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.

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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.

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