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Pharmacy & Acute Care University
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Pharmacotherapy of Status Epilepticus

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  1. Background

    Introduction
  2. Pathophysiology & Diagnostics
  3. Emergent Therapy
    Benzodiazepines For Status Epilepticus
  4. What Agents to Use When No IV Access with Kyle Hultz
  5. Clinical Trials for the Use of Benzodiazepines in SE
  6. Summary of The Use of Benzodiazepines for Emergent Therapy of SE
  7. Urgent Therapy
    What's Your Agent of Choice After Benzodiazepines in Status Epilepticus with Kyle Hultz
  8. Anti-Epileptic Drugs (AED) in SE
  9. Clinical Trials for the Use of Anti-Epileptic Drugs in SE
  10. Refractory Status Epilepticus
    Pharmacologic Agents For Refractory Status Epilepticus
  11. Clinical Trials for the Use of Drugs in RSE
  12. Conclusion
    Summary & References
  13. The Decision to Intubate a Patient in Status Epilepticus with Richard Tsen

Participants 396

  • Allison Clemens
  • April
  • ababaabhay
  • achoi2392
  • adhoward1
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Pharmacotherapy of Status Epilepticus Clinical Trials for the Use of Benzodiazepines in SE
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Clinical Trials for the Use of Benzodiazepines in SE

Clinical Trials for the Use of Benzodiazepines in SE

AuthorDesign/SampleIntervention and ComparisonOutcome
Treiman DM et al, 1998Randomizedn=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, 2001Randomizedn=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, 2012Multi-center, double-blind randomized noninferiority comparisonn=893Comparison 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, 2008Cohortn = 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, 1983Randomizedn = 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, 2000Single-dose, Randomized,double-blindn=52Comparative 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, 2001Four-arm double blind RCTSuccess 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.

References

  • Treiman DM, Meyers PD, Walton NY, Collins JF, Colling C, Rowan AJ, Handforth A, Faught E, Calabrese VP, Uthman BM, Ramsay RE, Mamdani MB. A comparison of four treatments for generalized convulsive status epilepticus. Veterans Affairs Status Epilepticus Cooperative Study Group. N Engl J Med 1998;339:792–798.
  • Alldredge BK, Gelb AM, Isaacs SM, Corry MD, Allen F, Ulrich S, Gottwald MD, O’Neil N, Neuhaus JM, Segal MR, Lowenstein DH. A comparison of lorazepam, diazepam, and placebo for the
  • treatment of out-of-hospital status epilepticus. N Engl J Med 2001;345:631–637.
  • Silbergleit R, Durkalski V, Lowenstein D, Conwit R, Pancioli A, Palesch Y, Barsan W; NETT Investigators. Intramuscular versus intravenous therapy for prehospital status epilepticus. N Engl J Med 2012;366:591–600.
  • Leppik IE, Derivan AT, Homan RW, Walker J, Ramsay RE, Patrick B. Double-blind study of lorazepam and diazepam in status epilepticus. JAMA 1983;249:1452–1454.
  • Gilad R, Izkovitz N, Dabby R, Rapoport A, Sadeh M, Weller B, Lampl Y. Treatment of status epilepticus and acute repetitive seizures with i.v. valproic acid vs phenytoin. Acta Neurol Scand 2008;118:296–300.
  • DeToledo JC, Ramsay RE. Fosphenytoin and phenytoin in patients with status epilepticus: Improved tolerability versus increased costs. Drug Saf 2000;22:459–466.