A proposal for a shared therapeutic algorithm in children with prolonged convulsive seizures and status epilepticus

KEYWORDS:

• Pediatrics
• seizures
• status epilepticus
• pharmacological treatment

1. Introduction and definition

Status epilepticus (SE) is a medical emergency that can lead to permanent neurological damage if not adequately managed [1]. The incidence in the pediatric population is approximately 20 cases per 100,000 children per year, with a peak in children under the age of 2 years. The mortality rate is about 3%, but it can overcome 10% in children admitted to the intensive care unit (ICU) for refractory SE [2].

Over the past decades, it has become clear that the most efficient way to prevent SE is to stop the seizure as fast as possible, and early treatment of prolonged convulsive seizures has become an integral part of the overall treatment strategy in epilepsy. Additionally, the terms ‘early’ or ‘impending’ SE have been defined as continuous or intermittent seizures lasting longer than 5 minutes without full recovery of consciousness between seizures [3].

Currently, the appropriate treatment of SE is hindered by numerous factors, including the underdosed use of ‘rescue medications’ by caregivers and pre-hospital healthcare providers and the inadequate application of defined (also in timing) treatment protocols upon arrival in the emergency department (ED) [4,5]. In general, 10% of epilepsy patients have a prescription for rescue medications, most of whom are of pediatric age, especially patients with febrile convulsions. The pre-hospital availability of rescue medications and adequate training of operators and caregivers in managing the episode are capable of reducing rescue times and the risk of prolonged seizures evolving into SE, consequently improving the outcome. Specifically, caregivers should be able to recognize seizures, know which medications to administer (correct route and dosage), and under which circumstances to seek help from healthcare professionals [6].

While some therapeutic strategies are supported by Level I evidence, such as the use of benzodiazepines as first-line drugs, others are based on limited data, especially in pediatric settings. This variability is due to the scarcity of studies aimed at comparing the effectiveness of individual second and third-line drugs on an appropriate population (heterogeneous case studies and low sample size). For purely practical purposes, this editorial divides the recommended treatment into phases (Figure 1).

Figure 1. Proposed protocol for pediatric status epilepticus (created with BioRender.com).

2. Treatment protocol

2.1. PHASE I. Stabilization and pre-hospital treatment

2.1.1. General measures

• Evaluate the level of consciousness.

• Measure the duration of the seizure episode.

• Initiate pre-hospital treatment and call emergency services (911 or equivalent).

• Assess and stabilize vital functions following the ABC sequence of Basic Life Support (Airway, Breathing, Circulation).

2.1.2. Pharmacological treatment

The ideal drug in the early phases of the seizure should: 1) have a rapid and sustained action, 2) be easy to administer, 3) ensure an acceptable safety profile with limited adverse events (AEs), especially in terms of respiratory depression and hemodynamic stability, 4) be socially acceptable, easy to store, transport, and use. In general, the early and adequate use of benzodiazepines is the preferred treatment [7,8]. This therapy can be repeated a second time after about 5 minutes if the seizure persists [8]. In the absence of intravenous access, buccal midazolam and rectal diazepam are the first-line treatments for prolonged seizures and convulsive SE [8]. Midazolam owns pharmacokinetic properties that ensure rapid action and a short half-life, supporting its use with various administration routes (intravenous, intramuscular, buccal, intranasal). Diazepam has rapid action, but rectal absorption is variable and not always predictable. Additionally, the use of diazepam is associated with an increased risk of recurrence and respiratory depression [9]. However, in our experience, we prefer rectal administration for children younger than 3 years of age (Table 1).

Table 1. Extra-hospital pharmacological treatment of prolonged convulsive seizures.

	Doses and routes of administration	Main adverse events
Midazolam	Buccal: 0.5 mg/Kg Repeatable once after 5 minutes if no response Available pre-dosed syringe formulations: 2.5 mg (6–12 months) 5 mg (1–4 years) 7.5 mg (5–9 years) 10 mg (10–18 years)	Respiratory depression
	Intranasal*: 0.2 mg/kg (administered via a mucosal atomization device),divided between the two nostrils Maximum dose: 10 mg Repeatable once after 5 minutes if no response	Respiratory depression
	Intramuscular: 0.2 mg/Kg Maximum dose: 10 mg Repeatable once after 5 minutes if no response	Respiratory depression
Diazepam	Rectal: 5 mg in children aged below age 3 years 10 mg after 3 years of age Repeatable once after 5 minutes if no response	Respiratory depression, somnolence
	Intranasal*: in children aged 6 years or older 0.2 mg/Kg o 0.3 mg/Kg Repeatable once after 5 minutes if no response	Respiratory depression, somnolence

*not yet available in some Countries.

2.2. PHASE II. Intra-hospital treatment at the first and second levels

Intra-hospital treatment should be based on the application of institutional protocols/algorithms that define the different phases of treatment and their respective medications (administration route, dosage, timing). The main published algorithms are divided into the following phases:

STABILIZATION (0–5 minutes): Initial phase where general supportive measures are applied.

FIRST-LINE TREATMENT (5–20 minutes): Administration of benzodiazepines.

SECOND-LINE TREATMENT (20–40 minutes): Lack of response to benzodiazepines indicates the administration of antiseizure medications (ASMs) belonging to different pharmacological classes.

THIRD-LINE TREATMENT (40–60 minutes): Refractoriness to at least two adequately dosed second-line ASMs leads to admission to the ICU for treatment with anesthetic drugs [8,10].

2.2.1. Pharmacological treatment at the first and second levels

In addition to its use in pre-hospital treatment, the effectiveness of benzodiazepines has also been demonstrated in the ED in 40–80% of cases [7,8]. The intravenous route should be preferred if venous access is present. However, no more than two doses of intravenous benzodiazepines should be administered (including any pre-hospital dose) as the effectiveness of a third dose would be limited and increase the risk of respiratory depression [11].

Table 2 lists the benzodiazepines commonly used in a hospital setting.

Table 2. Intra-hospital pharmacological treatment of status epilepticus.

Level	Drug	Mechanism of action	Dosage	Main adverse events	Note
First-line treatment (5–20 minutes)	Midazolam	positive allosteric modulation of the GABAA receptor	0.2 mg/Kg IV (maximum dose: 5 mg) if VA unavailable: 0.2 mg/Kg IM or 0.5 mg/Kg oromucosal (maximum dose: 10 mg)	respiratory depression	Maximum 2 doses (including pre-hospital if administered) separated from each other by 5 minutes
	Diazepam	positive allosteric modulation of the GABAA receptor	0.15–0.4 mg/Kg IV (maximum dose: 10 mg) if VA unavailable: 5 mg rectally for children aged ≤3 years or 10 mg for children aged >3 years	respiratory depression, somnolence	Maximum 2 doses (including pre-hospital if administered) separated from each other by 5 minutes
	Lorazepam	positive allosteric modulation of the GABAA receptor	0.1 mg/Kg IV (maximum dose: 4 mg); same dose applies for oromucosal administration, if VA unavailable	respiratory depression, somnolence	Maximum 2 doses (including pre-hospital if administered) separated from each other by 5 minutes Not recommended/contraindicated in pediatric population in some Countries
Second-line treatment (20–40 minutes)	Phenytoin	blockade of sodium channels	15–20 mg/Kg IV (maximum dose: 2000 mg)	arrhythmias, hypotension, local toxicity, severe cutaneous adverse reactions*	It should be administered at a rate not exceeding 50 mg/min, diluted in normal saline Monitor blood level 15 minutes after the end of infusion (target 20–30 mcg/ml) Contraindications: long QT syndrome, AV block, hypotension, Dravet syndrome
	Valproic Acid	not fully known, among various mechanisms, it is reported the increase in GABA levels and the blockade of sodium and calcium channels	20–40 mg/Kg IV (maximum dose: 3000 mg)	hepatotoxicity	Contraindications: hepatic or metabolic diseases (especially urea cycle defects), coagulopathy, age <2 years.
	Levetiracetam	binding to the synaptic vesicle protein 2A	40–60 mg/Kg IV (maximum dose: 4500 mg)	behavioral effects	Halve the dose if renal function is compromised.
	Phenobarbital	positive allosteric modulation of the GABAA receptor, leading to a reduction in excitatory synaptic responses	20 mg/Kg IV (maximum dose: 2000 mg)	respiratory depression, hypotension, severe cutaneous adverse reactions	Contraindications: porphyria, severe renal and hepatic impairment, severe heart diseases.
Third-line treatment (40–60 minutes)	Midazolam	positive allosteric modulation of the GABAA receptor	bolus: 0.2 mg/Kg IV (maximum dose: 5 mg), continuous infusion: 0.2–0.3 mg/Kg/hour	respiratory depression, hypotension
	Thiopental	positive allosteric modulation of the GABAA receptor results in a reduction of excitatory synaptic responses	bolus: 3–5 mg/Kg IV, continuous infusion: 3–5 mg/Kg/hour	respiratory depression, hypotension, reduced cardiac output, arrhythmias, anaphylactoid reactions, immunomediated reactions
	Ketamine	blockade of NMDA receptors of glutamate	bolus: 1–2 mg/Kg IV, continuous infusion: 3–5 mg/Kg/hour	hypertension, tachycardia increased secretions
Other pharmacological options include: topiramate, isoflurane, lidocaine, high-dose phenobarbital, lacosamide, perampanel, zonisamide, brivaracetam

*severe cutaneous reactions include Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS).

Legend: AV atrioventricular, IM intramuscular, IV intravenous, VA venous access.

If the seizure persists (more than 5 minutes after the last administration), the administration of a second ASM not belonging to the benzodiazepine class is indicated. Phenytoin and phenobarbital have specific indications and are present in most of the protocols [8]. However, in recent years, other drugs such as levetiracetam, valproic acid, lacosamide, and brivaracetam have also become available, albeit ‘off-label’ [9]. Large randomized controlled studies in pediatric patients published in recent years have shown that phenytoin, levetiracetam, and valproic acid have comparable efficacy, but the following considerations should be made: ease of administration, pharmacokinetic characteristics, and safety profile make levetiracetam a valid alternative to phenytoin; the use of valproic acid is limited due to its contraindications (metabolic diseases, mitochondrial disorders, liver disease), particularly in young children where these conditions cannot be ruled out at the onset [9,12,13]. The dosage and administration methods of second-line drugs are summarized in Table 2.

In patients under 12 months old, the administration of pyridoxine as a bolus can be considered under EEG monitoring: 100 mg IV (for pyridoxine-dependent epilepsy) [14].

If the seizures persist after 5 minutes from the administration of the first second-line drug, another second-line drug with a different mechanism of action should be administered, paying attention to pharmacological interactions (e.g. phenytoin and valproic acid compete for the protein binding site). If the seizure continues beyond this point, further treatments should be avoided as they are ineffective in over 85% of cases and may delay the appropriate management in intensive care [1,8].

2.3. PHASE III. Intensive care management and third-level treatment

Intensive care treatment of SE is indicated in case of no response to first and second-line drugs (refractory SE) or in the presence of systemic complications such as hemodynamic instability and/or respiratory failure. In this phase, continuous EEG monitoring is mandatory for diagnostic purposes (identification of non-convulsive SE) and for monitoring the treatment with continuous infusion anesthetic drugs.

2.3.1. Pharmacological therapy

The commonly used medications in children and adults, with induction and continuous infusion doses, are midazolam, thiopental, ketamine (Table 2). Propofol is not recommended in pediatric patients due to the potentially fatal risk of propofol infusion syndrome (rhabdomyolysis, acidosis, cardiac arrhythmia) for infusions at doses greater than 4 mg/kg/h for more than 24–48 hours. Other pharmacological options include topiramate, isoflurane, lidocaine, valproic acid, high-dose phenobarbital, lacosamide, perampanel, zonisamide, and brivaracetam, and adjuvant therapies can be applied, such as ketogenic diet, hypothermia and vagus nerve stimulation.

There are no randomized clinical trials supporting the choice of a particular pharmacological strategy. The EEG target of the pharmacological treatment is not well defined and could be represented by either suppression of paroxysmal activity or burst suppression for at least 24–48 hours.

SE persisting at least 24 hours after onset of anesthesia, either without interruption despite appropriate treatment with anesthesia, or recurring while on appropriate anesthetic treatment, or recurring after withdrawal of anesthesia is defined as super refractory SE. In cases of super-refractory SE caused by autoimmune encephalitis (confirmed or suspected diagnosis), immunomodulating therapy includes first-line treatment (steroids, intravenous immunoglobulins, plasmapheresis) and second-line drugs if indicated (rituximab, anakinra, bortezomib, tocilizumab, cyclophosphamide) [15].

3. Conclusions

Status epilepticus is a neurological emergency that must be recognized and treated promptly to prevent progression to refractory SE and secondary neurological damage. Institutional protocols and structured algorithms from the first to the third level (timings, medications, doses) are essential to implement appropriate and timely treatment strategies and ensure the best prognosis.

4. Expert opinion

The purpose of this editorial is to share a therapeutic algorithm that can be helpful in clinical practice, especially for first and second-line treatment of SE. In fact, involvement of specialized neurologists often occurs only at a later stage, starting from the second or third-line treatments.

Additionally, recent advancements in epilepsy pharmacology imply a continuous need for updates, and the complex dynamics of drug authorization by regulatory agencies for the specific region become more and more relevant. For example, oromucosal midazolam in its pre-dosed form is currently approved by the European Medical Agency but not yet by the Food and Drug Administration. On the other hand, the use of intranasal benzodiazepines (midazolam or diazepam) is not yet available in some Countries. Consequently, protocols primarily reflect the current approvals from the drug regulatory agencies of the Countries where they are applied.

An interesting point of development for the coming years is the placement of new-generation ASMs in future protocols, ‘gaining positions’ as therapeutic options after the failure of benzodiazepines. Moreover, ketamine, commonly used in anesthesia and in the ED for short procedures, presents antiepileptic and neuroprotective properties and has been recently proposed as second-line agent for its unique pharmacological and safety profiles [16].

As shown in our protocol, in choosing a second-line drug, it is essential to consider the patient’s comorbidities and, if known, the cause of epilepsy. Therefore, the use of a sodium blocker as phenytoin should be avoided in the case of specific channelopathies such as Dravet syndrome [17], such as the use of valproic acid if an underlying metabolic disorder is even just suspected.

Not least important for the prevention and management of SE is caregiver education, in the case of known epileptic patients. Caregivers must be able to recognize and promptly handle all ‘urgency/emergency’ situations that require access to the emergency room or call to 911: typically a prolonged seizure lasting more than 5 minutes and/or a seizure cluster without recovery to the baseline neurological state between seizures (for which we suggest management according to the ‘SE protocol’), the presence of respiratory impairment, or failure to regain consciousness at the end of the seizure.

Seizure clusters, also called acute repetitive seizures, are defined as a series of grouped seizures that have short interictal periods. The exact definition is still controversial, but it refers to a condition of a significant increase in the frequency of epileptic seizures, which puts the patient at risk of developing SE [18]. A seizure cluster, unlike SE, implies a complete recovery to the baseline neurological state between episodes.

Epileptic patients at risk of developing acute repetitive seizures should have an extra-hospital plan, often including the administration of benzodiazepines, in an attempt to prevent the cluster from progressing.

A discussion on the different treatment options for repetitive acute seizures, as well as the treatment of neonatal seizures, is beyond the scope of this editorial.

Declaration of interest

IRCCS ‘G. Gaslini’ is a member of ERN-Epicare. A Riva has received honoraria from Kolfarma, Proveca Pharma, PTC Therapeutics, Jazz Pharmaceuticals, and UCB Pharma; E Russo has received speaker fees or funding from, and has participated in advisory boards for, Angelini Pharma, Eisai, Pfizer, GW Pharmaceuticals, Jazz pharmaceuticals, UCB and Kolfarma; P Striano has received speaking grants from Neuraxpharma, Jazz pharma, BioMarin, Proveca, UCB Pharma. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Acknowledgments

We would like Dr. Luigi Francesco Iannone for the creation of the figure.

Additional information

Funding

This work was supported by #NEXTGENERATIONEU (NGEU) and funded by the Ministry of University and Research (MUR), National Recovery and Resilience Plan (NRRP), project MNESYS (PE0000006)—A Multiscale Integrated Approach to the Study of the Nervous System in Health and Disease (DN. 1553 11.10.2022). This work was also supported by the Italian Ministry of Health, RICERCA CORRENTE 2023.