The goal of treatment is seizure control as soon as possible and within 30 minutes of presentation (Figure 171–1). Examination; identification of potential causes; checking the airway, breathing, and circulation; and treatment all begin simultaneously. Direct a focused history and physical examination toward possible causes and subsequent injuries.
Guidelines for management of active seizures and status epilepticus. ICU = intensive care unit; PE = phenytoin equivalents.
Establish large-bore IV access and determine a bedside glucose. Administer normal saline, avoiding IV fluids containing glucose because phenytoin is not compatible with glucose-containing solutions. Place the patient on oxygen, a cardiac monitor, a pulse oximeter, and end-tidal capnography.
In established status epilepticus, consider endotracheal intubation for airway protection, oxygenation, and ventilation. If a paralytic agent is used for intubation, use a short-acting agent so as not to mask ongoing seizure activity. Arrange for continuous EEG monitoring as soon as possible after paralytic agents have been used.
Initial laboratory evaluation includes blood glucose, a metabolic panel including calcium and magnesium, lactate, and if appropriate, a pregnancy test, a toxicology screen, and anticonvulsant levels.
Administer glucose IV if hypoglycemia is suspected or confirmed. Monitor temperature continuously, and treat hyperthermia with passive cooling. Place a urinary catheter to monitor urine output, and insert a nasogastric tube to help prevent aspiration.
If toxic ingestion is suspected as the cause of seizures, proceed with GI decontamination (as appropriate). Do not attempt lumbar puncture during status epilepticus. If bacterial meningitis or encephalitis is suspected, start empiric antibiotic or antiviral therapy. Status epilepticus can induce a brief peripheral leukocytosis as well as a mild cerebrospinal fluid pleocytosis. Radiographic studies, such as a CT scan, will usually need to be delayed until seizures are controlled.
ANTICONVULSANT DRUGS IN STATUS EPILEPTICUS
The drugs most often used in the therapy of status epilepticus are the benzodiazepines (lorazepam or, if not available, diazepam) and phenytoin or fosphenytoin (Figure 171–1). Benzodiazepines are used in patients with continuous or very frequent seizures to temporarily control the seizures until more specific agents can be given. IV lorazepam (2 to 4 milligrams) and IV diazepam (5 to 10 milligrams) have equal efficacy in controlling status epilepticus.8 Compared to diazepam, lorazepam has a slightly slower onset (3 vs 2 minutes) but a significantly longer duration of action (12 to 24 hours vs 15 to 60 minutes) and is associated with fewer seizure recurrences. In one prehospital study, IM midazolam demonstrated decreased seizure time and fewer intensive care unit admissions when compared to lorazepam if no IV access was available26; however, IV lorazepam is still considered the initial agent of choice. Lorazepam is also more effective than phenytoin or phenobarbital as the initial drug.27 Respiratory depression and hypotension may occur, especially in young children and in patients taking alcohol, barbiturates, narcotics, or other sedatives. In patients with difficult IV access and emergent need for seizure control, there may be a role for rectal diazepam gel or buccal midazolam. Although there have been no trials in adults, rectal diazepam has been used by EMS providers in children with good success for years, and recent trials of buccal midazolam (0.5 milligram/kg, up to 10 milligrams) show more efficacy than rectal diazepam in the pediatric population.28,29
In established status epilepticus, follow benzodiazepines with a longer-acting antiepileptic agent: fosphenytoin or phenytoin, levetiracetam, valproate, or lacosamide. One of these antiepileptic agents should be started within 20 minutes of diagnosis.1
Fosphenytoin is a water-soluble prodrug of phenytoin that is converted to phenytoin in the plasma. Fosphenytoin has similar time of onset, effectiveness, and cardiac effects as phenytoin. It has much fewer infusion-site reactions due to the lack of propylene glycol and ethanol as the diluents. Fosphenytoin may be infused quickly, and for that reason, it is preferred over phenytoin. Fosphenytoin dosing is expressed as phenytoin equivalents (PE) to prevent confusion. The loading dose is 20 PE/kg, which can be infused at 150 PE/minute over 10 to 15 minutes.9 Fosphenytoin can also be given IM, which may be useful if the patient does not have IV access.
The loading dose for phenytoin is 20 milligrams/kg IV. Doses in excess of the usual 1000 milligrams are often required. Due to myocardial depression from its propylene glycol diluent, phenytoin is typically infused no faster than a rate of 25 milligrams per minute (taking about 1 hour to administer). The rate may be increased to 50 milligrams per minute during status epilepticus as long as hypotension does not develop. Place patients on a cardiac monitor, with blood pressure assessments every 5 to 15 minutes during the infusion and every 15 minutes for 1 hour after infusion.30 Phenytoin should not be mixed with any glucose-containing IV fluid and should not be given IM due to erratic absorption. The drug is contraindicated in patients with second- or third-degree atrioventricular block. Other adverse effects include infusion site reactions, hypotension, and cardiac dysrhythmias. If side effects develop, stop the infusion and restart at a lower rate after side effects have resolved.
Valproic acid is effective but has serious side effects compared to the agents listed above. The U.S. Food and Drug Administration has issued a black box warning for hepatic failure and pancreatitis, and valproic acid should not be administered along with phenytoin. The dose is 20 milligrams/kg IV.1,9,22,31,32
Levetiracetam is very effective, is quick to administer, and has few interactions and side effects. The precise mechanism of action is unknown, but it may inhibit voltage-dependent calcium channels and facilitate γ-aminobutyric acid inhibitory transmission. The dose is 20 milligrams/kg IV. Although it is not yet approved by the Food and Drug Administration for status epilepticus, it is rapidly gaining favor as a first-line drug for established status epilepticus.1,9,33,34,35
Lacosamide is a potential alternative for status epilepticus with limited availability and limited data on its use. The dose is 200 milligrams IV given over 15 minutes.1,36
REFRACTORY STATUS EPILEPTICUS
Refractory status epilepticus is defined as persistent seizure activity despite the IV administration of adequate amounts of two antiepileptic agents and usually exceeds 60 minutes.1 One study found that up to 31% of patients with status epilepticus went on to develop refractory status epilepticus.37
Various approaches to refractory status epilepticus have been suggested (Figure 171–1).1,7,9,22,32–43 Overall, there are few controlled trials that strongly support a single agent or combination of agents. Current recommendations include propofol, midazolam, and barbiturates such as phenobarbital or pentobarbital given as infusions.1 All of these agents can lead to hypotension, sometimes requiring concomitant vasopressor use, and require intubation. Ideally, treatment is in consultation with a neurologist and in an intensive care setting, because advanced respiratory support, cardiovascular support, and EEG monitoring are all needed.
Propofol is a widely used, lipophilic, general anesthetic that has come into favor for refractory status epilepticus. It can be started as an infusion at typical rates of 2 to 10 milligrams/kg/h and titrated up to effect seizure cessation. Propofol has the added benefit of a short half-life, allowing for quicker neurologic recovery after seizure control is achieved. At higher doses (>40 milligrams/kg/h), patients are at increased risk for hemodynamic instability, including hypotension, as well as propofol infusion syndrome.1,7,9,22,39
Midazolam is an easily titrated, infusible benzodiazepine that can also be used in the ongoing treatment of refractory status epilepticus. Midazolam can be started at 0.05 to 0.4 milligram/kg/h and is titrated up to seizure cessation.1,9,40 Midazolam can accumulate in peripheral soft tissues, particularly with renal insufficiency, leading to a prolonged recovery period.
Barbiturates, such as phenobarbital (up to 20 milligrams/kg IV) or pentobarbital, may be considered as third-line drugs in patients whose seizures are not controlled despite full loading doses of benzodiazepines and other agents. However, patients in refractory status may not respond to barbiturates. One study found no added seizure control with phenobarbital.32 A subsequent meta-analysis showed improved seizure control with pentobarbital compared to propofol or midazolam but no differences in mortality.38 Respiratory depression and hypotension are more common when using barbiturates, especially at higher doses or when diazepam or lorazepam is also given.1,9,22 Additionally, midazolam and propofol have the advantage over barbiturates of having a shorter half-life and rapid clearance, allowing for earlier extubation and clinical assessment.1 For these reasons, current recommendations are to use propofol and midazolam infusions as first- and second-line agents, respectively, in refractory status epilepticus with barbiturates as third-line agents.1,9,22,39,40
Finally, ketamine may also be considered as a third-line agent in refractory status epilepticus. Ketamine is an N-methyl-d-aspartate receptor antagonist and helps block the hyperexcitatory pathway, which is thought to be a greater culprit in refractory status epilepticus. Ketamine can be administered as a bolus dose of 0.5 to 4.5 milligrams/kg or as an infusion up to 5 milligrams/kg/h. Multiple case reports and one retrospective study have demonstrated its safe use and likely benefit in terminating refractory status epilepticus.22,41,42,43