status epilepticus first and second line management

  • related: Neurology
  • tags: #literature #neuro

Status epilepticus is considered a medical emergency, not only for the complications that can arise from the seizure itself (eg, aspiration, rhabdomyolysis, airway compromise, lactic acidosis) but also because of the potential for neurological damage that has been demonstrated in animal models. Thus, an older definition of status epilepticus as seizures lasting beyond 30 min has been superseded by an approach encouraging clinicians to escalate treatments when seizures persist beyond 5 min.

The appropriate first-line management for convulsive status epilepticus has been understood for decades. Both lorazepam and midazolam IV and diazepam (Valium) administered rectally have been shown to stop status epilepticus. The best evidence in the hospital setting suggests that 0.1 mg/kg lorazepam is effective at stopping approximately 70% of episodes of convulsive status epilepticus.

The question of what to do if the first-line management does not stop seizures is, until recently, less well studied. A number of protocols have been proposed, but only one has been tested systematically, in the ESETT trial. In this trial, patients in EDs in whom 0.1 mg/kg lorazepam failed were randomly assigned to administration of levetiracetam (Keppra), fosphenytoin (Cerebyx), or sodium valproate (Depakote). The results showed that the three regimens were equivalent and stopped about 50% of the remaining seizures (about 85% of total seizures with lorazepam and the study drug). Each agent led to approximately 50% of patients having cessation of seizures within 1 h. The drugs were also equivalent with regard to the incidence of predefined adverse events. There was a trend toward more rapid seizure control favoring valproate, but the differences between agents were small. There were no differences between the agents in terms of need for intubation or acute respiratory depression. These results suggest these drugs are equally efficacious for seizure control, and one may be selected based on individual patient characteristics, such as drug allergy, hepatic and renal function, cardiac susceptibility to arrhythmias, or other considerations.

Two interesting findings from this study are that (1) the most common study breach was the hesitance of ED physicians to administer 0.1 mg/kg of lorazepam and (2) in patients who received both lorazepam and the study drug, only 24.5% needed intubation and mechanical ventilation.

The third-line treatment of status epilepticus, required in the ICU when the above treatments fail, is not supported by high-quality evidence to guide a specific approach. Recommendations tend to focus on the use of drugs used essentially as anesthetic agents, including high-dose midazolam, propofol, or thiopental by continuous infusion. General anesthesia has also been employed. It is strongly recommended that continuous EEG monitoring be employed during the management of status epilepticus because the existence of continued seizures despite the cessation of tonic-clonic motor activity (subclinical status epilepticus) is well described. Also interesting in this regard was the observation in the ESETT trial that 10% of patients thought to have status epilepticus actually were presenting with pseudoseizures.

Other agents were not studied in the ESETT trial, but some have been subject to observational or retrospective analysis. Other treatment strategies that have been proposed take one of two approaches (and are not validated in randomized studies). One strategy suggests use of additional doses of antiepileptics, including smaller doses of benzodiazepines (BZDs) and older medications such as phenobarbital. Evidence from animal studies suggests that the BZD receptor becomes internalized during status epilepticus such that with each minute of seizures, the cell surface BZD receptor decreases by half. Larger doses of BZD may work, but half doses are unlikely to be successful. Phenobarbital, because of adverse effects, including hypotension and cardiac conduction delays, is administered over 30 to 40 min, which is a long time to allow a patient to seize.

The second strategy bypasses the second-line therapies in favor of anesthetic agents to decrease neuronal conduction. These agents are most often administered in patients who have undergone intubation and mechanical ventilation. Ketamine has become an agent of interest because of its favorable hemodynamic profile, although anesthetic doses of ketamine still require mechanical ventilation. As seen in the ESETT trial, mechanical ventilation can be obviated in almost 75% of patients who respond, decreasing the risk associated with mechanical ventilation.1234567

Footnotes

  1. SEEK Questionnaires ↩

  2. Dreifuss FE, Rosman NP, Cloyd JC, et al. A comparison of rectal diazepam gel and placebo for acute repetitive seizures. N Engl J Med. 1998;338(26):1869-1875. PubMed ↩

  3. Guterman EL, Sanford JK, Betjemann JP, et al. Prehospital midazolam use and outcomes among patients with out-of-hospital status epilepticus. Neurology. 2020;95(24):e3203-e3212. PubMed ↩

  4. Kapur J, Elm J, Chamberlain JM, et al; NETT and PECARN Investigators. Randomized trial of three anticonvulsant medications for status epilepticus. N Engl J Med. 2019;381(22):2103-2113. PubMed ↩

  5. Treiman DM, Meyers PD, Walton NY, et al. A comparison of four treatments for generalized convulsive status epilepticus. Veterans Affairs Status Epilepticus Cooperative Study Group. N Engl J Med. 1998;339(12):792-798. PubMed ↩

  6. Betjemann JP, Lowenstein DH. Status epilepticus in adults. Lancet Neurol. 2015;14(6):615-624. PubMed ↩

  7. Kapur J, Elm J, Chamberlain JM, et al; NETT and PECARN Investigators. Randomized trial of three anticonvulsant medications for status epilepticus. N Engl J Med. 2019;381(22):2103-2113. PubMed ↩