Pediatric Status Epilepticus Treatment & Management

Status epilepticus (SE) treatment should follow a logical sequence of interventions. Evidence strongly suggests that aggressive early intervention leads to timely seizure termination and improved outcomes. ^[47]  Institutions caring for pediatric patients should have an SE care pathway plan that is based on current best practice authoritative sources. ^[3]  Once developed, SE care pathways should be communicated to the medical staff and reviewed annually.

The lack of a structured protocol has been associated with increased morbidity from SE. ^[48] Litigation involving patients suffering sequelae of SE is often based on perceptions that treatment deviated from established standards of practice.

The lack of a structured protocol has been blamed for increased morbidity from SE. ^[48] Litigation involving patients suffering sequelae of SE is often based on perceptions that treatment deviated from established standards of practice.

Physicians should become familiar with the pharmacology of the drugs used to treat SE. Rapidly accessible resources with anti-seizure dosing regiments should be placed in visible locations within emergency departments (EDs) pediatric units, and pharmacies.

Treatment for convulsive 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.

The following example of a protocol with time points for convulsive SE:

First Line (5–10 min)

• Lorazepam IV or IO (0.05-0.1 mg/kg) max 4 mg, can be repeated once

• Diazepam per rectum (0.5 mg/kg), max 20 mg, single dose

• Diazepam IV (0.2 mg/kg IV) max 10 mg, can be repeated once

• Midazolam IM/IV/buccal (0.2 mg/kg) single dose

• IN midazolam (0.2/kg) divided dose between nares, can be repeated once.

Second Line (10–30 min)

• Fosphenytoin IV or IM (20 mg PE/kg), max 1500 mg/dose

• Levetiracetam IV (60 mg/kg), max 4500 mg/dose

• Valproic acid IV (40 mg/kg), max 3000 mg/dose

• Phenobarbital IV (20 mg/kg), max 1500 mg/dose

• Lacosamide IV (8 mg/kg), max 200 mg initial dose. Can be repeated - max 20 mg/kg/day or 400 mg/day, whichever is less. 

Third Line (30+ min - failed first two lines of therapy - Refractory Status Epilepticus)

• Repeat alternative second line therapies

• Transfer to ICU for infusion of IV anesthetics and antiseizure medications. Under EEG guidance, treatment should involve rapid escalation of therapy using repeated boluses, as NCSE is a high risk in these patients. 

Examples of infusions are listed below:

1. Pentobarbital 5 mg/kg initial load with additional 5 mg/kg repeated every 5 minutes until seizure ends or burst suppression on EEG. Infusion 0.5–5 mg/kg/hr titrated to clinical/electrographic seizure control

2. Midazolam 0.2 mg/kg initial load with additional 0.2 mg/kg repeated every 5 minutes until seizure ends or burst suppression on EEG. Infusion 0.05–2 mg/kg/hr titrated to clinical/electrographic seizure control

3. Propofol 2 mg/kg initial load with additional 2 mg/kg repeated every 5 minutes until seizure ends or burst suppression on EEG. Infusion 30–67 mcg/kg/min titrated to clinical/electrographic seizure control. Avoided in pediatrics due to risk of propofol infusion syndrome (highest risk with infusions longer than 48 hr and infusions higher than 67 mcg/kg/min)

4. Ketamine 1-2 mg/kg initial load with additional 1–2 mg/kg repeated every 5 minutes until seizure ends or burst suppression on EEG. Infusion 1.2–7.5 mg/kg/hr titrated to clinical/electrographic seizure control

Note: While phenobarbital is listed as a second line in this algorithm, it, along with levetiracetam, is routinely used as first line in neonatal SE. Recent evidence suggests that phenobarbital is superior to levetiracetam in neonatal SE. ^[4]

Other treatments may be indicated if the clinical evaluation identifies precipitants of the seizures. Selected agents and indications are as follows:

• Naloxone - 0.1 mg/kg/dose, IV preferably (if needed may administer IM or SQ) for narcotic overdose

• Pyridoxine - 50–100 mg IV/IM for possible dependency, deficiency, or isoniazid toxicity

• Antibiotics - If meningitis is strongly suspected, initiate treatment with antibiotics prior to CSF analysis or CNS imaging

Supportive care, including management of airway, breathing, and circulation (the ABCs), must be addressed in the prehospital setting. Emergency medical system (EMS) personnel should proceed as follows:

• Timing of the seizure

• Secure the airway

• Administer supplemental 100% oxygen

• Infuse isotonic intravenous fluids and dextrose

• Immobilize the cervical spine in patients with possible trauma

If the seizure fails to stop within 4-5 minutes or if the patient is continuing to seize at the time of EMS arrival, prompt administration of anticonvulsants may be indicated, if permitted by local protocols. Consider rectally administered diazepam (0.5 mg/kg/dose) or intramuscularly administered midazolam (0.1-0.2 mg/kg/dose; not to exceed a cumulative dose of 10 mg). ^[49]

If persons who know the patient, or who witnessed the onset of the seizures, are present at the scene, EMS providers may be able to collect information that offers clues to the cause of the status epilepticus (SE).

As in any medical emergency, attend to the ABCs first, before starting any pharmacologic intervention. 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). Immobilize the cervical spine if trauma is suspected.

Administer 100% oxygen by facemask. Assist ventilation using bag mask ventilatio and endotracheal intubation if needed. Suction secretions and decompress the stomach with a nasogastric tube.

Respiratory depression is a common complication of the management of prolonged seizures. Ensure that equipment is available to deliver non-invasive ventilatory support while preparing for potential intubation 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.

Obtain a rapid bedside glucose determination

In the first 5 minutes of seizure activity, before starting any medications, try to establish intravenous (IV) access and obtain blood samples for laboratory tests and for seizure medication levels (see Workup). Infuse isotonic intravenous fluids plus glucose at a rate of 20 mL/kg/h (eg, 200 mL dextrose 5% in normal saline [D5NS] over 1 h for a 10-kg child).

In children younger than 6 years, use intraosseous (IO) infusion if intravenous access cannot be established within 5–10 minutes. Anticonvulsants can be administered via the intravenous or intraosseous route.

If serum glucose is low or cannot be measured, give children 2 mL/kg of 25% glucose. Adults should receive 50 mL of 50% glucose, along with 100 mg of thiamine to avoid Wernicke-Korsakoff syndrome.

Other specific treatments may be indicated if the clinical evaluation identifies precipitants of the seizures. Selected agents and indications are as follows:

• Naloxone - 0.1 mg/kg/dose intravenously preferably (if needed may administer intramuscularly/subcutaneously) for narcotic overdose

• Pyridoxine - 50–100 mg intravenously/intramuscularly for possible dependency, deficiency, or isoniazid toxicity

• Antibiotics - If meningitis is strongly suspected, initiate treatment with antibiotics prior to cerebrospinal fluid (CSF) analysis or CNS imaging

If the onset of the seizure was 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 (PICU) service and respiratory therapists (or anesthesiologists) if seizures persist for more than 20 minutes.

The Table below is based on the Emergency Management Guidelines of Children's Hospital and Regional Medical Center. Step 1, which encompasses the first 0-5 minutes of care and thus precedes the actions outlined in this table, consists of addressing the patient's ABCs.

Table 1. Examples of Medical Treatment of Seizures and Convulsive Status Epilepticus Based on Time Elapsed Since Seizure Onset (Steps 2-4) (Open Table in a new window)

Status epilepticus (SE) management is a race against time; the goal is to abort a prolonged seizure before injury to the patient occurs. Complicating this is the unfortunate reality that the longer a seizure lasts, the more difficult it can be to abort due to the paradoxical loss of inhibitory and simultaneous increase in excitatory receptors, making medications less effective. ^{[6, 18, 23]}  Therefore, the focus of pharmacotherapy should be seizure control with benzodiazepines in the emergent phase, followed by urgent control with the administration of intravenous (IV) anti-seizure drugs if benzodiazepines are unsuccessful as well as to prevent recurrence. ^{[14, 50, 47, 51]}

Prospective and retrospective trials and hospital surveys all support the idea that the optimal protocol for management of SE begins with a benzodiazepine, either lorazepam, midazolam or diazepam. ^{[52, 3, 13, 9, 19, 53, 54, 47, 51]}  Early and appropriate therapy with a benzodiazepine universally resulted in a significantly shorter time until SE cessation. ^[47]  In the United States, lorazepam is often the drug of choice in patients with intravenous or intraosseous access. Lorazepam (0.05-0.1 mg/kg IV or IO slowly infused over 2-5 min) has rapid onset and long duration of anticonvulsant action with some evidence that it is superior to diazepam.  ^{[55, 56]}

If IV or IO access cannot be rapidly established there are a number of options available, including rectal diazepam, buccal, IM, and IN midazolam (0.1-0.2 mg/kg), sublingual lorazepam (0.1 mg/kg), and IN diazepam. Midazolam can be administered safely intramuscularly while providing rapid onset equivalent to that of intravenous agents, however, IM midazolam is not approved by the US Food and Drug Administration (FDA) for that indication.

With regards to the absolute best first-line agent for pediatric SE the data is less clear, as multiple studies found similar efficacy between IV lorazepam, rectal diazepam, IN diazepam, and IN and buccal midazolam. ^{[57]   [58, 59, 50, 53, 54, 60, 61, 62]}  In practice, since the shorter the time between onset of convulsive SE and treatment initiation is a strong factor in seizure cessation, the best medication to use is the one that can be provided the fastest. In the case of pediatric SE, training caregivers in the use of a rescue medication (eg, rectal or IN diazepam or IN midazolam) often means the difference between early SE cessation and escalation in therapy to second- and third-line agents. Parents typically report higher levels of satisfaction with IN rather than rectally administered medications. ^[57]

If the seizures cease, no further drugs are immediately necessary. The etiology of SE should then be investigated.

If benzodiazepine therapy proves ineffective, IV, IO ,or IM fosphenytoin, IV valproic acid, or IV levetiracetam is used as the second-line in pediatric SE. ^{[3, 19, 63, 64]}  These agents are effective for most idiopathic generalized seizures and for posttraumatic, focal, or psychomotor SE.

Fosphenytoin has been used as a second-line agent in SE for many years, with many studies supporting its efficacy. A 2018 review of randomized controlled trials in IV phenytoin in convulsive SE supported its use as a second-line therapy for benzodiazepine-resistant convulsive SE, as well as the use of IV phenytoin immediately after IV diazepam even when seizures have not recurred. ^[65] Fosphenytoin offers the advantage of a potentially rapid rate of administration with less risk of venous irritation and vascular compromise of the infused limb (eg, purple-glove syndrome). The loading dose of phenytoin is 20 mg/kg IV or IO; for fosphenytoin, it is 20 mg/kg PE IV or IO. A full loading dose should be delivered unless the patient is known to have a current therapeutic level. Although respiratory depression that requires endotracheal intubation may occur at any time during treatment of GTCSE, it is especially common during administration of phenytoin/fosphenytoin.

Other agents have gained popularity as second-line agents in SE, particularly levetiracetam and valproic acid. Recent RCTs have supported that in the context of benzodiazepine-refractory convulsive status epilepticus, levetiracetam, fosphenytoin, and valproate had similar levels of seizure cessation with similar incidences of adverse events. ^{[66, 67, 68, 63, 64]}  Dosing suggestions from the trials are 40 mg/kg (max 3000 mg) as a single dose for valproic acid and 60 mg/kg (max 4500 mg) as a single dose for levetiracetam when used as second-line agents in SE.

If SE is unresponsive to one of the three first-line agents, use of phenobarbital or lacosamide is reasonable.

Phenobarbital (20 mg/kg IV/IO) is used as therapy in SE at all ages, but particularly in neonatal SE where it has shown to be superior to other agents like levetiracetam. ^{[69, 4]}  Phenobarbital's major disadvantages are that it significantly depresses mental status and causes respiratory difficulty and does not appear to have significant benefit over other ages outside of the neonatal period. 

Lacosamide is another antiseizure drug with an IV formulation that allows its use in SE (8 mg/kg with max 400 mg). While there has not yet been a large RCT, multiple small studies show that it is generally well tolerated and has good efficacy. ^[70]  However, it can make generalized epilepsy worse, thus etiology of the SE should be considered before administration. 

For more information, see the Medscape Reference article Antiepileptic Drugs.

Refractory status epilepticus

The term refractory GTCSE has been used when seizures do not respond to benzodiazepines and second-line agents (phenytoin/fosphenytoin, levetiracetam, valproic acid and phenobarbital). Several options are presently available for these patients, including a variety of antiseizure agents thatcan be administered as IV infusions. Prior to initiation of these agents, patients should be transferred to an intensive care unit and EEG monitoring should be initiated. Under EEG guidance, treatment should involve rapid escalation of therapy using repeated boluses, as NCSE is a high risk in these patients. 

Barbiturate anesthesia was historically among the most popular third-line treatments, although midazolam infusions (neither is approved by the FDA) have gained growing acceptance in the United States. In the United States, barbiturate anesthesia is commonly performed with pentobarbital infusions. Pentobarbital is given in a loading dose of 5 mg/kg IV or IO, followed by 0.5-5 mg/kg/hr. In the United Kingdom, thiopental (thiopentone) is often used rather than pentobarbital. 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.

Midazolam and propofol are gaining increasing acceptance throughout the world as alternative treatments for refractory GTCSE, thanks to the comparative ease of handling these drugs in a continuous infusion. ^[71] However, propofol is not currently recommended for long-term control of SE due to reports of severe acidosis and movement disorder after prolonged (> 48 h) use. Also worrisome is the association of propofol-related metabolic acidosis in patients on the ketogenic diet.

Midazolam has been effectively used in pediatrics, even in neonates, and has a predictable pharmacology, although movement disorders have been reported from prolonged use of midazolam for sedation. ^[72] Midazolam is given in a loading dose of 0.2 mg/kg IV or IO, followed by 0.75-10 mcg/kg/min.

Ketamine has a unique mechanism of action (NMDA receptor antagonist) and limited respiratory depression when compared to other infusion agents. Coupled with the recognition that there is increasing neuronal abundance of NMDA receptors likely contributing to SE, ketamine is becoming more commonly used in refractory SE with good efficacy (> 70% response in some studies). ^{[73, 74]}

Examples of infusions are listed below:

1. Pentobarbital 5 mg/kg initial load with additional 5 mg/kg repeated every 5 minutes until seizure ends or burst suppression on EEG. Infusion 0.5-5 mg/kg/hr titrated to clinical/electrographic seizure control

2. Midazolam 0.2 mg/kg initial load with additional 0.2 mg/kg repeated every 5 minutes until seizure ends or burst suppression on EEG. Infusion 0.05-2 mg/kg/hr titrated to clinical/electrographic seizure control

3. Propofol 2 mg/kg initial load with additional 2 mg/kg repeated every 5 minutes until seizure ends or burst suppression on EEG. Infusion 30-67 mcg/kg/min titrated to clinical/electrographic seizure control. Avoided in pediatrics due to risk of propofol infusion syndrome (highest risk with infusions longer than 48 h and infusions higher than 67 mcg/kg/min)

4. Ketamine 1-2 mg/kg initial load with additional 1-2 mg/kg repeated every 5 minutes until seizure ends or burst suppression on EEG. Infusion 1.2-7.5 mg/kg/hr titrated to clinical/electrographic seizure control

Infusions and the need for repeated boluses require simultaneous EEG monitoring to guide therapy. (See Long term Monitoring.)

Other treatments

High-dose topiramate via nasogastric tube has been used in adults with SE, at doses as high as 1600 mg/day. ^[75] One pediatric study used relatively lower initial doses of 2-3 mg/kg/day before proceeding within 48-72 hours to a maintenance dose of 5-6 mg/kg/day (in 2 divided doses daily), which terminated the episode of SE. ^[76] Another study reported a loading dose of 10 mg/kg followed by 5 mg/kg/day maintenance (in 2 divided doses daily). ^[77] Treatment of SE 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.

Intravenous valproic acid is used for 3-Hz spike and wave stupor (absence SE) and myoclonic SE in cases of juvenile myoclonic epilepsy and post-anoxic myoclonus. ^{[78, 79]} Treatment of convulsive status (ie, GTCSE) with IV valproic acid after failure of other drugs (eg, benzodiazepines, phenytoin, phenobarbital) has been rarely reported. Both secondary and primary GTCSE seem to equally respond to IV valproic acid. A loading dose of 20-40 mg/kg over 5 minutes is recommended, followed by an infusion at a rate of 5 mg/kg/h. ^[80] 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 at 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. ^[81] The adult dose is 5 mL PR diluted on the same volume of water. 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.

A therapeutic trial with folic acid (0.5-1 mg/kg) and enteral pyridoxine (up to 30 mg/kg/day) for a week is worth considering in prolonged refractory status epilepticus, especially in neonates. EEG monitoring is required during these vitamin trials to track response. 

The ketogenic diet is increasingly used in super-refractory SE and a number of small studies demonstrate that is practical to achieve ketosis within 2 days of initiation, with minimal adverse effects. Within 7 days of initiation, many of the pediatric patients in ketosis had resolution of seizures and had anesthesia lifted. ^{[82, 83, 84, 85]}

Rarely, in super-refractory SE, therapies such as hypothermia, surgery (resective vs palliative - VNS) and electroconvulsive therapy have been tried with varying degrees of success. 

Most children with an episode of status epilepticus (SE) should be admitted for inpatient observation, evaluation, and treatment. Any child with persistent altered mental status (despite cessation of seizure activity) or with prolonged SE should be admitted to a pediatric critical care unit.

Treat patients with SE who have suspected infection with antibiotics as appropriate. Treatment with acyclovir in all patients with concern for herpes encephalitis should be continued 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 spread.

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

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. Correction of hypocalcemia with IV calcium gluconate should be performed under electrocardiographic (ECG) monitoring because of the possibility of cardiac arrhythmias.

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

No long-term therapy is indicated for SE caused by transient problems (eg, metabolic disturbances such as hyponatremia, intoxications). No consensus has been reached regarding the need for treatment after an instance of febrile SE or when a first unprovoked seizure is an SE episode.

Knowledge of the seizure type and EEG pattern can help confirm the diagnosis of an epileptic syndrome and guide the selection of anticonvulsant medication. Patients with focal motor, focal impaired awareness, and focal with bilateral tonic clonic epilepsy respond well to levetiracetam, carbamazepine, oxcarbazepine, lacosamide, phenytoin (avoided in pediatric), and phenobarbital (infants).

Valproic acid, levetiracetam, brivaracetam, topiramate, and phenobarbital are good treatments for patients with generalized epilepsy. Valproic acid carries a higher risk of liver failure in patients younger than 2 years and those on polypharmacy.

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

After initial emergency stabilization, consider consultation with the following specialists:

• Pediatric emergency or critical care specialist or general pediatrician

• Pediatric neurologist

• Pediatric neurosurgeon if needed

• Pediatric Rheumatology

• Pediatric Infectious Disease

• Genetics

Transfer is prudent unless the hospital facility has a pediatric critical care unit and staff familiar with the risks and complications of status epilepticus (SE) in children.

A child who has a single tonic-clonic seizure often does not receive long-term anticonvulsant therapy. Consult a pediatric neurologist.

The use of continuous EEG monitoring in patients who ultimately require continuous anesthetic or anti-seizure infusions is vital. Patients at this stage are often unresponsive and there are a number of reasons why patients cannot be aroused following the end of a clinical seizure: nonconvulsive status epilepticus (NCSE), postictal state-related depression, sedation from medication, and unresponsiveness from metabolic (renal and hepatic) or anoxic encephalopathies. Without EEG monitoring, it can be impossible to differentiate these etiologies and manage them appropriately.

In the case of ongoing seizure activity, EEG monitoring is required to direct escalation of infusions. All infusions should follow a pattern of rapid (every 5 minutes) escalation of therapy with repeated boluses followed by increases in infusion rate until seizure cessation +/- burst suppression is achieved. The choice of titrating therapy to EEG burst suppression vs seizure cessation varies with roughly 50% of centers in a US survey choosing each endpoint. However, there appears to be some evidence for targeting a more suppressed (low-amplitude bursts, prolonged interburst intervals) background rather than simple seizure cessation. In several studies and reviews, there was increased success in weaning IV medications with fewer breakthrough seizures following more pronounced EEG suppression. ^{[86, 87, 88, 89]}

As SE progresses and is complicated by increasing doses and numbers of sedating medications, the EEG can become more difficult to interpret, with various degrees of suppression, slowing, rhythmicity, and periodicity that are not always clearly ictal. Knowing when not to escalate treatment further is an important part of SE management, and the EEG is crucial in deciding when someone's seizure has stopped.