February 1, 2023

2018 Murata study: does it change management?

There i was standing in the pediatric idi when an anxious dad brought in his 19 month old toddler to be evaluated after having a febrile seizure the toddler still had a fever but was already back to her baseline self and besides some viral upper respiratory signs she looked overall well appearing prior to the patient’s arrival i reviewed the management and guidance

For one of the many questions i knew the dad would ask if i give my child acetaminophen or ibuprofen when she has a fever will this decrease the chance she will have another seizure in medical school i was taught that reassurance reassurance and reassurance were the keys to parental guidance in simple febrile seizures with no red flag features antipyretics such as

Acetaminophen or ibuprofen do not prevent recurrent seizures and their use is to relieve discomfort from the infection and not for treating the fever therefore i was surprised when i looked to see if there were any new updates and i came across the 2018 study by mirada and all published in pediatrics in this single center study at a hospital in japan they randomized

438 children into two groups ages 6 to 60 months one group received rectal acetaminophen 10 milligrams per kilogram every six hours after the first seizure if the fever was greater than 38 degrees celsius the other group was told to give no antipyretics they were interested to see if there was a difference in the number of recurrences during the same febrile illness

And man were their results donk’ if we convert the results in terms of a hundred children 24 out of a hundred children that did not receive anything had another seizure during the same febrile illness that is a greater than 20% recurrence rate while only nine out of a hundred children that received the rectal acetaminophen had another seizure during the same febrile

Illness that is less than a 10% recurrence rate with an absolute reduction of 15% if i could trust the results i would definitely need to rethink my clinical recommendations however i realized my source of knowledge to that point was authoritative i knew what i had been taught in medical school but i had not personally evaluated the studies that supported what

I had been taught this like all authoritative knowledge left me susceptible to erratic changes in practice based on the next new exciting study therefore i know i needed to do a fair amount of legwork to adequately review this study first thing first i always try to figure out if the control groups numbers are reasonable if it’s outside the norm it can sometimes

Be a hint that something is off before diving too deep into the study the problem is i had no idea what i should expect for their current rate in the same febrile illness for the control i did a quick search and compiled the data of an assortment of randomized control trials retrospective and prospective studies for a total of four thousand two hundred and thirty

Five children with febrile seizures four hundred and ninety two of them had a repeat seizure within the same febrile episode this was a quick and dirty search so don’t take my numbers as gospel but i needed a reference point to start from the evidence is muddied but i came up with a recurrence rate of 12% in the same febrile episode here’s the graph weighted by

Numbers in each of the twelve trials i looked at looking at the studies weighted this way shows that only a small proportion of the evidence points to recurrence rates greater than 20% the problem with these studies is that most of these individuals most likely received antipyretics for discomfort and a small subset may have received benzodiazepines additionally

The murata study was in japan which in general has a higher rate of febrile seizures so all of this has to be taken into context the second thing i always look at is how closely the control group was treated in comparison to the intervention group and here i found a big red flag no placebo was given to the control group therefore no blinding took place now some

Might argue that placebos are more important in subjective outcomes but seizures are so objectively obvious that using a placebo would not make that much of a difference in the results that belief is simply not true for example patient with epilepsy assigned to sham stimulation in a trial testing responsive neurostimulation had a 27 percent response rate even

Though they were not receiving any therapy and in open-label trials of the anti epileptic drug lamotrigine for lenox gusto showed that about 70 percent of the patients had a 50% reduction in seizure frequency when taking lamotrigine however when a well conducted double blinded randomized placebo control trial was done the responder rate plummeted to 33 percent

In the study arm and 16 percent in the placebo arm that means only 17 percent of the patients not 70 percent were true responders systematic reviews of antiepileptic medications estimate the placebo arm has a response of 4 to 19 percent with some studies showing a response rate of up to 40 percent surprisingly the response rate has been increasing over time and

Children tend to have a higher rate of response rate than adults a fair amount of the response can be the result of a regression to the mean and natural fluctuations in seizure frequency but observer biases including the hawthorn and pygmalion effect are also likely influencing the placebo response these biases can lead to less recognition in underreporting if

The patients or their parents believe they are receiving the treatment or vice-versa over reporting if they believe they are not receiving the treatment personally i can empathize with anxious parents that have a child at risk for seizure soon after my son was diagnosed with periventricular nodular heterotopia my wife and i panicked over some unusual movements and

Behaviors and what felt to us as unresponsiveness we freaked out and we started loading him into the car to go to the emergency department when i sent a video of the episode to a pediatric neurologist she watched the video and then calmly explained how the movements were not consistent with seizure activity today however it is still difficult not to over scrutinize

Any twitcher change in behavior knowing that several folks i said in my son’s brain that could one de cause epilepsy the placebo response in seizure research is no secret and marauder and all cite previous antipyretic studies that had placebo arms what’s more the duration of this study was only over one febrile illness the other placebo control trials were over

Months to two years implementing a placebo in the mirada at all study would have been far simpler it should also be noted that in these longer and more robust studies antipyretics do not prevent recurrences in subsequent febrile illnesses so it is surprising to see it result that prevents recurrence is in the same febrile opposite the decision to not incorporate a

Placebo into this study is straight donkey it makes the result incredibly difficult to interpret additionally they could have included the current standard treatment which is to treat the fever if the child has discomfort an rct that compared scheduled tylenol versus unscheduled tylenol found no difference of recurrence rates in the same febrile illness unfortunately

They did not have a placebo arm so there is still a gap between that study and the murata and all study there are also some annoying peculiarities that do not really threaten the validity of the study but unnecessarily make the study less endearing for example the authors chose to do a per protocol analysis rather than an intention-to-treat analysis despite only

10 out of more than 400 patients failed to follow protocol it is doubtful this would have impacted the results by very much at all so why do the per protocol analysis it just seems silly and odd that the authors do not comment on why they chose this analysis that tends to be more biased the authors also only recorded body temperature at presentation but did not

Collect data on temperature control during the entirety of the febrile illness in the conclusion section the authors hypothesize why lowering temperature may prevent seizures but they did not collect data showing that body temperatures were actually lowered they acknowledge this is a wee miss but failed to mention that multiple studies have shown that antipyretics

Were helpful in febrile episodes without seizures but that antipyretics were unable to significantly lower body temperatures during febrile illnesses that resulted in seizure recurrence so where does this leave me would i schedule an antipyretic after a febrile seizure if i had a child without an underlying neurological condition i would certainly be pretty shaken

Up if i saw my child seizing for me personally it’s often difficult to judge a sick toddler’s level of discomfort and 24 hours of responsible scheduled antipyretic use would unlikely do much harm to be clear when i discuss antipyretics with parents with a child that just had a febrile seizure i would tell them there is no good evidence that using acetaminophen

Or ibuprofen will prevent another seizure in the current or subsequent illnesses if anything the majority of the evidence makes it doubtful that antipyretics will prevent seizures this might sound hypocritical that i might schedule antipyretics for 24 hours and my own child however i would make my personal choice known to the parents but i would emphasize that

Their ability to decrease the risk of recurrence is unlikely the larger body of evidence conflicts with this single sub-optimal study improperly presenting this study as significant can cause harm for one as mentioned previously studies show that elevated body temperatures are less responsive to antipyretics during illnesses in which febrile seizures do occur in

An effort to bring down the temperature nervous parents that view seizures more harmful than ibuprofen or acetaminophen may give additional futile doses which will cause more harm with little evidence for benefit secondly giving parents the false impression that they can prevent subsequent seizures sets the parents up for an undue amount of guilt that they failed

Their child if they miss a dose due to any number of factors including stress or fatigue with all that said it would be very easy to have my mind changed about antipyretics and febrile seizures if the marauder at all study was repeated with a placebo in a multicenter trial a representative of my patients was analyzed by intention-to-treat body temperatures were

Recorded and it showed similar results i would have no problem supporting the conclusions you

Transcribed from video
Febrile seizures and Acetaminophen: Murata Study By Fourkcandles