Emergent Therapy

Benzodiazepines For Status Epilepticus

Benzodiazepine is the standard of care for emergency treatment of SE. The most commonly used Benzodiazepines are: Lorazepam, Midazolam, and Diazepam.

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A. Lorazepam

• Mechanism of Action: binds to Benzodiazepine receptors on the post-synapse to enhance the inhibitory effects of GABA
• Route of Administration: Intraveous
• Dose: 0.1 mg/kg with a maximum single dose of 4mg
• Pharmacokinetics: onset of action – 1 to 3 minutes
  • Longer duration of action compared to IM Midazolam

• Adverse Effects: hypoventilation, hypotension, and cardiac rhythm disturbance
• Pearls: Best agent for SE patients with IV access

B. Midazolam

• Mechanism of Action: related to accumulation of GABA to inhibit seizure and affinity to benzodiazepine receptors
• Route of Administration: Intramuscular and Intranasal
• Dose: 0.2 mg/kg, with maximum single dose of 10mg IM ; 5 – 10 mg (0.2 mg/kg) IN
• Pharmacokinetics: half-life of 1.5 to 2.5 hours
• Adverse Effects: pain on injection site, hypoventilation, hypotension, and cardiac rhythm disturbance
• Pearls: drug of choice for patients for SE patients with no IV access; IM Midazolam shows similar response rate to IV Lorazepam in that pharmacologic effect of both for the cessation of seizure happens at the same time only that because of the route of administration of IM Midazolam, drug can be administered faster

C. Diazepam

• Mechanism of Action: facilitates inhibitory activity of GABA at various sites
• Route of Administration: Intravenous, Intrarectal, Intramuscular
• Dose: 10 mg IV, may repeat q5-10 minutes with a maximum cumulative dose of 30mg ; 5 – 20 mg IR
• Pharmacokinetics: half-life of 1.5 to 2.5 hours
• Adverse Effects: withdrawal symptoms, hypotension, and cardiovascular collapse
• Pearls: rapidly re-distributes into adipose with short-lived efficacy

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Clinical Trials for the Use of Benzodiazepines in SE

Author	Design/Sample	Intervention and Comparison	Outcome
Treiman DM et al, 1998	Randomizedn=570	Comparison of 4 different IV treatments: Lorazepam (0.1 mg/kg) vsDiazepam (0.15 mg/kg) followed by Phenytoin (18 mg/kg)vsPhenobarbital(18 mg/kg)vsPhenytoin alone(18 mg/kg)	Lorazepam superior to Phenytoin
Alldredge BK et al, 2001	Randomizedn=205	Seizure cessation performance of 2 mg IV Lorazepam vs5 mg IV DiazepamvsIV Placebo Repeat dose is allowed if the seizure continued after 4 minutes	Both Lorazepam and Diazepam were superior to placebo Llorazepam (59.1%) > placebo (21.1%)AndDiazepam (42.6%) > placebo (21.1%)
Silbergleit R et al, 2012	Multi-center, double-blind randomized noninferiority comparisonn=893	Comparison of Test drug IM Midazolam 10mg (5mg in children weighing 13-40kg)vsIV Lorazepam 4mg (2mg in children weighing 13-40kg) in treatment of adults and children with SE	Primary efficacy endpoint was achieved in 73% of subjects in IM Midazolam group compared with 63% in the IV Lorazepam group group, resulting in an absolute difference between groups of 10%
Leppik IE et al, 1983	Randomizedn = 70	Seizure Cessation performance of IV Lorazepam 4mgvsIV Diazepam 10mg in adults with convulsive SE, absence SE, or complex partial SE Second dose of medication is given if seizure continues after 10 minutes	No statistically significant difference between IV Lorazepam and IV Diazepam in seizure cessation after 1 or 2 medication administration
Gilad R et al, 2008	Cohortn = 9 to 41 patients	Efficacy of IV Valproic AcidvsIV PhenytoinVsIV PhenobarbitalVsIV Diazepam plus PhenytoinVsIV LevetiracetamvsRectal DiazepamVsIV Lorazepam	Valproic Acid had higher efficacy than phenytoin in one study (Valproic Acid, 66%, vs Phenytoin, 42%; p = 0.046) and was similar to Phenytoin in the other (Valproic Acid, 87.8%, vs Phenytoin, 88%)
Leppik IE et al, 1983	Randomizedn = 273 children(aged 3 months to18 years)	Efficacy of Initial Therapy of IV Diazepam 0.2 mg/kg vsIV Lorazepam 0.1 mg/kg If seizures continued after 5 more minutes, then half of the initial study drug dose could be repeated. If seizures continued another 7 more minutes, then Fosphenytoin was given.	There was no difference between IV diazepam (101/140, 72.1%) and IV lorazepam (97/133, 72.9%) in the primary efficacy outcome of termination of SE by 10 minutes without reappearance within 30 minutes (absolute differenceof 0.8%, 95%) No evidence support that IV Lorazepam was superior to IV Diazepam as initial therapy for pediatric SE
DeToledo JC et al, 2000	Single-dose, Randomized,double-blindn=52	Comparative tolerability of IV FosphenytoinvsIV Phenytoinin patients needing infusion of Phentoin compared Fosphenytoin to Phenytoin	In contrast to Phenytoin, there were no Fosphenytoin-related significant cardiac arrhythmias, change in heart rate, respiration or blood pressure
DeToledo JC et al, 2000	Randomized,double-blindn=116	Comparison of IV FosphenytoinVsIV Phenytoin for patients needing infusion and maintenance	Pain at the infusion site was greater for Phenytoin compared to Fosphenytoin (17% vs 2%)
Alldredge BK et al, 2001	Four-arm double blind RCT	Success rate of therapy for SE	In adultswith overt SE, the overall success rate of the first administered therapy was 55.5%. If the first study drugdid not succeed, the second study drug was able to stop the SE for an additional 7.0% of the total population; the third drug helped only an additional 2.3% of patients.

Conclusions

1. IV Lorazepam is better to be used than IV Phenytoin.
2. No statistically significant difference between IV Lorazepam and IV Diazepam in seizure cessation
3. For children, IV Lorazepam given at 0.05-0.1 mg/kg and IV Diazepam at 0.3/0.4 mg/kg is established as most efficacious at stopping seizures lasting at least 5 minutes. IV Lorazepam shows superiority over the latter in that fewer Lorazepams patients required multiple doses or additional anticonvulsants to completely eliminate seizures.
4. There are lesser adverse effects for IV Fosphenytoin compared to IV Phenytoin.
5. IV Phenytoin presents more pain at the infusion site compared to IV Fosphenytoin.

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Summary of Benzodiazepines for Emergent Therapy

Drug	Route of Administration and Corresponding Dose	Adverse Effects	Pearls
Lorazepam	Intravenous: 0.1 mg/kg with a maximum single dose of 4mg	Hypoventilation, Hypotension, and Cardiac Rhythm Disturbance	Best agent for SE patients with IV access
Midazolam	Intramuscular: 0.2 mg/kg, with maximum single dose of 10mg Intranasal: 5 – 10 mg (0.2 mg/kg)	Pain on injection site, Hypoventilation, Hypotension, and Cardiac Rhythm Disturbance	Drug of choice for patients for SE patients with no IV access IM Midazolam shows similar response rate to IV Lorazepam in that pharmacologic effect of both for the cessation of seizure happens at the same time
Diazepam	Intravenous: 10 mg, may repeat q5-10 minutes with a maximum cumulative dose of 30mg Intrarectal: 5 – 20 mg	Withdrawal Symptoms, Hypotension, and Cardiovascular Collapse	Rapidly re-distributes into adipose Short-lived efficacy

Several factors remain relevant for an effective initial therapy of SE: the pharmacologic agent, adequacy of dose, and timing. For Emergent Therapy of SE, treatment focuses on the rapid termination of seizure activity to relatively minimize systemic dysfuction, neurological injury, pharmacoresistance, and ultimately morbidity and mortality. All of which are associated with uncontrolled SE.

Benzodiazepines are the standard of care for emergency treatment of SE with IV Lorazepam as the drug of choice for initial emergency therapy. 

For maximum benefits for the patient, Benzodiazepine therapy must be dosed appropriately and in a timely manner. Lorazepam given at doses of 0.1mg/kg with the maximum single dose of 4mg shows satisfactory seizure cessation. For patients where intravenous access is deemed unavailable, IM Midazolam given at 10mg for patients weighing more than 40kg is as efficacious and beneficial as IV Lorazepam.

If seizure persists after Benzodiazepine treatment, consider a repeat or following with an anti-epileptic drug (AED).

For stabilization from hyperexcitability, the initial therapy phase should begin when the seizure duration reaches 5 minutes and should conclude by the 20-minute mark. By this time, response from initial therapy should be apparent, whether it is responsive or non-responsive. It should be noted that in SE, a progressive decrease of the γ2 subunit is associated with benzodiazepine resistance and reduction to benzodiazepine drug potency reduces up to 20-fold if seizures persists for more than 30 minutes so a response from the initial therapy is necessary for assessment of the second stage of therapy.