What to do if benzodiazepines (BZDs) don't work for status epilepticus?

From the Guidelines

If benzodiazepines don't work for status epilepticus, move to second-line agents such as fosphenytoin (20 mg PE/kg IV), valproic acid (40 mg/kg IV), or levetiracetam (60 mg/kg IV, max 4500 mg) as recommended by the most recent guidelines 1. These second-line agents should be administered promptly, as delays increase the risk of treatment resistance. Some key points to consider when choosing a second-line agent include:

• Fosphenytoin, levetiracetam, or valproate may be used with similar efficacy 1
• Valproate has been shown to be at least as effective as phenytoin for refractory status epilepticus, with potentially fewer adverse effects 1
• Levetiracetam is also a viable option, with a recommended dose of 30–50 mg/kg IV load at 100 mg/min 1 If seizures continue, proceed to third-line therapy with either phenobarbital (20 mg/kg IV) or additional doses of second-line agents. For refractory status epilepticus (continuing beyond 30 minutes despite adequate treatment), initiate continuous infusion of either midazolam (loading dose 0.2 mg/kg, then 0.1-2 mg/kg/hr), propofol (1-5 mg/kg/hr), or ketamine (1-5 mg/kg/hr) to achieve burst suppression on EEG 1. Throughout treatment, maintain airway protection, monitor vital signs, and address potential causes such as metabolic abnormalities, infection, or medication withdrawal. Continuous EEG monitoring is essential during anesthetic infusions to guide therapy. The escalation to more aggressive treatments is necessary because prolonged seizures become increasingly resistant to medications due to GABA receptor internalization and glutamate receptor upregulation, making early and decisive intervention critical for preventing neuronal damage and improving outcomes.

From the FDA Drug Label

Because the full antiepileptic effect of phenytoin, whether given as fosphenytoin sodium injection or parenteral phenytoin, is not immediate, other measures, including concomitant administration of an IV benzodiazepine, will usually be necessary for the control of status epilepticus If administration of fosphenytoin sodium injection does not terminate seizures, the use of other anticonvulsants and other appropriate measures should be considered.

If benzodiazepines don't work for status epilepticus, other measures should be considered, including:

• Concomitant administration of other anticonvulsants
• Other appropriate measures to control status epilepticus It is essential to continuously monitor the patient's electrocardiogram, blood pressure, and respiratory function during treatment 2.

From the Research

What to Do if Benzodiazepines Don't Work for Status Epilepticus

If benzodiazepines (BZDs) don't work for status epilepticus, there are several alternative treatment options available.

• The patient should be treated in an intensive care unit, with artificial ventilation and haemodynamic support as required 3.
• Invasive haemodynamic monitoring and EEG monitoring are essential for managing refractory status epilepticus 3.
• The drug treatment of refractory status epilepticus involves general anaesthesia with continuous intravenous anaesthetics, such as barbiturate anaesthetics (e.g., pentobarbital or thiopental sodium), midazolam, or propofol 3, 4, 5.
• Regardless of the drug selected, intravenous fluids and vasopressors are usually required to treat hypotension 3.
• Once seizures have been controlled for 12-24 hours, continuous intravenous therapy should be gradually tapered off, and intravenous phenytoin/fosphenytoin or valproate should be continued to prevent the recurrence of status epilepticus 3.

Alternative Treatment Options

• Barbiturate anaesthetics, such as pentobarbital or thiopental sodium, are highly effective for refractory status epilepticus and remain the only way to stop seizure activity with certainty in severely refractory cases 3.
• Midazolam and propofol are alternative options for adults, while midazolam can also be used for children 3, 4, 5.
• Levetiracetam and topiramate may be considered as additional medication for patients with refractory status epilepticus 3.
• Pyridoxine may be given if isoniazid poisoning is a possibility 4.

Important Considerations

• The prognosis of status epilepticus is related to etiology, age, type, and duration of the status, and drug treatment should be started without delay 6.
• Mortality in patients who experience refractory status epilepticus is high, and new treatment options are urgently needed 3.
• Continuous EEG monitoring is required during high-dose treatment and while therapy is gradually withdrawn 3.