WORKUP	Section 5 of 10
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Lab Studies:

• Stabilization phase: While attending to the airway, breathing, and circulation (ABCs) and inserting an IV line, obtain laboratory studies for anticonvulsant medications levels, electrolytes, BUN/creatinine, calcium, magnesium, and CBC.

• Serum glucose measurement should be performed by a fast assay (eg, Dextrostix); this measurement is particularly important because hypoglycemia may be a contributing factor or cause of seizures in adults or children.

• Although routine laboratory studies are not always useful in assessing patients with brief seizures who present to the ED, children with GTCSE require a more aggressive workup. Other necessary tests may include urine/serum toxicology, especially in teenagers with unexplained seizures. If school-aged children who have cats (particularly kittens) at home present with unexplained mental status changes and prolonged seizures, evaluate for catscratch fever based on elevated indirect fluorescent antibody titers to B henselae. A lumbar puncture is commonly indicated in children with GTCSE, especially those with unexplained fever or mental status changes preceding or following the seizure episode.

• Continued evaluation: Continue evaluation after seizures are controlled.

• Basic tests recommended by the Epilepsy Foundation Working Group on SE are liver function tests (LFTs), toxicology screen, and brain imaging.

• After an SE episode, perform a lumbar puncture for individuals with fever or other evidence of CNS infection. Remember that febrile convulsive status may be associated with CNS infection without typical meningeal signs.

Imaging Studies:

• Imaging studies are indicated in patients with GTCSE once they are stabilized. In many centers, head computed tomography (CT) scanning is available on an emergency basis. If CT scanning is unavailable and the patient is stable and has no signs of increased intracranial pressure, CT scanning can be deferred temporarily.

• Perform an imaging study for all patients who have histories of neurologic (including mental status) changes and for patients who have actual deficits on the neurologic examination that persist after cessation of seizures.

• Brain imaging should be part of the workup for SE prior to lumbar puncture for patients with acute neurologic changes as evidenced by increased intracranial pressure.

• Children with complex partial seizures preceding or leading to the episode of GTCSE should have brain magnetic resonance imaging (MRI). (In many centers, CT scanning is performed in the ED because MRI services are often unavailable after hours. If not immediately available, MRI should be performed in the following days.)

• Brain imaging may be unnecessary for patients who have already had MRI performed as part of workup for epilepsy or when the cause or precipitant for their episode of SE is obvious (eg, low anticonvulsant levels, acute infection).

• On follow-up, many patients with documented a priori normal findings on MRI may develop increased T2, diffusion, and fluid attenuated inverted recovery (FLAIR) signal. This is especially true in cases of prolonged partial seizures leading to secondary GTCSE. Most of these changes are either due to transient vasogenic or cytotoxic edema.

Other Tests:

• Electroencephalography

• Every patient who presents with SE needs an EEG, but do not delay treatment to wait for EEG results. When a seizure persists longer than 30-60 minutes, making immediate arrangements for an EEG is advisable.

• The EEG helps the differentiation of convulsive status from pseudoseizure (nonepileptic or psychogenic seizure). NCSE may need to be differentiated from postictal state–related depression and unresponsiveness from metabolic (renal and hepatic) as well as anoxic encephalopathies. This is especially important when the treatment with anticonvulsant medication does not help improve the patient's alertness.

• Patients who ultimately require continuous infusion with a barbiturate or benzodiazepine (see Medical Care) should have continuous EEG monitoring.

• During a prolonged seizure, EEG manifestations follow a sequence of partial (focal) EEG seizures leading to discrete generalized tonic-clonic seizures that eventually become fused (ie, continuous EEG seizure). Rhythmic lateralized or generalized discharges later appear to slow in frequency and may appear similar to PLEDs. A patient arriving at the ED may be at any of these EEG stages; historical information concerning seizure progression usually correlates somewhat with stage. Patients at the later stages of EEG with GTCSE may be more difficult to treat.

• Patients who cannot be aroused following a seizure should have an EEG performed to rule out subclinical SE. An EEG can confirm the seizure pattern and help indicate the most appropriate long-term treatment, if that is necessary. For example, a toddler with a history of 1 unprovoked seizure presents with a generalized tonic-clinic convulsion lasting 45 minutes, but after the event, her EEG findings show frequent unilateral spikes. In this situation, the treating physician would probably recommend treatment with a medication effective against partial seizures (eg, carbamazepine, phenytoin) as the child leaves the hospital.

	TREATMENT	Section 6 of 10
Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Bibliography

Medical Care: 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 SE. Physicians should become familiar with the pharmacology of the drugs used to treat SE. Prudence calls for doses of these drugs to be placed in visible locations within EDs, pediatric units, and nursing stations.

Treatment for generalized SE 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. (Note that the following medications marked by an asterisk are not approved by the Food and Drug Administration [FDA] for the indicated use.) 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, attend first 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 IV access and to draw 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 are other tests commonly performed for 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 Intensive Care Unit service and respiratory therapists (or anesthesiologists) if seizures persist for more than 20 minutes.

• After addressing the patient's ABCs 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), begin the following treatment steps outlined in the table.

  Treatment of Seizures/SE Based on Time Elapsed Since Seizure Onset

  Step	Medication	Dose	Alternatives
  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/kg	If IV line is unavailable, use PR diazepam 0.5 mg/kg (not to exceed 10 mg) or midazolam (Versed) 0.2 mg/kg IM*, IV, or intranasal*
  	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 D5W If seizures persist, administer 5 mg/kg for 2 doses (if BP 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
  Step 4 (45-60 min)‡	Pentobarbital anesthesia (patient already intubated)	Loading dose: 5-7 mg/kg; may repeat 1- to 5-mg/kg boluses until EEG exhibits burst suppression Maintenance dose: 0.5-3 mg/kg/h; monitor EEG to keep burst suppression pattern at 2-8 bursts per min	Midazolam* infusion loading dose: 100-300 mcg/kg followed by infusion of 1-2 mcg/kg/min; 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 same dose for 48 h then wean by decrements of 1-2 mcg/kg/min q15min Propofol* initial bolus: 2 mg/kg IV; repeat if seizures continue and follow by infusion of 5-10 mg/kg/h, if necessary, guided by EEG monitoring; taper dose 12 h after seizure activity stops With phenobarbital-induced anesthesia, repeated boluses of 10 mg/kg are administered until cessation of ictal activity or appearance of hypotension

  *Not approved by the FDA for the indicated use
  †Doses for fosphenytoin administered in PE (phenytoin equivalents)
  ‡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 GTCSE

• Following the early stabilization phase (the first 5-10 min after seizure onset) the treatment sequence for GTCSE 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 FDA-approved for that indication.

• 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.

• While respiratory depression requiring endotracheal intubation may occur at any time during treatment of GTCSE, 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 FDA-approved), barbiturate, or propofol (not FDA-approved) 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 pharmacologic therapy.

• Transfer to an ICU any child requiring continuous infusion of medications (eg, midazolam, barbiturate) because of prolonged seizure; EEG monitoring is strongly advised.

• Refractory GTCSE
  • The term refractory GTCSE 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 (not FDA-approved) 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, but in the United Kingdom, thiopental (thiopentone) is often used. High-dose phenobarbital has been used in patients with GTCSE.

  • 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 GTCSE relates to the comparative ease of handling these drugs in a continuous infusion. Reports of severe acidosis and movement disorder after propofol use in infants have caused a significant decrease in its use within that age group. This complication may be related to prolonged use, which would explain the rarity of this complication in short surgical anesthesia and the reports of it in children undergoing prolonged use for sedation and treatment of SE. 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.

  • In a few cases, adding a maintenance anticonvulsant medication to the patient's regimen may help wean the patient off a continuous barbiturate infusion. Even though experience is still limited, both IV valproic acid and topiramate via nasogastric tube have been used with that goal.

  • Relatively high-dose topiramate has been used in adults, starting with 500 mg bid for 2 days and 20 mg bid for maintenance. One pediatric study used relatively lower initial doses of 2-3 mg/kg/d, converted within 48-72 hours to maintenance doses of 5-6 mg/kg/d (divided bid), which terminated the episode of SE. The rationale for treating SE with topiramate is based on the neuroprotective action of this drug in animal models. Nonetheless, further data are necessary to show similar action in humans.

  • Intravenous valproic acid is used for 3-Hz spike and wave stupor (absence SE) and myoclonic status in cases of juvenile myoclonic epilepsy and postanoxic myoclonus. Experience is more limited in treating convulsive SE (GTCSE) with valproic acid IV after other drugs (ie, benzodiazepines, phenytoin, phenobarbital) have failed. Both secondary and primary GTCSE seem to respond equally to IV valproic acid. A loading dose of 15-20 mg/kg is used and is followed by 10 mg/kg every 6 hours. Alternatively, the Uberall et al protocol uses a loading dose of 20-40 mg/kg over 5 minutes followed by an infusion at a rate of 5 mg/kg/h. 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 (in Sweden and the United Kingdom), and chlormethiazole (mostly in the United Kingdom) have been used. Paraldehyde is no longer commercially available in the United States, whereas chlormethiazole is not FDA approved. Lidocaine is unpopular in the United States because of its narrow therapeutic index and proconvulsant effect in toxic levels.

  • Paraldehyde is an effective drug in spite of its problems, such as sterile abscess and pulmonary edema. Respiratory failure and hypotension of sudden onset has been described. In a 1994 article, Shorvon recommends pediatric doses of 0.07-0.35 mL/kg, but the adult dose is 5 mL PR diluted in the same volume of water. Exposure to air and light causes conversion of paraldehyde to acetaldehyde and then to acetic acid, causing subsequent metabolic acidosis on administration. Paraldehyde dissolves some plastic syringes and tubing if not used immediately. About 80% of the paraldehyde is absorbed after a single rectal dose. Because of the high solubility of paraldehyde in lipids, 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, which have higher blood flow than the rest of the brain during seizures.

• Inhalatory anesthetics
  • Inhalatory anesthetics have also been used for the treatment of SE. Occasionally, when other agents such as high-dose barbiturate are unsuccessful, patients may respond to isoflurane. One of the main disadvantages of inhalatory agents is their tendency to increase intracranial pressure due to vasodilation, this effect is especially seen with halothane. Halothane also has potential toxicity (especially hepatic) from its metabolites. On the other hand, only 0.2% of isoflurane and 0.02% of desflurane are metabolized. Interest in using inhalatory anesthesia for the treatment of refractory SE has increased recently.

  • Nonetheless, inhalatory anesthesia is often impractical in the ICU because it requires an operating room setting with special delivery systems for the gaseous agents. As reviewed by Kennedy and Longnecker in 1996, the gas anesthesia delivery systems are temperature dependent and affected by the amount of humidification, the patient's uptake of the anesthetics, and generation of nitrogen and carbon dioxide. During inhalatory anesthesia, the partial pressures of carbon dioxide and oxygen must be continuously measured, as well as the anesthetic gas being delivered. Administrating relatively high concentration boluses is also a risk simply by connecting and reconnecting the system such as when readjusting the position of the gas delivery system (Jardine, 2005).

	MEDICATION	Section 7 of 10
Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Bibliography

For the sequence of pharmacologic interventions in seizures and SE, see the Table. This section primarily addresses dosages and pharmacologic properties of anticonvulsant medications used to treat GTCSE.

Drug Category: Anticonvulsant benzodiazepines -- This class of medications has long been used to treat GTCSE 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 GTCSE, human data are lacking. Experience with benzodiazepines in the treatment of SE is large. This class of drugs has been described as the most potent used in SE 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 SE; however, late SE 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 SE cases occurring in partial epilepsy, but they are effective in only 15-59% of cases of tonic SE or various types of absence seizure SE (eg, atypical absence) occurring in secondary generalized epilepsy, although no other drug is more effective.

Drug Name	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 also is 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 Dose	5-10 mg/dose IV; 10-20 mg/dose PR
Pediatric Dose	0.2-0.3 mg/kg/dose IV; 0.5 mg/kg/dose PR
Contraindications	Documented hypersensitivity; narrow-angle glaucoma
Interactions	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
Pregnancy	D - Unsafe in pregnancy
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

Drug Name	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 Dose	2-4 mg IV slowly; not to exceed 2 mg/min; may repeat dose in 15 min if warranted
Pediatric Dose	0.05-0.1 mg/kg/dose IV; not to exceed 0.05 mg/kg over 2-5 min
Contraindications	Documented hypersensitivity; preexisting CNS depression; hypotension; narrow-angle glaucoma
Interactions	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
Pregnancy	D - Unsafe in pregnancy
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

Drug Name	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 FDA approved 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 (see 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 Dose	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 Dose	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
Contraindications	Documented hypersensitivity; preexisting hypotension; narrow-angle glaucoma
Interactions	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
Pregnancy	D - Unsafe in pregnancy
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

Drug Category: Hydantoins -- These agents may act in the motor cortex where they may inhibit the spread of seizure activity.

Drug Name	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 Dose	20 mg/kg IV; not to exceed infusion rate of 50 mg/min
Pediatric Dose	Administer as in adults; not to exceed infusion rate of 1 mg/kg/min
Contraindications	Documented hypersensitivity; sinoatrial block; second- and third-degree AV block; sinus bradycardia; Adams-Stokes syndrome
Interactions	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
Pregnancy	D - Unsafe in pregnancy
Precautions	Perform blood 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

Drug Name	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 (PE). 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 usually is necessary to control SE. Can be dissolved readily in any of commercially available solutions (eg, 5% dextrose, 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. In spite of all these factors, when comparing the maximum phenytoin infusion rate of 50 mg/min (1 mg/kg/min in children) to 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 Dose	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 Dose	Administer as in adults
Contraindications	Documented hypersensitivity; sinoatrial block; second- and third-degree AV block; Adams-Stokes syndrome
Interactions	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
Pregnancy	D - Unsafe in pregnancy
Precautions	Blood dyscrasias have occurred; thus, perform blood 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

Drug Category: Barbiturates -- Have sedative, hypnotic, and anticonvulsant properties. Can produce all levels of CNS mood alteration.

Drug Name	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 while the latter tend to increase it. At concentrations <10 µmol, 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 µmol, 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, while 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 Dose	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 Dose	Administer as in adults
Contraindications	Documented hypersensitivity; variegate (South African) and acute intermittent porphyria
Interactions	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
Pregnancy	D - Unsafe in pregnancy
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

Drug Name	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 Dose	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 Dose	1-3 mg/kg IV bolus, followed by 3-5 mg/kg/h IV continuous infusion (titrate to maintain EEG in burst-suppression)
Contraindications	Documented hypersensitivity; variegate (South African) and acute intermittent porphyria; inability to maintain airway
Interactions	Coadministration with CNS depressants, salicylates, or sulfisoxazole increases toxicity
Pregnancy	C - Safety for use during pregnancy has not been established.
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)

Drug Name	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 they use a binding site different from 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 µmol, phenobarbital is capable of increasing Cl conductance in the absence of GABA. At high concentrations, it 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 Dose	300-700 mg IV; not to exceed infusion rate of 50 mg/min
Pediatric Dose	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
Contraindications	Documented hypersensitivity; severe respiratory disease; marked liver impairment; nephritis
Interactions	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)
Pregnancy	D - Unsafe in pregnancy
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 occasionally may induce laryngospasm, cough, and cardiovascular collapse; enhance synthesis of porphyrin and are contraindicated in variegate and acute intermittent porphyria

Drug Category: General anesthetics -- Phenolic compound unrelated to other types of anticonvulsants. Has general anesthetic properties when administered IV.

Drug Name	Propofol (Diprivan) -- Used to treat SE. Has been subject of many reports in European literature in the past decade. Although not FDA approved for this purpose, now gaining US acceptance for 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, there are reports of metabolic acidosis in children undergoing prolonged propofol use for sedation and treatment of SE. 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 Dose	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 Dose	Administer as in adults
Contraindications	Documented hypersensitivity; metabolic acidoses; absence of mechanical ventilation
Interactions	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
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Metabolic acidosis; 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 use (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

	FOLLOW-UP	Section 8 of 10
Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Bibliography

Further Inpatient Care:

• Treat patients with suspected herpes encephalitis with acyclovir until the diagnosis can be confirmed. Suspect herpes virus encephalitis in all patients with fever, mental status changes, and de novo onset of partial seizures, with or without secondary generalization.

• Treatment of catscratch disease is not universally efficacious; rifampin, ciprofloxacin, and trimethoprim-sulfamethoxazole have been used successfully.

• Electrolyte disturbances may cause or perpetuate seizures; hypocalcemia and hyponatremia are the most common. Efforts to correct hyponatremia should be performed carefully because quick shifts in serum osmolality may cause irreversible brain damage from central pontine myelinolysis. Correcting hypocalcemia with IV calcium gluconate should be performed under ECG monitoring because of the possibility of cardiac arrhythmias.

Further Outpatient Care:

• Long-term antiepileptic therapy after GTCSE includes the following:

• Although a complete guide for outpatient management of epilepsy is beyond the scope of this article, the Epilepsy Foundation Working Group on SE recommends starting some patients, including those with a history of epilepsy or brain lesion, on long-term antiepileptic therapy after an SE episode.

• No long-term therapy is indicated for SE caused by transient problems (eg, metabolic disturbances [hyponatremia], intoxications).

• No consensus currently exists regarding the need for treatment after an instance of febrile SE or when a first unprovoked seizure is an SE episode.

• While many studies have shown that recurrent seizure risk is unrelated to seizure duration, a recurring GTCSE episode is more likely to be a prolonged seizure.

• Choose long-term treatment medications based on the patient's seizure type and EEG pattern. Knowledge of the seizure type and EEG pattern should help the physician confirm the diagnosis of an epileptic syndrome and improve selection of anticonvulsant medication.

• Patients with partial seizures respond better overall to carbamazepine, phenytoin, and phenobarbital (infants). Valproic acid and phenobarbital are better treatments for patients with generalized tonic-clonic seizures, although carbamazepine and phenytoin can also be administered for patients with secondary generalized seizures. Valproic acid carries a higher risk of liver failure in patients younger than 2 years and those on polypharmacy.

Complications:

• The most feared complication of GTCSE is brain damage associated with neuronal loss mediated by sustained EEG seizure activity.

• Among many other complications described in patients who have had prolonged seizures are fluid/electrolyte/metabolic disturbances, trauma, and cardiopulmonary problems.

• Fluid/electrolyte/metabolic complications include lactic acidosis, dehydration, and hypotension.

• Myoglobinuria caused by muscle breakdown during a seizure may lead to renal dysfunction.

• Craniofacial injuries include oral trauma, both internal (eg, biting the tongue or oral mucosa) and external (eg, hitting the lips). Many patients also have closed head or facial injuries during the clonic phase of seizures.

• Pulmonary edema and cardiac arrhythmias may be complications of SE or its treatment.

• Disseminated intravascular coagulation in association with significant leukocytosis and mild cerebrospinal fluid pleocytosis may produce a clinical picture similar to sepsis or CNS infection. In these cases, patients are often treated for a severe infection until sepsis or meningitis/encephalitis can be ruled out safely.

• See phenobarbital in the "Medication" section for information on well-known complications associated with barbiturate-induced coma (ie, general anesthesia).

Prognosis:

• GTCSE seizures of less than 1-hour duration have a better prognosis than do those lasting longer.

• Children have a much lower mortality rate after GTCSE.

• See Mortality/Morbidity for information on GTCSE outcome, sequelae, morbidity, and mortality.

• Patients with refractory SE requiring high-dose suppressive therapy (eg, barbiturate coma, midazolam infusion) often need prolonged therapy. The long-term outcome in previously healthy children who survived prolonged barbiturate coma or midazolam infusion for SE is not particularly favorable. In one study done at Boston Children's Hospital, all patients developed intractable epilepsy, and none returned to baseline.

• De novo development of hippocampus sclerosis (ie, mesial temporal lobe sclerosis) is one of the possible complications of SE and possibly the reason why the survivors may develop chronic recurrent and refractory complex partial seizures.

Patient Education:

• For excellent patient education resources, visit eMedicine's Brain and Nervous System Center. Also, see eMedicine's patient education articles Seizures Emergencies, Seizures in Children, and Epilepsy.

	MISCELLANEOUS	Section 9 of 10
Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Bibliography

Medical/Legal Pitfalls:

• Every institution treating patients who have GTCSE should have a treatment protocol. This protocol should be based on current information derived from authoritative sources, as well as on recent reviews of the literature, and the protocol should be communicated to the medical staff. Review treatment protocols at least annually.

• Litigation is often based on perceptions that treatment deviated from established standards of practice. Because standards of practice can be difficult to define, physicians and institutions can avoid many legal problems by establishing and following institutional parameters for managing GTCSE.

• Seizure-related brain damage is another potential source of litigation in GTCSE management.

• Patients with epilepsy present at different ages, even when the etiology of their epilepsy is genetic or cryptogenic.

• Although learning disabilities and mental retardation are more common among children with epilepsy than in the general population, cognitive problems often remain undiagnosed until the patient's first seizure and sometimes not until the first prolonged seizure. Physicians can occasionally obtain a history of abnormal language development and cognition prior to the seizures.

• Once seizures are controlled in the ED or ICU and the patient is stabilized, the treating physician should (1) obtain a full history, including detailed developmental history, for documentation and (2) fully document procedures used to manage the GTCSE episode, including all medications with doses and routes of administration. Physicians or nurses should also record vital signs, oxygen saturation, and arterial blood gas (ABG) levels.

• Case discussion

• A 10-year-old boy who is obese and who has a history of grand mal seizures presents to the ED with a generalized tonic-clonic convulsion. By the time the patient is seen by an ED physician, the seizure has lasted 45 minutes. About 60 minutes after initial assessment, a venous cutdown