+ Shake It Up: Seizure Prophylaxis and Status Epilepticus Management Emily Yarborough, PharmD PGY2 Critical Care Pharmacy Resident January 4, 2018
+ Patient Case 1
+ Patient Case 1 n JM is a 68 yo M involved in serious MVC n PMH: HTN, hyperlipidemia, T2DM, atrial fibrillation n Home Medications: Aspirin 81 mg PO daily, atorvastatin 40 mg PO daily, lisinopril 20 mg PO daily, warfarin 5 mg PO daily n Physical Exam: Intubated, 5 cm laceration across the forehead, displaced shoulder n Head CT: R frontal region skull fracture, small R frontal lobe contusion 125 102 20 3.8 28 1.2 225
+ Traumatic Brain Injury (TBI) Seizure Prophylaxis
+ TBI Related Seizures n Seizure onset n Early 0-7 days n Late > 7 days n Risk factors for seizure development n Alcoholism n Intracranial hemorrhage n Loss of consciousness n Penetrating injuries n Severity of injury n Lesion location Carney N, Totten AM, Oʼreilly C, et al. Neurosurgery. 2017 Jan 1;80(1):6-15.
+ TBI Seizure Prophylaxis Early Seizures Phenytoin preferred Levetiracetam as alternative Late Seizures Antiepileptic prophylaxis not recommended Mild - Moderate TBI Lower rates of seizures Phenytoin appropriate Carney N, Totten AM, Oʼreilly C, et al. Neurosurgery. 2017 Jan 1;80(1):6-15.
+ Early vs Late Seizure Prophylaxis p<0.001 p>0.2 Temkin NR, Dikmen SS, et al. N Engl J Med. 1990;323(8):497-502.
+ Phenytoin Pharmacological class Mechanism Loading dose Maintenance dose Serum levels Drug-drug interactions Adverse effects Hydantoin anticonvulsant Increases efflux or decreases influx of sodium ions across cell membranes 15-20 mg/kg IV over 30 60 minutes 300 mg PO q6h for 3 doses (900 mg total) 5 mg/kg/day IV or PO divided in 1 to 3 doses or 300-400 mg/day in divided doses 10 20 mg/l Amiodarone, warfarin, digoxin, birth control, H2RAs, antidepressants Confusion, drowsiness, bradycardia, ataxia, hypotension Serious: Stevens-Johnson syndrome, arrhythmias, CNS depression, purple glove syndrome Phenytoin. [package insert]. Pfizer. New York, NY. 2011.
+ Levetiracetam Pharmacological class Mechanism Dose Serum levels Drug-drug interactions Adverse effects Hydantoin anticonvulsant Increases efflux or decreases influx of sodium ions across cell membranes Prolongs effective refractory period 1000 mg IV every 12 hours Needs renal dose adjustment Not required Opioids, SSRIs Vomiting, increased intracranial pressure, behavioral problems (anxiety, aggression), hypertension, anemia, abnormal AST/ALT Keppra. [package insert]. UCB. Smyrna, GA. 1999.
Inaba K, Menaker J, Branco BC, et al. J Trauma Acute Care Surg. 2013;74(3):766-71. Jones KE, Puccio AM, Harshman KJ, et al. Neurosurg Focus. 2008;25(4):E3. Szaflarski JP, Sangha KS, Lindsell CJ, et al. Neurocrit Care. 2010;12(2):165-72. + Phenytoin vs Levetiracetam Title Population Intervention Results Inaba et al 2013 KE Jones et al 2008 Szaflarski et al 2010 Severe blunt TBI LEV 1g IV q12h PHT 20 mg/kg IV load followed by maintenance 5 mg/kg/ day divided TID Severe TBI LEV or PHT monotherapy Severe TBI or subarachnoid hemorrhage LEV 20 mg/kg IV load, maintenance of 1g IV q12h Fosphenytoin 20 mg/kg IV load, maintenance PHT 5 mg/kg/day divided BID N=813 No significant differences in seizure rates (1.5% vs 1.5%, p=0.997) More treatment discontinuation with phenytoin due to ADRs (0% vs 2.9%, p< 0.001) 32 LEV, 41 PHT LEV and PHT had equivalent incidence of seizure activity (p=0.556) Higher incidence of abnormal EEG findings with LEV (p=0.003) 52 patients (34 LEV, 18 PHT) LEV patients experienced better long term outcomes than those on PHT; lower disability rating scale score at 3 months (p=0.042); higher GCS at 6 months (p=0.039)
+ Other Pharmacological Agents n Potential role n Carbamazepine n Avoid n Valproate n Phenobarbital Carney N, Totten AM, Oʼreilly C, et al. Neurosurgery. 2017 Jan 1;80(1):6-15. Dikmen SS, Machamer JE, Winn HR, et al. Neurology. 2000;54(4):895-902. Torbic H, Forni AA, et al. Am J Health Syst Pharm. 2013;70(9):759-66.
+ Valproate Results: Late Seizures p=0.19 Temkin NR, Dikmen SS, Anderson GD, et al. J Neurosurg. 1999;91(4):593-600.
+ Valproate Results: Mortality p=0.07 Temkin NR, Dikmen SS, Anderson GD, et al. J Neurosurg. 1999;91(4):593-600.
+ Phenobarbital Primary Literature Cooperative Prospective Study on Posttraumatic Epilepsy: Risk Factors and the Effect of Prophylactic Anticonvulsant Comparison Group I- Severe head injury A-phenobarbital B- control Group II- Mild head injury Primary outcome Incidence of epilepsy Secondary outcomes Factors influencing posttraumatic epilepsy Results N=191 (50 phenobarbital, 76 placebo, 65 mild injury) Epileptic attacks occurred in 15 cases (12.7% of group I), consisting of 8 (16.0%) in group IA, 8 in group IB (10.5%) and 0 in group II Risk factors associated with epilepsy: disturbance of consciousness, neurological sign, abnormal CT findings Manaka S. Jpn J Psychiatry Neurol. 1992;46(2):311-5.
+ Phenobarbital Results Manaka S. Jpn J Psychiatry Neurol. 1992;46(2):311-5.
+ Patient Case 2
Accessed at: https://www.thoracic.org. November 27, 2017. + Patient Case 2 n AW is a 21 yo M who presents with complaint of severe headache. He was found in a gym bathroom with L sided weakness and urinary incontinence after lifting weights. In the ED he follows commands but does have L hemiparesis. n PMH: Asthma, ADHD n Home Medications: Albuterol inhaler, lisdexamphetamine 30 mg PO QAM n Imaging: Emergent non contrast head CT reveals R frontal intracerebral hemorrhage (ICH) 136 100 24 3.8 23 1.5 117
+ ICH Seizure Prophylaxis
+ ICH Guidelines n Clinical seizures should be treated with antiseizure drugs n Patients with a change in mental status, electrographic seizures on EEG should be treated n Continuous EEG monitoring is indicated in ICH patients with depressed mental status n Prophylactic antiseizure medication is not recommended Hemphill JC, Greenberg SM, Anderson CS, et al. Stroke. 2015;46(7):2032-60.
Naidech AM, Garg RK, Liebling S, et al. Stroke. 2009;40(12):3810-5. + ICH Primary Literature Phenytoin was associated with: Increased fever (p=0.03) Worse NIHSS at 14 days (p=0.003) Worse modified Rankin scale at 14 days, 28 days, and 3 months
. Messé SR, Sansing LH, Cucchiara BL, et al. Neurocrit Care. 2009;11(1):38-44. Gilad R, Boaz M, Dabby R, Sadeh M, Lampl Y. Epilepsy Res. 2011;95(3):227-31. + ICH Primary Literature Title Population Intervention Results Messé et al 2009 Primary ICH PHT, VPA, or lamotrigine within 6h of symptom onset compared to placebo N=295 Initiation of AEDs was associated with poor outcome (OR 6.8; 95% CI 2.2-21.2, p=0.001) Gilad et al 2011 Non-traumatic, nonaneurysmatic spontaneous ICH VPA or placebo for 1 month N=72 (36 VPA, 36 placebo) 21% of patients developed seizures with a by-treatment difference in incident seizures not detected (p=0.5) but a reduction in early seizures was observed with VPA
+ Patient Case 3
Accessed at: https://medium.com/@drjavahery/case-study-seriessubarachnoid-hemorrhage-sah-ce0ef1bf59d0. November 24, 2017. + Patient Case 3 n CM is a 48 yo F who presents with loss of consciousness followed by a severe headache after regaining consciousness. n PMH: T2DM, HTN, osteoarthritis n Physical exam: R gaze preference, diaphoretic, GCS 15, L facial droop n Imaging: CT head shows extensive subarachnoid hemorrhage (SAH) Home Medications Metformin 500 mg PO BID Amlodipine 10 mg PO daily
+ SAH Seizure Prophylaxis
Connolly ES, Rabinstein AA, Carhuapoma JR, et al. Stroke. 2012;43(6):1711-37. + SAH Guidelines n The use of prophylactic anticonvulsants may be considered n Routine long-term use of anticonvulsants is not recommended but may be considered n Prior seizure n Intracerebral hematoma n Intractable hypertension n Infarction or aneurysm at the middle cerebral artery
+ SAH Seizure Prophylaxis Prophylactic Antiepileptics and Seizure Incidence Following Subarachnoid Hemorrhage Design Retrospective propensity score-matched analysis Comparison Patients receiving antiepileptics versus those not Primary outcome Seizure occurrence diagnosed clinically and with EEG Secondary outcomes Results 353 patients Timing, type of seizure activity, incidence of delayed ischemic neurologic deficits, 12-month functional outcome on modified Rankin Score Overall, the incidence of seizures did not vary significantly based on the use of prophylactic antiepileptics (11% vs 8%, p=0.33) Panczykowski D, Pease M, Zhao Y, et al. Stroke. 2016;47(7):1754-60.
+ SAH Seizure Prophylaxis with PHT Associated with Worse Outcomes TICS: telephone interview for cognitive status Naidech AM, Kreiter KT, Janjua N, et al. Stroke. 2005;36(3):583-7.
Rosengart AJ, Huo JD, Tolentino J, et al. J Neurosurg. 2007;107(2):253-60. + SAH Seizure Prophylaxis Title Population Intervention Results Rosengart et al 2007 Aneurysmal SAH from four randomized, double-blind placebocontrolled trials AED (phenytoin, phenobarbital, carbamazepine) N=3552 Patients treated with AEDs had worse outcomes based on GCS Increased odds Cerebral vasospasm Neurological deterioration Cerebral infarction Elevated temperature
Connolly ES, Rabinstein AA, Carhuapoma JR, et al. Stroke. 2012;43(6):1711-37. + SAH Seizure Prophylaxis: Who? Increased risk - Intracerebral hemorrhage - Middle cerebral and anterior communicating artery aneurysms - Increased thickness of SAH clot - Rebleeding - Infarction - Poor neurological grade
+ Patient Case 4
Chye CL, Lin KH, Ou CH, Sun CK, Chang IW, Liang CL. BMC Surg. 2015;15:60. + Patient Case 4 n PK is a 69 yo F referred to CRMH with progressive headache, nausea and vomiting for the past 3 days n PMH: NSTEMI, CVA, HTN n Imaging: Brain CT reveals L temporal subdural hematoma (SDH) with slight mass effect Home Medications Aspirin 81 mg PO daily Atorvastatin 80 mg PO daily Lisinopril 20 mg PO daily Metoprolol tartrate 50 mg PO BID
+ SDH Guidelines n Use of seizure prophylaxis recommended for 7 days n Increased risk for seizures n Isolated acute SDH n Evacuation by craniotomy n Worse GCS before and after surgery n Agents n Phenytoin preferred n Levetiracetam as an alternative Gerard C, Busl KM. Neurol. 2014;16(1):275.
Radic JA, Chou SH, Du R, Lee JW. Neurocrit Care. 2014;21(2):228-37. Won SY, Dubinski D, Herrmann E, et al. World Neurosurg. 2017;101:416-424. + SDH: Primary Literature Title Population Intervention Results Radic et al 2014 Acute or subacute SDH LEV 1g IV load then 500-1000 mg IV/PO BID PHT 15-20 mg/kg IV load followed by 15-20 mg/g/ day IV/PO divided TID N=284 (124 PHT, 164 LEV) No significant difference in clinical and/or electrographic seizure risk Decreased risk of adverse events in LEV arm (p<0.001) Won et al 2017 Acute SDH No intervention (Comparison of seizure and antiseizure groups) N=139 Overall incidence of seizures was 38% Independent predictors of seizures: GCS < 9 Operation after 24 hrs Anticoagulation
+ Patient Case 5
Cook A, Brophy G. Critical Care Pharmacy Preparatory Review Course. 2015;(2):51-93. + Patient Case 5 n CH is a 37 year-old M admitted to the ED after sustaining a traumatic subdural hematoma n On admission, his GCS score falls from 10 to 7 over 10 minutes and his nurse notices facial twitching Current Medications Fosphenytoin 200 mg PE IV q12h Famotidine 20 mg IV q12h Heparin 5000 units SC q8h Docusate 250 mg NG BID
+ Status Epilepticus Management
Brophy GM, Bell R, Claassen J, et al. Neurocrit Care. 2012;17(1):3-23. Glauser T, Shinnar S, Gloss D, et al. Epilepsy Curr. 2016;16(1):48-61. + SE Treatment Benzodiazepine preferred Diazepam 0.15-0.2 mg/ kg/dose IV Lorazepam 0.1 mg/kg IV (max 4 mg/dose) Midazolam 5-10 mg IM Emergent Urgent Initiate antiepileptic Fosphenytoin 18-20 mg/kg IV Levetiracetam 60 mg/kg IV Phenobarbital 20 mg/kg IV Valproate 20-40 mg/kg IV Repeat urgent therapy or use additional urgent therapy Lacosamide 200-400 mg IV Midazolam 0.5-2 mg/kg/hr infusion Pentobarbital 25 mg/kg load then 1-5 mg/kg/hr infusion Propofol 20 mcg/kg/min Refractory
Silbergleit R, Durkalski V, Lowenstein D, et al. N Engl J Med. 2012;366(7):591-600. + IV Lorazepam vs IM Midazolam: Results
Agarwal P, Kumar N, Chandra R, Gupta G, et al. Seizure. 2007;16(6):527-32. Alvarez V, Januel JM, Burnand B, Rossetti AO. Epilepsia. 2011;52(7):1292-6. + SE Second Line Management Title Population Intervention Results Agarwal et al 2007 Benzodiazepine refractory patients with SE VA 20 mg/kg IV load or PHT 20 mg/kg IV N=100 (50 VA, 50 PHT) IV VA was successful in 88% and IV PHT in 84% (p>0.05) of SE patients Total number of adverse events did not differ significantly between the two groups (p>0.05) Alvarez et al 2011 Benzodiazepine refractory patients with SE VA 20 mg/kg IV load followed by 1000-2500 mg PHT 20 mg/kg IV load followed by 300-400 mg LEV 20 mg/kg IV load followed by 1000-3000 mg N=167 (198 SE episodes: 70 PHT, 59 VA, 58 LEV) LEV failed to control SE in 48.3%, PHT in 41.4%, VA in 25.4% LEV was related to a higher risk of second-line treatment failure compared to VA (OR 2.7 [1.2,6.1])
Prasad A, Worrall BB, Bertram EH, Bleck TP. Epilepsia. 2001;42(3):380-6. Claassen J, Hirsch LJ, Emerson RG, Mayer SA. Epilepsia. 2002;43(2):146-53. + Refractory SE Management Title Population Intervention Results Prasad et al 2001 Refractory SE patients Propofol (PROP) 1-3 mg/kg bolus, 1-10 mg/kg/hr infusion Midazolam (MDL) 2-12 mg bolus, 0.05-0.8 mg/kg/hr infusion N=20 (14 PROP, 6, MDL) PROP and MDL therapy achieved 64 and 67% complete clinical seizure suppression and 78 and 67% electrographic seizure suppression, respectively Claassen et al 2002 Refractory SE patients PROP, MDL, or pentobarbital (PTB) N=193 (54 MDL, 33 PROP, 106 PTB) Mortality was not associated with choice of agent or titration goal PTB treatment was associated with a lower frequency of short-term treatment failure (p<0.01), breakthrough seizures but had a higher frequency of hypotension (p<0.001)
Brophy GM, Bell R, Claassen J, et al. Neurocrit Care. 2012;17(1):3-23. Glauser T, Shinnar S, Gloss D, et al. Epilepsy Curr. 2016;16(1):48-61. + Summary: SE Medications Medication Dosing Adverse Effect Lorazepam 0.1 mg/kg IV (max 4 mg/dose up to 8 mg total) Sedation, hypotension Midazolam 0.2 mg/kg IM (max dose 10 mg) Sedation, hypotension Diazepam Fosphenytoin Phenytoin Valproic acid Levetiracetam 0.15-0.20 mg/kg IV (max 10 mg/dose, may repeat dose once) 18-20 mg PE/kg IV (max dose 1500 mg PE/dose, max rate 150 mg PE/min) 18-20 mg/kg IV (max rate 50 mg PE/min) 20-40 mg/kg IV (max 3000 mg/dose, max rate 6 mg/kg/ min) 60 mg/kg (max 4500 mg/dose, max rate 5 mg/kg/min) Sedation, hypotension Hypotension, arrhythmia Hypotension, arrhythmia, phlebitis, purple glove syndrome Hyperammonemia Sedation, irritability Lacosamide 200-400 mg IV (over 15-30 min) Dizziness, bradyarrhythmia
Brophy GM, Bell R, Claassen J, et al. Neurocrit Care. 2012;17(1):3-23. Glauser T, Shinnar S, Gloss D, et al. Epilepsy Curr. 2016;16(1):48-61. + Summary: SE Medications Medication Dosing Adverse Effect Topiramate Load of 500 mg PO BID x 2 days, taper to 200 mg BID by 200 mg/ day every 2 days Metabolic acidosis Phenobarbital 20 mg/kg IV (max rate 100 mg/min) Sedation, hypotension, respiratory depression Pentobarbital 10 mg/kg IV Sedation, hypotension, respiratory depression Midazolam highdose infusion 0.05-2 mg/kg/hr IV Sedation, hypotension, respiratory depression Propofol 20-200 mcg/kg/min IV, titrate by 5 mcg/kg/min Sedation, hypotension, PRIS
+ Summary: TBI and Brain Bleeds TBI Seizure prophylaxis: phenytoin or levetiracetam Avoid valproate and phenobarbital ICH No seizure prophylaxis due to increased mortality SAH? Depends on risk Consider phenytoin or levetiracetam SDH Phenytoin, levetiracetam preferred (similar to TBI)
+ Shake It Up: Seizure Prophylaxis and Status Epilepticus Management Emily Yarborough, PharmD PGY2 Critical Care Pharmacy Resident January 4, 2018