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Objectives
1. Describe the pathophysiology and etiology of status epilepticus
2. List the current guidelines for pharmacological treatment of status epilepticus 3. Examine recently published literature on new treatment options for refractory status epilepticus
Epidemiology
Incidence of 10-40 persons per 100,000
2nd most common neurological emergency 23-43% develop refractory SE
Pathophysiology
Glutamate
Most common excitatory neurotransmitter Excess excitation mediated through the
Huff JS, Fountain NB. Emerg Med Clin N Am. 29 (2011) 1-13.
Pathophysiology
Gamma-aminobutyric acid (GABA)
Most common inhibitory neurotransmitter GABAA receptor prevents excess excitation
Huff JS, Fountain NB. Emerg Med Clin N Am. 29 (2011) 1-13.
GABA
Pathophysiology
Voltage gated Na channels - Phenytoin - Lacosamide Synaptic Vesicle Proteins - Levetiracetam
Primary outcome:
- Termination of seizures prior to ED arrival without administration of rescue therapy
RAMPART
IM Midazolam
Seizures had terminated upon arrival to ED, no rescue therapy given % (95% CI)
IV Lorazepam
73.4% (69.377.5)
63.4 (58.967.9)
292 (65.6)
161 (36.2)
Phenytoin
Purple Glove Syndrome
Phenytoin
Other adverse effects include:
Hypotension Arrhythmia
Thrombophlebitis
Dizziness
Refractory GCSE
Midazolam*
- 0.2 mg/kg IV bolus - continuous IV infusion at 0.8- 6.5 mcg/kg/min, titrate for seizure suppression Propofol* - 2-3 mg/kg bolus - continuous IV infusion at 66-166 mcg/kg/min, titrate for burst suppression on EEG
* Unlabeled Use
Refractory GCSE
Pentobarbital
- 5-15mg/kg over 1 hour - continuous IV infusion at 0.5-1 mg/kg/hr
Learning Assessment
Which of the following is considered first line treatment in status epilepticus?
A.Phenobarbital
B.Lorazepam
C.Phenytoin D.Valproic Acid
Refractory CPSE
Valproic Acid*
Loading dose 15-45mg/kg Continuous infusion 1-4 mg/kg/hr OR
500-1000 mg IV q6h
Goal level 50-100 mcg/ml
Works to increase the amount of GABA available to neurons or enhance the action of GABA
* Unlabeled Use Shearer P, Riviello J. Emerg Med Clin N Am 2011;29:51-64.
Refractory CPSE
Phenobarbital
20 mg/kg bolus May give additional 10 mg/kg bolus in 20 minutes if needed Max infusion rate of 50 mg/min Side effects include hypotension and respiratory depression
Refractory CPSE
Levetiracetam*
Loading dose of 1000-3000 mg over 15 min. 500 1500mg IV BID
Efficacy of intravenous levetiracetam as an add-on treatment in status epilepticus: A multicentric observational study
Purpose
To determine if IV levetiracetam (LEV) is safe and effective in patients in SE Unless contraindicated, all patients received a benzodiazepine + phenytoin or valproic acid as first line treatment
Efficacy of intravenous levetiracetam as an add-on treatment in status epilepticus: A multicentric observational study
Refractory CPSE
Lacosamide*
IV bolus of 200-400 mg Maintenance dose of 100-200 mg BID
Stabilizes hyperexcitable neuronal membranes and inhibits repetitive neuronal firing by enhancing inactivation of sodium channels
* Unlabeled Use
39 patients who received IV lacosamide at 3 European hospitals over a two year period were retrospectively analyzed
11
17 (44%)
SE terminated
18
11
34 (87%)
SE not terminated
5 (13%)
- Sedation in 25 patients
Conclusion
Retrospectively reviewed 187 cases of SE where either phenytoin, valproate, or levetiracetam was used after benzodiazepine failure
Primary outcome was failure of the secondline agent
95% CI
p value
Phenytoin
1.88
0.85-4.14
0.119
Levetiracetam
2.69
1.19-6.08
0.017
Summary
Benzodiazepines
Phenytoin/Fosphenytoin
Learning Assessment
Which medication is not considered as a treatment for CPSE?
1. Pentobarbital
2. Valproic Acid
3. Levetiracetam 4. Lacosamide
Questions?
References
1. Meierkord H, Boon P, Engelsen B, Gocke K, Shorvon S, Tinuper P, et al. EFNS guideline on the management of status epilepticus in adults. Eur J Neurol 2010;17:348-355. Rosetti AO, Lowenstein DH. Management of refractory status epilepticus in adults: still more questions than answers. Lancet Neurol 2011;10:922-30. Huff JS, Fountain NB. Pathophysiology and Definitions of Seizures and Status Epilepticus. Emerg Med Clin N Am 2011;11:1-13. McGraw-Hill. Antiseizure Drugs. Available at http://basic-clinicalpharmacology.net/chapter%2024_%20antiseizure%20drugs.htm. Accessed March 12, 2012. Silbergleit R, Durkalski V, Lowenstein D Consit R, Pancioli A, Palesch Y, et al. Intramuscular versus Intravenous Therapy for Prehospital Status Epilepticus. N Engl J Med 2012;366:591-600. Lorazepam. Lexi-Drugs Online. Lexi-Comp Online. Lexi-Comp, Inc. Hudson, OH. Available at: http://online.lexi.com/crlonline Accessed March 5, 2012. Diazepam. Lexi-Drugs Online. Lexi-Comp Online. Lexi-Comp, Inc. Hudson, OH. Available at: http://online.lexi.com/crlonline Accessed March 5, 2012. 2. 3. 4.
5.
6. 7.
8.
Phenytoin. Lexi-Drugs Online. Lexi-Comp Online. Lexi-Comp, Inc. Hudson, OH. Available at: http://online.lexi.com/crlonline Accessed March 5, 2012.
References
9. Fosphenytoin. Lexi-Drugs Online. Lexi-Comp Online. Lexi-Comp, Inc. Hudson, OH. Available at: http://online.lexi.com/crlonline Accessed March 5, 2012. 10. Shearer P, Riviello J. Generalized convulsive status epilepticus in adults and children: Treatment guidelines and protocols. Emerg Med Clin N Am 2011;29:51-64. 11. Phenobarbital. Lexi-Drugs Online. Lexi-Comp Online. Lexi-Comp, Inc. Hudson, OH. Available at: http://online.lexi.com/crlonline Accessed March 5, 2012.
12. Levetiracetam. Lexi-Drugs Online. Lexi-Comp Online. Lexi-Comp, Inc. Hudson, OH. Available at: http://online.lexi.com/crlonline Accessed March 5, 2012.
12. Aiguabella M, Falip M, Villaneuva V, de la Pena P, Molins A, Garcia-Morales I, et al. Efficacy of intravenous levetiracetam as an add-on treatment in status epilepticus: A multicentric observational study. Seizure 2011:20;60-64. 13. Lacosamide. Lexi-Drugs Online. Lexi-Comp Online. Lexi-Comp, Inc. Hudson, OH. Available at: http://online.lexi.com/crlonline Accessed March 5, 2012. 14. Kellinghaus C, Berning S, Immisch I, Larch J, Rosenow F Rossetti AO, et al. Intravenous lacosamide for treatment of status epilepticus. Acta Neurol Scand 2011;123:137-141. 15. Alvarez V, Januel J, Burnand B, Rossetti AO. Second-line status epilepticus treatment: Comparison of phenytoin, valproate, and levetiracetam. Epilepsia 2011;52:1292-1296.