Without evidence of benefit, an intervention should not be presumed to be beneficial or safe.

- Rogue Medic

If your Versed (midazolam) isn’t working, maybe it’s Zofran (ondansetron)

 
If you were giving a lot more midazolam (Versed) by intramuscular injection to stop a seizure and the seizure just would not stop, or got worse, maybe you were giving ondansetron (Zofran).

If you were giving a lot more midazolam by injection to sedate a patient and the sedation just wasn’t having its usual effect, maybe you were giving ondansetron. While rare, there can be very serious side effects from too much ondansetron.
 

Dose-dependent serious cardiac arrhythmias may be observed with higher dosages of ondansetron in those patients with certain pre-existing cardiac conditions. Patients may also be at risk for serotonin syndrome. Serotonin syndrome is associated with increased serotonergic activity in the central nervous system. Most reports of serotonin syndrome have been associated with concomitant use of certain drugs, some commonly used during surgery, such as fentanyl. Some of the reported cases of serotonin syndrome were fatal.[1]

 

How do you recognize serotonin syndrome?
 

Serotonin syndrome (SS) is a group of symptoms that may occur following use of certain serotonergic medications or drugs. [1] The degree of symptoms can range from mild to severe.[2] Symptoms include high body temperature, agitation, increased reflexes, tremor, sweating, dilated pupils, and diarrhea.[1][2] Body temperature can increase to greater than 41.1 °C (106.0 °F).[2] Complications may include seizures and extensive muscle breakdown.[2] [2]

 

2 mg of midazolam is much too low a dose to try to stop a seizure, unless it is the only packaging you have and you are giving 5 intramuscular injections at a time. The best response to prehospital treatment of seizures was by giving 10 mg of intramuscular midazolam to adults (over 40 kg) and 5 mg of intramuscular midazolam to children (under 40 kg).

Maybe you think that is too much midazolam. The highest quality and largest pre-hospital study does not support using lower doses.
 

Our data are consistent with the finding that endotracheal intubation is more commonly a sequela of continued seizures than it is an adverse effect of sedation from benzodiazepines.11 [3]

 

There are other uses for midazolam, so you should be aware of the possibility that what you think is midazolam is really ondansetron.

Are the syringes labeled incorrectly for the contents?
 

Fresenius Kabi USA is voluntarily recalling Lot 6400048 of Midazolam Injection, USP, 2 mg/2 mL packaged in a 2 mL prefilled single-use glass syringe to the hospital/user level. The product mislabeled as Midazolam Injection,
USP, 2 mg/2 mL contains syringes containing and labeled as Ondansetron Injection, USP, 4 mg/2 mL.
[1]

 

Based on that, the syringes should be correctly labeled as ondansetron, but they are in blister packs labeled as containing midazolam or they are in boxes of blister packs listed as containing midazolam or both or something else.

If you use this packaging of midazolam, check the lot number, the syringe, and any other labels to make sure that they all agree.

What if you need some ondansetron pre-filled syringes?

Send them back anyway. Maybe only some of the syringes are labeled correctly.

What do the syringes look like?
 


 

What does the ondansetron syringe look like? This one is with a blister pack.
 


 

There are other possibilities for mislabeling that could be much more harmful, so read the syringe before you push anything by any manufacturer.
 


 

That probably would not be as harmful as it seems, because it would be pushed slowly, so it might be metabolized as quickly as it is pushed. The ones below would still be expected to produce a much greater respiratory depression than even an extreme midazolam respiratory depression.
 


 

Footnotes:

[1] Fresenius Kabi Issues Voluntary Nationwide Recall of Midazolam Injection, USP, 2 mg/2 mL Due to Reports of Blister Packages Containing Syringes of Ondansetron Injection, USP, 4 mg/2 mL
For Immediate Release
November 3, 2017
Voluntary Recall
Recall announcement

[2] Serotonin syndrome
Wikipedia
Article

[3] 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]

Free Full Text from N Engl J Med.

.

Benzodiazepines are often misused – Part I

 
The most commonly used benzodiazepines in EMS/EM (Emergency Medical Services/Emergency Medicine) are diazepam (Valium), lorazepam (Ativan), and midazolam (Versed). It should be relatively easy to look at the best research and determine –

1. Should benzodiazepines be the first parenteral medication given for seizures?

2. Should benzodiazepines be the first parenteral medication given for agitated delirium/excited delirium (it is a real condition that results in death in custody much more often than intentional police misbehavior)?

3. Should benzodiazepines be the first parenteral medication given for sedation?

In EMS/EM, some of the important things to consider are the time it takes for the drug to take effect, the likelihood that the drug will produce the desired effect, the seriousness of adverse effects and rate at which the most serious adverse effects occur.

Seizures

Is there any evidence that anything works quicker than IM (IntraMuscular) midazolam, when the patient does not already have an IV (IntraVenous line)?

Is there any evidence that an initial dose of 10 mg IM midazolam is too high of an initial dose for an adult (over 40 kg) or that 5 mg is too high of an initial dose for a child (40 kg or less)?

Is there any evidence that this dosing increases the rate of airway compromise above what would occur with lower doses?

The Rampart study[1] strongly suggests that 10 mg of IM midazolam is the best approach for the seizing patient who does not already have an IV, when IM midazolam is available. If midazolam is not available, such as due to poorly written protocols, midazolam is not an option and delaying less effective care to wait for the ideal treatment would be reckless.

There do not appear to be any studies that show any better outcomes with any other benzodiazepoines or with any other doses.
 

What about when an IV is already in place?

Should IV midazolam be used?

Should IV lorazepam be used?

Should IV diazepam be used?

Should some other drug be used?

The evidence is not clear, but is there any reason to believe that lorazepam, or diazepam, works as quickly as midazolam, when given intravenously?

Is there any reason to believe that lorazepam, or diazepam, produce fewer, or less serious, adverse effects than midazolam, when given IV?

I don’t know of any valid evidence to suggest that midazolam is inferior to either diazepam or lorazepam.

There is also the benefit in EMS of a much shorter time of effect for midazolam.

A drug that wears off quickly is going to be the safer EMS drug – unless there is a good reason to use a drug that lasts longer.

I will explain why wearing off quickly is important in EMS treatment of seizures in Part II (not yet posted).

Footnotes:

[1] 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]

Free Full Text from N Engl J Med.

I have written about this in Intramuscular Midazolam for Seizures – Part I,
Part II,
Part III,
Part IV,
Part V,
Part VI,
Misrepresenting Current Topics in EMS Research from EMS Expo – RAMPART,
and Images from Gathering of Eagles Presentation on RAMPART.

.

Images from Gathering of Eagles Presentation on RAMPART

Some images from the Gathering of Eagles presentation on RAMPART[1] can help to give an idea of what was done to blind EMS to the treatment being given, while minimizing any delay in care that might result from being part of a study. Thank you to Happy Medic for clarifying some of the information not spelled out in the paper.

 

First is the study kit that was used.

For subjects who met the eligibility criteria, the paramedics began the study procedure by opening an instrumented box containing a study drug kit. Each kit contained two color-coded, shrink-wrapped study-drug bundles, one for each dose tier; each bundle consisted of one intramuscular autoinjector (Investigational Midazolam Autoinjector [Meridian Medical Technologies]) and one prefilled intravenous syringe (Carpuject System [Hospira]).[2]

A voice recorder was activated by opening the study box. Paramedics were instructed to record oral statements when intramuscular treatment was administered, when intravenous access was obtained, when the intravenous study drug was administered, when any rescue treatments were given, and when convulsions were observed to stop. Each statement was time-stamped by the study box’s internal clock. Paramedics also stated whether the subject was convulsing on arrival at the emergency department.[1]

This is the autoinjector.

To assess the weight of the patient for the study, they used a simplified length-based resuscitation tape to measure children to determine whether they were large enough to participate in the trial (at least 13 kg – 28.6 pounds) and whether they would receive the adult dose (over 40 kg – 88 pounds). The low dose was 2 mg lorazepam (Ativan) IV (IntraVenous) or 5 mg midazolam (Versed) IM (Intramuscular). The standard adult dose was 4 mg lorazerpam IV or 10 mg of midazolam IM.

It took me a while to figure out what this was. I initially thought that it was just a label from the side of the study drugs, but when I read it, I realized that this is an image of a full-sized length-based resuscitation tape, just shrunk to fit on the page. That would be about 5 feet long. This is conveniently marked with sections stating DO NOT ENROLL at one end and USE 10 MG DOSE at the other end.

For those who think that randomized placebo controlled studies would interfere with patient care, or delay patient care, this demonstrates that it is pretty easy to get around obstacles and even deliver care faster than outside of the study.

This appears to be an excellent way of designing a randomized double-blind controlled trial.

I tried to get some sort of confirmation of the numbers on the IM midazolam group in this last image, but Dr. Jason McMullan does not have them and only the IV lorazepam numbers are in the original paper. I sent a couple of emails to Dr. Robert Silbergleit (the contact person for the paper), but I have not received any response.

The percentage of patients who had their seizures stop prior to starting an IV in the IV lorazepam matches the placebo group from the lorazepam vs. diazepam vs. placebo study.[3]

The IV lorazepam group had 21% of the patients not receive IV medication because the seizure stopped without medication.

The placebo group had 21.1% of the seizures stop without any active medication.

The IM midazolam group had 39% of the patients not receive IV medication (just saline since their package included the active midazolam auto-injector) because the seizure stopped before the IV could be started.

The seizures stopped at almost twice the rate that seizures have stopped with placebo treatment. These are just the seizures that stopped before an IV could be started.

This study is an excellent example of a prehospital randomized double-blind controlled study that would serve as a great model for a placebo controlled trial of epinephrine.

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

Footnotes:

[1] Epileptic Fix: Hot-Off-the-Press Results from the RAMPART Trial
Jason T. McMullan, MD (Cincinnati)
Gathering of Eagles
Friday, February 24, 2012
Presentation

[2] 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]

Free Full Text from N Engl J Med.

[3] 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]

Free Full Text from N Engl J Med. with link to PDF Download

.

Intramuscular Midazolam for Seizures – Part VI


ResearchBlogging.org
Also posted over at Paramedicine 101 (now at EMS Blogs) and at Research Blogging. Go check out the excellent material at these sites.

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)?

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]


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]

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?

See also Part I, Part II, Part III, Part IV, Part V, and Images from Gathering of Eagles Presentation on RAMPART.

Footnotes:

Correction 01/15/2014 15:00 – I had the wrong paper listed as the source of the material in Footnote [1]. I listed the RAMPART study, but the source is the editorial that was published in the same issue. The correct source is below with the paper I originally cited below it. There is nothing wrong with the paper crossed out – only with my use of it as the source of the material I included above.
 

[1] Intramuscular versus intravenous benzodiazepines for prehospital treatment of status epilepticus.
Hirsch LJ.
N Engl J Med. 2012 Feb 16;366(7):659-60. doi: 10.1056/NEJMe1114206. No abstract available.
PMID: 22335744 [PubMed – indexed for MEDLINE]

Free Full Text PDF Download from the RAMPART Group.
 

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]

Free Full Text from N Engl J Med.

[2] MIDAZOLAM HYDROCHLORIDE injection, solution
[Hospira, Inc.]

DailyMed
FDA Label

[3] ATIVAN (lorazepam) injection, solution
[Baxter Healthcare Corporation]

DailyMed
FDA Label

[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]

Silbergleit, R., Durkalski, V., Lowenstein, D., Conwit, R., Pancioli, A., Palesch, Y., & Barsan, W. (2012). Intramuscular versus Intravenous Therapy for Prehospital Status Epilepticus New England Journal of Medicine, 366 (7), 591-600 DOI: 10.1056/NEJMoa1107494

Hirsch LJ (2012). Intramuscular versus intravenous benzodiazepines for prehospital treatment of status epilepticus. The New England journal of medicine, 366 (7), 659-60 PMID: 22335744

Hirsch LJ (2012). Intramuscular versus intravenous benzodiazepines for prehospital treatment of status epilepticus. The New England journal of medicine, 366 (7), 659-60 PMID: 22335744

.

Intramuscular Midazolam for Seizures – Part V


ResearchBlogging.org
Also posted over at Paramedicine 101 (now at EMS Blogs) and at Research Blogging. Go check out the excellent material at these sites.

How should this large double-blind, randomized, noninferiority trial comparing IM (IntraMuscular) midazolam (Versed) with IV (IntraVenous) lorazepam (Ativan) affect the way we treat patients with seizures?


Click on image to make it larger.

21.3% of patients had their seizures stop before they could be given IV lorazepam, while none of the IM midazolam patients had seizures stop before being given medication.

Does that provide a bias toward improved outcomes with IM midazolam?

Study Outcomes
The primary outcome was termination of seizures before arrival in the emergency department without the need for the paramedics to provide rescue therapy.
[1]

 

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%) (difference, 10 percentage points; 95% confidence interval [CI], 4.0 to 16.1; P<0.001 for noninferiority and P<0.001 for superiority) (Fig. 2).[1]

 

The patients who had seizures stop without any lorazepam are included in those considered successfully treated.

This is appropriate, since we can expect a similar rate of spontaneous resolution among the patients receiving IM midazolam. The only difference is that those patients will have received the midazolam so quickly that the seizure will not yet have stopped.
 

Status epilepticus was terminated by the time of arrival at the emergency department in 59.1 percent of patients given lorazepam, 42.6 percent of patients given diazepam, and 21.1 percent of patients given placebo (P=0.001)[2]

 

Is this a reason to avoid/delay administration of IM midazolam?

No.

The greater risk appears to be to the patients with continuing seizures. The primary benefit of IM midazolam is the rapid administration.

There is no evidence of any harm to the patients who would have their seizures stop without midazolam. There is evidence of harm from delaying/avoiding treatment. Most seizures will stop prior to the arrival of EMS. Delays in treatment should probably only be for those known to have self-limiting seizures and EMS is at the patient’s side in less than 5 minutes.

An out-of-hospital complication (hypotension, cardiac dysrhythmia, or respiratory intervention) occurred in 7 (10.6 percent) of the patients treated with lorazepam, 7 (10.3 percent) of the patients treated with diazepam, and 16 (22.5 percent) of the patients given placebo (P=0.08). The most common complication was a change in respiratory status requiring ventilation assistance by bag valve-mask or an attempt at intubation (7 patients given lorazepam, 6 given diazepam, and 11 given placebo).[2]

 

Those who did not receive benzodiazepines did not do as well as those who did receive benzodiazepines – this includes the most worrisome side effect of benzodiazepines – respiratory compromise. We are not improving outcomes by delaying care or by using low doses.

Among subjects admitted to the hospital, the lengths of stay in the intensive care unit and in the hospital did not differ significantly between the groups, but 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).[1]

 

If there is no IV already in place, is there much reason to not use IM midazolam for active seizures?

No.

Our data are consistent with the finding that endotracheal intubation is more commonly a sequela of continued seizures than it is an adverse effect of sedation from benzodiazepines.11 [1]

 

High dose benzodiazepines appear to be more likely to prevent intubation, than to result in intubation. This is something that many medical directors do not seem to have considered.

See also Part I, Part II, Part III, Part IV, Part VI, and Images from Gathering of Eagles Presentation on RAMPART.

Footnotes:

[1] 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]

Free Full Text from N Engl J Med.

[2] 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]

Free Full Text from N Engl J Med. with link to PDF Download

Silbergleit, R., Durkalski, V., Lowenstein, D., Conwit, R., Pancioli, A., Palesch, Y., & Barsan, W. (2012). Intramuscular versus Intravenous Therapy for Prehospital Status Epilepticus New England Journal of Medicine, 366 (7), 591-600 DOI: 10.1056/NEJMoa1107494

Alldredge BK, Gelb AM, Isaacs SM, Corry MD, Allen F, Ulrich S, Gottwald MD, O’Neil N, Neuhaus JM, Segal MR, & Lowenstein DH (2001). A comparison of lorazepam, diazepam, and placebo for the treatment of out-of-hospital status epilepticus. The New England journal of medicine, 345 (9), 631-7 PMID: 11547716

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Intramuscular Midazolam for Seizures – Part IV


ResearchBlogging.org
Also posted over at Paramedicine 101 (now at EMS Blogs) and at Research Blogging. Go check out the excellent material at these sites.

What does this study mean for the treatment of patients who are having seizures?

The median time to administration of active treatment was significantly shorter by the intramuscular route than by the intravenous route (1.2 vs. 4.8 minutes), but the onset of action (i.e., termination of convulsions) occurred sooner after intravenous administration than after intramuscular administration (1.6 vs. 3.3 minutes).[1]


Click on images to make them larger.

The good news for fans of IV (IntraVenous) drugs for seizures is that giving IV lorazepam at the same time as giving IM (IntraMuscular) midazolam will result in faster termination of seizures.

If an IV is already in place, the average time for the IV lorazepam to stop the seizure is about 1.6 minutes after the lorazepam is pushed into the IV line.

The average time for the IM midazolam to stop the seizure is about 3.3 minutes after the midazolam is injected into the muscle.

If an IV is already in place, IV lorazepam should be significantly faster.

Would IV midazolam also work faster than IM midazolam?

Probably, but that was not demonstrated in this study. My preference is to give IV midazolam, rather than IV lorazepam, because the midazolam will wear off more quickly.

I am initially much more interested in stopping the seizure, than in the side effects that might be present as a result of aggressive dosing of benzodiazepine.

After the seizure, I want any side effects to stop as quickly as possible. Midazolam is going to be metabolized much more quickly than lorazepam. In the hospital, the continuing treatment of the patient will be in the hands of the emergency physician who will have a much broader selection of medications available to treat against further seizures.

Benzodiazepines appear to be the best emergency treatment for seizures, but they may not be good for longer term treatment of the same seizures.

The problem is that EMS and ED (Emergency Department) patients rarely have an IV in place when seizures begin and it is not easy to start an IV on a patient while the patient is seizing.


Image credit.

If an IV is NOT in place, then the delay in giving the medication is both dramatic and significant enough to completely eliminate the difference in absorption that favors giving IV medication.

With average times of 1.2 minutes from opening the medication box to injecting the medication IM and 4.8 minutes from opening the medication box to injecting the IV medication, the difference is 3.6 minutes.

The IV lorazepam works 1.7 minutes faster, but it takes 3.6 minutes longer before the IV lorazepam can be given, on average.

That difference means that the IM midazolam stops the seizure 1.9 minutes faster than the IV lorazepam.

The average total time to termination of seizure after opening the medication container was 6.4 minutes with IV lorazepam.

The average total time to termination of seizure after opening the medication container was 4.5 minutes with IM midazolam.

 

After 4.5 minutes, the medic is still working on starting the IV, but the seizure has already stopped in the IM midazolam group.

 

This should not be a difficult decision.

See also Part I, Part II, Part III, Part V, Part VI, and Images from Gathering of Eagles Presentation on RAMPART.

Footnotes:

[1] 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]

Free Full Text from N Engl J Med.

Silbergleit, R., Durkalski, V., Lowenstein, D., Conwit, R., Pancioli, A., Palesch, Y., & Barsan, W. (2012). Intramuscular versus Intravenous Therapy for Prehospital Status Epilepticus New England Journal of Medicine, 366 (7), 591-600 DOI: 10.1056/NEJMoa1107494

.

Intramuscular Midazolam for Seizures – Part III


ResearchBlogging.org
Also posted over at Paramedicine 101 (now at EMS Blogs) and at Research Blogging. Go check out the excellent material at these sites.

I have already pointed out my disappointment with the references of this large double-blind, randomized, noninferiority trial comparing IM (IntraMuscular) midazolam (Versed) with IV (IntraVenous) lorazepam (Ativan). One of those criticisms appears to be just due to a typographical error. The footnote in the text was 11, but the footnote should have been 1.
 

The relationships among benzodiazepine dose, respiratory depression, and subsequent need for endotracheal intubation are poorly characterized, but higher doses of benzodiazepines may actually reduce the number of airway interventions. Our data are consistent with the finding that endotracheal intubation is more commonly a sequela of continued seizures than it is an adverse effect of sedation from benzodiazepines.11 [1]

Here is some of the information from footnote 1. One interesting aspect of this double-blind study is that there is a placebo group. Patients received 2 mg IV lorazepam, 5 mg IV diazepam (Valium), or IV placebo. Treatment could be repeated one time if seizures continued for more than 4 minutes or if seizures recurred.
 

Cardiorespiratory complications before arrival at the hospital and at the time of transfer were important secondary outcomes that relate to the safety of out-of-hospital therapy with intravenous benzodiazepines. Despite concern regarding the adverse effects of these agents, we found a trend toward lower rates of out-of-hospital complications (primarily respiratory compromise) in the active-treatment groups than in the placebo group. This suggests that respiratory complications associated with prolonged seizures may be more pronounced than those caused by intravenous lorazepam and diazepam given at relatively low doses.[2]


 

The doses are low. The lorazepam dose is only half of the 4 mg used in the IV lorazepam vs. IM midazolam study.
 

The doses of midazolam and lorazepam used in this trial are consistent with the most effective doses for the treatment of status epilepticus that are reported in the literature.9,10 Although these initial doses are higher than the ones used by many EMS systems and emergency physicians, they are the same as those approved for this indication and are in line with those used by epileptologists.[1]

Is there added safety from the lower doses?

The epilepsy specialists and the FDA (Food and Drug Administration) do not recommend lower doses.

Were the low doses effective?

2 mg midazolam?

Does anyone really expect such a small dose to make a difference?

Despite the beneficial outcomes associated with intravenous lorazepam and diazepam, 41 to 57 percent of patients who received active treatment were still in status epilepticus at the time of arrival at the emergency department. These patients were more than twice as likely to require intensive medical care as those whose seizures ended outside the hospital. Differences in the causes of the episodes of status epilepticus are unlikely to account for this difference. These observations, coupled with the favorable risk–benefit profile associated with lorazepam and diazepam in this trial, suggest that higher doses should be studied to define the optimal therapy for patients with out-of-hospital status epilepticus.[2]

 

An editorial refers to the study just published[1] and to the benzodiazepine vs. placebo study.[2] Describing the complications in the placebo study, the author wrote –
 

Successful termination was much more common in the two groups that received benzodiazepines (59% with lorazepam, 43% with diazepam, and 21% with placebo). Since respiratory distress was twice as common in the group given placebo as in either of the groups given a benzodiazepine, the best way to avoid the need for intubation is to stop seizure activity.[3]

 

This presents an interesting conundrum. Doses of benzodiazepines (midazolam, lorazepam, diazepam, . . .) are often limited, due to a fear of causing respiratory complications.

When treating seizures, higher doses of benzodiazepines may actually protect patients from respiratory complications.

With a fatality rate around 10%, seizures are certainly not benign.

Maybe early treatment with high dose benzodiazepines can significantly decrease that fatality rate.

Finally, relatively few out-of-hospital interventions have been evaluated in randomized controlled trials,16 and when they have been evaluated carefully, therapies with intuitive appeal have often been found either to lack benefit or to cause harm to patients.17-20 [2]

 

The irony is that we may be doing the opposite by limiting doses of benzodiazepines to less than what is recommended by the FDA.

What do you think?

See also Part I, Part II, Part IV, Part V, Part VI, and Images from Gathering of Eagles Presentation on RAMPART.

Footnotes:

[1] 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]

Free Full Text from N Engl J Med.

[2] 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]

Free Full Text from N Engl J Med. with link to PDF Download

[3] 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]

Silbergleit, R., Durkalski, V., Lowenstein, D., Conwit, R., Pancioli, A., Palesch, Y., & Barsan, W. (2012). Intramuscular versus Intravenous Therapy for Prehospital Status Epilepticus New England Journal of Medicine, 366 (7), 591-600 DOI: 10.1056/NEJMoa1107494

Alldredge BK, Gelb AM, Isaacs SM, Corry MD, Allen F, Ulrich S, Gottwald MD, O’Neil N, Neuhaus JM, Segal MR, & Lowenstein DH (2001). A comparison of lorazepam, diazepam, and placebo for the treatment of out-of-hospital status epilepticus. The New England journal of medicine, 345 (9), 631-7 PMID: 11547716

Hirsch LJ (2012). Intramuscular versus intravenous benzodiazepines for prehospital treatment of status epilepticus. The New England journal of medicine, 366 (7), 659-60 PMID: 22335744

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Intramuscular Midazolam for Seizures – Part II


ResearchBlogging.org
Also posted over at Paramedicine 101 (now at EMS Blogs) and at Research Blogging. Go check out the excellent material at these sites.

While there have been studies comparing IM (IntraMuscular) midazolam (Versed) with IV (IntraVenous) anti-epileptic medications, this is a large study that compares IM midazolam with the best IV anti-epileptic medication in a double-blind, randomized, noninferiority trial.
 

All adults and those children with an estimated body weight of more than 40 kg received either 10 mg of intramuscular midazolam followed by intravenous placebo or intramuscular placebo followed by 4 mg of intravenous lorazepam.[1]

For the study, there were two different doses for the auto-injector (similar to an EpiPen auto-injector). The doses were not small.

Midazolam for seizures is an off-label use both when given IM and when given IV.[2]

The lorazepam IV doses in the study are according to the FDA label –
 

For the treatment of status epilepticus, the usual recommended dose of Lorazepam Injection is 4 mg given slowly (2 mg/min) for patients 18 years and older. If seizures cease, no additional Lorazepam Injection is required. If seizures continue or recur after a 10- to 15- minute observation period, an additional 4 mg intravenous dose may be slowly administered.[3]

 

Unfortunately, my protocols only permit 1/4 or 1/2 the dose of lorazepam for seizures, which may be repeated every 5 minutes up to a maximum of one full dose recommended as the initial dose by the FDA.[4] There is no adult IM use of midazolam.

There is often a concern about carefully adjusting pediatric doses. How did they handle that in this study?
 

In children with an estimated weight of 13 to 40 kg, the active treatment was 5 mg of intramuscular midazolam or 2 mg of intravenous lorazepam.[1]

But such high doses will lead to deadly outcomes

Except that this excuse to give low doses is not supported by the authors of this study.
 

The relationships among benzodiazepine dose, respiratory depression, and subsequent need for endotracheal intubation are poorly characterized, but higher doses of benzodiazepines may actually reduce the number of airway interventions. Our data are consistent with the finding that endotracheal intubation is more commonly a sequela of continued seizures than it is an adverse effect of sedation from benzodiazepines.11 [1]

 

That is a very interesting comment. The authors believe that intubations are increased by not controlling the seizure, rather than by giving large doses of a benzodiazepine. Unfortunately. I did not see anything to support that statement in the paper they cited as footnote 11.[5] This is explained in Part III.

See also Part I, Part III, Part IV, Part V, Part VI, and Images from Gathering of Eagles Presentation on RAMPART.

Footnotes:

[1] 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]

Free Full Text from N Engl J Med.

[2] MIDAZOLAM HYDROCHLORIDE injection, solution
[Hospira, Inc.]

DailyMed
NLM
FDA label

I checked all of the injectable formulations of midazolam. They are the same. None include recommended dosing for seizures, but all include warnings about midazolam possibly causing seizures.

[3] Lorazepam (lorazepam) Injection, Solution
[Baxter Healthcare Corporation]

DailyMed
NLM
FDA label

[4] Seizure
Pennsylvania Statewide Advanced Life Support Protocols
7007 – ALS – Adult/Peds
Page 100/128
Free Full Text PDF of All ALS Protocols

Titrate until seizure stops.

or

Split the dose in half. Repeat the dose in 5 minutes.

There is no option for adult IM dosing.

[5] A prospective, randomized study comparing intramuscular midazolam with intravenous diazepam for the treatment of seizures in children.
Chamberlain JM, Altieri MA, Futterman C, Young GM, Ochsenschlager DW, Waisman Y.
Pediatr Emerg Care. 1997 Apr;13(2):92-4.
PMID: 9127414 [PubMed – indexed for MEDLINE]

Silbergleit, R., Durkalski, V., Lowenstein, D., Conwit, R., Pancioli, A., Palesch, Y., & Barsan, W. (2012). Intramuscular versus Intravenous Therapy for Prehospital Status Epilepticus New England Journal of Medicine, 366 (7), 591-600 DOI: 10.1056/NEJMoa1107494

Chamberlain JM, Altieri MA, Futterman C, Young GM, Ochsenschlager DW, & Waisman Y (1997). A prospective, randomized study comparing intramuscular midazolam with intravenous diazepam for the treatment of seizures in children. Pediatric emergency care, 13 (2), 92-4 PMID: 9127414

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