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Management of convulsive status epilepticus in children

Management of convulsive status epilepticus in children
Author:
Angus Wilfong, MD
Section Editors:
Douglas R Nordli, Jr, MD
Susan B Torrey, MD
Deputy Editors:
John F Dashe, MD, PhD
James F Wiley, II, MD, MPH
Literature review current through: Dec 2022. | This topic last updated: Nov 23, 2021.

INTRODUCTION — Generalized convulsive status epilepticus (SE) is a serious and potentially life-threatening medical emergency that requires prompt intervention.

The management of SE in children is reviewed here. The definition, pathophysiology, risk factors, and outcome of this disorder are discussed separately. (See "Clinical features and complications of status epilepticus in children".)

DEFINITION AND DIFFERENTIAL DIAGNOSIS

Status epilepticus – An accepted definition for the purposes of clinical practice defines SE as either a single unremitting seizure lasting longer than five minutes or as frequent clinical seizures without an interictal return to the baseline clinical state. The five-minute window corresponds with the time at which urgent treatment should begin. If SE continues beyond 30 minutes, then long-term consequences including neuronal injury, alteration of neuronal networks, and neuronal death can occur. (See "Clinical features and complications of status epilepticus in children", section on 'Definition'.)

SE is categorized according to whether seizure activity is focal or generalized. In many cases, however, generalized convulsive SE cannot be separated easily into cases with a primarily generalized onset versus those with focal onset and secondary generalization. Both generalized and focal SE can be further classified according to whether clinical seizure activity is convulsive or nonconvulsive (table 1).

Convulsive status epilepticus – Convulsive SE is the focus of this topic and is a clinical diagnosis, confirmed in most cases by the presence of sustained and rhythmic generalized tonic and clonic motor activity lasting for longer than five minutes or repetitive convulsive seizures without a return to baseline consciousness between seizures. Although the diagnosis of convulsive SE is usually obvious, a detailed neurologic examination is important in making the diagnosis of more subtle or focal forms of SE.

Nonconvulsive status epilepticus – Nonconvulsive SE is defined as status epilepticus without prominent motor symptoms. (See "Nonconvulsive status epilepticus: Classification, clinical features, and diagnosis".)

Brief generalized seizures – Children with brief, generalized motor seizures and relatively preserved interictal consciousness are not considered to have SE; most of these patients will not be seizing on arrival to the emergency department and do not require emergency intravenous medication [1]. Common scenarios include:

Febrile seizures – Febrile seizures are the most common type of brief, generalized seizures in children and, in the absence of signs of meningitis or encephalitis, do not require extensive laboratory evaluation or anticonvulsant therapy. (See "Clinical features and evaluation of febrile seizures" and "Treatment and prognosis of febrile seizures".)

First-time afebrile seizure – A first afebrile seizure requires a careful history, physical examination, and focused evaluation to exclude nonepileptic medical conditions that may have provoked the seizure, such as fever, serious infection, head trauma, hypoglycemia, electrolyte disturbance, cardiac arrhythmia, or a space-occupying intracranial lesion.

If an acute medical cause cannot be found during the emergency department visit, then the child may be experiencing the initial seizure of an epileptic disorder. These patients warrant referral to a pediatric neurologist. Most children diagnosed with an unprovoked seizure or epilepsy of unknown etiology will need a scheduled electroencephalography (EEG) and neuroimaging, preferably with magnetic resonance imaging. (See "Seizures and epilepsy in children: Classification, etiology, and clinical features" and "Seizures and epilepsy in children: Initial treatment and monitoring".)

Children with a first, unprovoked seizure, particularly patients with a normal EEG and neuroimaging, do not typically receive anticonvulsant medications. (See "Seizures and epilepsy in children: Initial treatment and monitoring", section on 'First unprovoked seizure'.)

Breakthrough seizures in children with known epilepsy – Children with a known seizure disorder may have brief, breakthrough convulsive seizures that are commonly caused by an intercurrent illness or subtherapeutic anticonvulsant levels. Many of these patients can be managed by adjustment of oral anticonvulsant therapy after consultation with the prescribing pediatric neurologist.

Focal seizures – Seizures that are not generalized convulsive (tonic, clonic, tonic-clonic) require a different approach to evaluation and treatment, as discussed separately. (See "Focal epilepsy: Causes and clinical features" and "Seizures and epilepsy in children: Initial treatment and monitoring".)

Psychogenic nonepileptic seizures – Psychogenic nonepileptic seizures (PNES) are usually dramatic behavioral events in a conscious individual that are often misdiagnosed as epileptic seizures and are sometimes treated with large doses of antiseizure medications. The history and presentation may provide clues to diagnosis. PNES typically occur in teenage patients, predominately in females, with affective or anxiety disorders, and a family history of seizures may be present. Many patients who have PNES also have or have had epileptic seizures, so a past medical history of PNES should not be used to rule out the possibility of epileptic status. PNES include a variety of clinical manifestations, some of which are suggestive, although not independently diagnostic, in distinguishing PNES from other differential diagnoses (table 2); these are discussed in detail elsewhere. (See "Psychogenic nonepileptic seizures: Etiology, clinical features, and diagnosis", section on 'Clinical manifestations'.)

In many patients, PNES can be distinguished from SE based upon clinical features or responsiveness to brief, painful stimuli (eg, nailbed pressure). When there is clinical uncertainty, PNES can be definitively distinguished from SE by an urgent EEG (see 'Electroencephalography' below). Therapy may need to be initiated before an EEG can be obtained, especially in patients with prior epileptic seizures. In this case, sedating medication should be avoided, if possible. Fosphenytoin or valproate are reasonable alternatives to benzodiazepines in this setting.

PNES and other nonepileptic paroxysmal disorders are discussed in detail separately. (See "Nonepileptic paroxysmal disorders in children" and "Psychogenic nonepileptic seizures: Etiology, clinical features, and diagnosis".)

RAPID RECOGNITION OF STATUS EPILEPTICUS — The diagnosis of convulsive SE is clinical and is confirmed by verifying the presence of either an unremitting generalized seizure lasting longer than five minutes or frequent seizures without an interictal return to the baseline level of consciousness. (See 'Definition and differential diagnosis' above.)

Patients with generalized motor seizures that are frequent or separated by a period of significantly impaired consciousness or who are medically unstable require immediate assessment and treatment in an acute care setting (emergency department or intensive care unit).

URGENT FOCUSED EVALUATION — During the course of resuscitation, the clinician or designee should obtain a focused history from a parent or caregiver to determine:

Prehospital administration of benzodiazepines and any other antiseizure medications

Patient history of epilepsy

Precipitating factors prior to seizure (eg, febrile illness, possible toxic exposure, trauma, change in antiseizure medications) (see "Clinical features and complications of status epilepticus in children", section on 'Causes')

Current medications, including prior or current use of antiseizure medications

For patients with prior SE, history of treatment response (see 'Factors influencing choice of agent' below)

Other active medical diagnoses, especially those associated with hypoglycemia (table 3), hyponatremia, or hypocalcemia (table 4)

Allergies to any medications

In patients with SE, the initial physical examination is limited. In addition to assessing vital signs, airway, breathing, and circulation, the clinician should identify:

Signs of head trauma (eg, swelling, ecchymosis, or lacerations)

Signs of sepsis or meningitis (eg, fever, poor perfusion, or rash [eg, petechiae, erythroderma, or cellulitis])

Seizure characteristics (eg, focal or generalized) (see "Clinical features and complications of status epilepticus in children", section on 'Classification')

IMMEDIATE SUPPORTIVE CARE

Approach — In children with convulsive SE, rapid supportive care must occur simultaneously with prompt administration of antiseizure medications (algorithm 1).

The main goals of treatment are [2]:

Establish and maintain adequate airway, breathing, and circulation (see 'Airway and breathing' below)

Identify and treat hypoglycemia (table 5)

Stop the seizure and thereby prevent brain injury (see 'Emergency antiseizure treatment' below)

Identify and treat life-threatening causes of SE such as trauma, sepsis, meningitis, encephalitis, or structural brain lesion

Monitoring — All patients with generalized convulsions should have continuous monitoring of heart rate and rhythm, breathing, and pulse oximetry along with periodic measurement of blood pressure and temperature. However, myoclonic jerks may interfere with the ability of electronic monitors to detect abnormalities. Thus, frequent clinical assessment of breathing, pulse, and color must supplement monitor readings to ensure rapid detection of apnea, cyanosis, or shock.

Airway and breathing — Important airway interventions in children with SE include:

Open the airway and maintain it through positioning (picture 1), jaw thrust (picture 2), and/or airway adjuncts (eg, nasopharyngeal (picture 3) or oropharyngeal (picture 4) airways) as needed.

Suction secretions using a Yankauer (tonsil tip) suction catheter; have an additional large-bore suction device available in case the patient vomits.

Administer 100 percent oxygen; use pulse oximetry and visual appearance to assess for cyanosis. When feasible, quantitative, sidestream end-tidal CO2 (EtCO2) monitoring can help supplement the visual assessment of respiratory rate and ventilation when the wave form is used to interpret the EtCO2 reading. Myoclonus may interfere with the accuracy of monitor readings.

For children with transient apnea or hypoxemia, the clinician may use bag-mask ventilation as long as the airway can be maintained and spontaneous breathing with adequate oxygenation resumes within a short period of time. Two rescuers are typically necessary to maintain the airway during bag-mask ventilation in children with SE (picture 5).

The patients with any one of the following should undergo rapid sequence endotracheal intubation (RSI) and mechanical ventilation:

Unprotected or unmaintainable airway

Apnea or inadequate ventilation

Hypoxemia

SE lasting 30 minutes

The tables provide a rapid overview of RSI in children (table 6) and initial settings for volume-controlled (table 7) and pressure-controlled (table 8) mechanical ventilation. Emergency endotracheal intubation in children and pediatric RSI are discussed in detail separately. (See "Emergency endotracheal intubation in children" and "Rapid sequence intubation (RSI) outside the operating room in children: Approach".)

Special considerations for children with SE undergoing RSI include:

Propofol and midazolam have antiepileptic properties, and either agent may be used for induction in hemodynamically stable patients. Propofol has a shorter onset of clinical effect.

Short-acting muscle relaxants, either rocuronium or, in patients without contraindications, succinylcholine should be given so that visual confirmation of continued seizures is preserved once the brief paralysis resolves. However, an urgent EEG should be obtained to look for electrographic seizures if prolonged paralysis is indicated, as may be the case for patients with hyperthermia or rhabdomyolysis.

Circulation and vascular access

Establish venous access – Patients with SE require timely vascular access for sampling of blood and administration of medications and fluids. Peripheral intravenous (IV) access should be established as soon as possible. Alternative routes of antiseizure medication administration (eg, rectal, intramuscular, buccal, or intranasal) should be used if IV administration is not possible within the first five minutes; an intraosseous (IO) line should be placed if IV access is further delayed.

For patients whose seizures do not resolve with benzodiazepine therapy, a second IV access should be obtained to facilitate the administration of two separate antiseizure medications and/or continuous anesthetic infusions.

Hemodynamic support Most children with SE initially have elevated blood pressure and do not require circulatory support. Heart rate and blood pressure may be elevated in patients with SE but typically normalize once seizures resolve [2].

In general, SE does not independently cause systemic hypotension. The presence of low blood pressure in children presenting with SE should prompt consideration of an underlying systemic illness, traumatic hemorrhage, or infection. These patients warrant rapid infusion of isotonic crystalloid (eg, normal saline or Ringer lactate) and further treatment based upon the type of shock that is present (algorithm 2). (See "Initial management of shock in children".)

In addition, the presence of bradycardia, hypotension, and poor perfusion are warning signs that point to hypoxia. Children with these signs require immediate attention to improve oxygenation and ventilation and, if not already done, RSI with mechanical ventilation [2].

Clinicians should anticipate hypotension for children who require continuous infusions of medications for refractory SE. Rapid infusion of isotonic crystalloid (eg, 20 mL/kg of normal saline or Ringer lactate) followed by a continuous infusion of a vasopressor such as epinephrine or norepinephrine are frequently necessary to maintain adequate tissue perfusion and blood pressure.

Initial studies — Initial blood and urine studies should be obtained for rapid determination of:

Plasma glucose and a rapid "finger-stick" or point-of-care glucose

Serum electrolytes and calcium

Serum antiseizure medication levels, if applicable

If substance use or poisoning is suspected, urine and blood toxicology

In postmenarchal females, qualitative pregnancy test (urine or blood)

Other studies may also be indicated based upon the most likely underlying cause. (See 'Additional studies' below.)

Plasma glucose, serum electrolytes, and antiseizure medication serum levels (for children receiving them) are the most helpful in guiding initial care for children with SE. In a systematic review of 20 observational studies (almost 2100 children with SE), the yield of preliminary testing was as follows [3]:

6 percent had abnormal electrolyte or glucose levels

3.6 percent had evidence of toxin ingestion

Of children receiving antiseizure medications, almost 33 percent had subtherapeutic levels

While the yield of routine measurement of electrolytes, glucose, and qualitative toxin screens was relatively low in this study, abnormal findings affect management strategies and outcomes. The utility and interpretation of testing for drugs of abuse screen is discussed in detail separately. (See "Testing for drugs of abuse (DOAs)".)

Electroencephalogram (EEG) – When there is uncertainty regarding the presence of SE, an urgent portable EEG should be obtained. In the emergency department, this can be a limited study, with application of only a few electrodes to determine if the background is consistent with a normal awake individual (ie, psychogenic nonepileptic seizure) or the diffusely slow and depressed background of SE. (See "Psychogenic nonepileptic seizures: Etiology, clinical features, and diagnosis".)

If an urgent EEG cannot be obtained, or is not considered necessary in the case of an obvious clinical diagnosis of convulsive SE, an EEG should still be done to evaluate background activity as soon as possible after the seizure stops for patients with first-ever seizures or convulsive SE. Patients with known epilepsy who return to baseline may not require an EEG. (See 'Electroencephalography' below.)

Neuroimaging – Neuroimaging is generally deferred until the patient is stabilized. (See 'Neuroimaging' below.)

Correct hypoglycemia and metabolic abnormalities — Hypoglycemia may provoke seizures and convulsive SE. Although uncommon, either severe hyponatremia or hypocalcemia may cause SE that is refractory to antiseizure medication and requires timely correction. Metabolic acidosis is often present in patients with SE and can be severe, but it usually resolves without treatment once seizures are controlled.

Hypoglycemia – All children with SE should have measurement of a fingerstick or rapid point-of-care measurement of plasma glucose as soon as possible. In children with SE, including those who are just initiating the ketogenic diet for seizure control, hypoglycemia should be treated as outlined in the rapid overview table (table 5). For patients who are stable on the ketogenic diet for seizure control and present in SE, a plasma glucose ≤40 mg/dL (2.2 mmol/L) warrants treatment for hypoglycemia. Continued seizures, especially in the setting of hypoxemia, may lower brain glucose levels as the metabolic demands outstrip the supply, worsening brain lactic acidosis and leading to further neuronal damage if prolonged; this emphasizes the importance of ensuring adequate plasma glucose levels [4]. (See "Approach to hypoglycemia in infants and children" and "Ketogenic dietary therapies for the treatment of epilepsy".)

Children with diabetes and hypoglycemia may present in the emergency department with generalized or focal seizures, or focal syndromes such as hemitonic posturing and hemiparesis, which may mimic seizures or a postictal state, respectively. These children should be treated with glucose, not anticonvulsants. This situation emphasizes the importance of obtaining a rapid assessment of blood glucose in a child with seizures in order to provide appropriate therapy.

Most children with acute seizures have elevated blood glucose levels that do not require treatment. However, nonketotic or ketotic hyperglycemia can occasionally precipitate SE and may be an early manifestation of diabetes [5,6].

Hyponatremia – Severe symptoms, including seizures, are most commonly seen in children with severe hyponatremia (serum sodium <120 mEq/L) that develops acutely (over less than 48 hours). Initial therapy consists of 3 to 5 mL/kg of 3 percent saline administered over 15 minutes. After the initial hypertonic saline infusion, point-of-care serum sodium should be remeasured and, if seizures are ongoing, the infusion should be repeated. (See "Hyponatremia in children: Evaluation and management", section on 'Acute symptomatic hyponatremia'.)

Hypocalcemia – Seizures in the setting of hypocalcemia require therapy with IV calcium. The recommended dose of elemental calcium is 5 to 7 mg/kg. Dosing in this range can be achieved by giving 0.6 mL/kg of calcium gluconate 10 percent, which provides 5.6 mg/kg of elemental calcium or 0.2 mL/kg of calcium chloride 10 percent (must be given through a central venous line), which provides 5.4 mg/kg of elemental calcium. The maximum single dose is 540 mg of elemental calcium. The calcium should be administered over 5 to 10 minutes in patients with spontaneous circulation. (See "Primary drugs in pediatric resuscitation", section on 'Calcium'.)

The causes of hyponatremia or hypocalcemia in children are discussed separately. (See "Hyponatremia in children: Evaluation and management" and "Etiology of hypocalcemia in infants and children".)

Temperature control — Fever at presentation lowers the seizure threshold and requires treatment with acetaminophen in children with SE.

Ongoing monitoring of temperature is essential to detect hyperthermia associated with excess muscle activity during SE. If present, then the resuscitation team should rapidly stabilize airway, breathing, and circulation, and initiate cooling measures (eg, evaporative cooling supplemented by a cooling blanket) and assess for rhabdomyolysis and end-organ damage. Antipyretics are ineffective. Hyperthermia and rhabdomyolysis caused by persistent SE may require rapid sequence intubation and ongoing paralysis and necessitate continuous portable EEG monitoring to guide seizure management. (See "Heat stroke in children", section on 'Hospital management' and "Heat stroke in children", section on 'Diagnostic evaluation'.)

Suspicion for isoniazid poisoning — In addition to benzodiazepine administration, children with SE possibly due to isoniazid poisoning should receive pyridoxine 70 mg/kg IV, up to 5 g at a rate of 0.5 per minute, which should be repeated if seizures continue. A dose of 1 gram pyridoxine per gram of isoniazid ingested can be used (and may be necessary) after ingestion of a known quantity of isoniazid. (See "Isoniazid (INH) poisoning".)

EMERGENCY ANTISEIZURE TREATMENT

Approach — Although many protocols are available for treatment of pediatric SE, comparative data are limited, and these approaches have not been validated by clinical trials [7-9]. The approach presented below applies to children older than four weeks of age (ie, not newborns) with generalized convulsive SE (tonic-clonic, clonic, or tonic) is generally consistent with guidelines published by the Neurocritical Care Society [8]. The overall treatment approach is summarized in the algorithm (algorithm 1). The treatment of neonatal seizures is discussed separately. (See "Treatment of neonatal seizures".)

Clinically obvious convulsive SE should be treated immediately with a benzodiazepine, without waiting for an EEG or other studies. Treatment delay is associated with increased morbidity and mortality [10-12]. (See 'First therapy: Benzodiazepines' below.)

If seizures continue for 10 minutes after at least two injections of a benzodiazepine, a second therapy with a long-acting antiseizure medication should be given (table 9). (See 'Second therapy: Antiseizure medications' below.)

In patients with ongoing convulsive SE lasting longer than 30 minutes despite two initial doses of benzodiazepine and a second therapy antiseizure medication, preparation for a continuous infusion of midazolam or pentobarbital should occur simultaneously with administration of a different antiseizure medication. At this stage, the patient will require endotracheal intubation and mechanical ventilation (if not already performed), neurologic consultation, and transfer to a pediatric intensive care unit with continuous EEG monitoring capability, as described below. (See 'Refractory status epilepticus' below.)

There is controversy about whether to treat nonconvulsive SE (NCSE) as aggressively as convulsive SE. In all patients with NCSE, a concerted effort should be made to diagnose and treat seizures as quickly as possible but with minimal sedation to avoid inducing or prolonging coma and respiratory depression that requires endotracheal intubation and mechanical ventilation. In general, any fluctuating or unexplained alteration in behavior or mental status warrants consideration of NCSE and evaluation with EEG. The evaluation and treatment of NCSE is discussed in detail separately. (See "Nonconvulsive status epilepticus: Classification, clinical features, and diagnosis", section on 'Evaluation' and "Nonconvulsive status epilepticus: Treatment and prognosis".)

First therapy: Benzodiazepines — For children presenting with convulsive SE, we recommend immediate treatment with a benzodiazepine (algorithm 1). Benzodiazepines are the first-line treatment for SE because they can rapidly control seizures (see 'Benzodiazepine efficacy and pharmacokinetics' below). The three most commonly used benzodiazepines to treat SE are lorazepam, diazepam, and midazolam.

Prior to hospital arrival, benzodiazepine treatment may occur in the home or be performed by emergency medical services according to prehospital, pediatric seizure protocols. In these patients, the first dose of benzodiazepines given in the hospital counts as the second dose of benzodiazepines as long as prehospital dosing was appropriate and, in children who continue with SE, a second antiseizure medication should be given (table 9).

Prehospital treatment — Treatment of SE out-of-hospital by prehospital emergency responders appears to be safe and effective in children. Intramuscular (IM) midazolam (5 mg for children whose weight is 13 to 40 kg and 10 mg for those over 40 kg) or intravenous (IV) lorazepam (0.1 mg/kg) can be safely and effectively used in this setting. Additional options include intranasal midazolam, 0.2 mg/kg of parenteral solution per dose, or buccal midazolam, 0.3 to 0.5 mg/kg. (See 'Benzodiazepine efficacy and pharmacokinetics' below.)

In-hospital treatment — Benzodiazepines can be administered by a variety of routes. However, if IV access is available, drugs administered by this route are more effective [13]. (See "Seizures and epilepsy in children: Refractory seizures", section on 'Home rescue therapy (transmucosal antiseizure medications)'.)

When IV or IO access is availableLorazepam 0.1 mg/kg intravenously (IV/intraosseous [IO]) up to a maximum of 4 mg should be administered by slow IV push over one minute and its effect assessed over the next five to ten minutes [14]. An equally effective alternative is diazepam, although it has a shorter duration of action (<20 minutes) [14,15]. The recommended dose of diazepam is 0.2 mg/kg IV or IO (maximum dose 10 mg). Treatment with benzodiazepine doses that are lower than recommended has been associated with a decreased likelihood of seizure cessation [16]. Some UpToDate experts use a higher dose of diazepam (0.3 mg/kg) based upon clinical experience, recognizing that higher doses increase the risk of respiratory depression.

If seizures continue after five minutes, additional doses of lorazepam or diazepam can be given (table 9). The risk of respiratory depression increases after administration of more than two doses of benzodiazepines [13,17]. (See 'Benzodiazepine efficacy and pharmacokinetics' below.)

If IV access is not rapidly obtained, then IO placement should be performed. (See "Intraosseous infusion".)

When IV and IO access are unavailable – Placement of an intravenous catheter may be difficult in some patients. When IV and IO access cannot be achieved within the first three minutes, alternative first-line agents include [14,18]:

Intranasal midazolam – Intranasal midazolam 0.2 mg/kg of parenteral solution per dose, divide dose between nares, maximum single dose 10 mg (mucosal atomizer device recommended), may repeat once in 10 minutes; for children ≥12 years, midazolam nasal spray 5 mg (one spray) into one nostril, may repeat in 10 minutes.

Intranasal diazepam – Intranasal diazepam dosing is fixed and varies by age and weight; for children age 6 to 11 years, the dose is 0.3 mg/kg (table 10); for children age 12 or older, the dose is 0.2 mg/kg (table 11).

Rectal diazepam – Rectal diazepam 0.5 mg/kg, maximum 20 mg.

Intramuscular midazolam – IM midazolam 0.2 mg/kg once, maximum 10 mg; alternative fixed dosing is 5 mg for patients 13 to 40 kg, or 10 mg for patients >40 kg.

Buccal midazolam – Buccal midazolam 0.3 to 0.5 mg/kg once, maximum 10 mg.

Among these alternatives, IM midazolam is rapidly effective. Buccal or intranasal midazolam may be more effective than rectal diazepam but may raise the risk of aspiration [14]. (See "Seizures and epilepsy in children: Refractory seizures", section on 'Home rescue therapy (transmucosal antiseizure medications)'.)

Benzodiazepine efficacy and pharmacokinetics — Benzodiazepines are the first-line treatment for SE because they can rapidly control seizures [4,8]. The three most commonly used benzodiazepines to treat SE are lorazepam, diazepam, and midazolam; for first-line IV therapy, lorazepam or diazepam are the preferred agents. Lorazepam has a longer duration of action, which may provide continued seizure control until a loading dose of a second agent can be completed. For that reason, lorazepam is preferred by most pediatric experts for in-hospital treatment of SE.

The efficacy of lorazepam and diazepam was demonstrated in a multicenter trial in which 273 children (aged 3 months to 18 years) with convulsive SE were randomly assigned to receive lorazepam (0.1 mg/kg IV) or diazepam (0.2 mg/kg IV) upon presentation to the emergency department [15]. Half of the initial dose was repeated at 5 minutes if necessary, and fosphenytoin was administered if seizures continued at 12 minutes. The primary outcome measure was cessation of SE by 10 minutes without recurrence in 30 minutes. SE was successfully terminated in 73 percent of those treated with lorazepam and 72 percent of those treated with diazepam (95% CI -11.4 to 9.8 percent). There was no difference in the rate of assisted ventilation for patients treated with lorazepam versus diazepam (17.6 versus 16 percent; 95% CI -9.9 to 6.8 percent). Patients treated with lorazepam were more likely to be sedated (67 versus 50 percent) and had a longer time to return of baseline mental status.

These results contrast with prior observational studies and one small randomized trial in children, which suggested that lorazepam was more effective than diazepam in the treatment of SE and caused less respiratory depression [19-21]. Randomized trials in adults with convulsive SE have found a trend toward improved efficacy of lorazepam over diazepam and similar safety profiles [22-24].

Additional pharmacokinetic and dosing considerations include the following:

Lorazepam – The time from injection to lorazepam's maximum effect can be as long as two minutes. The effective duration of action, as long as four to six hours, is longer than diazepam because of its less pronounced redistribution into adipose tissue. The half-life of lorazepam (which is much longer than the period of seizure suppression) is significantly prolonged in newborns (approximately 40 hours) compared with older children or adults (10 and 13 hours, respectively) [25-27].

As with diazepam, rectal administration of lorazepam can be effective when IV access cannot be achieved. An intranasal formulation of lorazepam is another probably effective treatment option [28].

DiazepamDiazepam has high lipid solubility, rapidly crosses the blood-brain barrier, and is highly effective in terminating seizures. An effect upon seizure activity can be seen as early as 10 to 20 seconds after administration; cerebrospinal fluid (CSF) concentrations reach one-half of their maximum value in three minutes. However, because of subsequent redistribution of the drug into adipose tissue, the duration of diazepam's acute anticonvulsant effect is typically <20 minutes.

Diazepam has been the drug of first choice in many settings, especially outside the emergency department, because it is stable in liquid form for long periods at room temperature. Therefore, diazepam is available in resuscitation kits in premixed form, whereas lorazepam, midazolam, and phenytoin are not.

A rectal gel formulation of diazepam (Diastat) provides rapid delivery when IV access is problematic. Some families and caregivers will have this at home and may have already administered to the child prior to evaluation in the emergency department. A nasal spray formulation of diazepam is also available; it is approved by the US Food and Drug Administration (FDA) for the acute treatment of intermittent, stereotypic episodes of frequent seizure activity (ie, seizure clusters, acute repetitive seizures) in patients age six years and older [29].

MidazolamMidazolam is also very effective in acutely terminating seizures, frequently in less than one minute, but it has a short half-life in the central nervous system. In addition to IV administration, it can be given by the IM, intranasal, oral, buccal, or rectal routes [4,30,31]. Thus, it is a useful agent when intravenous access cannot be established [18]. (See "Seizures and epilepsy in children: Refractory seizures", section on 'Buccal therapy'.)

In a clinical trial of 893 patients (including 120 children younger than 18 years) treated in the prehospital setting, IM midazolam was shown to be at least as effective as IV lorazepam in terminating SE [32,33]. Overall, seizure remission upon arrival to the emergency department was more likely in patients treated with IM midazolam compared with IV lorazepam (73 versus 63 percent) [32]. In a secondary analysis limited to patients <18 years of age, seizure remission rates were similar for midazolam versus lorazepam (68 versus 72 percent) [33]. The dose of midazolam was 5 mg for children whose weight was 13 to 40 kg and 10 mg in those over 40 kg. While lorazepam treatment was associated with a shorter median time from active treatment to cessation of convulsions (1.6 versus 3.3 minutes) among responders, this was offset in the prehospital setting by a longer median time to active treatment administration in the lorazepam group (4.8 versus 1.2 minutes) because of the need to place an IV catheter. The need for endotracheal intubation, recurrence of seizures, and other adverse event rates were similar in the two treatment groups. (See 'Prehospital treatment' above.)

Buccal administration of midazolam was found in one study of 177 children to be more effective than rectal diazepam in terminating seizures [30]. Fewer children required further antiseizure medication treatment in the midazolam compared with the diazepam-treated group. (See "Seizures and epilepsy in children: Refractory seizures", section on 'Home rescue therapy (transmucosal antiseizure medications)'.)

Nasal midazolam is approved by the FDA for the acute treatment of intermittent, stereotypic episodes of frequent seizure activity (ie, seizure clusters, acute repetitive seizures) in patients age 12 years and older [34].

Midazolam can be given as a continuous infusion for refractory SE, but this mode of administration is not recommended as a first-line treatment for SE. (See 'Midazolam' below.)

ClonazepamClonazepam has been used to treat SE outside the United States in settings where intravenous formulations are available. It has effects similar to those of other benzodiazepines, with a rapidity of onset that is intermediate between that of lorazepam and diazepam and a more prolonged duration of action than diazepam.

Second therapy: Antiseizure medications — If seizures continue for 10 minutes after at least two injections of lorazepam or diazepam, a second therapy with a long-acting antiseizure medication is indicated. Levetiracetam, phenytoin/fosphenytoin, and valproate are reasonable choices in this setting [9]. The onset of action is delayed with these drugs. Therefore, it may be helpful to give an additional dose of a benzodiazepine as the antiseizure medication is being administered. (See 'In-hospital treatment' above.)

In patients with ongoing SE lasting longer than 30 minutes despite two initial doses of benzodiazepine and a second therapy antiseizure medication, preparation for a continuous infusion of midazolam, propofol, or pentobarbital should occur simultaneously with administration of a different second therapy antiseizure medication. At this stage, the patient will require endotracheal intubation, mechanical ventilation, transfer to a pediatric intensive care unit, and, if not already obtained, emergency neurologic consultation. (See 'Refractory status epilepticus' below.)

Choosing an agent — For children with SE that continues for 10 minutes after at least two doses of a benzodiazepine, we suggest treatment with levetiracetam rather than another antiseizure medication.

When IV or IO access is available – We begin treatment with levetiracetam 60 mg/kg IV/IO (maximum single dose 4500 mg), which we prefer over phenytoin because of ease of use, more rapid administration, and equivalent efficacy. (See 'Antiseizure medication efficacy' below.)

Alternatively, fosphenytoin can be given at a dose of 20 mg phenytoin equivalents (PE)/kg IV or IO and a rate of 2 mg PE/kg per minute (maximum rate 150 mg PE/min) (table 9). Although high-quality evidence is lacking, some UpToDate experts give fosphenytoin at a higher initial dose of 30 mg PE/kg IV, which in their experience is associated with excellent seizure control and tolerability. If seizures persist, an additional 5 to 10 mg PE/kg IV of fosphenytoin can be given 10 minutes after the loading dose. The maximum suggested single dose in children is 1500 mg.

Phenytoin and fosphenytoin may be less effective for the treatment of seizures due to toxins or drugs (eg, children with seizures caused by lidocaine, cocaine, amphetamines, lindane, or theophylline); in such cases, an alternative such as levetiracetam, phenobarbital, or valproate should be used.

Valproate or phenobarbital IV/IO may also be used as initial therapy in children who did not respond to levetiracetam or fosphenytoin in previous episodes of SE or in children with a hypersensitivity to phenytoin. The clinician should anticipate respiratory depression and apnea when phenobarbital is given with benzodiazepines.

In addition, valproate may also be used as the initial treatment in children on chronic valproate therapy who are known to have had recent nonadherence and in whom valproate levels are suspected to be low.

When IV and IO access are not available – When either IV or IO access is delayed or unavailable, fosphenytoin can be given by intramuscular injection.

Factors influencing choice of agent — Knowledge of the patient's previous response to antiseizure medications and current medication use may guide the approach to management. In deciding initial antiseizure therapy for SE, the following issues should be considered:

Previous response – If the child has a history of previous SE, knowing which antiseizure medication was effective in arresting the seizures is helpful. If the child did not respond to phenytoin or fosphenytoin, for example, another drug, such as phenobarbital or valproate, would be preferable.

Trauma – In the setting of trauma, levetiracetam is generally the preferred antiseizure medication for treating SE, and fosphenytoin is also a reasonable choice. Concerns about adverse effects of phenobarbital (sedation) and valproate (thrombocytopenia and other coagulation disturbances) make them less useful in for patients with trauma.

Antiseizure medication adherence – If the child is on long-term antiseizure medication therapy, it should be determined whether the medication has been recently missed or if prescriptions have not been refilled. Serum antiseizure medication levels obtained upon admission may not be available for many hours, and initial treatment decisions may be made without them. If, for example, valproate has provided good seizure control and the child is known to have missed one or more doses, intravenous valproate, rather than phenytoin, should be considered as initial treatment.

Low antiseizure medication levels may contribute to SE in up to one-third of patients [3]. In one series of 51 children with SE, at least one or all antiseizure medication levels were therapeutic in 82 and 66 percent, respectively [35]. In addition to nonadherence, there are a number of other clinical scenarios that may lead to an unexpectedly low serum level of an antiseizure medication. These include medical conditions such as vomiting or malabsorption and administration of concomitant medications that may increase clearance of a particular antiseizure medication.

Paradoxical effects of antiseizure medications – Elevated levels of certain antiseizure medications, including phenytoin, carbamazepine, gabapentin, tiagabine, and vigabatrin, can paradoxically trigger generalized convulsive SE, particularly the myoclonic type, as well as nonconvulsive (absence) SE. The underlying mechanisms are poorly understood [36]. When suspected, paradoxical seizures caused by phenytoin or carbamazepine should be managed with benzodiazepines and phenobarbital. (See "Carbamazepine poisoning" and "Phenytoin poisoning".)

Even benzodiazepines can rarely worsen seizures and precipitate tonic SE, particularly in children with Lennox-Gastaut syndrome [37], although this should not alter the standard initial approach to therapy.

Some antiseizure medications commonly used to treat SE may worsen seizures caused by illicit drugs. As an example, phenytoin could worsen the toxicity of lidocaine or cocaine, because both block sodium channels [38].

Selected antiseizure medications may also precipitate or worsen other types of seizures [36]:

Carbamazepine, phenytoin, and lamotrigine may worsen myoclonic seizures.

At high serum levels, carbamazepine and phenytoin may worsen focal seizures with impairment of consciousness (previously called complex partial seizures) and increase generalized tonic-clonic seizures.

Carbamazepine is known to precipitate drop attacks, often with atypical absence seizures.

Carbamazepine and lamotrigine may worsen seizures in patients with Dravet syndrome. (See "Dravet syndrome: Management and prognosis".)

Change in antiseizure medications – Seizures may be worsened or precipitated even when antiseizure medication blood levels are in the therapeutic range [39]. If a new antiseizure medication has been added or the dose has been increased in the previous months, the drug may be causing seizures and should not be used in an attempt to control SE.

Nonprescription and illicit drugs – Nonprescription medications, including over-the-counter drugs such as antihistamines or other agents with anticholinergic effects, illicit substances, and, rarely, herbal preparations, can precipitate seizures. Specific questioning may uncover the use of these substances, especially illicit drug use. Since this information is typically unavailable early in the course of managing SE, we obtain a urine drug screen as part of the initial evaluation in at-risk patients (eg, adolescents and older school children, and younger children if there is suspicion for illicit drug exposure). (See 'Initial studies' above.)

Antiseizure medication efficacy — Mounting evidence from randomized controlled trials and observational studies suggests that levetiracetam, fosphenytoin/phenytoin, and valproate have similar efficacy for convulsive SE in children [40,41]. Phenytoin and fosphenytoin may be less effective for the treatment of seizures due to toxins or drugs and may intensify seizures caused by cocaine, other local anesthetics, theophylline, or lindane [42-44]. In such cases, levetiracetam, valproate, or phenobarbital should be used.

Comparative efficacy – Among the antiseizure medications that can be loaded intravenously, the Established Status Epilepticus Treatment Trial (ESETT) found that fosphenytoin, valproate, and levetiracetam are equally effective and have similar rates of adverse effects [45]. The trial enrolled 384 children (aged 2 to 17 years) and adults with convulsive SE refractory to benzodiazepines. The patients were randomly assigned to receive levetiracetam (n = 145), fosphenytoin (n = 118), or valproate (n = 121). The trial was stopped early when an interim analysis met criteria for futility. The composite outcome (cessation of SE and improvement in the level of consciousness at 60 minutes) was achieved in 47 percent (95% CI 39-55) of the levetiracetam group, 45 percent (95% CI 36-54) of the fosphenytoin group, and 46 percent of patients (95% CI 38-55) in the valproate group. Although not statistically significant, there were more episodes of hypotension and intubation in the fosphenytoin group and more deaths in the levetiracetam group compared with the other groups. Limitations to the ESETT include a substantial rate (approximately 50 percent) of unblinding of investigators and clinicians to permit choosing a second antiseizure medication for ongoing seizures, inadvertent enrollment of patients without SE, including patients with psychogenic nonepileptic seizures (approximately 10 percent of the study population), and absence of confirmatory electroencephalography.

In an extension of ESETT, which enrolled an additional 78 children with SE, there was no difference in the efficacy of levetiracetam, fosphenytoin, or valproate by age group comparing children, younger adults (ages 18 to 65 years), and older adults (age >65 years) [40].

Data from two open-label trials suggest that levetiracetam is equivalent but not superior to phenytoin for the treatment of convulsive SE. The ConSEPT trial randomly assigned 233 children (aged 3 months to 16 years) presenting to emergency departments with convulsive SE who failed initial benzodiazepine treatment to phenytoin 20 mg/kg infusion (IV or IO) over 20 minutes or levetiracetam 40 mg/kg infusion (IV or IO) over 5 minutes [46]. At five minutes after the end of infusion, the proportion of patients with clinical cessation of seizure activity in the phenytoin and levetiracetam groups was similar (60 versus 50 percent, respectively; risk difference -9.2 percent, 95% CI -21.9 to 3.5), and there was no difference between groups in any of the other primary or secondary outcomes. Similarly, the EcLiPSE trial evaluated 286 children (aged 6 months to 18 years) with convulsive SE requiring second-therapy treatment who were randomly assigned to levetiracetam 40 mg/kg IV over 5 minutes or phenytoin 20 mg/kg IV over at least 20 minutes [47]. There was no significant difference between groups in any of the prespecified outcomes. The proportion of patients with cessation of convulsive SE was similar for the levetiracetam and phenytoin groups (70 and 64 percent), as was the primary outcome of median time to cessation of SE with levetiracetam and phenytoin (35 and 45 minutes, hazard ratio 1.20, 95% CI 0.91-1.60). In both trials, levetiracetam and phenytoin had similar safety profiles [46,47].

In one of the larger retrospective series, 78 children (median age 31 months) with SE refractory to initial benzodiazepines and two second-therapy antiseizure medications (phenytoin and phenobarbital) were treated with either levetiracetam (20 mg/kg IV at 5 mg/kg per minute, maximum 3 grams) or valproate (20 mg/kg IV), prior to continuous infusional therapy [48]. The rate of seizure control was similar for levetiracetam and valproate (78 versus 63 percent, p = 0.12). An adjusted analysis was not presented. No specific adverse effects were ascribed to levetiracetam; valproate caused reversible liver enzyme elevation in four patients (13 percent).

Levetiracetam – The ConSEPT and EcLiPSE trials both used levetiracetam 40 mg/kg dosing for convulsive SE [46,47], while most earlier and smaller reports used a dose of 20 to 30 mg/kg [48-52]; single doses of up to 60 mg/kg had been endorsed by at least two guideline panels [8,9]. Levetiracetam is available in intravenous as well as oral formulations.

Fosphenytoin and phenytoinPhenytoin is a long-acting drug that has been widely used to treat acute and chronic seizures in children [4]. Its principal advantage is in preventing recurrence of SE for extended periods of time.

FosphenytoinFosphenytoin is a pro-drug of phenytoin that is preferred over phenytoin in the treatment of SE because it has a better safety profile and can be infused more rapidly than phenytoin. Fosphenytoin is highly water soluble at neutral pH and therefore unlikely to precipitate during intravenous administration. Compared with phenytoin, the drug has fewer side effects, including a reduced risk of local irritation at the site of infusion; therefore, fosphenytoin can be infused much more rapidly. Hypotension and cardiac arrhythmias remain a risk, so cardiac monitoring is still required.

Little information is available on the pharmacokinetics of fosphenytoin in infants and children. Subtherapeutic free phenytoin levels may occur rarely in children after fosphenytoin infusion [53].

Since fosphenytoin is converted on a 1:1 molar basis to phenytoin, the dosing of fosphenytoin in terms of moles is identical. However, the molecular weight of fosphenytoin is greater than that of phenytoin; hence, a greater weight of fosphenytoin must be given in order to yield the same concentration of phenytoin. To eliminate potential confusion, fosphenytoin is prescribed as milligrams of phenytoin equivalent (PE); as an example, 20 mg PE/kg load, at a rate of 2 mg PE/kg per minute.

Phenytoin – If fosphenytoin is unavailable, phenytoin can be given in an initial dose of 20 mg/kg IV at a rate of 1 mg/kg per minute (maximum rate 50 mg/min). Phenytoin is not water soluble; in order to have a liquid preparation, it is dissolved in propylene glycol at a very high pH. This contributes in large part to the phenytoin's side effects of hypotension and cardiac arrhythmias. Thus, heart rate and blood pressure should be monitored during the initial infusion. However, these complications are less common in children than adults and can be minimized by an infusion rate that does not exceed 1 mg/kg per minute (maximum 50 mg per minute) [4]. Phenytoin must not be infused along with a dextrose containing IV fluid, as it may form a precipitate.

The risks of local pain and injury, including venous thrombosis and the purple glove syndrome, also increase with more rapid rates of infusion. The purple glove syndrome is characterized by edema, discoloration, and pain in the extremity distal to the site of phenytoin infusion. Severe cases can lead to skin necrosis and limb ischemia, sometimes requiring amputation. More common in older adults, a few cases have been reported in children, usually late in the first decade, and adolescents. Venous extravasation must be avoided because the high pH and osmolality of this drug cause tissue inflammation and necrosis.

ValproateValproate can be used if seizures continue for 10 minutes after at least two doses of a benzodiazepine. Valproate is given in a loading dose of 20 to 40 mg/kg IV (diluted 1:1 with normal saline or 5 percent dextrose in water) over 5 to 10 minutes (maximum 3000 mg per dose) and may be repeated after 10 to 15 minutes [54].

Valproate usually is well tolerated, even in clinically unstable patients, and is less sedating than barbiturates [4,55]. Severe hypotension was reported in an 11-year-old girl following intravenous administration [56].

PhenobarbitalPhenobarbital slowly infused IV (maximum infusion rate 2 mg/kg per minute with a ceiling of 50 mg/min) in an initial dose of 20 mg/kg, and followed by repeated increments of approximately 8 to 10 mg/kg every 30 minutes, can achieve high levels and seizure control, usually without significant hypotension or respiratory depression.

Phenobarbital is a long-acting antiseizure medication that has been used for many years to treat seizures. Side effects of IV administration include sedation and respiratory depression, especially when it is preceded by a benzodiazepine. As a result, phenobarbital is considered a second-line long-acting agent after levetiracetam, fosphenytoin or phenytoin, and valproate, and usually is used only when these agents are not effective. Respiratory and cardiac monitoring should be performed because endotracheal intubation and mechanical ventilation may be needed. The risk of prolonged sedation with phenobarbital is greater than with the other anticonvulsants because its half-life is 87 to 100 hours, and often longer in newborns [57].

REFRACTORY STATUS EPILEPTICUS

Medications for refractory status epilepticus — If convulsive SE persists for 30 minutes after initial measures are instituted (immediate benzodiazepine treatment followed by second therapy with an antiseizure medication), further pharmacologic therapy (third therapy) is required (algorithm 1), usually with continuous infusion of midazolam (preferred) or pentobarbital [58].

Among these, midazolam is the most frequent first-choice sedative-anesthetic agent, followed by pentobarbital. Although propofol has been used to treat SE, data are limited, and significant associated complications have been reported. Propofol should not be used in children on the ketogenic diet; a report of a fatality in a 10-year-old boy illustrates the incompatibility of these treatments, which both involve fatty acid metabolism [59].

The patient's hemodynamic status will bear on the choice, because pentobarbital and propofol may exacerbate cardiovascular complications including hypotension. Dosing of these agents and important contraindications are discussed below. (See 'Specific agents' below.)

At this stage, the patient will require endotracheal intubation, mechanical ventilation, emergency neurologic consultation if not already obtained, and transfer to a pediatric intensive care unit with continuous EEG capability. The clinician should also anticipate the need to treat iatrogenic hypotension. Rapid infusion of isotonic crystalloid (eg, 20 mL/kg of normal saline or Ringer lactate) followed by a continuous infusion of a vasopressor such as epinephrine or norepinephrine are frequently necessary to maintain adequate tissue perfusion and blood pressure.

Continuous EEG monitoring — Continuous EEG (cEEG) monitoring is critical during the treatment of refractory SE. The longer convulsive SE continues, the less convulsive it appears clinically, and continuous electroencephalogram (cEEG) monitoring should be instituted. Once infusion of midazolam or pentobarbital has begun, cEEG monitoring is necessary to confirm that seizures have been treated adequately; to guide use of antiseizure medications and assess the level of suppression achieved; and to monitor for relapse of seizures and SE, especially when infusions are tapered.

Goals of therapy — The primary goal of therapy is to stop both clinical and electrographic seizures. There is no conclusive evidence that a burst-suppression EEG pattern is necessary, and more suppression equates to more sedation and a longer intensive care unit course of treatment. The cEEG must be followed closely, as recurrent seizures often appear on the EEG before they are evident clinically. However, the optimal electroclinical endpoint of treatment has not been studied rigorously.

Specific agents

Midazolam — Midazolam can be given as a continuous intravenous (IV) infusion for refractory SE and is usually associated with minimal cardiovascular side effects [60-64]. Midazolam is given as an initial bolus infusion of 0.2 mg/kg IV followed by a continuous infusion of 0.05 to 2 mg/kg per hour; for breakthrough seizures, additional 0.1 to 0.2 mg/kg boluses can be given and the continuous infusion rate increased by 0.05 to 0.1 mg/kg per hour every three to four hours [8].

Hypotension may be less common than with pentobarbital but commonly occurs at higher doses of midazolam. The short half-life of midazolam (one to four hours) can increase markedly after days of use. Tachyphylaxis is common, and the anticonvulsant effects of midazolam can cease rapidly when it is stopped. Withdrawal seizures and recurrent SE are therefore an important concern.

In a prospective multicenter study of 54 children with refractory SE who underwent continuous infusion of an anesthetic drug, 78 percent received midazolam as the first-choice agent [58]. Pentobarbital was the most commonly used therapy after midazolam failure (82 percent). Seizure termination was achieved in 30 out of 42 patients (71 percent) who received first-line midazolam, and an additional eight patients achieved seizure termination with one more drug (mostly pentobarbital). The median length of intensive care unit stay was 10 days in the entire cohort, and 28 percent of patients required vasopressor support.

Pentobarbital — Pentobarbital is given as an initial bolus infusion of 5 to 15 mg/kg IV followed by a continuous infusion of 0.5 to 5 mg/kg per hour [4].

Significant side effects include respiratory depression, hypotension, myocardial depression, and reduced cardiac output. Thus, intubation and mechanical ventilation with intravascular pressure monitoring are required prior to treatment, and inotropic agents frequently are needed. Other important potential complications include pulmonary edema, ileus, and prolonged sedation.

Propofol — Propofol is rarely used for the treatment of SE in children because doses and duration of therapy necessary to control refractory seizures are associated with life-threatening propofol infusion syndrome characterized by one or more of severe metabolic acidosis, rhabdomyolysis, and ECG changes, with or without cardiovascular collapse, hyperlipidemia, renal failure, elevated liver enzymes, or elevated lactate [65-67]. Risk factors for the propofol infusion syndrome include high infusion doses (>67 mcg/kg per minute or >4 mg/kg per hour), prolonged administration (>48 hours), and administration to children on the ketogenic diet [59]. Others have found that propofol may be used without severe adverse effects if the dose is not titrated above 5 mg/kg per hour and with continuous monitoring and stopping the infusion if side effects appear [68]. However, these doses may be insufficient to control refractory SE.

Other therapies — In addition to levetiracetam, observational data suggest that other antiseizure medications, including lacosamide, and topiramate, may play a role in the management of SE, particularly in the refractory setting. Other emerging therapies include ketamine [69] and the ketogenic diet [70-72]. (See "Ketogenic dietary therapies for the treatment of epilepsy", section on 'Super-refractory status epilepticus'.)

LacosamideLacosamide is also available in both oral and intravenous formulations, and there are an increasing number of case reports and case series describing its utility in adults with refractory SE [73-75]. The bolus dose most often used in adults is 200 to 400 mg IV infused over three to five minutes [73]. Published data in children are limited [76-79]. One small, retrospective case series suggests that infusions of 50 mg or 100 mg in children and young adults can be effective in cases of refractory tonic SE [77]. Another cases series of nine patients treated with a mean initial loading dose of 8.7 mg/kg reported no serious adverse effects and one episode of bradycardia [78].

TopiramateTopiramate has a broad spectrum of efficacy against many seizure types. Case reports and small case series report that it may be efficacious in refractory SE [80-82]. Some have used low initial doses [80,81], others a higher loading dose [82]. There is no formulation for parenteral administration. Further prospective study is needed to define the role of topiramate in SE.

Duration of continuous infusions — Continuous infusions of sedative-anesthetic agents for refractory SE require management by pediatric neurology and critical care specialists in a pediatric intensive care unit.

Therapy with midazolam (preferred) or pentobarbital is titrated to induce cessation of clinical and electrographic seizures, as confirmed by cEEG monitoring. The dose is then slowly reduced while monitoring to ensure that seizures do not reappear. If seizures recur, the dose is increased to achieve seizure suppression again for a period of time, followed by attempts to reduce the infusion while maintaining control of seizures.

POSTICTAL RECOVERY AND FURTHER EVALUATION

Pace of recovery — Most children begin to recover responsiveness within 20 to 30 minutes after generalized convulsions, although there is a broad range of duration. Close monitoring during the immediate postictal phase is critical, particularly for respiratory status. This is a vulnerable time, as some patients may not be able to maintain their airway without basic airway maneuvers such as a jaw thrust or chin lift or insertion of airway adjuncts such as a nasopharyngeal or oral airway; monitoring the end-tidal CO2 can help assess adequacy of ventilation. (See "Basic airway management in children".)

The two most common reasons for delayed postictal recovery are sedation from medications and ongoing nonconvulsive seizures [83], and these two causes can be impossible to distinguish clinically. Note that benzodiazepine reversal with flumazenil is contraindicated in this setting, as reversal can precipitate seizures.

All children who do not return to a normal level of consciousness within a few hours after initial treatment of SE should therefore undergo an emergency EEG; continuous EEG monitoring and escalation of treatment is indicated if the routine EEG shows nonconvulsive SE. (See 'Electroencephalography' below and "Nonconvulsive status epilepticus: Classification, clinical features, and diagnosis" and "Nonconvulsive status epilepticus: Treatment and prognosis".)

History and physical examination — During the postictal recovery period. it is important to perform a detailed history, physical examination, and a full neurologic examination that looks for asymmetric or focal findings or signs of increased intracranial pressure that may suggest clues to the underlying etiology.

The causes of SE and the evaluation and diagnosis of seizures in children are discussed in detail separately. (See "Clinical features and complications of status epilepticus in children", section on 'Causes' and "Seizures and epilepsy in children: Clinical and laboratory diagnosis".)

Electroencephalography — For patients with SE as the first presentation of seizures or epilepsy, an EEG should be done to evaluate background activity as soon as possible after the seizure stops, ideally within one to two hours. An EEG may not be necessary for patients with known epilepsy who are recovering normally from SE if the clinicians are confident the clinical seizures have stopped and there is no other independent reason that the child would benefit from ongoing EEG monitoring. Useful clues to the cessation of a clinical seizure are eye closure and resumption of a normal breathing pattern. An EEG may be useful if the eyes remain open or there is any lingering doubt as to the continuation of subclinical seizures.

EEG monitoring may be useful if the patient does not return to normal mentation in an appropriate time after cessation of SE. The clinician may also elect to perform cEEG in patients with acute symptomatic causes where the etiology could potentially cause further neurologic injury (eg, meningitis, trauma, etc.).

The EEG background usually remains abnormally slow for hours or even days after generalized convulsive or prolonged partial SE, but it is normal in psychogenic nonepileptic seizures unless large doses of sedating antiseizure medications have been given. If the patient has not regained a relatively normal mental state within a few hours after SE has stopped, an EEG should be performed to evaluate the possibility of subclinical electrographic seizures [84].

Studies of critically ill children who undergo continuous EEG monitoring indicate that electrographic seizures are present in approximately 30 to 40 percent of recordings, often without clinical accompaniment [85-87]. Similar findings have been reported in critically ill adults. The benefit of continuous EEG monitoring in unselected patients is unclear. However, the possibility of nonconvulsive seizures should be considered in such patients when the degree of coma is not adequately explained by their underlying condition.

Neuroimaging — A neuroimaging study is essential when SE is the first presentation of epilepsy as well as in children whose recovery from SE does not follow the expected course [88,89]. Computed tomography may be performed in the emergency department setting, but magnetic resonance imaging has superior yield for determining the underlying etiology. (See "Clinical features and complications of status epilepticus in children", section on 'Causes'.)

Additional studies — Additional laboratory studies may be warranted for selected patients with SE based upon the most likely etiology as discussed separately:

Septic shock. (See "Systemic inflammatory response syndrome (SIRS) and sepsis in children: Definitions, epidemiology, clinical manifestations, and diagnosis", section on 'Laboratory studies'.)

Meningitis or encephalitis. (See "Bacterial meningitis in children older than one month: Clinical features and diagnosis", section on 'Evaluation' and "Viral meningitis in children: Clinical features and diagnosis", section on 'Evaluation'.)

Metabolic studies for inborn errors of metabolism in infants younger than six months of age or children with other suggestive indicators. (See "Seizures and epilepsy in children: Clinical and laboratory diagnosis", section on 'Laboratory and genetic testing in undiagnosed epilepsy'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Seizures and epilepsy in children".)

SUMMARY AND RECOMMENDATIONS

Clinical presentation – Convulsive status epilepticus (SE) is a clinical diagnosis, confirmed in most cases by the presence of sustained and rhythmic generalized tonic and clonic motor activity lasting for longer than five minutes or repetitive convulsive seizures without a return to baseline consciousness between seizures. Although the diagnosis of convulsive SE is usually obvious, a detailed neurologic examination is important in making the diagnosis of more subtle or focal forms of SE. (See 'Definition and differential diagnosis' above and 'Urgent focused evaluation' above.)

Supportive care – The initial assessment, stabilization, and treatment of a child presenting with SE should proceed in quick succession and include the following (algorithm 1):

A brief physical examination to assess respiratory and circulatory status, with immediate interventions as necessary, and a rapid neurologic examination to confirm the presence of SE. (See 'Rapid recognition of status epilepticus' above and 'Immediate supportive care' above.)

Maintenance of an adequate airway, breathing, and circulation, along with continuous pulse oximetry and cardiac monitoring performed simultaneously with initiation of emergency antiseizure treatment. (See 'Immediate supportive care' above.)

Laboratory studies (table 12) including (see 'Initial studies' above):

-Plasma glucose and a rapid "finger-stick" or point-of-care glucose

-Serum electrolytes and calcium

-Serum antiseizure medication levels, if applicable

-If substance use or poisoning is suspected, urine and blood toxicology

-In postmenarchal females, qualitative pregnancy test (urine or blood)

Clinically obvious SE should be treated immediately, without waiting for an EEG. When there is uncertainty regarding the presence of SE, an urgent EEG should be obtained. In the emergency department, this can be a limited study. (See 'Approach' above and 'Electroencephalography' above.)

Management The management of convulsive SE in children is summarized in the algorithm (algorithm 1).

First therapy – For children presenting with convulsive SE, we recommend immediate treatment with a benzodiazepine (Grade 1B). For children with intravenous (IV) access, the preferred benzodiazepines are either lorazepam 0.1 mg/kg IV (maximum 4 mg per dose) or diazepam 0.2 mg/kg IV (maximum 10 mg per dose), administered by slow IV push over one minute. The dose can be repeated in 5 to 10 minutes if seizures persist. (See 'First therapy: Benzodiazepines' above and 'Benzodiazepine efficacy and pharmacokinetics' above.)

In the prehospital setting, or if IV access is delayed or impossible, an alternative to IV lorazepam or IV diazepam for initial therapy is intramuscular (IM) midazolam at a dose of 0.1 to 0.2 mg/kg up to a maximum of 10 mg. Other options if IV access cannot be established are intranasal midazolam, intranasal diazepam, rectal diazepam (0.5 mg/kg, maximum 20 mg), and buccal midazolam (0.2 mg/kg, maximum 10 mg). (See 'Prehospital treatment' above and 'In-hospital treatment' above.)

Second therapy – For children with SE that continues for 10 minutes after at least two doses of a benzodiazepine, additional antiseizure medication is required; for such patients, we suggest treatment with levetiracetam rather than another antiseizure medication (Grade 2C). Levetiracetam is given at a dose of 60 mg/kg IV. Fosphenytoin is our preferred alternative to levetiracetam except for toxin-induced seizures. Phenobarbital and valproate are additional antiseizure medications for second therapy in this setting. (See 'Second therapy: Antiseizure medications' above and 'Choosing an agent' above and 'Antiseizure medication efficacy' above.)

Refractory status epilepticus – If SE persists for 30 minutes after initial measures are instituted, further pharmacologic therapy usually consists of continuous infusion of midazolam (preferred) or, if hemodynamic status permits, pentobarbital. At this stage, the patient will require intubation, mechanical ventilation, neurologic consultation if not already obtained, and transfer to a pediatric intensive care unit with continuous EEG capability. (See 'Refractory status epilepticus' above.)

Postictal recovery – Most children begin to recover responsiveness within 20 to 30 minutes after generalized convulsions, although there is a broad range of duration. Close monitoring during this period is critical. An emergency EEG should be obtained in all children who do not return to a relatively normal mental state within a few hours after SE has stopped to evaluate for the possibility of subclinical seizures. (See 'Postictal recovery and further evaluation' above.)

During the postictal recovery period, it is important to perform a detailed history, physical examination, and a full neurologic examination that looks for asymmetric or focal findings or signs of increased intracranial pressure that may suggest clues to the underlying etiology. The causes of SE and the evaluation and diagnosis of seizures in children are discussed in detail separately. (See "Clinical features and complications of status epilepticus in children", section on 'Causes' and "Seizures and epilepsy in children: Clinical and laboratory diagnosis".)

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