Intramuscular Midazolam for Seizures – Part VI

Also posted over at Rogue Medic (now at EMS Blogs).

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How aggressive should we be in treating seizure patients based on this large double-blind, randomized, noninferiority trial comparing IM (IntraMuscular) midazolam (Versed) with IV (IntraVenous) lorazepam (Ativan)?

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Which seizure patients should be treated with benzodiazepines?

Most patients stop seizing without any treatment and benzodiazepines can cause respiratory depression, so we need to be careful.

You can’t be too careful!

Right?

status epilepticus . . . occurs in approximately 6% of visits to the emergency department for seizures. . . . Although the term “prolonged” was previously used to refer to seizures lasting 30 minutes or longer, this interval has been shortened to 5 to 10 minutes in recent studies. This change occurred for several reasons. First, almost all convulsive seizures in adults cease in less than 5 minutes without treatment; seizures lasting longer than this are more likely to be self-sustained and to require intervention.^{3,4 [1]}

We used to be much more careful. We would wait half an hour before treating seizures out of a fear of making things worse. That fear caused us to make things worse by being too careful.

5 minutes seems to be the dividing line between seizures that will stop on their own and seizures that require treatment.

Second, the longer seizures persist, the harder they are to terminate pharmacologically.^{5 [1]}

Being too careful resulted in higher doses of medication being given, because the dose that could have worked earlier in the seizure is no longer effective. The larger dose is also not effective. A different medication may also need to be added, even though it may not be effective, because we waited too long by being too careful!.

Delaying by more than 5 minutes increases the likelihood of not being able to stop the seizure with any medication. This is far worse than the potential side effects of giving a benzodiazepine to a patient who would otherwise have his seizure resolve spontaneously.

Third, outcome tends to correlate with seizure duration even after one controls for other factors. Mortality among patients who present in status epilepticus is 15 to 22%; among those who survive, functional ability will decline in 25% of cases.^{6 [1]}

Benzodiazepine side effects should be easily managed, even by people with just advanced first aid training – protect the airway and make sure the patient is breathing. In the absence of adequate breathing, getting the patient to talk is most effective. If getting the patient to talk is unsuccessful, painful stimulus is indicated. If painful stimulus is unsuccessful, rescue breathing is indicated.

The effects of midazolam on the CNS are dependent on the dose administered, the route of administration, and the presence or absence of other medications. Onset time of sedative effects after IM administration in adults is 15 minutes, with peak sedation occurring 30 to 60 minutes following injection.^[2]

Midazolam given IM is not metabolized as quickly as when given IV, but midazolam should still be metabolized more quickly than IV lorazepam (Ativan). Unfortunately, the label does not include information about the time to return to being alert following IM midazolam, so I can only make this apples and oranges comparison. When I have given midazolam IV, I have had to give more midazolam before arriving at the hospital (after I had given a total dose that was successful) or more sedation has had to be given the hospital (after I had given a total dose that was successful). I have never seen IV lorazepam metabolized that quickly. So midazolam is metabolized much more quickly IV, than lorazepam is metabolized IV. Unfortunately, I could not find more appropriate information to compare the metabolism of IM midazolam and IV lorazepam.

The intended effects of the recommended adult dose of ATIVAN Injection usually last 6 to 8 hours.^[3]

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Image credit.

This study does show that the patients receiving IM midazolam did not end up hospitalized as often, which may be due to more rapid metabolism of IM midazolam.

the proportion of subjects admitted was significantly lower (and the proportion discharged from the emergency department was significantly higher) in the intramuscular group than in the intravenous group (P=0.01).^[4]

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What is needed is a good study comparing buccal midazolam, IN (IntraNasal) midazolam, and IM midazolam to find out which works best. Perhaps a rectal diazepam group could be included to put another nail in that coffin, but rectal diazepam has the one thing going for it that no amount of evidence seems to be able to overcome – tradition. We need to stop killing our patients with tradition.

Multiple studies have shown that nasal or buccal midazolam stops seizures faster than rectal or intravenous diazepam¹³ and is absorbed faster than intramuscular midazolam.^{13 – 15 [1]}

Buccal or IN midazolam stops seizures faster than IV or rectal diazepam, but is only absorbed faster than IM midazolam?

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See also Part I, Part II, Part III, Part IV, and Part V.

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Footnotes:

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^[1] Intramuscular versus intravenous benzodiazepines for prehospital treatment of status epilepticus.
Hirsch LJ.
N Engl J Med. 2012 Feb 16;366(7):659-60. No abstract available.
PMID: 22335744 [PubMed - in process]

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^[2] MIDAZOLAM HYDROCHLORIDE injection, solution
[Hospira, Inc.]
DailyMed
FDA Label

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^[3] ATIVAN (lorazepam) injection, solution
[Baxter Healthcare Corporation]
DailyMed
FDA Label

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^[4] Intramuscular versus intravenous therapy for prehospital status epilepticus.
Silbergleit R, Durkalski V, Lowenstein D, Conwit R, Pancioli A, Palesch Y, Barsan W; NETT Investigators.
N Engl J Med. 2012 Feb 16;366(7):591-600.
PMID: 22335736 [PubMed - in process]

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