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Status Epilepticus: Treatment & Medication

Author: Marcio Sotero de Menezes, MD, Associate Professor, Department of Neurology, Division of Pediatric Neurology, Children's Hospital of Seattle, University of Washington
Coauthor(s): Ednea Simon, MD, Acting Assistant Professor, Department of Neurology, University of Washington
Contributor Information and Disclosures

Updated: Jul 13, 2009

Treatment

Medical Care

Status epilepticus (SE) treatment should follow a logical sequence of interventions. Every institution dealing with this problem should design a thoughtful and periodically revised plan, such as the plan outlined below. The lack of a structured protocol has been blamed for increased morbidity in the treatment of status epilepticus. Physicians should become familiar with the pharmacology of the drugs used to treat status epilepticus. Prudence calls for doses of these drugs to be placed in visible locations within emergency departments (EDs), pediatric units, and nursing stations.

Treatment for generalized status epilepticus should be part of a continuum of the management for seizures of shorter duration. Any algorithm for treating seizures should consider the time of onset of the ictal activity (continuous or intermittent without recovery of consciousness) and the number and type of drugs that did not control the seizures, despite appropriate dosages and routes of administration. Remember that seizures of longer duration tend to be more difficult to treat. Before starting any pharmacologic intervention, be mindful of the patient's basic care. Thus, attend to the ABCs first as in any emergency situation. The table below is based on the Emergency Management Guidelines of Children's Hospital and Regional Medical Center.

  • Early management to stabilize patient
    • As in any medical emergency, first attend to the ABCs. Place patients in the lateral decubitus position to avoid aspiration of emesis and to prevent epiglottis closure over the glottis. Further adjustments of the head and neck may be necessary to improve patency of the airways (use care in the setting of potential neck trauma without full radiographic evaluation).
    • Respiratory depression is a common complication of the management of prolonged seizures. Ensure that equipment is available to deliver supplemental oxygen and positive pressure ventilation when initiating anticonvulsant therapy.
    • Carefully monitor the patient's vital signs, including blood pressure.
    • Carefully monitor the patient's temperature because hyperthermia may worsen brain damage caused by seizures.
    • In the first 5 minutes of seizure activity, before starting any medications, try to establish intravenous (IV) access and to obtain samples for laboratory tests and for seizure medication levels.
    • Perform blood glucose measurement by a fast assay (eg, Dextrostix); this is particularly important because hypoglycemia may be a contributing factor or cause of seizures in adults or children.
    • Administer IV glucose if serum glucose is low or cannot be measured. In these instances, children should receive 2 mL/kg of 25% glucose, and adults should receive 50 mL of 50% glucose, as well as 100 mg of thiamine. The latter drug is used to avoid Wernicke-Korsakoff syndrome.
    • Electrolytes and BUN/creatinine levels are also commonly measured in these patients.
    • Calcium and magnesium measurement may also be important, especially for infants fed with cows' milk and, in some special situations, in adults (eg, renal failure, hypoparathyroidism).
    • If the onset of the seizure is witnessed, initiate anticonvulsant treatment only after 5 minutes of seizure duration. Most seizures stop without intervention.
    • Obtain a history of the prehospital treatment of the seizures. Cumulative doses of benzodiazepine medication (prehospital included) increase the risk of respiratory failure.
    • In cases of repetitive convulsions without recovery of consciousness, the duration of the seizure is defined as the time elapsed from the onset of the first seizure to the termination of the last.
    • Call for the pediatric ICU (PICU) service and respiratory therapists (or anesthesiologists) if seizures persist for more than 20 minutes.
After addressing the patient's ABCs (step 1) during the first 0-5 minutes of care (ie, check airways, turn the patient's head to the side, check oxygen saturation, start an IV line), begin the following treatment steps outlined in the table below.

MedicalTreatment of Seizures and Status Epilepticus Based on Time Elapsed Since Seizure Onset (Steps 2-4)

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Table
StepMedicationDoseAlternatives
Step 2 (6-15 min)Diazepam (Valium)5-20 mg IV slowly; not to exceed infusion rate of 2 mg/min; pediatric dose is 0.3 mg/kgIf IV line is unavailable, use rectally administered (PR) diazepam at 0.5 mg/kg (not to exceed 10 mg) or midazolam (Versed) at 0.2 mg/kg intramuscularly (IM)*, IV, or intranasally*
Lorazepam* (Ativan)2-4 mg IV slowly*; not to exceed infusion rate of 2 mg/min or 0.05 mg/kg over 2-5 min; pediatric dose is 0.05-0.1 mg/kg
Step 3 (16-35 min)Phenytoin (Dilantin) or fosphenytoin (Cerebyx)† 20 mg/kg IV over 20 min; not to exceed infusion rate of 1 mg/kg/min; do not dilute in 5% dextrose in water (D5W)

If seizures persist, administer 5 mg/kg for 2 doses (if blood pressure is within the reference range and no history of cardiac disease is present)

If unsuccessful, administer phenobarbital 10-20 mg/kg IV (not to exceed 700 mg IV); increase infusion rate by 100 mg/min; phenobarbital may be used in infants before phenytoin; be prepared to intubate patient; closely monitor hemodynamics and support blood pressure as indicated
Step 4 (45-60 min)‡ Pentobarbital anesthesia (patient already intubated)Loading dose: 5-7 mg/kg IV; may repeat 1-mg/kg to 5-mg/kg boluses until EEG exhibits burst suppression; closely monitor hemodynamics and support blood pressure as indicated 

Maintenance dose: 0.5-3 mg/kg/h IV; monitor EEG to keep burst suppression pattern at 2-8 bursts/min

Midazolam* infusion loading dose: 100-300 mcg/kg IV followed by IV infusion of 1-2 mcg/kg/min; increase by 1-2 mcg/kg/min every 15 min if seizures persist (effective range 1-24 mcg/kg/min); closely monitor hemodynamics and support blood pressure as indicated; when seizures stop and/or burst suppression is achieved, continue same dose for 48 h then wean by decrements of 1-2 mcg/kg/min every 15 min

Propofol* initial bolus: 2 mg/kg IV; repeat if seizures continue and follow by IV infusion of 5-10 mg/kg/h, if necessary, guided by EEG monitoring; taper dose 12 h after seizure activity stops; closely monitor hemodynamics and support blood pressure as indicated 

With phenobarbital-induced anesthesia, repeated boluses of 10 mg/kg are administered until cessation of ictal activity or appearance of hypotension; closely monitor hemodynamics and support blood pressure as indicated

StepMedicationDoseAlternatives
Step 2 (6-15 min)Diazepam (Valium)5-20 mg IV slowly; not to exceed infusion rate of 2 mg/min; pediatric dose is 0.3 mg/kgIf IV line is unavailable, use rectally administered (PR) diazepam at 0.5 mg/kg (not to exceed 10 mg) or midazolam (Versed) at 0.2 mg/kg intramuscularly (IM)*, IV, or intranasally*
Lorazepam* (Ativan)2-4 mg IV slowly*; not to exceed infusion rate of 2 mg/min or 0.05 mg/kg over 2-5 min; pediatric dose is 0.05-0.1 mg/kg
Step 3 (16-35 min)Phenytoin (Dilantin) or fosphenytoin (Cerebyx)† 20 mg/kg IV over 20 min; not to exceed infusion rate of 1 mg/kg/min; do not dilute in 5% dextrose in water (D5W)

If seizures persist, administer 5 mg/kg for 2 doses (if blood pressure is within the reference range and no history of cardiac disease is present)

If unsuccessful, administer phenobarbital 10-20 mg/kg IV (not to exceed 700 mg IV); increase infusion rate by 100 mg/min; phenobarbital may be used in infants before phenytoin; be prepared to intubate patient; closely monitor hemodynamics and support blood pressure as indicated
Step 4 (45-60 min)‡ Pentobarbital anesthesia (patient already intubated)Loading dose: 5-7 mg/kg IV; may repeat 1-mg/kg to 5-mg/kg boluses until EEG exhibits burst suppression; closely monitor hemodynamics and support blood pressure as indicated 

Maintenance dose: 0.5-3 mg/kg/h IV; monitor EEG to keep burst suppression pattern at 2-8 bursts/min

Midazolam* infusion loading dose: 100-300 mcg/kg IV followed by IV infusion of 1-2 mcg/kg/min; increase by 1-2 mcg/kg/min every 15 min if seizures persist (effective range 1-24 mcg/kg/min); closely monitor hemodynamics and support blood pressure as indicated; when seizures stop and/or burst suppression is achieved, continue same dose for 48 h then wean by decrements of 1-2 mcg/kg/min every 15 min

Propofol* initial bolus: 2 mg/kg IV; repeat if seizures continue and follow by IV infusion of 5-10 mg/kg/h, if necessary, guided by EEG monitoring; taper dose 12 h after seizure activity stops; closely monitor hemodynamics and support blood pressure as indicated 

With phenobarbital-induced anesthesia, repeated boluses of 10 mg/kg are administered until cessation of ictal activity or appearance of hypotension; closely monitor hemodynamics and support blood pressure as indicated

*Not approved by the FDA for the indicated use

†Doses for fosphenytoin administered in phenytoin equivalents (PE)

‡An alternative third step preferred by some authors is midazolam* administered by continuous IV infusion with a loading dose 0.1-0.3 mg/kg followed by infusion at a rate of 0.1-0.3 mg/kg/h.

  • Sequence of pharmacologic treatment for generalized tonic-clonic status epilepticus (GTCSE)
    • Following the early stabilization phase (the first 5-10 min after seizure onset) the treatment sequence for generalized tonic-clonic status epilepticus includes IV administration of a benzodiazepine (lorazepam or diazepam) under cardiorespiratory monitoring.
    • If an IV line cannot be established in a child after 5-10 minutes, use PR diazepam. IM midazolam has recently been used as an alternative to PR medication, but IM midazolam is not approved by the FDA for that indication. Intranasal midazolam may also be an option in children with prolonged seizure without an IV access.
    • When benzodiazepines do not stop the seizures, start phenytoin (or fosphenytoin) as the second medication. If phenytoin/fosphenytoin is ineffective in arresting the ictal activity, then use phenobarbital. Many pediatric institutions use benzodiazepine as the first treatment for infants with seizures, followed by phenobarbital and phenytoin/fosphenytoin as the third option if ictal activity persists.
    • Although respiratory depression that requires endotracheal intubation may occur at any time during treatment of generalized tonic-clonic status epilepticus, it is especially common during administration of phenytoin/fosphenytoin.
    • If seizure activity persists despite appropriate treatment with a benzodiazepine, phenobarbital, or phenytoin/fosphenytoin, then start midazolam drip (not approved by the FDA), barbiturate, or propofol (not approved by the FDA) anesthesia. PR paraldehyde can be tried before midazolam drip or barbiturate anesthesia, although paraldehyde requires knowledge of techniques for handling a drug that may dissolve plastic syringes. In recent years, paraldehyde has become more difficult to obtain commercially.
    • Begin cardiorespiratory monitoring with initiation of pharmacological therapy.
    • Transfer any child who requires continuous infusion of medications (eg, midazolam, barbiturate) because of prolonged seizure to an ICU; EEG monitoring is strongly advised.
  • Refractory generalized tonic-clonic status epilepticus
    • The term refractory generalized tonic-clonic status epilepticus has been used when seizures do not respond to benzodiazepines, phenytoin/fosphenytoin, and phenobarbital. Several options are presently available for these patients.
    • Barbiturate anesthesia is among the most popular treatments, although midazolam infusions (neither are approved by the FDA) have gained growing acceptance in the United States over the past 5 years. In the United States, barbiturate anesthesia is commonly performed with pentobarbital infusions; in the United Kingdom, thiopental (thiopentone) is often used. High-dose phenobarbital has been used in patients with generalized tonic-clonic status epilepticus.
    • All barbiturates used in anesthetic doses have been associated with such complications as hypotension, cardiac depression, and infections.
    • Increasing acceptance throughout the world of midazolam and propofol as alternative treatments for refractory generalized tonic-clonic status epilepticus relates to the comparative ease of handling these drugs in a continuous infusion. Due to reports of severe acidosis and movement disorder after prolonged propofol use, this agent is not currently recommended for long-term status epilepticus control. Also worrisome is the association of propofol related metabolic acidosis with the use of the ketogenic diet. Midazolam has been used, even in neonates, and has a reasonably predictable pharmacology, although movement disorders have been reported from prolonged use of midazolam for sedation. (See Medication for barbiturate, midazolam, and propofol dosages.)
    • In a few cases, adding a maintenance anticonvulsant medication to the patient's regimen may help wean the patient off a continuous barbiturate infusion. Although the experience is still very small, both IV valproic acid and topiramate via nasogastric tube have been used with that goal.
    • High-dose topiramate has been used in adults with status epilepticus, with doses as high as 1600 mg/d. One pediatric study used relatively lower initial doses 2-3 mg/kg/d before proceeding within 48-72 hours to a maintenance of 5-6 mg/kg/d (divided twice daily), which terminated the episode of status epilepticus.6 Another study reported loading dose of 10 mg/kg followed by 5 mg/kg/d maintenance (divided twice daily).7 Treatment of status epilepticus with topiramate is suggested by the neuroprotective action of this drug in animal models. Nonetheless, further data are necessary to show similar action in humans.
    • IV valproic acid is used for 3-Hz spike and wave stupor (absence status epilepticus) and myoclonic status in cases of juvenile myoclonic epilepsy and postanoxic myoclonus.8,9 Treatment of convulsive status (ie, generalized tonic-clonic status epilepticus) with IV valproic acid after other drugs (eg, benzodiazepines, phenytoin, phenobarbital) have failed has been rarely reported. Both secondary and primary generalized tonic-clonic status epilepticus seem to equally respond to IV valproic acid. A loading dose of 15-20 mg/kg is used, followed by 10 mg/kg every 6 hours. Alternatively, Uberall et al recommend a loading dose of 20-40 mg/kg over 5 minutes, followed by an infusion at a rate of 5 mg/kg/h.10 After 12 hours of clinical and EEG cessation of seizures, the dose is reduced to 1 mg/kg every 2 hours.
    • In Europe, alternative agents such as paraldehyde, lidocaine (Sweden and United Kingdom), and chlormethiazole (mostly United Kingdom) have been used. Paraldehyde is no longer commercially available in the United States whereas chlormethiazole is not approved by the FDA. Lidocaine is unpopular in the United States because of its narrow therapeutic index and proconvulsant effect in toxic levels.
    • Paraldehyde is a very effective drug, despite problems (eg, sterile abscess, pulmonary edema), but was discontinued from the US market in 2008. Respiratory failure and hypotension of sudden onset has been described. Shorvon recommends pediatric doses of 0.07-0.35 mL/kg.11  The adult dose is 5 mL PR diluted on the same volume of water. Exposure to air and light causes conversion of paraldehyde to acetaldehyde and then to acetic acid, with subsequent metabolic acidosis when administrated. Paraldehyde dissolves some plastic syringes and tubing if not used immediately. Approximately 80% of the paraldehyde is absorbed after a single rectal dose. Because of the high solubility of paraldehyde in lipids, the passage through the blood brain barrier may depend more on the cerebral blood flow; this is an attractive quality because of the possibility of a differential absorption concentration of the drug by the regions of the cortex involved in the epileptiform activity because they have higher blood flow than the rest of the brain during seizures.
    • Reports have shown the efficacy of levetiracetam in the management of status epilepticus as an add-on therapy in adults with refractory cases, with reported loading doses of 500-3000 mg/d and maintenance dose of 2000-3000 mg/d; in children, the reported loading dose is 30-40 mg/kg.12,13,14

Consultations

  • Consultation with a neurologist is recommended for patients whose seizures last longer than 15-30 minutes.

Medication

For the sequence of pharmacologic interventions in seizures and status epilepticus (SE), see the Table. This section primarily addresses dosages and pharmacologic properties of anticonvulsant medications used to treat generalized tonic-clonic status epilepticus (GTCSE).

Anticonvulsant benzodiazepines

This class of medications has long been used to treat generalized tonic-clonic status epilepticus and is often mentioned as first-line treatment for seizures in general. Diazepam has been advocated as a first-line agent alone or in combination with phenytoin. Whether a benzodiazepine followed by phenytoin is really the ideal sequence for this combination or if phenytoin (or fosphenytoin) should be followed by a benzodiazepine is unclear. Although the latter sequence appears better in animal models of generalized tonic-clonic status epilepticus, human data are lacking. Experience with benzodiazepines in the treatment of status epilepticus is large. This class of drugs has been described as the most potent used in status epilepticus management.

Although benzodiazepines have presynaptic, postsynaptic, and nonsynaptic actions, probably only their action at the GABA receptor level and their reduction of repetitive firing occur at the unbound drug concentrations observed in vivo.

Benzodiazepines increase chloride conductance by interacting with the GABA receptor. In animals and humans, benzodiazepines effectively stop early status epilepticus; however, late status epilepticus is less responsive to treatment with these drugs. Availability and pharmacokinetic differences should determine the choice of benzodiazepine.

Benzodiazepines are reportedly more effective against primary generalized epilepsy (90-100% effective) and partial hemiclonic convulsions in children without brain lesions. This class of drugs is effective in approximately 60% of status epilepticus cases occurring in partial epilepsy, but they are effective in only 15-59% of cases of tonic status epilepticus or various types of absence seizure status epilepticus (eg, atypical absence) occurring in secondary generalized epilepsy, although no other drug is more effective.


Diazepam (Valium, Diastat)

Depresses all levels of CNS (eg, limbic system, reticular formation), possibly by increasing activity of GABA. Highly lipophilic drug that quickly crosses the blood-brain barrier but is also rapidly redistributed to lipid-rich tissues. PR diazepam has been found to be effective in the control of cluster and prolonged seizures. Tends to be more effective when administered within 15 min of seizure onset.

Adult

5-10 mg/dose IV; 10-20 mg/dose PR

Pediatric

0.2-0.3 mg/kg/dose IV; 0.5 mg/kg/dose PR, not to exceed 10 mg PR

Increases CNS toxicity with coadministration of phenothiazines, barbiturates, ethanol, opiates, or MAOIs; cimetidine, disulfiram, fluoxetine, isoniazid, ketoconazole, metoprolol, propanolol, PO contraceptives, propoxyphene, and valproic acid may increase effect of benzodiazepines because of decreased metabolism

Documented hypersensitivity; narrow-angle glaucoma

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Caution with other CNS depressants, low albumin levels, or hepatic disease (may increase toxicity); may precipitate porphyria attack; monitor for respiratory depression; mild effects on blood pressure and cardiac output may be observed, which may be significant in patients with preexisting cardiac dysfunction; ataxia, irritability, and sedation are common adverse effects; patients may occasionally have psychotic reactions or suicidal ideation after use


Lorazepam (Ativan)

Sedative hypnotic with short onset of effects and relatively long half-life. By increasing the action of GABA, which is a major inhibitory neurotransmitter in the brain, may depress all levels of CNS, including limbic and reticular formation. Longer effective duration of action against GTCSE (6-8 h) than diazepam. Important to monitor patient's blood pressure after administering dose. Adjust prn.

Adult

2-4 mg IV slowly; not to exceed 2 mg/min; may repeat dose in 15 min if warranted

Pediatric

0.05-0.1 mg/kg/dose IV; not to exceed 0.05 mg/kg over 2-5 min

CNS toxicity increases when coadministered with ethanol, phenothiazines, barbiturates, opiates, or MAOIs; cimetidine, disulfiram, fluoxetine, isoniazid, ketoconazole, metoprolol, propanolol, PO contraceptives, and valproic acid may increase effects

Documented hypersensitivity; preexisting CNS depression; hypotension; narrow-angle glaucoma

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Caution in renal or hepatic impairment, myasthenia gravis, organic brain syndrome, or Parkinson disease; may precipitate porphyria attack; monitor for respiratory depression; mild effect on blood pressure and cardiac output, which may be significant in preexisting cardiac dysfunction; ataxia, irritability, and sedation are common; patients may occasionally have psychotic reactions or suicidal ideation after use of benzodiazepines


Midazolam (Versed)

Depresses all levels of CNS (eg, limbic system, reticular formation), possibly by increasing activity of GABA. Used as alternative in termination of refractory SE. Although not approved by the FDA for treatment of seizures in the United States, has long record of safety that probably is similar to other benzodiazepines. Used in at least 2 scenarios: (1) for initial treatment of relatively brief seizures (>5-10 min) as an alternative to diazepam or lorazepam and (2) to treat SE refractory to other benzodiazepines, phenytoin, and phenobarbital. Because water soluble, peak EEG effect takes approximately 3 times longer than diazepam; thus, 2-3 min are required to fully evaluate sedative effects before initiating procedure or repeating dose. Commercially available solutions contain 1% benzyl alcohol and 0.01% edetate sodium.

Adult

First-line treatment of seizures: 2.5-5 mg IV
Refractory SE: 200 mcg/kg IV bolus infused over 2-5 min loading dose, followed by 45-660 mcg/kg/h (0.75-11 mcg/kg/min) IV continuous infusion

Pediatric

First-line treatment of seizures: 0.2 mg/kg IV/IM
Refractory SE: 100-300 mcg/kg IV bolus infused over 2-5 min loading dose, followed by 1-2 mcg/kg/min IV continuous infusion; increase by 1-2 mcg/kg/min q15min if seizures persist (effective range 1-24 mcg/kg/min)
When seizures stop and/or burst suppression is achieved, continue dose for 48 h, then wean by increments of 1-2 mcg/kg/min q15min

Sedative effects may be antagonized by theophyllines; opiates and erythromycin may accentuate sedative effects of midazolam because of decreased clearance; increases CNS toxicity with coadministration of phenothiazines, barbiturates, and MAOIs; cimetidine, disulfiram, fluoxetine, isoniazid, ketoconazole, metoprolol, PO contraceptives, propanolol, and valproic acid may increase effect of benzodiazepines

Documented hypersensitivity; preexisting hypotension; narrow-angle glaucoma

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Caution in congestive heart failure, pulmonary disease, renal impairment, and hepatic failure; may precipitate porphyria attacks; respiratory depression is among the main concerns when using this drug; mild effect on blood pressure and cardiac output, which may be significant in patients with preexisting cardiac dysfunction; ataxia, irritability, and sedation are common; patients may occasionally have psychotic reactions or suicidal ideation after use

Hydantoins

These agents may act in the motor cortex where they may inhibit the spread of seizure activity.


Phenytoin (Dilantin)

Slows rate of recovery of voltage-activated sodium channels in the inactivated state, preventing rapid repetitive firing of neurons. Activity of brainstem centers responsible for tonic phase of grand mal seizures may also be inhibited. Incompatible when mixed with dextrose-containing solutions because of risk of precipitation; instead, dissolve drug in NaCl 0.9%. Propylene glycol and sodium hydroxide in IV preparation are thought to be responsible for pain during infusion, phlebitis, and local tissue damage.
Approximately 90% of serum phenytoin is bound to protein, mainly albumin, and an increase in unbound phenytoin is observed in patients with lower albumin levels (eg, neonates, people with renal or hepatic failure, nephrotic syndrome, pregnancy, or severe burns). Fast brain uptake equivalent to that of phenobarbital and diazepam.
CSF concentration is similar to unbound serum fraction.
Maximal IV infusion rates (1 mg/kg/min in children and 50 mg/min in adults) are to be respected because of the many cardiovascular actions from its quinidinelike effects.

Adult

20 mg/kg IV; not to exceed infusion rate of 50 mg/min

Pediatric

Administer as in adults; not to exceed infusion rate of 1 mg/kg/min

Amiodarone, benzodiazepines, chloramphenicol, cimetidine, fluconazole, isoniazid, metronidazole, miconazole, phenylbutazone, succinimide, sulfonamides, omeprazole, phenacemide, disulfiram, ethanol (acute ingestion), trimethoprim, and valproic acid may increase phenytoin toxicity; phenytoin effects may decrease when taken concurrently with barbiturates, diazoxide, ethanol (chronic ingestion), rifampin, antacids, charcoal, carbamazepine, theophylline, and sucralfate; may decrease effects of acetaminophen, corticosteroids, dicumarol, disopyramide, doxycycline, estrogens, haloperidol, amiodarone, carbamazepine, cardiac glycosides, quinidine, theophylline, methadone, metyrapone, mexiletine, PO contraceptives, and valproic acid

Documented hypersensitivity; sinoatrial block; second- and third-degree AV block; sinus bradycardia; Adams-Stokes syndrome

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Obtain CBC counts and urinalyses when therapy is begun and at monthly intervals for several months thereafter to monitor for blood dyscrasias; discontinue if rash appears and do not resume use if rash is exfoliative, bullous, or purpuric; discontinue use if hepatic dysfunction occurs; rapid IV infusion may result in death from cardiac arrest, marked by QRS widening; caution in acute intermittent porphyria and diabetes mellitus (may elevate blood sugars); monitor ECG, blood pressure, and respiration during infusion; slow infusion rates if patient develops hypotension or if seizure stops; local irritation at IV site is common after use, including severe phlebitis and tissue necrosis when phenytoin extravasates to surrounding tissues; purple-glove syndrome has been associated with its use


Fosphenytoin (Cerebyx)

Key drug to treat GTCSE. Diphosphate ester salt of phenytoin that acts as water-soluble prodrug of phenytoin. Following administration, plasma esterases convert fosphenytoin to phosphate, formaldehyde, and phenytoin. Phenytoin in turn stabilizes neuronal membranes and decreases seizure activity. Dose is expressed as phenytoin sodium equivalents. Although it can be administered IV and IM, IV is the route of choice and should be used in emergency situations.
Concomitant administration of an IV benzodiazepine is usually necessary to control SE. Can be readily dissolved in any of commercially available solutions (eg, D5W, isotonic sodium chloride solution).
When patients become alert during infusion, they may report perineal itching. Slow the infusion for individuals appearing uncomfortable and whose seizures have stopped.
Three times more avidly bound to serum protein than phenytoin, displacing the latter from its protein-binding sites. Can be infused 3 times faster than phenytoin. Despite these factors, when comparing the maximum phenytoin infusion rate of 50 mg/min (1 mg/kg/min in children) with that of fosphenytoin 150 mg/min (3 mg/kg/min for children), the rates at which free and total serum phenytoin levels increase show very similar curves that overlap at many points in time. The main advantage of fosphenytoin is its relatively low level of local irritation, avoiding serious local tissue damage with IV extravasation, and potential use in IM injection. Disadvantage is high price.

Adult

20 mg PE/kg IV; not to exceed infusion rate of 3 mg/kg/min (150 mg PE/min); administer 15 mg PE/kg for patients with cardiac problems

Pediatric

Administer as in adults

Amiodarone, benzodiazepines, chloramphenicol, cimetidine, disulfiram, ethanol (acute ingestion), omeprazole, phenacemide, phenylbutazone, succinimide, fluconazole, isoniazid, metronidazole, miconazole, sulfonamides, trimethoprim, and valproic acid may increase phenytoin toxicity; effects may decrease when taken concurrently with barbiturates, carbamazepine, theophylline, diazoxide, ethanol (chronic ingestion), rifampin, antacids, charcoal, and sucralfate; phenytoin may decrease effects of acetaminophen, corticosteroids, dicumarol, disopyramide, doxycycline, estrogens, haloperidol, amiodarone, carbamazepine, cardiac glycosides, methadone, metyrapone, mexiletine, PO contraceptives, quinidine, theophylline, and valproic acid

Documented hypersensitivity; sinoatrial block; second- and third-degree AV block; Adams-Stokes syndrome

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Blood dyscrasias have occurred; thus, obtain CBC counts and urinalyses when therapy is begun and at monthly intervals for several months thereafter; discontinue use if rash appears; if rash is exfoliative, bullous, or purpuric, do not resume use; death from cardiac arrest has occurred after too-rapid IV administration preceded sometimes by marked QRS widening; administer cautiously in acute intermittent porphyria; exercise caution when administering in diabetes mellitus; may raise blood sugar levels; discontinue drug if hepatic dysfunction occurs

Barbiturates

These agents have sedative, hypnotic, and anticonvulsant properties and can produce all levels of CNS mood alteration.


Pentobarbital (Nembutal)

Use pentobarbital anesthesia when seizures persist after 60 min of appropriate treatment. Patient should be already intubated. Advantage over inhalation anesthetics is that it decreases intracranial pressure whereas the latter tend to increase it.
At concentrations <10 mcmol, potentiates GABA-induced increase in Cl conductance and decreases voltage-activated Ca currents in hippocampal neurons. At subanesthetic concentrations, barbiturates decrease glutamate-induced depolarizations (an effect mediated by the AMPA receptors). At concentrations >100 mcmol, is capable of increasing Cl conductance in the absence of GABA. At high (anesthetic) concentrations, inhibits Na channels that reduce high-frequency rapid repetitive firing. Indirect evidence suggests Na channel blockade may be a main mechanism of general anesthesia.
Decreases cation flux after cholinergic activation of nicotinic receptors. Interaction with nicotinic receptors at the autonomic ganglia and at the neuromuscular junction explains hypotension and potentiation of the action by neuromuscular-blocking agents. Approximately 35-45% of serum pentobarbital is protein bound. Like all highly lipid-soluble barbiturates, the total terminal half-life of pentobarbital does not have a direct relationship with the duration of its efficacy as an anesthetic because of the redistribution effect.
Serum pentobarbital levels achieved in adults and adolescents range from 5-100 mg/L. Some authors emphasize the need to reach burst-suppression pattern on EEG, whereas others have shown that this pattern is neither necessary nor sufficient because breakthrough seizures may occur coming out of this pattern. Much easier to teach burst-suppression pattern recognition than to diagnose seizures on EEG. EEG monitoring is often used to adjust infusion to keep the burst-suppression pattern within 2-8 bursts/min. Some authors recommend continuous EEG monitoring for the first 6 h, followed by 10-min samples q30 min.
Patients requiring pentobarbital anesthesia after prolonged seizures lasting 16 h to 3 wk may have poor outcome (may be related to underlying pathology such as cancer or drug overdose rather than to use of pentobarbital). Pentobarbital anesthesia is also effective in children with SE refractory to other medications, but pediatric experience is limited, and prognosis may be somewhat better than in adults. Vasopressors are commonly needed during pentobarbital anesthesia in children.

Adult

Loading dose: 5-7 mg/kg IV; not to exceed infusion rate of 50 mg/min; 1-5 mg/kg bolus may be repeated until burst-suppression pattern observed in EEG
Continuous infusion: 0.5-3 mg/kg/h IV to maintain EEG burst suppression

Pediatric

Administer as in adults

Concomitant use with alcohol may produce additive CNS effects and death; chloramphenicol may inhibit pentobarbital metabolism; pentobarbital may enhance chloramphenicol metabolism; MAOIs may enhance sedative effects of barbiturates; valproic acid appears to decrease barbiturate metabolism, increasing toxicity; barbiturates can decrease effects of anticoagulants (patients may require dosage adjustments if barbiturates added to or withdrawn from regimen); decreased contraceptive effect may occur because of induction of microsomal enzymes (alternate form of birth control suggested); barbiturates may decrease corticosteroid and digitoxin effects through induction of hepatic microsomal enzymes, which increase metabolism; barbiturates decrease theophylline levels and may decrease effects; pentobarbital may decrease verapamil bioavailability

Documented hypersensitivity; variegate (South African) and acute intermittent porphyria

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Patient may become tolerant to hypnotic effects; caution in hypovolemic shock, respiratory dysfunction, renal or hepatic dysfunction, congestive heart failure, previous addiction to sedative hypnotics, and congestive heart failure; complications include transient neurologic deficits after stopping the drug (eg, ataxia, hypotonia, muscle weakness, ocular motor dysfunction, oscillopsia, diplopia, confusion), skin edema, ileus, infections (eg, pneumonia, urinary tract infection), and anemia requiring transfusion; IV preparations contain 20-40% propylene glycol and up to 10% alcohol (administration of high doses of propylene glycol to infants may be associated with metabolic acidosis); acutely, IV barbiturates in high doses may occasionally induce laryngospasm, cough, and cardiovascular collapse; enhance synthesis of porphyrin and are contraindicated in variegate and acute intermittent porphyria; to be administered in ICU environment; use in children not approved by FDA; long-term use not currently recommended because of reports of metabolic acidosis and potential poor effects on outcomes


Thiopental (Pentothal)

Differs from other barbiturates because of a sulfur replacement of the oxygen on the C2 position, which confers increased lipid solubility, faster onset of action, and accelerated degradation. Widely used to treat refractory SE in Europe and Australia, although less frequently used in the United States. Elimination half-life is directly proportional to duration of infusion. Slowly metabolized by the CYP450 microsomal enzyme system in the liver. CSF concentration is more variable than pentobarbital.
Burst-suppression pattern is observed on EEG when serum levels of >30-40 mg/L are reached, although higher levels may be necessary in patients undergoing prolonged treatment. EEG silence is usually observed with levels >70 mg/L.
Other factors that influence the effectiveness of thiopental include protein binding, pH-dependent changes of nonionized fraction of drug, and blood flow distribution.
Effective IV anesthetic dose of 2.5% thiopental induces loss of consciousness in 10-20 s, maximal brain concentration achieved in 30 s, and consciousness regained in 20-30 min of single dose. Nonetheless, when a single dose is injected IV, effects last only a few min because of redistribution to less vascular tissues (eg, muscle, fat) leading to drop in CNS concentrations. Prolonged administration and use of doses >1 g may be associated with prolonged recovery (hours to days) because of saturation of lipid stores. Monitor levels daily during thiopental infusions.

Adult

100-200 mg IV over 20 s, followed by 50 mg IV bolus q3min until seizures controlled; then 3-5 mg/kg/h IV continuous infusion (titrate to maintain EEG in burst-suppression)

Pediatric

1-3 mg/kg IV bolus, followed by 3-5 mg/kg/h IV continuous infusion (titrate to maintain EEG in burst-suppression)

Coadministration with CNS depressants, salicylates, or sulfisoxazole increases toxicity

Documented hypersensitivity; variegate (South African) and acute intermittent porphyria; inability to maintain airway

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in hepatic or renal insufficiency, asthma, severe cardiovascular disease, unstable aneurysm, hypotension (high dose or fast infusion), laryngospasm, or bronchospasm; a few authors have found thiopental infusions to have more significant cardiovascular toxicity than pentobarbital; IV concentrations >2.5% may be associated with endothelial damage, arteriolar spasm, tissue ischemia, and necrosis (if occurs, treat with local injection of 5-10 mL procaine, regional sympathetic block, and heparin to prevent thrombosis)


Phenobarbital (Luminal)

Many pediatric neurologists and pediatricians use phenobarbital (instead of phenytoin) as a second-line treatment to treat seizures in infants and toddlers if seizures did not respond to benzodiazepines. No controlled studies have demonstrated superiority of either phenobarbital or phenytoin to treat seizures.
Site of action may be post-postsynaptic (eg, cortex thalamic relay nuclei, pyramidal cells of cerebellum, substantia nigra) or pre-presynaptic in spinal cord. Inhibitory action relates to interaction with GABAa receptor, increasing duration of opening bursts of chloride channel. Barbiturates increase binding of GABA to GABAa receptor but use a binding site different from the site to which benzodiazepines attach. Promotes binding of benzodiazepines to GABAa receptor.
Similar efficacy to diazepam plus phenytoin and lorazepam. Administered to older children and adults when adequate doses of benzodiazepines and phenytoin do not control seizures. When administered after benzodiazepines, creates significant risk for respiratory impairment.
At concentrations >200-300 mcmol, phenobarbital is capable of increasing Cl conductance in the absence of GABA. At high concentrations, decreases voltage-activated Ca currents in hippocampal neurons.
High-dose phenobarbital has achieved reasonable results when used in children with status refractory to other medications. The presence of cardiovascular complications appears to be related to the rate of rise in levels rather than to absolute values.

Adult

300-700 mg IV; not to exceed infusion rate of 50 mg/min

Pediatric

20 mg/kg IV; not to exceed infusion rate of 1 mg/kg/min
Phenobarbital anesthesia: 10 mg/kg IV q30min; total dose per 24 h is 30-120 mg/kg with a median of 60 mg/kg; levels range from 70-334 mcg/mL with a median of 114 mcg/mL

May decrease effects of chloramphenicol, digitoxin, corticosteroids, carbamazepine, theophylline, verapamil, metronidazole, and anticoagulants (patients stabilized on anticoagulants may require dosage adjustments if added to or withdrawn from their regimen); coadministration with alcohol may produce additive CNS effects and death; chloramphenicol, valproic acid, and MAOIs may increase phenobarbital toxicity; rifampin may decrease phenobarbital effects; induction of microsomal enzymes may result in decreased effects of PO contraceptives in women (must use additional contraceptive methods to prevent unwanted pregnancy; menstrual irregularities may also occur)

Documented hypersensitivity; severe respiratory disease; marked liver impairment; nephritis

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

In prolonged therapy, evaluate hematopoietic, renal, hepatic, and other organ systems; caution in fever, hyperthyroidism, diabetes mellitus, and severe anemia because adverse reactions can occur; caution in myasthenia gravis and myxedema; decreases total duration of REM and slow-wave sleep; discontinuation may produce rebound REM sleep with vivid dreams and nightmares; may cause respiratory depression, especially if taking other CNS depressants, in patients with other conditions that alter respiratory drive/dynamics (eg, prolonged seizures) or gas exchange (eg, pulmonary insufficiency); IV barbiturates in high doses may occasionally induce laryngospasm, cough, and cardiovascular collapse; enhance synthesis of porphyrin and are contraindicated in variegate and acute intermittent porphyria

General anesthetics

Propofol is a phenolic compound unrelated to other types of anticonvulsants that has general anesthetic properties when administered IV. The development of propofol infusion syndrome, an irreversible chain of events associated with significant morbidity and mortality, is a concern. Propofol infusion syndrome was first described in 1992 by Parke et al.15 Since then, numerous case reports and reviews have been published.16,17,18,19,20  For more information, see Medscape Medical News. 


Propofol (Diprivan)

Used to treat SE. Has been subject of many reports in European literature in the past decade. Although not approved by the FDA for this purpose, now gaining US acceptance in SE. Advantages include relatively low toxicity for short-term use, quick onset of action, and fast recovery upon discontinuation. Reports of severe acidosis and movement disorder after propofol use in infants have caused a significant decrease in its use within that age group.
Metabolic acidosis may be a complication related to prolonged use of propofol, explaining the rarity of this complication in short surgical anesthesia. In contrast, metabolic acidosis in children with prolonged propofol use for sedation and treatment of SE has been reported. Also worrisome is the association of propofol related metabolic acidosis with the use of the ketogenic diet.
Only slightly soluble in water, but highly soluble in lipids. CNS penetration primarily depends on cerebral blood flow. Emergence from anesthesia faster than with thiopental, even with prolonged infusions. Accumulation effect after continued use is theoretical risk not often observed in practice. Even though respiratory depression is likely in the doses used to treat SE, status hypotension tends to be only mild.

Adult

2 mg/kg IV bolus initial; repeat prn; then 5-10 mg/kg/h IV infusion guided by EEG monitoring; gradually taper 12 h after seizure activity stops

Pediatric

Administer as in adults

Reduce propofol dose when administered concomitantly with benzodiazepines, opiates, phenothiazines, ethanol, and narcotics; propofol may potentiate neuromuscular blockade of vecuronium; theophylline may weaken effects of propofol, and dose increase may be needed

Documented hypersensitivity; metabolic acidoses; absence of mechanical ventilation

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Metabolic acidosis may occur and may lead to propofol infusion syndrome; do not administer with blood or blood products using the same IV catheter; patients may develop apnea; may experience decrease in systemic vascular resistance leading to hypotension; 30% decrease arterial blood pressure is expected when used in anesthetic doses; lipemia and accumulation of glucuronide derivatives may occur with long-term high-dose (can be problem, especially in infants treated for SE); involuntary movements, seizures, and, less frequently, SE has been reported when used in general anesthesia (in most instances, motor activity observed after propofol anesthesia is part of a transient movement disorder rather than seizures); to be administered in ICU environment

More on Status Epilepticus

Overview: Status Epilepticus
Differential Diagnoses & Workup: Status Epilepticus
Treatment & Medication: Status Epilepticus
Follow-up: Status Epilepticus
Multimedia: Status Epilepticus
References
[ CLOSE WINDOW ]

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Further Reading

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Keywords

status epilepticus, prolonged seizures, SE, generalized tonic-clonic status epilepticus, generalized tonic-clonic SE, GTCSE, nonconvulsive status epilepticus, nonconvulsive SE, NCSE, epilepsia partialis continua, complex partial and absence status epilepticus, simple partial status epilepticus, complex partial status epilepticus, epilepsy, seizures, violent seizures, hypoglycemia, head trauma, progressive encephalopathy, CNS lipid storage diseases, mitochondrial disorder, cerebral insult, electrolyte disturbance, zombie, hyperthermia, hypotension, periodic lateralizing epileptiform discharges, PLEDs, catscratch fever, meningitis, otitis media, pneumonia, lymphadenopathy, carbamazepine, tiagabine, treatment, diagnosis

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Contributor Information and Disclosures

Author

Marcio Sotero de Menezes, MD, Associate Professor, Department of Neurology, Division of Pediatric Neurology, Children's Hospital of Seattle, University of Washington
Marcio Sotero de Menezes, MD is a member of the following medical societies: American Academy of Neurology and American Epilepsy Society
Disclosure: Nothing to disclose.

Coauthor(s)

Ednea Simon, MD, Acting Assistant Professor, Department of Neurology, University of Washington
Ednea Simon, MD is a member of the following medical societies: American Academy of Neurology, American Epilepsy Society, and Child Neurology Society
Disclosure: Nothing to disclose.

Medical Editor

G Patricia Cantwell, MD, Associate Clinical Professor, Department of Pediatrics, University of Miami; Director of Pediatric Critical Care Medicine, Miller School of Medicine, Jackson Children's Hospital
G Patricia Cantwell, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Emergency Physicians, American Heart Association, American Trauma Society, National Association of EMS Physicians, Society of Critical Care Medicine, and Wilderness Medical Society
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from financial planner; Avanir Pharma Stock Investment from financial planner ; WebMD Salary and stock Employment and investment from financial planner

Managing Editor

Barry J Evans, MD, Assistant Professor of Pediatrics, Temple University Medical School; Director of Pediatric Critical Care and Pulmonology, Associate Chair for Pediatric Education, Temple University Children's Medical Center
Barry J Evans, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Chest Physicians, American Thoracic Society, and Society of Critical Care Medicine
Disclosure: Nothing to disclose.

CME Editor

Mary E Cataletto, MD, Associate Director, Division of Pediatric Pulmonology, Winthrop University Hospital; Professor of Clinical Pediatrics, State University of New York at Stony Brook; Director of Children's Sleep Services, Winthrop University Hospital
Mary E Cataletto, MD is a member of the following medical societies: American Academy of Pediatrics and American College of Chest Physicians
Disclosure: Shering Plough Pharmaceuticals Honoraria Consulting

Chief Editor

Timothy E Corden, MD, Associate Professor of Pediatrics, Co-Director, Policy Core, Injury Research Center, Medical College of Wisconsin; Associate Director, PICU, Children's Hospital of Wisconsin
Timothy E Corden, MD is a member of the following medical societies: American Academy of Pediatrics, Phi Beta Kappa, Society of Critical Care Medicine, and Wisconsin Medical Society
Disclosure: Nothing to disclose.

 
 
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