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Paracetamol PR for Febrile Seizures?


Today I am reviewing a paper from the Paediatric literature that has created a small stir.  Ever since I trained we have managed simple, febrile seizures with no active intervention other than symptom relief and watchfulness.  The Paediatric party-line, based on some data, is that using anti-pyretic medications will not change the prognosis or rate of recurrence of subsequent seizures.  However, this new paper from Japan has come to a different conclusion.  The paper is here:

Murata S, Okasora K, Tanabe T, et al. Acetaminophen and Febrile Seizure Recurrences During the Same Fever Episode. Pediatrics. 2018;142(5):e20181009

So I thought that I would run the EBM rake over this new data and try to decide how it fits in with our current practice and whether we should change our advice based on this evidence.  Let’s start with a PICO….

POPULATION:

Children with simple febrile seizures (FS), at a single, Japanese paediatric ED.

The risk with a small, single location trial is that it may not be generalisable to the wider population.  The local genetics, microbiology and environment may be quirky!

FS defined as :“a seizure accompanied by fever (body temperature ≥38.0°C), without central nervous system infection, that occurs in infants and children 6 through 60 months of age.”

EXCLUSION CRITERIA:

  • Patients who had already experienced 2 or more FSs during the current fever episode
  • seizures lasting >15 minutes
  • Patients with epilepsy, chromosomal abnormalities, inborn errors of metabolism, brain tumour, intracranial haemorrhage, hydrocephalus, or a history of intracranial surgery
  • Patients who had been administered diazepam suppository to prevent FSs and patients whose parents requested the use of diazepam suppository were excluded.
  • Patients who had taken antihistamines (may decrease seizure threshold)
  • Patients with diarrheal illness (may have Gastro-assoc. seizure) and PR meds are messy!

Here is how enrollment played out:

 

Marata et al, Paediatrics 2018

 

Now there are a few things to note here:

  • Nearly a quarter of the children screened received PR diazepam to prevent a seizure!
  • That seems like a very high number.  It is basically the same as the number of children who had had a prior FS on a previous episode of febrile illness
  • So, my guess, it seems that it is common practice for Japanese children to be prescribed PR diazepam for this scenario… this is not how we practice in Australia
  • This doesn’t really change the outcomes as these children were excluded, however, it does make me wonder if the numbers could have been diluted/skewed by selecting a subset of children who proportionally will be “first timers” and hence may include more “undiagnosed epileptic” children?

Otherwise, the two groups looked similar at baseline.

INTERVENTION / CONTROL:

The two groups were randomly allocated to receive either:

  1. Rectal acetaminophen (paracetamol) suppository at a dose of 10mg/kg IMMEDIATELY and then every 6 hours for 24 hours IF they remained febrile (T > 38 C)
  2. No intervention.  There was no placebo suppository used in this trial.  Parents were instructed to avoid any anti-pyretics for the first 24 hours.

There are a few issues with this trial design.

  • this is a no-placebo trial – this is problematic.  Giving a medication rectally is quite a significant thing to do to a small child and doing it 4 times in a day is more so!  There is certainly a risk of bias here.  It is not implausible that the manual stimulation of rectal stimulation may have some effect on seizures via the vagal-stimulation pathway.
  • 10 mg/kg is a low dose.  Most EDs would go with 15mg/kg and some load with 20mg/kg.  So it is hard to convert this intervention into our practice.  Though a low dose would tend to favour the null hypothesis.
  • There is an ethical question around instructing parents to stay away from “anti-pyretics” in the control group – these children are unwell with fevers and often pain/misery.  Is it ethical to withhold symptomatic relief in the context of a trial?  Sure, it makes the science clearer but at what cost…

OUTCOME:

The primary outcome was seizure recurrence rate in the same acute illness (all events occurred in the first 24hrs).

The seizures were reported by the parents… so a few may have been incorrectly identified events eg. Rigors

In the first 24-hours a total of 16% of all the included children had a subsequent seizure during the same episode of illness.

  • 9.1% in the PR paracetamol group
  • 23.5% in the “no intervention” arm.
  • This yielded a very impressive p-value of <0.001   If you believe the numbers then I think that as a parent I would consider this a clinically significant effect too.
  • a 14.4% absolute risk reduction gives an NNT of about 7.
  • The calculated odds ratio was 5.6 (CI = 2.3–13.3).  This seems like a potent intervention.

DISCUSSION

This is an interesting study that asks an important clinical question.  The data around the treatment of febrile seizures is not really that robust, with only a few small trials looking at acute seizure recurrence.

To summarise my PICO summary:

The study used sensible inclusion and exclusion criteria.  However, the big group excluded (rectal diazepam pre-treatment) makes me wonder if the baseline population is truly reflecting the “natural population” in the community.

The intervention design was potentially problematic – low dose, no placebo and slightly ethically troubling.  I think a placebo suppository would have been useful to eliminate doubts about the effect of the intervention providing manual stimulation and unintended therapeutic action.

It is possible that the parents’ reporting inflated the rate of seizures , we will never know.

My big concern with this study is the 16% overall recurrence rate – this is very high.  When I asked around a few experienced heads – that rate seemed to be around 5 times the rate we see in practice.  The authors also cited a previous paper on this question by Schnaiderman et al‍  – in this smaller trial (50 in each arm) the recurrence rates were basically the same and only 7 – 8% i.e. in that cohort the placebo group had lower rates of recurrence than in the treatment group in this Japanese data.  This makes me wonder that we may be dealing with a population in this Japanese centre that either has some predilection to FSs or that the population was artificially selected (maybe by excluding the diazepam users) to create a group of children who had a very high baseline risk for recurrent seizures.

The children who had the diarrheal illness and were subsequently excluded from the study went on to have an astronomically high seizure recurrence rate of 35%.  This is likely due to some local microbiological nasty that secretes an endotoxin that jiggles young brains.  So, given this common occurrence, it is entirely possible that some of the study population was “contaminated” i.e. they had the same microbe in their systems but had not yet developed symptoms.  Just a postulation, but it would explain the high numbers at baseline to some extent. Unfortunately, the kids were not followed to see who went on to be like Don Bradman – get a heap of runs!

BAYESIAN BOTTOM LINE:

Prior to seeing this data I/we did not believe that there was a significant effect from the use of antipyretics in the prevention of subsequent seizures in children with simple FSs.

This is a small trial which has some design flaws and potentially does not represent our natural population.

Despite a significant result, I do not believe that this data can change the probability for efficacy enough to make this a “practice changer”.

FINAL THOUGHTS

Simple febrile seizures (and even recurrent FSs) are a benign condition.  They are scary and not something that any parent wants to endure.  However, as doctor-scientists, we do need to decide which interventoins are useful.  The recurrence of a seizure in this trial was counted as a FAIL – a bad outcome.  Though, when you think about it, if the child comes to no real harm and we can educate and reassure parents then is it really a harm?  What exactly are we preventing with an invasive yet safe therapy such as rectal acetaminophen?

FYI – I cannot recall the last time I ordered/gave PR medication to an awake/well child.  Can we do the trial with orals next time?

Comments

  1. I recall a large trial being falsified in Japan – I think it was BMD results and bisphosphonates – it was to do w academic hierarchy and pressure to produce P values – it resulted in a suicide and jnl article retraction after years of dredging thru the skullduggery by Australasian researchers- It produced results that were spectaculaly signif and unreproducible elsewhere. I would be wary of too good to be true P values from Japan after reading the papertrail it took to uncover tortured data and tortured souls.

    • Thanks for the comments
      Agree that it is very problematic if there is systemic manipulation of data.
      However, I don’t think it is fair to label “Japan” as inherently bad as a result of a few bad apples
      We see similar issues in many countries unfortunately
      C

  2. High rate of “febrile seizure” recurrence. Suspiciously high. The seizures would have been identified by parents rather than medical personnel (that is, the outcome measure isn’t objective). I wonder how many seizures were misdiagnosed and were actually just rigors. If this were the case, it would explain both the observed effect and extraordinarily high seizure recurrence rate.

  3. Gav Cleland says:

    Glad you asked about orals – I read through your whole post thinking “why rectal?”

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