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Resident Eagle: Ketamine for Refractory Status Epilepticus

Resident Eagle is a new column authored by top EMS physicians and medical directors from the U.S. Metropolitan Municipalities EMS Medical Directors Consortium (the "Eagles"), who represent America’s largest and key international cities. Every month they will discuss the latest cutting-edge issues and findings in emergency care. 

Your 45-year-old male patient is still seizing after 10 mg of IM midazolam, yet you’re still 20 minutes from the closest emergency department. A rapid check of the patient’s blood glucose is 120 mg/dL, and his oxygen saturation is 88% on room air. Through the generalized tonic-clonic movements, you open his airway and place him on a nonrebreather while your partner struggles to place an IV. The patient’s medical history is positive for chronic seizure disorder treated with levetiracetam. His last reported seizure was six months ago.  

What would you do today at your agency if this was your patient? What are the consequences of refractory status epilepticus in children and adults?

The RAMPART trial, a landmark 2011 double-blinded randomized prehospital clinical trial, recognized that early and rapid cessation of seizure activity by paramedics was of paramount importance. Earlier studies demonstrated a 30-day mortality rate for status epilepticus of 20%, and in patients with refractory status epilepticus (RSE), only 20% had good neurologic outcomes.1,2 In children, while the death rate is lower, the morbidity secondary to poor neurologic outcomes is high.3 Of the 893 subjects enrolled in RAMPART, seizures had resolved in 73.4% of subjects who received midazolam IM, compared to 63.4% of those who received IV lorazepam. Patients still seizing received rescue medications, yet 18.5% of the midazolam group and 25.8% of the lorazepam group were still seizing upon ED arrival.4 

It is clear the early and rapid termination of status epilepticus is important. These patients are at great risk due to their absent gag reflex, insufficient respiratory drive, and susceptibility to aspiration. Prolonged convulsions result in hyperthermia, hypoglycemia, cerebral hypoxia, and neuronal death, which then yield the poor outcomes described in the literature. Most first-line seizure medications work via their effect on the brain’s GABA receptors. Seizures with prolonged duration limit the effectiveness of GABA-agonist therapies, namely benzodiazepines, because the available number of GABA receptors in the brain decreases as the seizure proceeds (i.e., GABA receptor downregulation). 

Most EMS agencies carry benzodiazepines as the singular therapeutic class of medications to address the seizing patient, making it difficult to effectively treat those refractory to standard care. Historically the only answer has been to drive faster and get the patient to an emergency department, where second-line drugs such as levetiracetam, fosphenytoin, and valproate are infused to stop the seizure. However, a 2019 study in the New England Journal of Medicine showed that in status epilepticus patients, these three medications were effective in only 45%–47% of cases, likely because they too work on the downregulated GABA receptors.5  

The message here is clear: Seizures should be stopped rapidly to prevent their detrimental sequelae and associated morbidity and mortality. Yet it is also impractical to require ALS ambulances to carry additional second-line medications, which bring high costs and complexities of administration.

Ketamine to the Rescue

Once considered only for anesthesiologists and forbidden for patients with TBI, ketamine has overcome numerous hurdles during the past two decades to rise to prominence in EMS. 

It was first considered for prehospital use when excited delirium (ExDS) became a recognized medical emergency that required chemical restraint instead of physically subduing the patient. Ketamine is rapidly acting, easily administered intramuscularly, maintains airway reflexes, and provides hemodynamic stability without a significant concern for airway compromise. EMS agencies across the nation rapidly adopted the drug for use in ExDS in place of benzodiazepines. 

In 2014 investigators found ketamine successfully sedated 96% (50/52) of violent or agitated patients with few significant side effects.6 Soon after, the prehospital use of ketamine significantly increased for violent and agitated patients across the nation, and this ultimately created a familiarity that led to an expanded role within EMS. The medication is now used for pain control, RSI/DSI, severe asthma, and sedation by many EMS professionals, with few reported side effects. 

In the outpatient setting ketamine is also being used for sickle cell disease, reflex sympathetic dystrophy, and even chronic depression. And just when it was thought no stone was left unturned, Florida emergency physician Ken Scheppke discovered another opportunity: Hidden in plain sight was ketamine’s mechanism of action as an NMDA antagonist, which, combined with earlier (prehospital) use, was an “a-ha” moment that led to its 2017 inclusion in the protocols of both Palm Beach County Fire Rescue and the Coral Springs-Parkland Fire Department. 

It’s the Receptor, Stupid!

Midazolam is the single most used benzodiazepine in EMS due its rapid onset and short half-life. GABA receptors are the principle target for benzodiazepines and many other seizure medications, yet the longer seizure convulsions last, the more downregulated the receptors become, making subsequent agents ineffective. 

Enter ketamine! It has been sporadically studied as a last effort in the hospital setting for refractory status epilepticus, and generally only after the patient had been seizing for hours or days despite the use of numerous other medications. The NMDA receptors are particularly important, since unlike the disappearing GABA receptors, NMDA receptors are upregulated during SE. Instead of attaching to the GABA receptor, ketamine blocks the upregulated NMDA receptor, which results in cessation of seizure activity. 

Considering historical data that demonstrates improved outcomes in RSE with earlier treatment, the Florida departments’ protocols were designed to rapidly stop seizures in patients prior to arrival at the ED. The ketamine protocol called for 1 mg/kg IV over two minutes (maximum 100 mg) or 3 mg/kg IM (maximum 300 mg) in pediatrics and adults. When administered IV, the age-appropriate ketamine dose is mixed into a 50-mL bag of normal saline and run wide open, mimicking a slow IVP and minimizing potential side effects. Intramuscular dosing is straightforward and uncomplicated. 

A Promising Pilot Study

The results of the first prehospital study to evaluate the use of ketamine after failure of the maximal parenteral dose of midazolam to stop seizure activity were reported at the 2020 meeting of the National Association of EMS Physicians. With a combined call volume of over 165,000 a year between the two departments, 22 consecutive patients with RSE were treated over the 2½-year period. A promising 95.5% achieved the primary outcome of RSE resolution after a single parenteral dose of ketamine. The one outlier had a significant reduction of seizure activity, yet had residual tonic-clonic activity upon arrival at the ED. All patients made full recoveries and were discharged from the hospital without complications. 

Benzodiazepines like midazolam continue to be the first-line medications used by EMS for seizing patients. However, if the positive results of this pilot study are any indication, you may soon see yet another formal recommendation for ketamine use.  

References

1. Logroscino G, Hesdorffer DC, Cascino G, Annegers JF, Hauser WA. Short-term mortality after a first episode of status epilepticus. Epilepsia, 1997; 38(12): 1,344–9. 

2. Treiman DM, Meyers PD, Walton NY, et al. A Comparison of Four Treatments for Generalized Convulsive Status Epilepticus. N Engl J Med, 1998; 339(12): 792–8.

3. Maegaki Y, Kurozawa Y, Hanaki K, Ohno K. Risk factors for fatality and neurological sequelae after status epilepticus in children. Neuropediatrics, 2005; 36(3): 186–92.

4. Silbergleit R, Lowenstein D, Durkalski V, Conwit R; Neurological Emergency Treatment Trials (NETT) Investigators. 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; 52 (suppl 8): 45–47.

5. Kapur J, Elm J, Chamberlain JM, et al. Randomized Trial of Three Anticonvulsant Medications for Status Epilepticus. N Engl J Med, 2019; 381: 2,103–13.

6. Scheppke KA, Braghiroli J, Shalaby M, Chait R. Prehospital use of IM ketamine for sedation of violent and agitated patients. West J Emerg Med, 2014 Nov; 15(7): 736–41. 

Peter Antevy, MD, is EMS medical director for the Coral Springs Fire Department, Davie Fire Rescue, Southwest Ranches, and American Ambulance in Florida. He is a member of the EMS World editorial advisory board.

Eric Scheppke, BS, is an ER scribe for Tallahassee Memorial Healthcare in Tallahassee, Fla. He is a 2019 graduate of Florida State University. 


 

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