Or, more accurately, is it reasonable to perform an intramuscular injection of midazolam rather than an intravenous injection of lorazepam for seizure-like activity in the prehospital setting?
Almost certainly.
In fact, some folks are taking this article and claiming that intramuscular midazolam is superior to intravenous lorazepam, that it’s a “game changer.”
Well, let’s not go crazy here.
As with any piece of literature, the more vocal the giddiness I see perpetuated about the internet, the more cautious I am with rushing to judgement. It is, of course, a very well-designed, prospective, double-dummy, randomized, non-inferiority comparison between midazolam and lorazepam. The aim of the study is, essentially, to show that, even though midazolam is not typically as rapidly effective at terminating seizures, the time difference is made up by intramuscular route versus the time required for an IV start.
What’s kind of odd that I see in this article is that nearly a third of the lorazepam group did not receive the benzodiazepine portion of the intervention – and they compare it to the midazolam group in which all but 5 patients received the intervention. When their primary outcome is the number of folks who arrived seizure-free in the Emergency Department – it seems as though the 7% absolute difference between the two groups could be easily explained by the fact that a third of the lorazepam group didn’t receive an intervention. Most of the lorazepam group had the intervention withheld because they stopped seizing of their own accord at the time of enrollment, with a minority having the intervention withheld because IV access could not be obtained.
And, the differences favoring midazolam are hard to pin down whether it’s actually medication superiority, or something different about the seizures. 42 patients in the lorazepam group failed to stop seizing after additional therapy, compared with only 22 in the midazolam group – is this a difference in efficacy, or a difference in the underlying disease process – which appears to be more resistant to any therapy, including rescue, in the lorazepam group?
But, in any event, this just nitpicking against the superiority argument, and not the non-inferiority argument. From a clinical standpoint, it is clearly safe and effective to use intramuscular midazolam for seizures in the prehospital setting. However, what I’d prefer to see is a similarly powered trial of intranasal midazolam, which takes all the injection risks for patient and provider out of the equation during the seizure. This is a good first step, but I think we can make effective treatment even safer if intranasal can be shown non-inferior as well.
“Intramuscular versus Intravenous Therapy for Prehospital Status Epilepticus”
http://www.nejm.org/doi/full/10.1056/NEJMoa1107494
We've had a good experience with intranasal midazolam in the field, although we don't exactly run enough active seizures to determine non-inferiority.
We've had a good experience with intranasal midazolam in the field, although we don't exactly run enough active seizures to determine non-inferiority.
Primary Outcome
Seizures were absent without rescue therapy on arrival in the emergency department in 329 of 448 subjects assigned to active treatment with intramuscular midazolam (73.4%) and in 282 of 445 assigned to active treatment with intravenous lorazepam (63.4%)
If the outcome is based on not having seizures, having 21% of the patients in one group stop seizing before treatment would seem to benefit that treatment group (IV lorazepam)
148 Did not receive intervention
95 Had convulsions stop before intervention
42 Had paramedics who could not start IV
42 patients could not have an IV started, but only 31 of those 42 did not receive lorazepam due to the inability to start an IV. 11 of the 42 appear to have not received lorazepam because the seizures stopped.
The quick administration of the midazolam appears to have prevented the same rate of spontaneous resolution in the IM midazolam group.
What is really curious is that there were so many failures to establish access in the IV group.
When it was difficult to obtain intravenous access, paramedics were instructed to continue attempts for at least 10 minutes, but they were permitted to use intraosseous access at any time in lieu of intravenous access.
If they were permitted start IOs at any time, why did they have a 9 1/2% failure rate?
There are plenty of other studies demonstrating the efficacy of IM midazolam, so this was not the groundbreaking trial that they suggested it is.
There is plenty of evidence that the first treatment for seizures should be midazolam. IM, IN, and buccal all have been demonstrated to work very quickly. There are still too many people using rectal diazepam.
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Primary Outcome
Seizures were absent without rescue therapy on arrival in the emergency department in 329 of 448 subjects assigned to active treatment with intramuscular midazolam (73.4%) and in 282 of 445 assigned to active treatment with intravenous lorazepam (63.4%)
If the outcome is based on not having seizures, having 21% of the patients in one group stop seizing before treatment would seem to benefit that treatment group (IV lorazepam)
148 Did not receive intervention
95 Had convulsions stop before intervention
42 Had paramedics who could not start IV
42 patients could not have an IV started, but only 31 of those 42 did not receive lorazepam due to the inability to start an IV. 11 of the 42 appear to have not received lorazepam because the seizures stopped.
The quick administration of the midazolam appears to have prevented the same rate of spontaneous resolution in the IM midazolam group.
What is really curious is that there were so many failures to establish access in the IV group.
When it was difficult to obtain intravenous access, paramedics were instructed to continue attempts for at least 10 minutes, but they were permitted to use intraosseous access at any time in lieu of intravenous access.
If they were permitted start IOs at any time, why did they have a 9 1/2% failure rate?
There are plenty of other studies demonstrating the efficacy of IM midazolam, so this was not the groundbreaking trial that they suggested it is.
There is plenty of evidence that the first treatment for seizures should be midazolam. IM, IN, and buccal all have been demonstrated to work very quickly. There are still too many people using rectal diazepam.
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Interesting take – I actually read the primary outcome not as "termination of initial seizure" but "seizure-free on arrival to the ED". A patient who does not get their IV diazepam is much more likely to have recurrent seizure prior to or on ED arrival, while someone receiving their IM midazolam will be more likely to remain seizure free.
But, yes, IM midazolam is quite adequate. Intranasal and buccal are also probably similarly effective, but should be further formally evaluated.
Interesting take – I actually read the primary outcome not as "termination of initial seizure" but "seizure-free on arrival to the ED". A patient who does not get their IV diazepam is much more likely to have recurrent seizure prior to or on ED arrival, while someone receiving their IM midazolam will be more likely to remain seizure free.
But, yes, IM midazolam is quite adequate. Intranasal and buccal are also probably similarly effective, but should be further formally evaluated.
A comparison of lorazepam, diazepam, and placebo for the treatment of out-of-hospital status epilepticus.
Alldredge BK, Gelb AM, Isaacs SM, Corry MD, Allen F, Ulrich S, Gottwald MD, O'Neil N, Neuhaus JM, Segal MR, Lowenstein DH.
N Engl J Med. 2001 Aug 30;345(9):631-7. Erratum in: N Engl J Med 2001 Dec 20;345(25):1860.
PMID: 11547716 [PubMed – indexed for MEDLINE]
The rate of termination among the placebo group was 21% in that study, which is the same as the rate of spontaneous termination among the lorazepam group, who did not receive any lorazepam due to the seizures stopping in this study.
Since most of these patients did have IV access (and could have received IV lorazepam for a recurrence of seizure activity), I interpreted this as the patients not having any further seizures. I would be surprised if EMS would not treat active seizures just because the seizure had stopped on its own, but resumed after IV placement.
In the good old days of low dose diazepam, I felt that more of the seizures were actually terminated spontaneously, rather than due to the nominal doses of diazepam we gave in EMS.
On the other hand, I am expecting this study to be used as a justification for patenting a midazolam auto-injector to be able to sell midazolam at much higher name brand prices, the way Diastat was patented for rectal diazepam. That would explain a lot of the hype.
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A comparison of lorazepam, diazepam, and placebo for the treatment of out-of-hospital status epilepticus.
Alldredge BK, Gelb AM, Isaacs SM, Corry MD, Allen F, Ulrich S, Gottwald MD, O'Neil N, Neuhaus JM, Segal MR, Lowenstein DH.
N Engl J Med. 2001 Aug 30;345(9):631-7. Erratum in: N Engl J Med 2001 Dec 20;345(25):1860.
PMID: 11547716 [PubMed – indexed for MEDLINE]
The rate of termination among the placebo group was 21% in that study, which is the same as the rate of spontaneous termination among the lorazepam group, who did not receive any lorazepam due to the seizures stopping in this study.
Since most of these patients did have IV access (and could have received IV lorazepam for a recurrence of seizure activity), I interpreted this as the patients not having any further seizures. I would be surprised if EMS would not treat active seizures just because the seizure had stopped on its own, but resumed after IV placement.
In the good old days of low dose diazepam, I felt that more of the seizures were actually terminated spontaneously, rather than due to the nominal doses of diazepam we gave in EMS.
On the other hand, I am expecting this study to be used as a justification for patenting a midazolam auto-injector to be able to sell midazolam at much higher name brand prices, the way Diastat was patented for rectal diazepam. That would explain a lot of the hype.
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