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

Figures & data

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

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.

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.