For more than seven years, Palm Beach County Fire Rescue in Palm Beach County, Fla., has been following a protocol to administer ketamine for midazolam-resistant status epilepticus (SE). The protocol calls for 100 mg intravenous, intraosseous, intramuscular, or intranasal ketamine for individuals with seizures persisting “despite sufficient midazolam dosings.”1
The protocol “was successful in just about every case in adults and most cases in kids,” said one of the thought leaders behind its use, Kenneth A. Scheppke, MD, deputy secretary for health for Florida’s Department of Health and chief medical officer for Palm Beach County Fire Rescue.
One of the next logical questions then, is whether this type of protocol would be effective and useful in emergency departments (EDs). With more than 30 years of experience working in EDs, Dr. Scheppke said he is no stranger to having SE cases come into the ED.
“Ketamine is something that EDs are familiar with because it is so well-tolerated and its effects relatively short-acting,” Dr. Scheppke said. “It would not be the only option that EDs have for midazolam-resistant SE, but based on our prehospital experience, it looks like a potentially viable option.”
Why Ketamine?
The current guideline-recommended prehospital therapy for convulsive SE is 10-mg midazolam, a recommendation based in part on the RAMPART trial, which showed that midazolam significantly increased absence of seizures at the time of arrival in the ED without the need for rescue therapy.2,3
“In this trial, even though they hand-picked 33 high-performance EMS systems, there was still over 25 percent of cases of SE with no response to benzodiazepines,” said Paul E. Pepe, MD, MPH, of Palm Beach County Fire Rescue. “In that situation, giving even more benzodiazepines would likely be futile and only increase the risk of respiratory depression. So, until now, we were left to somehow try to rapidly evacuate and transport those actively convulsing patients.”
Many current first- and second-line antiseizure medications target gamma-aminobutyric acid type a (GABAs) receptors, and as seizures continue, Dr. Pepe explained, the receptor sites downregulate, fatigue, and no longer work. In contrast, ketamine targets the N-methyl-D-aspartate (NMDA) receptors, which upregulate as seizures continue, offering a potential therapeutic option.
In their seven-year, observational study in Palm Beach County, 57 adults received ketamine for SE after midazolam failed in the prehospital setting; 98.2 percent had rapid termination of convulsions without recurrence during prehospital and hospital arrival phases.1 Only one patient had “a recurrence later on, after paramedics transferred care” but convulsions were terminated throughout the entire prehospital phase.
“Here is the interesting thing,” Dr. Pepe said. “In about 85 percent of cases, ketamine was given intravenously or intraosseous via 50 mL of fluid running over two to three minutes. [In interviews], paramedics said that in almost every case convulsions stopped when [ketamine] was only half in; it worked within the first minute or two.”
Use of ketamine in the prehospital setting for benzodiazepine refractory SE has now been implemented elsewhere in the United States as well, with one study reporting a 62 percent increase in its use from 2018 to 2021.4
“In the prehospital setting, given that [SE] is a critical, life-threatening event with limited therapeutic options, I think that this protocol should be considered by EMS medical directors now,” said Dr. Scheppke, who also emphasized the added advantage of the medication working intramuscularly when IV access is difficult in actively convulsing patients. “Many EMS agencies are already very familiar with the use of this medication and it has been shown to be quite safe in the prehospital setting when used with proper training and patient monitoring.”
Useful in the ED
EDs could also benefit from an agent that could stop seizures quickly without causing respiratory or cardiopulmonary suppression, according to Lori Shutter, MD, FNCS, FCCM, professor of critical care medicine, neurology, and neurosurgery at the University of Pittsburgh.
In fact, last year, ACEP published a clinical policy addressing critical issues for adult patients presenting to the ED with seizures incorporating evidence from a literature review that found that “about half” of patients in the ED with benzodiazepine-refractory SE failed to respond to traditional second-line antiseizure medications.5
“As an ICU doctor, I often admit patients who were seizing in the ED and the agents used to suppress the seizures resulted in the patients’ cardio-respiratory status become unstable, thus requiring intubation,” Dr. Shutter said. “If you could stop the seizure in the ED, you could potentially save ICU and hospital admissions.”
Before this type of protocol could be widely adopted in the ED, there are some unanswered questions that would need to be addressed.
“The next step would be a randomized control trial similar [to RAMPART], giving ketamine versus standard treatment with benzodiazepines to see how many seizures were controlled by the time patients showed up in the ED,” Dr. Shutter said. “It would also have to look at the frequency of breakthrough seizures, and how often patients were intubated.”
Additionally, Dr. Shutter pointed out that patients can have convulsive seizures controlled, but still have also electrographic seizures. Additional assessments would need to be done to make sure that patients are not having such ongoing seizures, despite the cessation of convulsions.
Finally, Dr. Scheppke said that studies also need to evaluate whether timing is important in the use of ketamine for SE in the ED.
“We know that it works early,” Dr. Scheppke said, “but once at the ED, sometime later, will ketamine still be as effective?”
Ms. Lawrence is a freelance health writer and editor based in Delaware.
References
1. Scheppke KA, Pepe PE, Garay SA, et al. Effectiveness of ketamine as a rescue drug for patients experiencing benzodiazepine-resistant status epilepticus in the prehospital setting. Crit Care Explor. 2024;6(12):e1186.
2. Glauser T, Shinnar S, Gloss D, 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;16(1):48–61.
3. Silbergleit R, Durkalski V, Lowenstein D, et al. Intramuscular versus intravenous therapy for prehospital status epilepticus. N Engl J Med. 2012;366(7):591-600.
4. Finney JD, Schuler PD, Rudloff JR, et al. Evaluation of the use of ketamine in prehospital seizure management: a retrospective review of the ESO Database. Prehosp Emerg Care. 2024:1-8.
5. American College of Emergency Physicians Clinical Policies Subcommittee (Writing Committee) on Seizures, Smith MD, Sampson CS, et al. Clinical policy: critical issues in the management of adult patients presenting to the emergency department with seizures: approved by the ACEP board of directors, April 17, 2024. Ann Emerg Med. 2024;84(1): e1–e12.
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