Status Epilepticus: A refresher. Objectives

Transcription

1 Status Epilepticus: A refresher Ruben D. Villanueva, Pharm.D., BCPS OU Medical Center Trauma ICU Pharmacist Objectives Define seizures, convulsive and non convulsive status epilepticus, and refractory status epilepticus Describe the pathophysiology of status epilepticus Summarize the elements of emergent initial therapy and urgent control therapy for status epilepticus Discuss the various treatment options for status epilepticus List treatment options for refractory status epilepticus Pre Assessment Questions 1) Which of the following would be consistent with the definition of SE per the 2012 Neurocritical Care guidelines: A. 30 minutes of continuous seizure activity B. 1 2 minutes of continuous seizure activity C. 5 minutes of continuous seizure activity D. 15 minutes of continuous seizure activity

2 Pre Assessment Questions 2) The fundamental pathophysiological mechanisms behind SE are: I. Abnormal neuronal excitation II. Increased endogenous inhibitor mechanisms III. NMDA receptor downregulation IV. Loss of endogenous inhibitor mechanisms A. I, II B. II, III C. I, III D. I, IV Pre Assessment Questions 3) Which of the following would be the preferred regimen for emergent initial therapy in a SE patient with IV access weighing 70kg per the 2012 Neurocritical Care SE guidelines: A. Midazolam 10mg B. Phenytoin 20mg/kg C. Diazepam 10mg D. Lorazepam 4mg Pre Assessment Questions 4) Which of the following was given the highest level of evidence for urgent control therapy by the 2012 Neurocritical Care SE guidelines: A. Levetiracetam B. Phenobarbital C. Valproic acid D. Phenytoin

3 Pre Assessment Questions 5) Barbiturates are the first line continuous infusion agent for refractory status epilepticus? A. True B. False Status Epilepticus BACKGROUND Status Epilepticus: The Numbers Estimated 50, ,000 cases/year % of adults with a new epilepsy diagnosis first present in status epilepticus (SE) 2,3 55,000 deaths/year associated with SE 3 30 day mortality rate estimated at 19 27% 4 Survivors of SE 5 ~41% will go on to develop epilepsy ~25% will have deterioration in functional outcome ~10% will need long term care 1. Claassen J, Chang I, Bleck TP. Neurocritical Care Society Practice Update. Found at: 2. Hauser WA. Neurology 1990; 40(suppl 2): Lowenstein DH and Alldredge BK. New Engl J Med 1998; 338: Claassen J, et al. Neurocrit Care 2012; 17: S73 S Foreman B and Hirsch L. Neurol Clin 2012; 30:

4 Status Epilepticus: Definitions Seizure 1 Finite episodes of disturbed cerebral function Status Epilepticus: historical definition 1,2 30 minutes of continuous seizure activity 2 seizures without full recovery of consciousness between the seizures Status epilepticus: 2012 guideline definition 3 5 minutes continuous clinical and/or electrographic seizure activity Recurrent seizure activity without recovery between seizures 1. Huff SJ and Fountain NB. Emerg Med Clin N Am 2011; Lowenstein DH and Alldredge BK. New Engl J Med 1998; 338: Brophy GM, et al. Neurocrit Care 2012; 17: Status Epilepticus: Classification Convulsive Tonic clonic movements Mental status impairment ±Temporary neurological deficit Non convulsive Seizure activity noted on EEG No typical clinical findings ±Altered mental status or subtle movements Refractory Patients not responding to standard treatment Brophy GM, et al. Neurocrit Care 2012; 17: Status Epilepticus: Pathophysiology Pathologic Mechanism Inhibition failure GABA responsive Excess excitation GABA unresponsive Receptor trafficking: GABA (endocytosis) NMDA upregula on Synaptic plasticity: GABA receptor composition changes Altered gene expression: Drug efflux transporters Drug resistance proteins Drug target alterations Systemic Pathology Sympathetic overdrive Homeostatic failure Time <2 min 10 min 30 min 1 hr 6 hr 10 hr Days Adapted from: Foreman B and Hirsch LJ. Neurol Clin 2012; 30:

5 Status Epilepticus: Etiology Acute Frequency (%) Mortality (%) Stroke Metabolic abnormalities* Hypoxia* Systemic infection 7 10 Anoxia* 5 71 Trauma 3 25 Drug/substance toxicity* 3 25 *Complications of critical illness Betjemann JP and Lowenstein DH. Lancet Neurol 2015; 14: Mirski MA and Varelas PN. Crit Care Clin 2008; 24: Status Epilepticus: Etiology Chronic Frequency (%) Mortality (%) Low AED levels 34 4 Remote symptomatic** EtOH misuse* Tumor 7 30 Idiopathic 3 25 CNS infection 3 0 CNS hemorrhage 1 0 AED, anti epileptic drug; EtOH, ethanol *Complications of critical illness **Tumor, stroke, trauma Betjemann JP and Lowenstein DH. Lancet Neurol 2015; 14: Mirski MA and Varelas PN. Crit Care Clin 2008; 24: Status Epilepticus: Systemic Complications Acidosis Hyperthermia Rhabdomyolysis Trauma Loss of protective airways Mirski MA and Varelas PN. Crit Care Clin 2008; 24:

6 Status Epilepticus: Background Summary Definitions and classifications 5 minutes continuous clinical and/or electrographic seizure activity Recurrent seizure activity without recovery between seizures GCSE, NCSE, RSE Pathophysiology Abnormal neuronal excitation Loss of endogenous inhibitor mechanisms Etiology Low levels of AEDs most common Systemic complications Status Epilepticus EMERGENT INITIAL THERAPY AND URGENT CONTROL THERAPY Status Epilepticus: Initial General Care ABCs Diagnostic workup Finger stick glucose Imaging (i.e. head CT, MRI) Labs (i.e. CBC, BMP, Ca, Mg, AEDs, tox screen, etc.) Continuous EEG (ceeg) Thiamine/dextrose Brophy GM, et al. Neurocrit Care 2012; 17: 3 23.

7 Status Epilepticus: Stages of Therapy Conventional/Historical 2012 Guidelines 1 st line (i.e. BZD) Emergent initial therapy 2 nd line (i.e. phenytoin) Urgent control therapy 3 rd line (i.e. midazolam) 4 th line (i.e. barbiturates) Refractory SE therapy ALL patients will need emergent therapy (i.e. 1 st line) and urgent control therapy (i.e. 2 nd line) Brophy GM, et al. Neurocrit Care 2012; 17: Status Epilepticus: Emergent Therapy Goal RAPID termination of seizure activity 1,2 Benzodiazepines are the drug of choice 1 IV route preferred Lorazepam preferred agent Alternative routes Intramuscular: midazolam preferred Rectal: diazepam preferred; midazolam Buccal, nasal: midazolam 1. Brophy GM, et al. Neurocrit Care 2012; 17: Betjemann JP and Lowenstein DH. Lancet Neurol 2015; 14: Status Epilepticus: Emergent Therapy Drug Lorazepam Midazolam Diazepam Phenytoin/fosphenytoin Phenobarbital Valproate sodium Levetiracetam 2012 Level of Evidence Class I, level A Class I, level A Class I, level A Class IIb, level A Class IIb, level A Class IIb, level A Class IIb, level C Brophy GM, et al. Neurocrit Care 2012; 17: 3 23.

8 Status Epilepticus: Emergent Therapy Study Population Intervention SE Termination (%) Trieman et al. New Engl J Med 1998 Allredge et al. New Engl J Med 2001 Silbergleit et al. New Engl J Med 2012 Veterans w/gcse or subtle SE Overt (N): 384 Subtle (N): 134 Adults w/out of hospital overt SE LOR (N): 66 DZP (N): 68 PBO (N): 71 Children and adults w/out of hospital overt SE MID (N): 448 LOR (N): 445 LOR: 0.1mg/kg IV O: 64.9* S: 17.9 PHB: 15mg/kg IV O: 58.2 S: 24.2 DZP+PHT: mg/kg IV O: 55.8 S: 8.3 PHT: 18mg/kg IV O: 43.6* S: 7.7 LOR: 2mg IV (NTE 4mg) 59.1 DZP: 5mg IV (NTE 10mg) 42.6 PBO 21.1 LOR: 2 4mg IV 63.4^ MID: 5 10mg IM 73.4^ GCSE, generalized convulsive status epilepticus; SE, status epilepticus; LOR, lorazepam; PHB, phenobarbital; DZP, diazepam; PHT, phenytoin; PBO, placebo; MID, midazolam; NTE, not to exceed *P = in pairwise comparison P<0.05 vs. PBO (adjusted and unadjusted ORs) P>0.05 vs. LOR (adjusted and unadjusted ORs) or PBO (adjusted ORs) ^P<0.001 for non inferiority of IM MID Status Epilepticus: Emergent Therapy Study Population Intervention SE Termination (%) Trieman et al. New Engl J Med 1998 Alldredge et al. New Engl J Med 2001 Silbergleit et al. New Engl J Med 2012 Veterans w/gcse or subtle SE Overt (N): 384 Subtle (N): 134 Adults w/out of hospital overt SE LOR (N): 66 DZP (N): 68 PBO (N): 71 Children and adults w/out of hospital overt SE MID (N): 448 LOR (N): 445 LOR: 0.1mg/kg IV O: 64.9* S: 17.9 PHB: 15mg/kg IV O: 58.2 S: 24.2 DZP+PHT: mg/kg IV O: 55.8 S: 8.3 PHT: 18mg/kg IV O: 43.6* S: 7.7 LOR: 2mg IV (NTE 4mg) 59.1 DZP: 5mg IV (NTE 10mg) 42.6 PBO 21.1 LOR: 2 4mg IV 63.4^ MID: 5 10mg IM 73.4^ GCSE, generalized convulsive status epilepticus; SE, status epilepticus; LOR, lorazepam; PHB, phenobarbital; DZP, diazepam; PHT, phenytoin; PBO, placebo; MID, midazolam; NTE, not to exceed *P = in pairwise comparison P<0.05 vs. PBO (adjusted and unadjusted ORs) P>0.05 vs. LOR (adjusted and unadjusted ORs) or PBO (adjusted ORs) ^P<0.001 for non inferiority of IM MID Status Epilepticus: Emergent Therapy Study Population Intervention SE Termination (%) Trieman et al. New Engl J Med 1998 Allredge et al. New Engl J Med 2001 Silbergleit et al. New Engl J Med 2012 Veterans w/gcse or subtle SE Overt (N): 384 Subtle (N): 134 Adults w/out of hospital overt SE LOR (N): 66 DZP (N): 68 PBO (N): 71 Children and adults w/out of hospital overt SE MID (N): 448 LOR (N): 445 LOR: 0.1mg/kg IV O: 64.9* S: 17.9 PHB: 15mg/kg IV O: 58.2 S: 24.2 DZP+PHT: mg/kg IV O: 55.8 S: 8.3 PHT: 18mg/kg IV O: 43.6* S: 7.7 LOR: 2mg IV (NTE 4mg) 59.1 DZP: 5mg IV (NTE 10mg) 42.6 PBO 21.1 LOR: 2 4mg IV 63.4^ MID: 5 10mg IM 73.4^ GCSE, generalized convulsive status epilepticus; SE, status epilepticus; LOR, lorazepam; PHB, phenobarbital; DZP, diazepam; PHT, phenytoin; PBO, placebo; MID, midazolam; NTE, not to exceed *P = in pairwise comparison P<0.05 vs. PBO (adjusted and unadjusted ORs) P>0.05 vs. LOR (adjusted and unadjusted ORs) or PBO (adjusted ORs) ^P<0.001 for non inferiority of IM MID

9 Status Epilepticus: Emergent Therapy Drug Initial Dosing Infusion rate SAE Considerations 0.15 mg/kg IV up to 10 Hypotension Rapid DZP mg/dose redistribution 5 mg/min Respiratory May repeat in 5 min depression Active metabolite 0.1 mg/kg IV up to 4 LOR mg/dose May repeat in 5 10 min 2 mg/min IV contains PG 0.2 mg/kg IM up to 10 mg Rapid redistribution MID 0.2 mg/kg intranasal NA Active metabolite 0.5mg/kg buccal Renal elimination DZP, diazepam; LOR, lorazepam; MID, midazolam; SAE, serious adverse effects; NA, not applicable PG, propylene glycol Brophy GM, et al. Neurocrit Care 2012; 17: Status Epilepticus: Emergent Therapy Summary Goal is RAPID termination of seizure activity BZD are drug of choice IV lorazepam preferred Alternative routes available, if needed Importance of appropriate dosing Most adults will require the max weight based dose Status Epilepticus: Urgent Therapy Response to emergent therapy Rapid attainment of therapeutic AEDs Failure of emergent therapy TERMINATE STATUS EPILEPTICUS!!! Continued maintenance dosing of AEDs Drug of choice not well established Drug Valproate sodium Phenytoin/fosphenytoin Midazolam CIV Phenobarbital Levetiracetam 2012 Level of Evidence **Class IIa, Level A** Class IIa, Level B Class IIb, Level B Class IIb, Level C Class IIb, Level C Brophy GM, et al. Neurocrit Care 2012; 17: 3 23.

10 Status Epilepticus: Urgent Therapy Study Population Intervention SE Termination (%) Alvarez, et al. Epilepsia 2011 Agarwal P, et al. Seizure 2007 Chakravarthi, et al. Journal of Clinical Neuroscience 2015 All SE pa ents 16yr treated w/2 nd line agent VPA (N): 59 PHT (N): 70 LEV(N): 58 Pa ents >2yr admi ed to ED or ICU after diazepam VPA (N): 50 PHT (N): 50 Uncontrolled GCSE after lorazepam PHT (N): 22 LEV (N): 22 VPA: 20mg/kg IV 74.58* PHT: 20mg/kg IV LEV: 20mg/kg IV 51.73* VPA 20mg/kg 88 PHT 20mg/kg 84 PHT: 20mg/kg IV 68.2** LEV: 20mg/kg IV 59.1** SE, status epilepticus; GCSE, generalized status epilepticus; VPA, valproate/valproic acid; PHT, phenytoin; LEV, levetiracetam *Failure to terminate SE, adjusted OR = 2.69 ( ) **24hr recurrence rates higher in LEV (40%) vs PHT (27.3%) ; p = 0.34 Mean age: Alvarez et al. 62yr; Agarwal et al. 27yr; Chakravarthi et al. 35yr Status Epilepticus: Urgent Therapy Study Population Intervention SE Termination (%) Alvarez, et al. Epilepsia 2011 Agarwal P, et al. Seizure 2007 Chakravarthi, et al. Journal of Clinical Neuroscience 2015 All SE pa ents 16yr treated w/2 nd line agent VPA (N): 59 PHT (N): 70 LEV(N): 58 Pa ents >2yr admi ed to ED or ICU after diazepam VPA (N): 50 PHT (N): 50 Uncontrolled GCSE after lorazepam PHT (N): 22 LEV (N): 22 VPA: 20mg/kg IV 74.58* PHT: 20mg/kg IV LEV: 20mg/kg IV 51.73* VPA 20mg/kg 88 PHT 20mg/kg 84 PHT: 20mg/kg IV 68.2** LEV: 20mg/kg IV 59.1** SE, status epilepticus; GCSE, generalized status epilepticus; VPA, valproate/valproic acid; PHT, phenytoin; LEV, levetiracetam *Failure to terminate SE, adjusted OR = 2.69 ( ) **24hr recurrence rates higher in LEV (40%) vs PHT (27.3%) ; p = 0.34 Mean age: Alvarez et al. 62yr; Agarwal et al. 27yr; Chakravarthi et al. 35yr Status Epilepticus: Urgent Therapy Study Population Intervention SE Termination (%) Alvarez, et al. Epilepsia 2011 Agarwal P, et al. Seizure 2007 Chakravarthi, et al. Journal of Clinical Neuroscience 2015 All SE pa ents 16yr treated w/2 nd line agent VPA (N): 59 PHT (N): 70 LEV(N): 58 Pa ents >2yr admi ed to ED or ICU after diazepam VPA (N): 50 PHT (N): 50 Uncontrolled GCSE after lorazepam PHT (N): 22 LEV (N): 22 VPA: 20mg/kg IV 74.58* PHT: 20mg/kg IV LEV: 20mg/kg IV 51.73* VPA 20mg/kg 88 PHT 20mg/kg 84 PHT: 20mg/kg IV 68.2** LEV: 20mg/kg IV 59.1** SE, status epilepticus; GCSE, generalized status epilepticus; VPA, valproate/valproic acid; PHT, phenytoin; LEV, levetiracetam *Failure to terminate SE, adjusted OR = 2.69 ( ) **24hr recurrence rates higher in LEV (40%) vs PHT (27.3%) ; p = 0.34 Mean age: Alvarez et al. 62yr; Agarwal et al. 27yr; Chakravarthi et al. 35yr

11 Status Epilepticus: Urgent Therapy Study Population Intervention SE Termination (%) Yasiry and Shorvon, Seizure 2014 Systematic review of BZD resistant GCSE studies 27 papers = 798 SE episodes LEV (N): 8; 206 SE episodes PHB (N): 2; 43 SE episodes PHT (N): 8; 294 SE episodes VPA (N): 9; 251 SE episodes LEV 68.5 ( ) PHB 73.6 ( ) PHT 50.2 ( ) VPA 75.5 ( ) SE, status epilepticus; GCSE, generalized status epilepticus; VPA, valproate/valproic acid; PHT, phenytoin; LEV, levetiracetam; PHB, phenobarbital Implications Little literature evaluating effectiveness of urgent control therapy (i.e. 2 nd line) 77% of studies of observational or retrospective Most prospective studies open label with risk of bias Only 1 study comparing interventions in a randomized double blinded fashion Status Epilepticus: Urgent Therapy The Established Status Epilepticus Trial Primary objective: determine the most effective and/or least effective treatment of BZD refractory SE Design: multicenter, randomized, double blinded Population: GCSE >2yr Drug Fosphenytoin Levetiracetam Valproic acid Dose 20 mg/kg 60 mg/kg 40 mg/kg Bleck T, et al. Epilepsia 2013; 54 (Suppl 6): Brophy GM, et al. Neurocrit Care 2012; 17: Status Epilepticus: Urgent Therapy Drug Initial Dosing Infusion rate SAE Considerations VPA FPHT PHB mg/kg IV May give additional 20 mg/kg 20 mg/kg PE IV May give additional 5mg/kg 20 mg/kg IV May give additional 5 10 mg/kg 3 6 mg/kg/min 150 mg PE/min mg/min LEV mg IV 2 5 mg/kg/min ammonia Pancreatitis TPA Hepatotoxicity Hypotension Arrhythmias Hypotension Respiratory depression NA Use w/caution in TBI May be preferred in GBM Compatible w/ns, D5W Consider in chronic PHT IV contains PG Minimal DDIs VPA, valproate/valproic acid; FPHT, fosphenytoin; PHT, phenytoin; PHB, phenobarbital; LEV, levetiracetam SAE, serious adverse effects; TPA, thrombocytopenia; TBI, traumatic brain injury; PG, propylene glycol; DDIs, drug drug interactions No hepatic metab.

12 Status Epilepticus: Urgent Therapy Summary Goals RAPID termination of seizure activity RAPID attainment of therapeutic AED levels ALL patients should receive urgent control therapy Preferred agent: PHT, LEV, VPA? Not firmly established Status Epilepticus REFRACTORY STATUS EPILEPTICUS Status Epilepticus: Refractory SE 23 43% of SE will progress to RSE 1 Continuous EEG and/or clinical exam 2 Immediately start additional agents 2 Repeat bolus vs. additional agents Continuous infusions 2 Consider after failure of bolus agents Insufficient data to suggest preferred agent 1. Betjemann JP and Lowenstein DH. Lancet Neurol 2015; 14: Brophy GM, et al. Neurocrit Care 2012; 17: 3 23.

13 Status Epilepticus: Refractory SE Drug Midazolam Propofol Pentobarbital/thiopental Valproate sodium Levetiracetam Phenytoin/fosphenytoin Lacosamide Topiramate Phenobarbtial 2012 Level of Evidence Class IIa, Level B Class IIb, Level B Class IIb, Level B Class IIa, Level B Class IIb, Level C Class IIb, Level C Class IIb, Level C Class IIb, Level C Class IIb, Level C Brophy GM, et al. Neurocrit Care 2012; 17: Status Epilepticus: Refractory SE Claassen J, et al. Epilepsia * ** ** Acute Fx BTS WDS HOTN MOR MID, midazolam, PRO, propofol, PTB, pentobarbital; Fx, failure; BTS, breakthrough seizures; WDS, withdrawal seizure; HOTN, hypotension requiring pressors, MOR, mortality *P <0.01 vs. other two treatments **P <0.001 vs. other two treatments ** ** MID PRO PTB Status Epilepticus: Refractory SE Rosetti AO, et al. Neurocrit Care 2011 Randomized, single blind, multicenter study Propofol vs. barbiturates (BBT) Halted early due to poor recruitment (N = 23) N = 9 for BBT, N = 14 for propofol No significant differences in outcomes RSE control, functional outcomes, mortality Longer duration (days) of intubation for BBTs 4 (2 28) vs (8 70); p = 0.03

14 Status Epilepticus: Refractory SE Drug Initial Dose Infusion rate* SAE Considerations MID PTB PRO 0.2mg/kg 5 15mg/kg 1 2mg/kg mg/kg/hr mg/kg/hr mcg/kg/min Respiratory depression Hypotension (MID<PRO<PENT) Respiratory depression Hypotension Cardiac depression Ileus Respiratory depression Hypotension Cardiac failure Rhabdomyolysis Metab. Acidosis Renal failure MID, midazolam; PTB, pentobarbital; PRO, propofol; SAE, serious adverse effects MV, mechanical ventilation; PG, propylene glycol; BTS, breakthrough seizures *Titrated to EEG Tachyphylaxis Active metabolite Renal elimination Rapid redistribution IV contains PG Prolonged MV vs. PRO Account for calories (1.1kcal/min) May have less BTS vs. MID Brophy GM, et al. Neurocrit Care 2012; 17: Status Epilepticus: Refractory SE Ketamine Listed as alternative treatment option 1 Optimal dose not known 2,3 2mg/kg loading dose mcg/kg/min maintenance infusion May be beneficial in late stage refractory SE 1. Brophy GM, et al. Neurocrit Care 2012; 17: 3 23c. 2. Claassen J, Chang I, Bleck TP. Neurocritical Care Society Practice Update. Found at: 3. Ziai WC and Kaplan PW. Semin Neurol 2008; 28: Status Epilepticus: Refractory SE Global Audit of 1st Line CIV Agent 8% 32% 59% Midazolam Propofol Barbiturates Ferlisi M, et al. Epilepsy and Behavior 2015; 49:

15 Status Epilepticus: Refractory SE Intensity and duration of treatment Goal: cessation of electrographic seizures or burst suppression 1 Intensity of treatment usually dictated by EEG findings 1 Optimal duration of EEG seizure control not known 1 Customarily hours Aim for high levels of the fewest AEDs 2 1. Brophy GM, et al. Neurocrit Care 2012; 17: 3 23c. 2. Mirski MA and Varelas PN. Crit Care Clin 2008; 24: Status Epilepticus: Refractory SE Summary Re bolus vs. additional agents Continuous infusions Very little data to guide therapy Consider PRO or MID as initial agent Consider PTB after failure of PRO and/or MID Consider ketamine as salvage/rescue in late RSE Continue x 24 48hr Status Epilepticus FINAL SUMMARY

16 Status Epilepticus: Final Summary Definitions and classifications 5 minutes continuous clinical and/or electrographic seizure activity Recurrent seizure activity without recovery between seizures GCSE, NCSE, RSE Pathophysiology Abnormal neuronal excitation Loss of endogenous inhibitor mechanisms Status Epilepticus: Final Summary Stages of therapy Emergent control therapy BZD well established Urgent control therapy VPA vs. LEV vs. PHT RSE Re bolus vs. additional agents Continuous infusions MID vs. PRO PTB after MID/PRO failure Ketamine Ensure adequate AED levels Post Assessment Questions 1) Which of the following would be consistent with the definition of SE per the 2012 Neurocritical Care guidelines: A. 30 minutes of continuous seizure activity B. 1 2 minutes of continuous seizure activity C. 5 minutes of continuous seizure activity D. 15 minutes of continuous seizure activity

17 Post Assessment Questions 2) The fundamental pathophysiological mechanisms behind SE are: I. Abnormal neuronal excitation II. Increased endogenous inhibitor mechanisms III. NMDA receptor downregulation IV. Loss of endogenous inhibitor mechanisms A. I, II B. II, III C. I, III D. I, IV Post Assessment Questions 3) Which of the following would be the preferred regimen for emergent initial therapy in a SE patient with IV access weighing 70kg per the 2012 Neurocritical Care SE guidelines : A. Midazolam 10mg B. Phenytoin 20mg/kg C. Diazepam 10mg D. Lorazepam 4mg Post Assessment Questions 4) Which of the following was given the highest level of evidence for urgent control therapy by the 2012 Neurocritical Care SE guidelines: A. Levetiracetam B. Phenobarbital C. Valproic acid D. Phenytoin

18 Post Assessment Questions 5) Barbiturates are the first line continuous infusion agent for refractory status epilepticus? A. True B. False Status Epilepticus: A refresher Ruben D. Villanueva, Pharm.D., BCPS OU Medical Center Trauma ICU Pharmacist