Feature Story

Consistently Controlling Continuous Convulsions

12/11/2024

For paramedics and emergency department (ED) staff, benzodiazepines (i.e., diazepam, midazolam, lorazepam) remain effective first-line therapies for most active seizures. Unfortunately, 25-50% of prehospital patients with status epilepticus (SE) continue to convulse despite sufficient dosings of these drugs.^1-4Even in a well-supervised National Institutes of Health trial involving 33 high-performance emergency medical services (EMS) agencies, 10mg of parenteral midazolam failed to terminate convulsions in >25% of cases.⁴ In the U.S. alone, this translates to at least 300-400 cases monthly and likely many more as numerous EMS systems use lower benzodiazepines doses.

Physiologically, rapid termination of SE is imperative. Persistent seizures can lead to progressive neurological damage and SE convulsions can impair breathing leading to sustained, clinically significant oxygen desaturation. A third of SE patients can have chronic functional impairment and the many forms of SE are associated, commonly, with in-hospital mortality.^5-7

However, persistent seizures also impose significant challenges for EMS providers. Absent feasible rescue interventions on-scene, hospital transport becomes the default management, a relatively risky task for paramedics. Extricating actively convulsing patients out of cramped quarters and down narrow, turning stairwells increases risk of physical harm for both patients and responders alike. These challenges can be amplified by weather, traffic or other environmental/logistical threats. With frightened family members looking on or, on occasion, the public at large, these benzodiazepine-resistant SE (BRSE) events become even more stressful.

Fortunately, there may now be a feasible “solution”—ketamine, a drug already carried by many EMS systems.

A decade ago, Dr. Kenneth Scheppke, a longstanding EMS medical director and now Florida Deputy Secretary of Health, had suggested this possible resolution for BRSE for EMS. Scheppke cited basic science data indicating that, when seizures persist, the number of activated gamma-aminobutyric acid-A receptors (GABA-A) in post-synaptic membranes progressively decline.⁸ Consequently, anti-seizure drugs that work through GABA-A receptors (e.g., benzodiazepine, valproate, phenobarbital), become less effective. Adding more of those would not only become relatively futile, but also create higher risks for significant respiratory depression.

In contrast, as active GABA-A receptors wane during SE, there is increasing expression of N‐methyl‐D‐aspartate (NMDA) receptors.⁹ Theoretically, ketamine, an NMDA receptor antagonist, might be more suited to terminate BRSE.⁹ Also, ketamine can be given intramuscularly (IM) with rapid onset, or even intra-nasally (IN) when intravenous (IV) or intraosseous (IO) access is hindered by active convulsions, particularly in young children.

Soon thereafter, Dr. Scheppke and his team at the Palm Beach County Fire Rescue (PBCFR) 9-1-1 service implemented a ketamine-rescue protocol and conducted a study of its effectiveness over seven years.

The remarkable results are now published in Critical Care Explorations, the Society of Critical Care Medicine’s open-access journal.¹⁰https://journals.lww.com/ccejournal/fulltext/2024/12000/effectiveness_of_ketamine_as_a_rescue_drug_for.4.aspx?context=latestarticles

The PBCFR adult/adolescent protocol called for 5mg IV, IO, IM or IN midazolam followed by another 5mg dose if seizures persisted. When midazolam failed, ketamine (100mg) was administered (children received corresponding per-kg doses IM/IN). Between 2016-2023, PBCFR treated 2,098 seizures including 81 SE cases in which ketamine was given as a rescue drug.

Among these 81, 57 adult and 15 adolescent/childhood events involved the SE-midazolam+ketamine protocol. In another nine (8 adults/1 child) cases, paramedics provided ketamine directly (with pre-approval), usually because family or medical facilities had administered sufficient benzodiazepine doses immediately before their arrival. For adults, ketamine was given IV most often (77%); 9% IM, 8% IO, 6% IN. For children/adolescents, nine were IV, four IM, three IN (all younger children).

In short, the study findings exceeded expectations.

Specifically, ketamine rapidly terminated the clinical seizures in 56/57 adult on-protocol cases without recurrence (98.2%). In fact, the lone exception, a chronically unresponsive 64-year-old (with in-dwelling tracheostomy and new-onset sepsis) did not re-seize until after hospital arrival. Even in that case, ketamine terminated convulsions rapidly without prehospital recurrence (>20 minutes), the main goal for EMS crews. Accordingly, convulsions were consistently controlled during the entire pre-hospital phase of care for 100% of on-protocol adults (n=57), but also among the eight “off-protocol” adult cases that had identical results (100% rapid, sustained termination) including one adult experiencing recurrent seizures >1.5 hours before EMS arrival.

Among 16 ketamine-treated adolescent/childhood cases, convulsions were rapidly terminated without prehospital recurrence in 12 cases, but only mitigated abnormal motor activity in four, including two receiving ketamine IN (a possible clinical signal). In these two IN cases, complete cessation was either delayed or remained unresolved. In the latter case, however, the abnormal motor activity was later assessed as being post-asphyxial anoxic posturing (not seizures). In a third case, despite immediate termination of convulsive activity, some abnormal motor activity persisted. However, that was later identified as typical syndrome-related post-ictal movements.

In essence, not counting that syndrome-related post-ictal case and the anoxic-posturing case, ketamine rapidly terminated actual convulsions for all patients during the prehospital phase of care in 77 of 79 cases (98%) and there were no apparent complications attributable to ketamine. More specifically, active post-ketamine interventions were never required in any of the 81 cases. Though pre-ketamine SpO2 and ETCO2 aberrations were identified in nearly a third, most abnormalities resolved or improved after ketamine.

Of interest, paramedics typically observed seizure cessations within 1-2 minutes of initiating treatment, well before the entire IV or IO doses (100mg in a 50-ml drip) were delivered (usually taking 2-3 minutes to fully infuse). While IM-route terminations could require 1-2 minutes longer, injections generally were delivered earlier.

For us, this investigation is particularly exciting because it also can be applicable to the ED. More importantly, for the study paramedics, the protocol was an invaluable advance that diminished risk to both patients and rescuers, including safer extrications and transport, and mitigation of convulsion-related respiratory compromise and progressive neurological damage. In short, ketamine provided a consistent multi-faceted protective effect for EMS, both physically and physiologically.

One caveat that Dr. Scheppke and the team expressed was that they did not perform comprehensive hospital follow-up and that, hypothetically, electrographic (EEG) seizures may persist in a finite number of cases despite termination of convulsions (motor activity). In turn, they prompted others to corroborate this study’s compelling results while also adopting more comprehensive evaluations.

Key Findings

In 100% of adult cases, ketamine provided immediate cessation of protracted midazolam-resistant convulsions with a sustained effect lasting throughout the entire prehospital phase of care
Near-similar results were found for minors (<17 years)
The rapid, sustained cessation of convulsions facilitated safer extrications/transport, mitigated convulsion-related respiratory compromise, and presumptively, averted progressive neurological damage
There were no clinically concerning adverse effects attributable to ketamine despite the protracted seizure scenario and prior ample infusions of benzodiazepines
Future investigations should include hospital follow-up including electrographic (EEG) studies to confirm full termination of seizures (and not just motor activity).
These results corroborate the accumulating basic science findings that first triggered this 7-year translational clinical study
Intranasal route may be less effective; beyond further research, one might prioritize the IM route if IV/IO infusions are not feasible or part of protocol.

References

1. Lowenstein DH, et al. It’s time to revise the definition of status epilepticus. Epilepsia 1999; 40:120–122.

2. Trinka E, et al. A definition and classification of status epilepticus: report of the ILAE task force on classification of status epilepticus. Epilepsia 2015;56:1515-1523

3. Glauser T, 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

4. Silbergleit R, et al. Intramuscular versus intravenous therapy for prehospital status epilepticus. N Engl J Med 2012;366:591-600

5. Rodin E, et al. High long-term mortality after incident status epilepticus in adults: Results from a population-based study. Epilepsia 2019;60:33-41. doi: 10.1111/epi.14602

6. Legriel S, et al. Functional outcome after convulsive status epilepticus. Crit Care Med 2010;38:2295–2303

7. Dingledine R, et al. When and how do seizures kill neurons, and is cell death relevant to epileptogenesis? Adv Exp Med Biol 2014;813:109-122.

8. Deeb TZ, Maguire J, Moss SJ. Possible alterations in GABA-A receptor signaling that underlie benzodiazepine-resistant seizures. Epilepsia 2012; 53: 79-88

9. Zeiler FA, Teitelbaum J, Gillman LM, West M. NMDA antagonists for refractory seizures. Neurocrit Care 2014;20:502-513.

10. Scheppke, et al. Effectiveness of ketamine as a rescue drug for patients experiencing benzodiazepine-resistant status epilepticus in the prehospital setting Critical Care Explorations December 6, 2024; 6 (12): p e1186. https://journals.lww.com/ccejournal/fulltext/2024/12000/effectiveness_of_ketamine_as_a_rescue_drug_for.4.aspx?context=latestarticles

ABOUT THE AUTHORS

Dr. Jeffrey M, Goodloe, MD, NRP, FACEP, FAEMS, is Chief Medical Officer for the Metropolitan Oklahoma City and Tulsa EMS Systems and Professor of Emergency Medicine at the University of Oklahoma; also Immediate-Past Chair, Board of Directors, American College of Emergency Physicians.

Christopher B. Colwell, MD, FACEP, FAEMS, is Chief of EMS, City of San Francisco, and Endowed Professor and Vice Chair of Emergency Medicine, University of California, San Francisco and Chief of Emergency Medicine, San Francisco General Hospital; also Chair, Standards and Clinical Practice Committee, National Association of EMS Physicians.

James J. Augustine, MD, FACEP, is Member and Medical Director, International Association of Fire Chiefs; Medical Director, Lee County and Collier County (Florida) EMS agencies, including City of Fort Myers Fire Rescue Department; Clinical Professor, Department of Emergency Medicine, Wright State University, Dayton, OH