A 32-year-old male presents to the ED in status. He’s received 5 mg of intramuscular (IM) midazolam in the field. Per EMS he was found by his friend on the floor seizing without cessation. Initial vital signs are BP 100/70, HR 118, RR 18, Sp)2 94% on room air. On exam the patient is somnolent and wakes with noxious stimuli, however, a minute later begins to seize again. What are your next steps from a medication standpoint? What do you think about the dose of midazolam given in the field?
Convulsive status epilepticus (SE) is dangerous and life-threatening with an overall mortality of 20%. Where most seizures are brief and self-limiting, convulsive SE is defined as a seizure that persists for at least 5 minutes or is the situation in which seizures are recurrent and there is no return to baseline in between. Seizure rates differ among different patient groups with the highest risk seen after acute ischemic stroke.
Time to treatment is critical for success with focus on the first 30 minutes before the patient becomes refractory.
Benzodiazepines are considered first line therapy followed by or in conjunction with other antiepileptics. It is imperative that pharmacologic therapy is initiated immediately with supportive care and that doses and administration techniques are optimized.
When approaching the SE patient in the ED, search for possible underlying conditions and correct:
Why is time to treatment critical?
START MEDICATIONS ASAP. Data shows worsening outcomes with increased duration of status epilepticus and time-dependent loss of synaptic GABAA receptors, which consequently means pharmaco-resistance, particularly to benzodiazepines as the duration of SE extends. Therefore the window for effective treatment is narrow.
In general, an EEG is not required to initiate anticonvulsant therapy and if an EEG is being completed, it should not delay therapy.
Stabilize the patient; assess airway, breathing, and circulation. The general ED slogan “IV, O2, monitor” is key.
Also, always check a glucose as it’s a common underlying metabolic disturbance.
If the patient requires immediate intubation- consider a short-acting paralytic (succinylcholine) instead of a long acting (rocuronium) to allow for assessment of ongoing seizure activity.
Benzodiazepines are considered first-line therapy for the emergent treatment of convulsive SE. Benzodiazepines utilize GABA receptors to suppress seizure activity. The intravenous route of administration is preferred but if not available, use intramuscular, intranasal, buccal, or rectal.
Doses should be optimized to suppress seizure activity. Inadequate dosing is responsible for higher rates of respiratory complication and refractory SE. Do not just give lorazepam 2 mg IV for all status epilepticus patients. Use the weight-based strategy and repeat as needed.
After benzodiazepines or in conjunction with benzodiazepines, alternative antiepileptic agents should be given if seizures have not ceased. The Established Status Epilepticus Treatment Trial (ESETT), published in 2019 was a randomized, blinded, adaptive trial that compared the safety and efficacy of intravenous levetiracetam 60 mg/kg, fosphenytoin 20 mg PE/kg, and valproate 40 mg/kg in children and adults with benzodiazepine refractory convulsive SE. The study concluded clinical cessation of SE with improvement in mental status at 60 minutes after the start of medication infusion was similar between all groups (45% fosphenytoin vs 47% levetiracetam vs 46% valproate). Additionally, no statistically significant adverse events were noted.
As phenytoin contains propylene glycol, it is associated with greater adverse risk compared to fosphenytoin. Fosphenytoin provides a safer alternative, which can be infused faster and is associated with less arrhythmia, hypotension, and infusion site pain risk than phenytoin.
Administration of Levetiracetam (LEV)
Recently, there has been a push for IV push LEV. Two particular articles come to mind. In 2020, Morgan et al proved that rapid administration of undiluted LEV doses ≤ 1000 mg were well tolerated with no concentration-related side effects. However, an adult patient of 70 kg-100 kg would require at least 2800 mg (40 mg/kg) which would mean, per this study, that we would need to give the full dose in at least 3 divided doses. Additionally, the rate of administration is over 2-5 minutes which would require the nurse to stand at the bedside slowly pushing the doses. Ideally, I would prefer to see a rapid IV push = 1 second.
Most recently, Haller and colleagues were able to solve the issue of dosing through their findings of safety and tolerability with doses up to 4500 mg and limited adverse effects (local injection site reactions). However, the issue of an administration still stands. Their institutional protocol calls for all doses of LEV to be administered over 5 minutes. The maximum loading dose was 4500 mg and doses that exceeded 1000 mg or 10 mL were encouraged to be administered in consecutive 10 mL increments until the total dose was administered (i.e. a 4500 mg dose would require 5 consecutive doses). To me, this has the potential to cause confusion with how much is given in an already high-stress critical scenario and is arguably still labor-intensive for the nurse.
Unpopular Opinion: Personally, I recommend using premix bags which can be stored in your ED automated dispensing cabinet, available on the override and obtained rapidly, and hung wide open or programmed in the pump for administration. Drawing up multiple vials and administering in aliquots is labor-intensive and increases the room for error. In scenarios where pre-mixed bags are unavailable, I would recommend the push dose technique over-preparing infusion bags.
Refractory Status Epilepticus
SE is considered refractory if there is a failure to the benzodiazepine plus an antiepileptic medication. Continuous infusion sedation with propofol, ketamine, midazolam or pentobarbital has been used once the patient has been mechanically ventilated; however, data is insufficient to suggest one over the other.
- Medication therapy should be initiated as soon as possible to avoid preventable treatment failure
- High-quality evidence supports lorazepam 0.1 mg/kg IV as first-line therapy. When IV is not an option use midazolam 10 mg IM.
- Consider loading with an antiepileptic drug such as levetiracetam, valproate, or fosphenytoin concurrently with benzodiazepine therapy or immediately after.
- Remember getting the drug on board fast is key so don’t waste time waiting for an EEG or obtaining premixed bags from the pharmacy. Use what’s available in the ED to allow for prompt administration.
- Chen JW, Wasterlain CG. Status epilepticus: pathophysiology and management in adults. Lancet Neurol. 2006;5(3):246-256. doi:10.1016/S1474-4422(06)70374-X
- Betjemann JP, Lowenstein DH. Status epilepticus in adults. Lancet Neurol. 2015;14(6):615-624. doi:10.1016/S1474-4422(15)00042-3
- DeWitt KM, Porter BA. Emergency Neuropharmacology. Emerg Med Clin North Am. 2021;39(1):133-154. doi:10.1016/j.emc.2020.09.008
- Crawshaw AA, Cock HR. Medical management of status epilepticus: Emergency room to intensive care unit [published correction appears in Seizure. 2020 Aug;80:282]. Seizure. 2020;75:145-152. doi:10.1016/j.seizure.2019.10.006
- Morgan O, Medenwald B. Safety and Tolerability of Rapid Administration Undiluted Levetiracetam. Neurocrit Care. 2020;32(1):131-134. doi:10.1007/s12028-019-00708-5
- Haller JT, Bonnin S, Radosevich J. Rapid administration of undiluted intravenous levetiracetam [published online ahead of print, 2021 Jun 24]. Epilepsia. 2021;10.1111/epi.16961. doi:10.1111/epi.16961