186 would be required for 80% power & type 1 error of 5%.
(Total of 231 entered into trial.)
Assumed that over two years probability of seizure recurrence in placebo group was 40%, high because inclusion criteria was to have at least 1 risk factor for seizure recurrence. Sample size of 220 calculated to give 80% power & type 1 error of 0.05.
(Total 230 entered trial.)

16. HOW ARE THE RESULTS PRESENTED & WHAT IS THE MAIN RESULT?
Results presented as numbers & percentages experiencing seizures or not, when they occurred in relation to when the medication was administered, extra antipyretics and maximum temperatures. A lot of figures and statistics to pick through, not clearly presented at all.
Main result – no difference in recurrence rates of febrile convulsions between the treatment groups.
Results presented as proportion reporting fever, febrile convulsions; mean temperatures. Also tables presenting numbers compliant per fever episode and temperature by treatment group.
Main result – ibuprofen does not prevent febrile convulsion recurrence.

17. HOW PRECISE ARE THE RESULTS?
Seizure recurred in 8 out of 34 in placebo group and 46 out of 197 in antipyretic group – confidence interval to 17.6; p=0.99.
Confidence intervals and p values reported for all outcomes (recurrence of seizures during each febrile episode, simple v complex, timing of medication, max temp.).
Seizure recurred in 31 of ibuprofen group and 36 of placebo group, no confidence interval or p value given.
2 year estimated recurrence probability ibuprofen 32%, placebo 39% p=0.70 CI (intention to treat), per protocol CI

18. WERE ALL IMPORTANT OUTCOMES CONSIDERED SO THE RESULTS CAN BE APPLIED?
Study population similar to own patients.
Highest recommended doses of medication given (15mg/kg paracetamol & 10mg/kg ibuprofen).
No adverse effects reported, EEG & neuro exam at end of trial all normal.
Acknowledged that extra dose of paracetamol might have caused dilutional bias, but found that amount given extra dose comparable in each group.
Study population similar to own.
5mg/kg used suggest unknown whether max dose of 10mg/kg would lower temp sufficiently to prevent recurrent seizures.
Relied on parents filling in form, assumed compliance but no paracetamol or ibuprofen blood levels done, temp reduction in ibuprofen group suggest unreported use of antipyretics & non-compliance unlikely.

19. IMPLICATIONS FOR PRACTICE
Although both studies found that paracetamol & ibuprofen were effective at reducing pyrexia, they were ineffective at reducing a pyrexia which occurs during episodes that led to a febrile convulsion. Therefore they are ineffective at preventing febrile seizure recurrence.
As advanced nurse practitioners we should be ensuring that our colleagues are aware of this and that appropriate information is given to parents.
That information being: while antipyretic drugs may still be administered during a febrile episode to make the child feel more comfortable they will not prevent a febrile convulsion from happening; ensure parents know the first aid of how to deal with one and reassure them of the relatively benign nature of febrile seizures (no long term consequences).

20. References
Moreno MA. (2009) Febrile Seizures in Children. Advice for Patients Archives of Pediatrics & Adolescent Medicine 163(9)872.
NICE (2007) Feverish illness in children, assessment & initial management in children younger than 5 years. Guideline available from (accessed 23/11/2009)
Public Health Research Unit (2006). CASP 10 questions to help you make sense of randomised control trials.
Strengell T., Uhari M., Tarkka R., Uusimaa J., Alen R., Lautala P., Rantala H (2009) Antipyretic Agents for Preventing Recurrence of Febrile Seizures Archives of Pediatrics & Adolescent Medicine 163(9)
Van Stuijvenberg M., Derksen-Lubsen G., Steyerberg E., Habbema J, Moll H., (1998) Randomized, Controlled Trial of Ibuprofen Syrup Administered During Febrile Illnesses to Prevent Febrile Seizure Recurrence Pediatrics 102(5)e51 (downloaded from 26/11/09)