At some point in your career, you’ll experience a patient in status epilepticus. At times, despite following your protocols, you may notice that they refuse to stop seizing. This can be problematic as a lot of the medications we give for seizures can drop BP; especially in large doses. So WHY might a seizing patient be refractory to benzos? Let’s take a look.
So before we get ahead of ourselves, we need to talk about what happens in a seizure. In a seizure, there is a storm of electrical activity in the brain caused by neurons. These neurons fire due to neurotransmitters that attach to an adjacent neuron on a receptor. These neurotransmitters will tell the neuron to open or close their ion channels. When transmitters tell the ion channels to open, they are called excitatory neurotransmitters. Those that tell the ion channels to close are called inhibitory neurotransmitters. So a seizure is when a part of the brain causes a large amount of excitatory signals to be transmitted repeatedly. There are two things that can cause this, too much excitation and too little inhibition. And status epilepticus is:
- Two or more seizures without gaining consciousness and having a complete recovery
- Prolonged seizure lasting over 5 minutes
The main excitatory neurotransmitter is called Glutamate and it attaches to the NMDA receptor in the brain which causes a large influx of positively charged calcium to enter. And no it’s not a MDMA receptor you party animal.
On the inhibition side, we have a neurotransmitter called GABA which binds to GABA receptors and causes negatively charged chlorine ions to enter which inhibits the signal. Some patients who have epilepsy seem have faster or longer-lasting activation of the NMDA receptors or dysfunctional GABA receptors.
So why do we use benzodiazepines? Well these medications stimulate the GABA receptors which try to inhibit the neurons and stop the seizure. So why do these not always work? Well in recent years, there has been more research coming out that states that the longer the seizure, the number of activated GABA receptors decreases. If you have heard of our site, you have definitely heard of FOAMfrat. In one of their lectures or podcasts, they say “the longer you seize, the more your brain learns how to seize” (FOAMfrat Podcast 106- When Benzos Won’t Stop The Seizure”). Which makes sense based off of the literature. Literature has also found that as the amount of active GABA receptors decreased, there was a significant increase in NMDA receptors in these patients (starting around 5 minutes).
So status epilepticus patients that are not responding to benzodiazepine treatments are termed: Benzodiazepine resistant status epilepticus and a study states that 10-15% of patients in status epilepticus will become resistant to benzodiazepine treatments. A RAMPART study also concluded that 18.5% of patients treated with midazolam and 25.8% of patients treated with lorazepam were still seizing upon ED arrival. So what medication do a lot of us have that might be able to treat this? Ketamine.
For our post on Ketamine and use in the prehospital environment, check out this post:
Ketamine? What is it? What’s it used for? Where did it even come from? Ketamine is a pharmacological drug that was discovered in 1962 and created by scientist Calvin Stevens, PhD. It was first tested on humans in 1964 and then was approved by the United States in 1970. During the Vietnam War (1955-1975), it… Read more Ketamine Use in the Prehospital Setting
Research has shown that Ketamine is a noncompetitive NMDA receptor antagonist that can stop NMDA receptors from firing. Now this can only work once the amount of GABA receptors have decreased and the number of NMDA receptors have subsequently increased from a prolonged seizure. As mentioned before, benzodiazepines can cause suppression of the cardiovascular system which will decrease BP. This makes it more difficult to continue with that treatment as we always want to keep the patient’s organs perfused. Ketamine can cause an increase in heart rate and blood pressure, thus making pressor therapy less likely.
While researching, I found a large range on dosing for ketamine for benzodiazepine resistant seizures. Some doses seemed like an astronomical amount and some appeared to be very small. Some literature had great results using 1mg/kg and slowly administering it until the seizure activity stopped. An infusion of around 2mg/kg/hr can be used. Literature has found that within 24 hours, 63% of patients had a complete cessation in seizure activity seen on an EEG (Alkhachroum). Now while reading this I had some concerns with the study including: physician discretion to administering ketamine and a lack of patients in the study who received benzodiazepines (control group). So with all of the information, what can we conclude?
We should still use benzodiazepines as our front line medication in the treatment of status epilepticus and eventually move to ketamine. There is a good amount of promise in ketamine use in status epilepticus patients but there needs to be more conclusive studies to say for certain.
This site is meant to be used for educational use only. We strive to push evidence based medicine with no bias to help you obtain all the important information. You should always follow your protocols that have been set in place.
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–Scopeducation Team (Matt)
(I have school access so you might not have full access to the literature)
Alkhachroum, A., Der-Nigoghossian, C. A., Mathews, E., Massad, N., Letchinger, R., Doyle, K., Chiu, W. T., Kromm, J., Rubinos, C., Velazquez, A., Roh, D., Agarwal, S., Park, S., Connolly, E. S., & Claassen, J. (2020). Ketamine to treat super-refractory status epilepticus. Neurology, 95(16), e2286–e2294. https://doi.org/10.1212/WNL.0000000000010611
Borris, D., Bertram, E., & Kapur, J. (2010, June 15). Ketamine controls prolonged status epilepticus. Retrieved March 17, 2021, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2885610/
Galanopoulou, A. (2008, March 6). GABA(A) receptors in normal development and seizures: Friends or foes? Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2645547/
Kapur, J. (2018, November 2). Role of NMDA receptors in the pathophysiology and treatment of status epilepticus. Retrieved March 17, 2021, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6293062/
Mion, G., & Villevieille, T. (2013, April 10). Ketamine Pharmacology: An UPDATE (pharmacodynamics and molecular ASPECTS, Recent Findings). Retrieved March 17, 2021, from https://onlinelibrary.wiley.com/doi/full/10.1111/cns.12099
Shrestha, G., Joshi, P., Chhetri, S., Karn, R., & Acharya, S. (2015, May). Intravenous ketamine for treatment of super-refractory convulsive status epilepticus with septic shock: A report of two cases. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4430749/