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Underdosing Initial Benzodiazepines? | #CodeBlueDebrief | Script

Updated: Nov 24, 2023

Let's get you familiar with the convulsive status epilepsy guideline recommendations and other available anticonvulsants to consider for status epilepticus.


 



Are you underdosing benzodiazepines for status epilepticus? What are the risks of subtherapeutic initial benzodiazepines? How concerned are we with benzodiazepine-induced respiratory depression?


Greetings Pharmers and Friends, Mark with PHARMWYZE. I'm a board-certified emergency medicine pharmacist and currently practice at a level I trauma center.


I make clinical pharmacotherapy content on the social medias for learners of all medicine backgrounds. Thanks for joining me on the Code Blue Debrief: A Clinical Pharmacotherapy YouTube & Podcast Series. The focus of our episode today is going to be on initial dosing of benzodiazepines in the treatment of status epilepticus.


Have you ever been caught in a dilemma rather than a problem? A problem is an unfavorable option, while a dilemma requires a decision between two unfavorable options.


One of the more adult dilemmas I've had was the good ol PGY2 residency preference submissions. By the way, shout out to any 2019-2020 COVID resident that didn't early commit and had to go through the PGY2 application and interview process.


I grew up a city boy in Los Angeles, California but had my fair share of the living with the trees, mountains, and lakes in Eastern Washington and Northern Idaho during pharmacy school. Between two equal programs that I had at the top of my list, one seemed more appealing in terms of location to settle down for a bit as it would be by 3rd city in three years. The other program felt similiar to Spokane, Washington in terms of area and let's just say I was initially excited about staying afterwards.


The determining factor of my decision was the presentation Q&A. Program #1 had a preceptor ask a pimped out defasciculation dosing question, laugh at my response, and not reply to my follow up emailed answer. Program #2 had a preceptor asked about considerations of succinylcholine in aspirin toxicity and we had more of a thought-provoking discussion. All other preceptors equal, you know who I wanted to learn from more.


There is always going to be a negative risk. When you're dealing with medications, we work on a spectrum of too much and toxicities, or too little and undertreating with general recommendations for a specific patient. You've got to work with the best literature and evidence available tailored toward the patient in front of you. Then, make the right decision with the information.


Looks like we've got a patient with seizures coming in via EMS. Let's discuss initial dosing of benzodiazepines for status epilepticus.


Status epilepticus (SE) is associated with significant morbidity and mortality, especially when not terminated early.


Persistent, abnormal electrical brain activity can contribute toward neurologic ischemia and cellular brain damage.


Termination of seizures is essential for prevention of progression into refractory status epilepticus. In simple terms, your brain is on overdrive with neurotransmitter hyperactivity and the goal is to stop further neurologic damage by slowing the brain down.


Guidelines recommend treating patients aggressively with benzodiazepines and other anticonvulsants.


The principal goal of treatment is to emergently stop both

clinical and electrographic seizure activity.


The initial treatment strategy includes addressing your ABCs; airway, breathing, circulation and benzodiazepine abortive seizure therapy, on top of assessing and treating underlying etiologies.


The focus of our discussion is going to be on benzodiazepine dosing, but we will tie in a key statistic about secondary anticonvulsants for some thought. It'll be good for us to review those guidelines recommendations.


Benzodiazepines potentiates GABA, an inhibitory neurotransmitter, through binding to the receptor and allowing an influx of Cl-. This results in hyperpolarization of the cell membrane and reduced neuron firing.


Per the American Society of Epilepsy Guidelines 2016

Initial Benzodiazepine Recommendations

Intramuscular midazolam 10 mg for > 40 kg, 5 mg < 13 - 40 kg, single dose

Intravenous lorazepam 0.1 mg/kg/dose (max 4 mg, may repeat x 1)

Intravenous diazepam 0.15 - 0.2 mg/kg/dose (max 10 mg, may repeat x1)


Even with trials that have showed their safety and tolerability, studies consistently show that initial benzodiazepines are sub-optimally dosed with some studies reporting up to 80-95%. Under-dosing may contribute to lower success rates for seizure termination.


Here is the statement from the ASCP Guidelines regarding anticonvulsant adverse drug reactions


Respiratory and cardiac symptoms are the most common encountered treatment-emergent adverse events associated with IV anticonvulsant administration in adults with status epilepticus (level A). The rate of respiratory depression in patients with status epilepticus treated with benzodiazepines is lower than in patients with status epilepticus treated with placebo (level A), indicating that respiratory problems are an important consequence of untreated status epilepticus.


Another thought to keep in mind with dosing is the etiology causing seizure and anticipated intubations, such as an intracranial injury.


A study I love discussing with learners is the Intramuscular versus Intravenous Therapy for Prehospital Status Epilepticus, or RAMPART trial. It allows for a great discussion on patient-centered care through an understanding of pharmacokinetics and prompt assessment.


This was a double blind, randomized, noninferiority trial with 448 evaluated patients comparing prehospital intramuscular midazolam to intravenous lorazepam in status epileticus for children and adults treated by paramedics.


Intramuscular 0.2 mg/kg with a max of 10 mg was given, while intravenous lorazepam was dosed as 0.1 mg/kg with a max of 4 mg.


In their primary outcome of absence of seizure upon arrival to ED, intramuscular midazolam was noninferior to lorazepam.


Just some thoughts: Seizure termination rate was 73.4% vs 63.4% for IM midazoam to IV lorazepam respectively. Endotracheal intubation rate was roughly 14% for both groups.


That is after a single dose of the guideline recommendation. What kind of effect would a second dose up to 4 mg of lorazepam do?


Benzodiazepines are underdosed in up to 95% of cases. Respiratory depression and cardiovascular complications are the primary adverse effects of anticonvulsants. Undertreating seizures also contributes to negative outcomes, including neurologic ischemia. The American Society of Epilepsy Guidelines recommend IM midazolam 0.2 mg/kg once, while IV lorazepam 0.1 mg/kg up to 4 mg with consideration of a repeat dose. It is difficult to understand the true efficacy of our secondary anticonvulsants since even the large trials we base our practices on underdosed their benzodiazepines. Based on current practices, our secondary anticonvulsants have roughly 50% of seizure termination. Guideline recommended doses from the RAMPART trial had a termination rate closer to 70%. What are your thoughts on giving up to 8 mg of IV lorazepam before secondary anticonvulsants? Let me know in the comments below.


Thanks for joining me on the Code Blue Debrief. Make sure to hit the like, subscribe, and notification bell. Follow my social medias for daily infographics, patient cases, reels. and I hope you learned something new.


Make sure to stop by my website at www.pharmwyze.com, or visit linktr.ee/pharmwyze for my SM accounts. If you want to support the work that I do, stop by www.patreon.com/pharmwyze or drop by the shop, pharmwyze.com/shop.


 

References

Lee, S. Diagnosis and Treatment of Status Epilepticus. J Epilepsy Res. 2020 Dec 31;10(2):45-54. Kapur et al. Randomized Trial of Three Anticonvulsant Medications for Status Epilepticus. N Engl J Med. 2019 Nov 28;381(22):2103-2113.

Kohl et al. Status epilepticus and benzodiazepine treatment: Use, underdosing and outcome - insights from a retrospective, multicentre registry. Seizure. 2023 Apr;107:114-120. doi: 10.1016/j.seizure.2023.03.020.

Silbergleit et al. 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. Epilepsia . 2011 Oct;52 Suppl 8(Suppl 8):45-7.

Sathe et al. Underdosing of Benzodiazepines in Patients With Status Epilepticus Enrolled in Established Status Epilepticus Treatment Trial. Acad Emerg Med . 2019 Aug;26(8):940-943.

Glauser et al. Evidence-Based Guideline: Treatment of Convulsive Status Epilepticus in Children and Adults: Report of the Guideline Committee of the American Epilepsy Society. Epilepsy Curr. 2016 Jan-Feb; 16(1): 48–61.

Leppik IE et al. Double-blind study of lorazepam and diazepam in status epilepticus. JAMA 1983;249:1452–1454.

Alldredge BK et al. A comparison of lorazepam, diazepam, and placebo for the treatment of out-of-hospital status epilepticus. N Engl J Med 2001;345:631–637.

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