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Anticonvulsants for Status Epilepticus in the ED

Roberts, James R. MD

doi: 10.1097/01.EEM.0000657660.07314.53
    status epilepticus, seizure, anticonvulsant. This patient, recently in the United States from Cambodia, became depressed and was coined, a common practice for many conditions in Southeast Asia. A coin is vigorously rubbed in various patterns and bruises the skin. Shortly after coining, she developed a seizure that proceeded to status epilepticus resistant to all medications. Because she required tracheal intubation, a chest x-ray was performed, demonstrating a right upper lobe infiltrate characteristic of pulmonary tuberculosis. Because of the suspected TB, an isoniazid overdose was considered. Isoniazid blocks the production of the neuroinhibitory GABA by blocking the pyridoxine-dependent (B-6) CNS production of GABA, so status epilepticus can occur. The seizures stopped after an IV infusion of 6 g pyridoxine.
    Figure
    Figure

    Patients frequently present to the ED after a seizure or have one while there. The causes are protean, as simple as a longstanding seizure disorder and lack of medication to the onset of a new serious neurological problem. Acute structural brain injuries, such as stroke, head trauma, subarachnoid hemorrhage, cerebral hypoxia, CNS infection, and brain tumors, are also common causes of seizures. Cocaine toxicity and withdrawal from alcohol, barbiturates, and benzodiazepines can also be culprits.

    Metabolic abnormalities such as hypoglycemia, hyponatremia, and hypocalcemia can cause seizures, as can a number of medications, such as theophylline, isoniazid, bupropion, lithium, and lidocaine. They can also lower the seizure threshold in someone with an existing seizure disorder. It is relatively straightforward to evaluate and treat a single seizure in the ED, but status epilepticus can develop if the seizures do not stop. The most dramatic form is generalized convulsive status epilepticus consisting of impaired consciousness and bilateral tonic stiffening, followed by symmetric clonic rhythmic jerking of the limbs.

    Status epilepticus is essentially a clinical diagnosis in the ED, generally defined as sustained and rhythmic generalized tonic and clonic motor activity lasting longer than two to five minutes or repetitive convulsive seizures with no return to baseline consciousness between seizures. The cause of status epilepticus is often unknown to emergency physicians, but aggressive interventions should be initiated to control the seizures. A workup following successful cessation of seizing is guided by numerous clinical and historical facts.

    Benzodiazepines are by far the most widely recommended initial treatment for seizures; patients with status epilepticus refractory to them require additional medications. Additional anticonvulsants are also required even if the seizures stop with benzodiazepines. A number of secondary medications are available to clinicians. The choices of drugs for patients with status epilepticus, however, have only been briefly studied, and each clinician has his favorite medication. No best treatment is currently known for status epilepticus. This month's column reviews a recent article on a randomized trial of status epilepticus with common anticonvulsive medications.

    Randomized Trial of Three Anticonvulsive Medications for Status Epilepticus

    Kapur J, Elm J, et al.

    N Engl J Med.

    2019;381(22):2103

    This article has 13 authors, including two well-known emergency physicians, William Barsan, MD, and Robert Silbergleit, MD. The three-year randomized blinded Established Status Epilepticus Treatment Trial involved 384 patients from 57 academic medical centers. The primary desired outcome was the absence of clinically evident seizures, with improvement in the level of consciousness within 60 minutes after starting one of three anticonvulsant infusions. No additional anticonvulsants were given. The three medications used have been recommended for status epilepticus. The drugs used and the number of patients treated were levetiracetam (145), fosphenytoin (118), and valproate (121).

    The authors agreed that using benzodiazepines as initial treatment for status epilepticus is well supported in the literature, but seizures do not respond in about a third of patients given benzodiazepines, requiring an additional medication. Interestingly, the FDA has approved fosphenytoin for status epilepticus only in adults, and no drug has FDA approval for children. It has been proven that early termination of convulsive status epilepticus decreases the risk of cardiac arrest, respiratory complications, mortality, and the need for ICU admission.

    To be eligible, patients were treated with a “generally accepted cumulative dose” of a benzodiazepine for convulsive seizures lasting more than five minutes. The drugs and doses included diazepam (10 mg), lorazepam (4 mg), and midazolam (10 mg). Exclusion criteria consisted of seizures secondary to major trauma, hypoglycemia, hyperglycemia, cardiac arrest, or post-anoxia. Those previously treated for the episode with an anticonvulsant other than benzodiazepines were also excluded, as were those who were intubated. Patients were assigned to a specific drug via a weight-based dose. Study anticonvulsants were administered intravenously one time over 10 minutes.

    The primary outcomes were the absence of clinically apparent seizures according to the onsite clinician and improving responsiveness at 60 minutes after the trial infusion began. Additional anticonvulsants were not given. The primary safety concerns were life-threatening hypotension or cardiac arrhythmias within 60 minutes after the drug was started.

    The authors found no significant difference in the percentage of patients with seizure cessation among the levetiracetam group (47%), fosphenytoin group (45%), or the valproate group (46%). Interestingly, all the drugs stopped status epilepticus in only about 50 percent of patients, with no difference between individual drugs. Also of interest was that 10 percent of patients enrolled in this study were eventually diagnosed with psychogenic nonepileptic seizures. No significant difference was seen among treatment groups in the frequency of life-threatening hypotension or cardiac arrhythmias (0.7-3.2%). Life-threatening hypotension was seen more frequently in four patients (3.2%) given fosphenytoin. Endotracheal intubation was necessary in 16-26 percent of subjects, most in the fosphenytoin group. The study was terminated because an interim analysis met a predetermined futility criterion.

    The authors concluded that fosphenytoin, valproate, and levetiracetam were effective in only approximately half of patients with benzodiazepine-refractory status epilepticus. No significant difference was seen in efficacy (seizure cessation) or safety among the three drugs.

    Comment: Regardless of the cause of seizures, the initial treatment for a seizure or status epilepticus is a benzodiazepine. Of course, the glucose should be checked immediately at the bedside, and blood should be sent to evaluate for electrolytes and other appropriate parameters, including anticonvulsant levels. About a quarter of patients with status epilepticus have preexisting epilepsy, and noncompliance to medication is common. Cardiac monitoring, pulse oximetry, and continuous blood pressure analysis are also routine. Anticonvulsant treatment should be started as soon as possible because the longer the seizure continues, the more difficult it is to control with an increased likelihood of complications. If a seizure lasts more than a few minutes, it is unlikely to stop spontaneously, which is why a seizure lasting more than five minutes is labeled status epilepticus. Some believe that a seizure lasting more than two minutes should define status.

    Figure
    Figure:
    Treatment of Status Epilepticus
    Table
    Table:
    Treatment of Status Epilepticus after Benzodiazepines

    GABA is the major CNS inhibitory neurotransmitter, and benzodiazepines are GABA agonists and potentiate GABAergic inhibition, making them effective anticonvulsants. The benzodiazepines of choice among clinicians are lorazepam (Ativan), diazepam (Valium), or midazolam (Versed), given intravenously. If no IV access is available, midazolam (Versed) can be given intramuscularly or intranasally, diazepam can be given rectally, and all can be given by intraosseous infusion. The dose of benzodiazepines used in this study seems rather low for treating status epilepticus. In fact, the median lorazepam dose prior to the institution of the second drug was only 4-7 mg. Once a benzodiazepine had been given, a second drug, one of three used in this study, was started to prevent recurrence or to treat status epilepticus further.

    Clinical studies show that lorazepam appears to be slightly superior among the benzodiazepines, but data are minimal. (N Engl J Med. 1998;339[12]:792; http://bit.ly/2RbSClU.) The effective duration of action of lorazepam is from four to 12 hours because of less pronounced redistribution into adipose tissue, but obtaining maximum anticonvulsant effect can take as long as two minutes. The recommended loading dose for lorazepam is 0.1 mg/kg, so 7-10 mg for an adult. Some authors recommend administering the loading dose over two minutes; others suggest a maximum of 2 mg/min or 4 mg boluses every two to three minutes. Many emergency physicians and nurses might be hesitant to give a bolus of 7-10 mg IV lorazepam even if the patient is seizing. There is no maximum dose of lorazepam, but intubation can be required with large doses. I would use at least 20 mg lorazepam, given in 4 mg aliquots before calling it quits.

    The initial dose of IV diazepam (Valium) is 10 mg for most adults. This drug's high lipid solubility allows it to cross the blood-brain barrier rapidly, so it can be effective 10-20 seconds after IV injection. This dose can be repeated in five minutes if the patient is still seizing. Due to rapid redistribution, the duration of antiseizure activity of diazepam is relatively short, typically only 15-20 minutes. I would recommend starting one of the three drugs used in this study right after diazepam injection, and I would use at least 50 mg diazepam before stopping.

    Midazolam (Versed) can be very effective in rapidly terminating a seizure. It can be given intravenously, intramuscularly, nasally, or buccally. The initial dose is 10 mg. This drug is also used as a continuous infusion for treating status epilepticus. I would use 30 mg as an upper limit for a loading dose before opting for bolus injections.

    The three drugs studied by these investigators are the ones most commonly used after the success or failure of benzodiazepines. A number of options are available for ICU use if these drugs fail, including a continuous infusion of IV midazolam or propofol, repeat doses of pentobarbital, or general anesthesia.

    Phenytoin used to be the go-to drug after benzodiazepines, but that was replaced with fosphenytoin because of ease of administration. Phenytoin is often ineffective for toxin-induced seizures. Benzodiazepines break the seizures, and secondary medications primarily prevent recurrence but also stop benzodiazepine-resistant seizures. It is discouraging that only 50 percent of patients were successfully treated with any of these drugs.

    The 10 percent rate of psychogenic seizures was interesting, but it usually requires an EEG to make that diagnosis, something not done in the ED. A rare cause of status epilepticus is an overdose of isoniazid, which blocks the production of GABA, the CNS inhibitory neurotransmitter. Most antiseizure drugs act by increasing GABA, an activity that is impossible in isoniazid overdose. Such patients respond rather quickly to pyridoxine. It is probably best given at 5-10 mg IV in patients with known tuberculosis. The prognosis for refractory status epilepticus is rather poor, and the high mortality rate is attributed almost invariably to the underlying etiology.

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    Dr. Robertsis a professor of emergency medicine and toxicology at the Drexel University College of Medicine in Philadelphia. Read the Procedural Pause, a blog by Dr. Roberts and his daughter, Martha Roberts, ACNP, PNP, athttp://bit.ly/EMN-ProceduralPause, and read his past columns athttp://bit.ly/EMN-InFocus.

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