Disclosure Statement. Status Epilepticus (SE) Objectives. Etiology. When Does SE Become Refractory?

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1 Disclosure Statement Controversial Role of Ketamine in Treatment of Refractory Status Epilepticus Senka Runjaic, PharmD PGY 1 Pharmacy Resident January 24 th, 2015 The author of this presentation has the following to disclose concerning possible financial or personal relationships with commercial entities that may have direct or indirect interest in the subject matter of this presentation Senka Runjaic, PharmD nothing to disclose Objectives Define status epilepticus (SE) and refractory status epilepticus () Review etiology and pathophysiology of SE Explain the role of ketamine for treatment of Discuss pharmacists role in improving clinical outcomes Status Epilepticus (SE) No consensus on exact definition Traditional definition Any seizure lasting longer than 30 min whether or not consciousness is impaired Modified definition Five minutes or more of continuous clinical and/or electrographic (EEG) seizure activity or Recurrent seizure activity without recovery (returning to baseline) between seizures Etiology When Does SE Become Refractory? Acute processes Sepsis Metabolic disturbance CNS Infection Stroke Head trauma Drug issues (toxicity, withdrawal, non compliance) Hypoxia, cardiac arrest Hypertensive encephalopathy Autoimmune encephalitis Chronic processes Preexisting epilepsy (breakthrough or discontinuation of medications) Chronic ethanol abuse (withdrawal) CNS tumors Patient who continues to experience either clinical or EEG seizures after initial doses of an initial benzodiazepine followed by a second acceptable AED will be considered refractory. 1

2 Time Dependent Pharmacoresistance Management of Refractory Status Epilepticus NEED FOR NMDA RECEPTOR ANTAGONISTS! Management of If has been established Consider repeat bolus of the urgent control AED Immediately initiate additional agents Start continuous infusion (CI) AEDs Midazolam Propofol Barbiturates Rossetti et al. Management of. Oct PMID: Anesthetic Agents for Midazolam LD 0.2 mg/kg, administer at 2 mg/min CI mg/kg/hr Predictable PK/PD profile Availability of antidote (flumazenil) Can be used in combination with propofol Tachyphylaxis Respiratory depression Hypotension Rossetti et al. Management of. Oct PMID: Anesthetic Agents for Propofol Loading dose (LD) 1 2 mg/kg CI mcg/kg/min Short T1/2, rapid titration/withdrawal Relative safety with prolonged use in ICU patients Propofol infusion syndrome (PRIS) Severe metabolic acidosis Rhabdomyolysis Renal failure; CV collapse Rossetti et al. Management of. Oct PMID: Anesthetic Agents for Pentobarbital LD 5 15 mg/kg, administer at <50 mg/min CI mg/kg/h Theoretical neuroprotectiveeffect Efficacy Very long T1/2, prolonged recovery Myriad of drug interactions Profound CV depression Ileus, suppressed immunity Rossetti et al. Management of. Oct PMID:

3 Emerging treatment for ketamine MOA: Non competitive NMDA receptor antagonist Pharmacokinetics: T1/2 greater than 2.5 hours Vd 3L/kg Metabolism CYP450, excretion primarily urine Dosing: Induction of anesthesia IM: 6.5 to 13 mg/kg IV: 1 to 4.5 mg/kg Emerging treatment for ketamine Indications: FDA labeled General anesthesia Procedural sedation Non FDA labeled Analgesia Bronchospasm Rapid sequence intubation, induction Major adverse effects: Common: BP HR Serious: cardiac dysrhythmias, apnea, respiratory depression Original Use of Ketamine for 1998 case report Previously healthy 13 y/o girl 3 day h/o muscle aches, fever, and GTC seizures Etiology could not be determined Treatment prior to introduction of ketamine IV diazepam, CI midazolam LD and CI of phenytoin and phenobarbital Pentobarbital coma x 4 weeks IV lorazepam, lidocaine, and valproate Propofol (bolus followed by CI) Sheth et al. Refractory SE: response to ketamine. Dec PMID: Original Use of Ketamine for IV ketamine 2 mg/kg bolus Controlled seizures after 90 sec CI up to 7.5 mg/kg/hr Remained on ketamine for 14 days Sheth et al. Refractory SE: response to ketamine. Dec PMID: case report 60 y/o with cerebral palsy and epilepsy Admitted for CAP Developed NCSE Coma, poor airway protection intubation Treatment prior to introduction of ketamine Escalating doses of midazolam Phenytoin LD Levetiracetam Propofol MAP compromised NE (max 0.26 mcg/kg/min) IV ketamine (within hours of ) 50 mg bolus, CI mg/kg/hr Seizures abolished within 12 hours After seizure free period of 48 hours sedatives weaned off Clinical outcome 24 hours after sedatives weaned off regained consciousness After 3 weeks of inpatient rehab complete return to baseline Kramer AH. Early ketamine to treat. Apr PMID: Kramer AH. Early ketamine to treat. Apr PMID:

4 Ketamine was used substantially early Immediate and sustained efficacy Excellent clinical outcome Vasopressor sparing role NMDA Antagonists for Review Overview: Systematic review 20 retrospective case series/reports Three prospective studies Evaluate use of NMDA receptor antagonists in Patient population: 162 patients (52 pediatric) End points: Seizure control Clinical outcomes and adverse effects Kramer AH. Early ketamine to treat. Apr PMID: NMDA Antagonists for Review Ketamine doses used Adults: Bolus max 5 mg/kg; CI mg/kg/hr Pediatrics: Bolus max 3 mg/kg; CI max 10 mg/kg/hr Time to administration of ketamine Five hours to 140 days Number of AEDs prior to ketamine introduction One to eleven Ketamine treatment duration Two hours to 27 days NMDA Antagonists for Review Results Adults Complete response 59 patients (53.6%) Treatment failure 51 (46.4%) Pediatrics Complete response 33 patients (63.5%) Treatment failure 19 patients (36.5%) Adverse effects Two patients cardiac arrhythmias NMDA Antagonists for Conclusions Efficacy of ketamine promising Response rate was highest when ketamine was introduced early Response was not likely if ketamine was introduced after seven days of Poor clinical outcomes associated with late administration Comparable efficacy with guideline recommended anesthetics Pharmacists Role To be familiar with recent guidelines and current institutional practice Make appropriate and timely recommendations in regards to pharmacotherapy Stay tune for further research on role of ketamine in treatment of 4

5 Summary Defined SE and Reviewed etiology and pathophysiology Analyzed the role of the emerging treatment for, ketamine Explained important role of pharmacists for successful treatment of References 1. Brophy GM et al. Guidelines for the evaluation and management of status epilepticus. Neurocrit Care Aug;17(1):3 23. doi: /s PMID: Treiman DM et al. A comparison of four treatments for generalized convulsive status epilepticus. Veterans Affairs Status Epilepticus Cooperative Study Group. N Engl J Med Sep 17;339(12): PubMed PMID: Alldredge BK et al. A comparison of lorazepam, diazepam, and placebo for the treatment of out of hospital status epilepticus. N Engl J Med Aug 30;345(9): PubMed PMID: Rossetti AO, Lowenstein DH. Management of refractory status epilepticus in adults: still more questions than answers. Lancet Neurol Oct;10(10): Review. PMID: Hocker S, Tatum WO, LaRoche S, et al. Refractory and super refractory status epilepticus an update. Curr Neurol Neurosci Rep Jun;14(6):452. PubMed PMID: Mayer SA, Claassen J, Lokin J, et al. Refractory status epilepticus: frequency, risk factors, and impact on outcome. Arch Neurol Feb;59(2): PMID: Claassen J, Hirsch LJ, Emerson RG, Mayer SA. Treatment of refractory status epilepticus with pentobarbital, propofol, or midazolam: a systematic review. Epilepsia Feb;43(2): PMID: Sheth RD, Gidal BE. Refractory status epilepticus: response to ketamine. Neurology Dec;51(6): PubMed PMID: Ubogu EE, Sagar SM, Lerner AJ, et al. Ketamine for refractory status epilepticus: a case of possible ketamine induced neurotoxicity. Epilepsy Behav Feb;4(1):70 5. PMID: Kramer AH. Early ketamine to treat refractory status epilepticus. Neurocrit Care Apr;16(2): PMID: Phelps S.J., Wheless J.W.(2014). Chapter 41. Status Epilepticus. In DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. DiPiro J.T., Talbert R.L., Yee G.C., Matzke G.R., Wells B.G., Posey L Eds. Joseph T. DiPiro, et al. (Eds), Pharmacotherapy: A Pathophysiologic Approach, 9e. Retrieved October 10, 2014 from Controversial Role of Ketamine in Treatment of Refractory Status Epilepticus Senka Runjaic, PharmD PGY 1 Pharmacy Resident January 24,