8.2 Anticonvulsant Pharmacotherapy: First-Line Benzodiazepines, Second-Line Agents & Refractory Infusions

Anticonvulsant Pharmacotherapy

Quick Answer: Give a benzodiazepine promptly for ongoing convulsive status and count doses given before arrival. If convulsions continue after adequate rescue, load an IV antiseizure medication promptly. Persistent seizures despite first- and second-line treatment require PICU and neurology involvement, with continuous EEG (cEEG) to guide escalation.

First-Line Benzodiazepines and Route Selection

Benzodiazepines enhance inhibitory signaling through GABA-A receptors. Select the route the team can use promptly, support ventilation as needed and track the response. If a first appropriate dose fails, repeat per the applicable protocol while preparing second-line therapy. Include doses administered by caregivers or EMS. The benzodiazepines given for status should not be reversed with flumazenil. The U.S. flumazenil label contraindicates reversal of benzodiazepines given to control a life-threatening condition such as status epilepticus. AES guideline · Flumazenil label

• IV lorazepam: Johns Hopkins All Children's uses 0.1 mg/kg IV, max 4 mg, for pediatric status. This is pediatric pathway use. The U.S. Ativan injection label gives an adult status regimen and states that pediatric safety has not been established. In the pediatric PECARN trial, 97/133 (72.9%) with lorazepam and 101/140 (72.1%) with diazepam reached the endpoint of cessation by 10 minutes without recurrence within 30 minutes. The trial did not show superiority for lorazepam. Pediatric pathway · Ativan label · PECARN trial
• Non-IV midazolam: The same pediatric pathway uses 0.2 mg/kg IM or 0.3 mg/kg intranasally, max 10 mg for either route. Atomized use of a 5 mg/mL injectable solution via the nose is protocol-directed off-label use. Confirm the concentration, device and dosing instructions. The commercial Nayzilam device delivers 5 mg in 0.1 mL and is labeled for seizure clusters in patients with epilepsy aged 12 and older. Its fixed spray and home dosing instructions differ from a hospital's weight-based rescue protocol. Riley preparation instructions · Nayzilam label
• Diazepam: One U.S. injection label uses 0.2 mg/kg IV, max 8 mg, as a slow one-minute dose in children from 3 months through 17 years, followed if necessary after five minutes by 0.1 mg/kg IV, max 4 mg. Rectal diazepam is a non-IV option in the AES guideline. U.S. diazepam rectal gel is labeled for seizure clusters from age two. The prescribed target dose is 0.5 mg/kg at ages 2–5, 0.3 at 6–11, and 0.2 at 12 or older, rounded to a labeled delivery setting (max 20 mg). Home rescue redosing follows the prescription and action plan. Diazepam injection label · Rectal gel label

What RAMPART Measured

In the mixed-age prehospital RAMPART trial, 73.4% given IM midazolam and 63.4% given IV lorazepam arrived without ongoing seizures or rescue therapy. In the secondary analysis of 120 participants younger than 18, seizure cessation before emergency department arrival was observed in 41/60 (68.3%) and 43/60 (71.7%), respectively. The pediatric analysis examined rescue medication use separately. The 99% confidence interval for the pediatric difference was wide (−24.9 to 18.2 percentage points). IM treatment could be administered sooner. In the overall trial, the median time from administration to cessation among those with prearrival cessation was shorter with IV treatment. A child without access should receive a protocol-approved rescue route without waiting for IV placement. The RAMPART trial used a fixed 5 mg IM dose for estimated weights 13–40 kg. The Johns Hopkins pathway uses weight-based dosing, so a 14-kg child receives 2.8 mg IM under that pathway. RAMPART · Pediatric RAMPART analysis

Second-Line Loading After Adequate Rescue

ESETT compared three IV loading agents in established convulsive status, with eligibility beginning at age two. Its endpoint at 60 minutes was cessation of clinically apparent seizures and improving responsiveness without additional antiseizure medication. The trial did not establish that one agent was more effective. The pediatric chart shows intubation within 60 minutes in the safety cohort, a secondary outcome. Fosphenytoin had more observed intubations, but the signal calls for cautious interpretation given the other outcomes and limited precision. Choose an agent for the child in front of you, including age, seizure syndrome, prior reaction, organ function and hemodynamics. ESETT age analysis

• Levetiracetam binds the synaptic vesicle protein SV2A and is cleared predominantly through the kidneys. Check renal function for subsequent dosing with pharmacy. ESETT infused the load over 10 minutes. The U.S. Keppra concentrate label gives a 15-minute infusion for labeled dosing and does not supply the ESETT emergency load. Use the institution's emergency concentration and infusion protocol. Keppra label
• Fosphenytoin is converted to phenytoin, which limits repetitive firing through voltage-gated sodium channels. Order in mg phenytoin equivalents (PE). The U.S. label uses 15–20 mg PE/kg for pediatric status and limits infusion to 2 mg PE/kg/min or 150 mg PE/min, whichever is slower. Monitor ECG, pressure and breathing during infusion and through the post-infusion peak, approximately 10–20 minutes after completion. Fosphenytoin can be diluted in saline or D5W and still carries risks of local injury and purple glove syndrome. The label discourages IM use for status because therapeutic concentrations may be delayed. Cerebyx label
• IV valproate: ESETT used a 10-minute off-label status load. The U.S. injection label's routine IV replacement regimen has different administration instructions. Avoid in known POLG-related disease, suspected POLG-related disease below age two, known urea-cycle disorders and hepatic disease or significant dysfunction. In older children with suspected hereditary mitochondrial disease, the label reserves it for use after other antiseizure drugs fail, with close liver monitoring. Consider thrombocytopenia and bleeding risk, and check ammonia if unexplained lethargy, vomiting or altered mental status develops. Valproate injection label
• Phenobarbital is an alternative in some pediatric pathways (Johns Hopkins example 20 mg/kg IV, max 1,000 mg, if the preferred agents are unavailable). Monitor for hypotension and respiratory depression, especially after benzodiazepines. Neonates follow separate protocols. A neonatal phenobarbital formulation (Sezaby) is labeled for neonatal seizures and does not contain benzyl alcohol. ILAE recommends phenobarbital first-line for most neonatal seizures, with a sodium-channel agent considered first when channelopathy is likely and several second-line alternatives if treatment fails. Pediatric pathway · ILAE neonatal recommendations · Sezaby label

Refractory Seizures and Continuous Infusions

Ongoing clinical or electrographic seizures after an adequate benzodiazepine and at least one appropriate second-line agent meet the usual refractory definition. Activate PICU and neurology and plan for airway and hemodynamic support, cEEG, and evaluation for reversible causes. Some pathways use another nonanesthetic load in selected patients while preparing an infusion. Escalation depends on response and physiology rather than a fixed elapsed time. With continuous anesthetics, closely monitor ventilation, blood pressure and electrographic response.

For unit checks, 0.1 mg/kg/hour = 1.67 mcg/kg/min. When an EEG endpoint has been reached, continue cEEG through titration and withdrawal. Seizure cessation and selected burst suppression are distinct EEG targets. Johns Hopkins pediatric pathway · Pediatric ketamine cohort · Neurocritical Care Society guidance

Propofol Infusion Syndrome

The U.S. propofol label does not indicate the drug for pediatric ICU sedation. The SCCM PANDEM guideline conditionally describes an off-label, short sedation strategy below 4 mg/kg/hour and below 48 hours in selected children. These figures do not define a safe status-epilepticus infusion regimen. The label identifies prolonged high-dose exposure (over 5 mg/kg/hour for over 48 hours) among the major risk factors, along with critical illness, impaired oxygen delivery and certain co-medications. Cases have also occurred after large short-term exposures. New acidosis, rhabdomyolysis, hyperkalemia, bradyarrhythmia or cardiovascular collapse during propofol should prompt immediate discontinuation if PRIS is suspected. Support ventilation and perfusion, treat cardiotoxic hyperkalemia immediately, and use renal support when indicated. Maintain seizure control with an alternative under cEEG. FDA propofol label · SCCM PANDEM guideline

When Seizures Continue During Anesthesia

Super-refractory status persists or recurs at least 24 hours after starting anesthetic treatment, including recurrence during reduction or withdrawal. Reassess for infection, immune-mediated disease, structural pathology and age-appropriate metabolic causes. For new-onset refractory status (NORSE), including its FIRES subtype, consult a specialist team promptly for directed sampling and treatment. International consensus supports early first-line immunotherapy in appropriate NORSE/FIRES cases once common infections are addressed, and early ketogenic therapy for selected persistent cases. A targeted pyridoxine trial may be appropriate in an infant with suspected vitamin-dependent epilepsy, with cardiorespiratory and EEG monitoring. Super-refractory status definition · NORSE/FIRES consensus · Pyridoxine-dependent epilepsy consensus