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

- Rogue Medic

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.

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.

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

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

.

Intramuscular Midazolam for Seizures – Part I

A study of IM (IntraMuscular) midazolam for EMS to treat seizures. The study looks at status epilepticus, but any seizure still present when EMS arrives should be treated. The terminology does not help. The only time I use the term status epilepticus is when teaching/writing about seizures; not when describing what I treated; not when thinking about what to do.
 

Many emergency medical services (EMS) systems, however, have begun to use intramuscular midazolam rather than an intravenous agent, largely because intramuscular administration is faster and is consistently achievable. 2 This practice has become increasingly common despite the lack of clinical-trial data regarding the efficacy and safety of intramuscular midazolam.[1]

 

Really?

In about an hour, using PubMed and Google, I found these. All of them examine the use of IM midazolam. Only one is not on humans.

1988

IM midazolam for status epilepticus in the emergency department.
Mayhue FE.
Ann Emerg Med. 1988 Jun;17(6):643-5.
PMID: 3377295 [PubMed – indexed for MEDLINE]
 

A 71-year-old man presented with a continuous generalized tonic-clonic seizure of 80 minutes duration. Multiple attempts to establish an IV line failed. Ten milligrams of midazolam hydrochloride was administered IM and was followed by prompt termination of seizure activity. This report discusses the pharmacokinetic and anticonvulsant properties of midazolam as an alternative to diazepam for the initial treatment of status epilepticus.

1991

A comparative pharmacokinetic study of intravenous and intramuscular midazolam in patients with epilepsy.
Bell DM, Richards G, Dhillon S, Oxley JR, Cromarty J, Sander JW, Patsalos PN.
Epilepsy Res. 1991 Nov-Dec;10(2-3):183-90.
PMID: 1817958 [PubMed – indexed for MEDLINE]
 

Since intravenous administration of AEDs including diazepam is not always feasible in status epilepticus there are obvious advantages in having an effective intramuscular formulation. Our data suggest that midazolam may be such a drug.

1992

Midazolam in treatment of epileptic seizures.
Lahat E, Aladjem M, Eshel G, Bistritzer T, Katz Y.
Pediatr Neurol. 1992 May-Jun;8(3):215-6.
PMID: 1622519 [PubMed – indexed for MEDLINE]
 

Midazolam (Versed), the first water-soluble benzodiazepine, has had widespread acceptance as a parenteral anxiolitic agent. Its antiepileptic properties were studied in adult patients with good results. Midazolam was administered intramuscularly to 48 children, ages 4 months to 14 years, with 69 epileptic episodes of various types. In all but 5 epileptic episodes, seizures stopped 1-10 min after injection. These results suggest that midazolam administered intramuscularly may be useful in a variety of epileptic seizures during childhood, specifically when attempts to introduce an intravenous line in convulsing children are unsuccessful.

1994

Intravenous versus intramuscular midazolam in treatment of chemically induced generalized seizures in swine.
Orebaugh SL, Bradford SM.
Am J Emerg Med. 1994 May;12(3):284-7.
PMID: 8179731 [PubMed – indexed for MEDLINE]
 

It is concluded that midazolam is effective in the control of tonic-clonic manifestations of generalized seizures when administered by the IV or the IM route

1997

Midazolam in treatment of various types of seizures in children.
Yakinci C, Müngen B, Sahin S, Karabiber H, Durmaz Y.
Brain Dev. 1997 Dec;19(8):571-2.
PMID: 9440805 [PubMed – indexed for MEDLINE]
 

No side effects were observed. These results suggest that i.m. administration of midazolam may be useful in a variety of seizures during childhood, especially in case of intravenous (i.v.) line problem.

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]
 

CONCLUSIONS:
IM midazolam is an effective anticonvulsant for children with motor seizures. Compared to IV diazepam, IM midazolam results in more rapid cessation of seizures because of more rapid administration. The IM route of administration may be particularly useful in physicians’ offices, in the prehospital setting, and for children with difficult IV access.

1999

Use of intramuscular midazolam for status epilepticus.
Towne AR, DeLorenzo RJ.
J Emerg Med. 1999 Mar-Apr;17(2):323-8. Review.
PMID: 10195494 [PubMed – indexed for MEDLINE]
 

The pharmacodynamic effects of midazolam can be seen within seconds of its administration, and seizure arrest is usually attained within 5 to 10 min. Case reports and a recent randomized trial that demonstrate the successful use of i.m. midazolam in the termination of epileptic seizures are reviewed.

2002

Midazolam for the treatment of out-of-hospital pediatric seizures.
Vilke GM, Sharieff GQ, Marino A, Gerhart AE, Chan TC.
Prehosp Emerg Care. 2002 Apr-Jun;6(2):215-7.
PMID: 11962570 [PubMed – indexed for MEDLINE]
 

CONCLUSION:
Prehospital IV midazolam is an effective intervention for pediatric seizures, while IM midazolam was associated with a 20% failure rate, with both having minimal risk of respiratory compromise.

 

This was the only study of midazolam cited as a midazolam study by the authors.

Controlling seizures in the prehospital setting: diazepam or midazolam?
Rainbow J, Browne GJ, Lam LT.
J Paediatr Child Health. 2002 Dec;38(6):582-6.
PMID: 12410871 [PubMed – indexed for MEDLINE]
 

CONCLUSION:
Midazolam controls seizures as effectively as diazepam in the prehospital setting. Furthermore, midazolam potentially reduces respiratory depression and time to treatment.

2005

Status epilepticus: an evidence based guide.
Walker M.
BMJ. 2005 Sep 24;331(7518):673-7. Review. No abstract available.
PMID: 16179702 [PubMed – indexed for MEDLINE]
 

Free Full Text from PubMed Central.

Intramuscular midazolam vs intravenous diazepam for acute seizures.
Shah I, Deshmukh CT.
Indian J Pediatr. 2005 Aug;72(8):667-70.
PMID: 16131771 [PubMed – indexed for MEDLINE]
 

CONCLUSION:
i.m. midazolam is an effective agent for controlling acute convulsions in children especially in children with febrile convulsions. It has relatively no side effects as compared to Intravenous diazepam and can be used as a first line agent for treatment of acute convulsions in patients with difficult intravenous access.

2010

Human safety and pharmacokinetic study of intramuscular midazolam administered by autoinjector.
Reichard DW, Atkinson AJ, Hong SP, Burback BL, Corwin MJ, Johnson JD.
J Clin Pharmacol. 2010 Oct;50(10):1128-35. Epub 2010 May 13.
PMID: 20466872 [PubMed – indexed for MEDLINE]
 

Midazolam in an autoinjector was evaluated in an open-label dose escalation study involving 39 healthy participants. Safety and pharmacokinetic parameters were determined for doses ranging from 5 to 30 mg. No serious adverse events were noted during the study.

2011

RAMPART (Rapid Anticonvulsant Medication Prior to Arrival Trial): a double-blind randomized clinical trial of the efficacy of intramuscular midazolam versus intravenous lorazepam in the prehospital treatment of status epilepticus by paramedics.
Silbergleit R, Lowenstein D, Durkalski V, Conwit R; Neurological Emergency Treatment Trials (NETT) Investigators.
Epilepsia. 2011 Oct;52 Suppl 8:45-7. doi: 10.1111/j.1528-1167.2011.03235.x.
PMID: 21967361

That is a preliminary release of information from the study that was just published in NEJM.
 

This practice has become increasingly common despite the lack of clinical-trial data regarding the efficacy and safety of intramuscular midazolam.[1]

 

I haven’t looked at the rest of the study, but I hope that more thought went into the study design than went into the search for other research.

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.

Footnotes:

[1] Intramuscular versus Intravenous Therapy for Prehospital Status Epilepticus
Robert Silbergleit, M.D., Valerie Durkalski, Ph.D., Daniel Lowenstein, M.D., Robin Conwit, M.D., Arthur Pancioli, M.D., Yuko Palesch, Ph.D., and William Barsan, M.D. for the NETT Investigators
N Engl J Med 2012; 366:591-600February 16, 2012
Preview from NEJM

Apparently, there is no PubMed abstract, yet.

Late entry 02/18/2012 22:27 – Correction, there is a PubMed abstract for this study –

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

Free Full Text from N Engl J Med.

.

Up to a Maximum of X Times vs. Titration

Over at Ridin’ the Bus, Gertrude was writing Who’s teaching the teachers? Well, my answer is that the teaching jobs are often as political as the desirable EMS jobs. Squad Y is a bunch of people friendly with So-and-So. Squad B is a bunch of people friendly with Whojamacallit. Whether these are 911 jobs, critical care jobs, flight medic/nurse jobs, or anything else does not matter. There is more of an old boy network involved than a critical examination of the qualifications of a job candidate. Teaching is no different.

The current teachers are not necessarily those who excelled in medic school, or EMT school, when they attended. They might not have learned things all that well, when they were in school. The instructor may have modified his understanding since then, but that does not mean that it was for any medical reason. A lot of what is taught is pure speculation.

I described this in several posts A, B, C, D, and E. I reference it in several others. We are poorly educated. The educators often do not know what they are doing well enough to be teaching it.

An excellent example of this is cardioversion. I have never seen anyone else do a good job of teaching cardioversion. That does not mean that it does not happen, but it is not encouraging that I do not see it taught well. ACLS (Advanced Cardiac Life Support) encourages us to just review the material, since the students are already supposed to be familiar with everything. How many nurses going to their first ACLS class have any experience with cardioversion? This is not something that you learn to do well from a book or a blog. You learn it by using the paddles, turning on the synchronizer, and delivering shocks to a mannequin or to a patient. Too many people learn, during their first cardioversion, that they never really understood cardioversion.

Anyway, the topic of Gertrude’s post was the rules that are taught to us. Her example is when a student asked her for the maximum number of times a patient can be suctioned.

Think about this.

Why do we suction patients?

We suction them because there is something in the airway that may interfere with ventilation. It may be a potential obstruction. It may be a partial obstruction. It may be a complete obstruction.

As long as we do what we can to maintain oxygenation, there is no maximum. For the complete obstruction, there is no reason to pause and ventilate in between suction attempts, or to limit the length of suctioning, unless there is the possibility that you have cleared, or partially cleared, the obstruction.

One of the other instructors had given them a number. What is a good number for this? 3? 5? 23? The patients weight in kilograms, divided by their SpO2 percent, multiplied by the number of synapses actually transmitting information in that instructor’s brain?

How about until the portable battery runs out? But remember there are other ways of creating suction – a large syringe, a bulb syringe from the OB kit, scooping things out of the airway, gravity, a vacuum cleaner in the residence. Who really cares how you do it, if you are able to provide the airway the patient needs?

Why do we feel the need to have a number? A limit on what we can do?

People like externally imposed limits. The idea of being responsible for making intelligent decisions is something that many people flee from.

“Responsibility? Just tell me what I have to do to avoid getting in trouble.”

“As long as I follow the protocol, I won’t get in trouble.”

Of course, if the protocol does not apply to your patient, or if you follow the wrong protocol (because you ignored assessment in favor of memorization of protocols) you might kill your patient in your devotion to keeping out of trouble.

Maximum of 3 NTG (NiTroGlycerin, overseas GTN – GlycerylTriNitrate).

Why?

Most likely because the AHA wants you to switch the patient to IV NTG as soon as possible. Not exactly common in the prehospital setting, but a very good idea. NTG is a drug that needs to be titrated. A maximum number prevents titration, so people teaching these maximums should not be teaching. Titration is adjusting the dose based on the response of the patient. Almost all EMS drugs need to be titrated.

Does a response mean that you stop? No, but you take that information into consideration in your continuing doses. Sometimes it will mean to stop. NTG + Syncope is more than a subtle hint to stop NTG. After blood pressure returns, then you may resume cautiously (perhaps after running a liter into the patient) or you may decide not to give any more, but initially your response should be to stop.

Atropine is not a titration drug. Fast push, a minimum adult dose of 0.5 mg and a maximum dose of 0.03 mg/kg if stable, 0.04 mg/kg if unstable. With atropine, you may get the opposite result of what you want, if you give it slowly or if you do not give enough. Another non-titration drug is adenosine. Also fast push. Maximum of 3 doses – 6 mg, 12 mg, and another dose of 12 mg. Glucagon is another drug not generally titrated (many places do not even carry more than one dose).

Some titration drugs:

Oxygen – titrate to adequate oxygenation.

Dextrose 50% in Water – titrate to adequate saccharinity.

Dopamine and dobutamine are given as drips, the dosage formula is for calculating a starting dose and for understanding the maximum dose rate, which does not mean that you stop, only that you stop increasing the dose rate.

NTG – I have given over 50 sprays (over 20 mg) to a single CHF patient on one call and the blood pressure never dropped below 200 mm/hg systolic. Maximum of 3? Not a chance.

Albuterol (Salbutamol overseas)- if the patient is not able to breathe adequately, we continue giving albuterol, but we add other beta 2 agonists, maybe some magnesium and methylprednisolone. There are some who will even tell you that you may not give albuterol to a tachycardic or hypertensive patient, since it is not completely selective for beta 2 and might make things worse. Yes, it will stimulate the heart to work harder, but if it opens the airways, the pressure and heart rate will come down in spite of that stimulus. If it doesn’t open the airways, the side effects are not the patient’s primary concern, not even a secondary concern.

Fentanyl/dilaudid/morphine – no minimum dose and no maximum dose. Only the response to treatment matters. No maximum of 6 mg, or 10 mg, or 20 mg, or even 100 mg of morphine (about 60 mcg/100 mcg/200 mcg/1 mg for fentanyl; 0.75 mg/1.25 mg/2.5 mg/12.5 mg for dilaudid). Anyone who tells you otherwise is a liar and/or incompetent.

Midazolam/lorazepam/diazepam – no minimum dose and no maximum dose. Only the response to treatment matters. No maximum of 5 mg, or 10 mg, or 20 mg, or even 100 mg of midazolam . . . .

Diltiazem is a slow push medication that has standard doses (0.25 mg/kg for the initial dose and 0.35 mg/kg for a repeat). If you are giving it slowly it isn’t just to minimize the side effects, but also to observe for side effects that would discourage you from continuing with the dose. Diltiazem is often given to little old people, who may not give much warning before dropping their blood pressure significantly. I like to keep them sitting up and talking to me while I slowly (over 5 minutes, not the recommended 2 minutes) push the diltiazem. If they are sitting up, the part of the body most likely to show signs of decreased perfusion is the brain – sooner than a repeat blood pressure, sooner than skin sign changes. If the behavior changes in any way, I stop and I do not give any more until after I have satisfied myself that this is not a sign of an adverse reaction. I can always give more later, but most likely it is an adverse reaction.

Naloxone – no minimum dose and no maximum dose. I like to give 20 mcg to 40 mcg at a time. Response is what tells me when to stop.

These are just some of the drugs that are only appropriately given when titrated.

.