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Shake It Up: Seizure Prophylaxis and Status Epilepticus Management

Emily Yarborough, PharmD PGY2 Critical Care Pharmacy Resident January 4, 2018

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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

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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

Carney N, Totten AM, Oʼreilly C, et al. Neurosurgery. 2017 Jan 1;80(1):6-15.

Early Seizures •  Phenytoin preferred •  Levetiracetam as

alternative

Late Seizures •  Antiepileptic

prophylaxis not recommended

Mild - Moderate TBI •  Lower rates of seizures •  Phenytoin appropriate

+Early vs Late Seizure Prophylaxis

Temkin NR, Dikmen SS, et al. N Engl J Med. 1990;323(8):497-502.

p<0.001 p>0.2

+Phenytoin

Pharmacological class Hydantoin anticonvulsant

Mechanism Increases efflux or decreases influx of sodium ions across cell membranes

Loading dose 15 - 20 mg/kg IV over 30 – 60 minutes 300 mg PO q6h for 3 doses (900 mg total)

Maintenance dose 5 mg/kg/day IV or PO divided in 1 to 3 doses or 300-400 mg/day in divided doses

Serum levels 10 – 20 mg/L

Drug-drug interactions Amiodarone, warfarin, digoxin, birth control, H2RAs, antidepressants

Adverse effects 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 Hydantoin anticonvulsant

Mechanism Increases efflux or decreases influx of sodium ions across cell membranes Prolongs effective refractory period

Dose 1000 mg IV every 12 hours Needs renal dose adjustment

Serum levels Not required

Drug-drug interactions Opioids, SSRIs

Adverse effects Vomiting, increased intracranial pressure, behavioral problems (anxiety, aggression), hypertension, anemia, abnormal AST/ALT

Keppra. [package insert]. UCB. Smyrna, GA. 1999.

+Phenytoin vs Levetiracetam

Title Population Intervention Results

Inaba et al 2013

Severe blunt TBI •  LEV 1g IV q12h •  PHT 20 mg/kg IV load

followed by maintenance 5 mg/kg/day divided TID

•  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)

KE Jones et al 2008

Severe TBI •  LEV or PHT monotherapy

•  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)

Szaflarski et al 2010

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

•  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)

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.

+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

Temkin NR, Dikmen SS, Anderson GD, et al. J Neurosurg. 1999;91(4):593-600.

p=0.07

+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.

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Patient Case 2

+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)

Accessed at: https://www.thoracic.org. November 27, 2017.

136 100 24

3.8 23 1.5 117

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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.

+ICH Primary Literature

Naidech AM, Garg RK, Liebling S, et al. Stroke. 2009;40(12):3810-5.

•  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

+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, non-aneurysmatic 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

. 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.

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Patient Case 3

+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

Accessed at: https://medium.com/@DrJavahery/case-study-series-subarachnoid-hemorrhage-sah-ce0ef1bf59d0. November 24, 2017.

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SAH Seizure Prophylaxis

+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

Connolly ES, Rabinstein AA, Carhuapoma JR, et al. Stroke. 2012;43(6):1711-37.

+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

•  Timing, type of seizure activity, incidence of delayed ischemic neurologic deficits, 12-month functional outcome on modified Rankin Score

Results •  353 patients •  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

Naidech AM, Kreiter KT, Janjua N, et al. Stroke. 2005;36(3):583-7. TICS: telephone interview for cognitive status

+SAH Seizure Prophylaxis

Title Population Intervention Results Rosengart et al 2007

Aneurysmal SAH from four randomized, double-blind placebo-controlled 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

Rosengart AJ, Huo JD, Tolentino J, et al. J Neurosurg. 2007;107(2):253-60.

+SAH Seizure Prophylaxis: Who?

- Intracerebral hemorrhage

- Middle cerebral and anterior communicating artery aneurysms

- Increased thickness of SAH clot

- Rebleeding

- Infarction

- Poor neurological grade

Incr

ease

d r

isk

Connolly ES, Rabinstein AA, Carhuapoma JR, et al. Stroke. 2012;43(6):1711-37.

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Patient Case 4

+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

Chye CL, Lin KH, Ou CH, Sun CK, Chang IW, Liang CL. BMC Surg. 2015;15:60.

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.

+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

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.

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Patient Case 5

+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

Cook A, Brophy G. Critical Care Pharmacy Preparatory Review Course. 2015;(2):51-93.

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Status Epilepticus Management

+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

•  Initiate antiepileptic • Fosphenytoin 18-20 mg/kg

IV • Levetiracetam 60 mg/kg IV • Phenobarbital 20 mg/kg IV • Valproate 20-40 mg/kg IV

Urgent • 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

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.

+IV Lorazepam vs IM Midazolam: Results

Silbergleit R, Durkalski V, Lowenstein D, et al. N Engl J Med. 2012;366(7):591-600.

+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])

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.

+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)

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.

+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 0.15-0.20 mg/kg IV (max 10 mg/dose, may repeat dose once)

Sedation, hypotension

Fosphenytoin 18-20 mg PE/kg IV (max dose 1500 mg PE/dose, max rate 150 mg PE/min)

Hypotension, arrhythmia

Phenytoin 18-20 mg/kg IV (max rate 50 mg PE/min)

Hypotension, arrhythmia, phlebitis, purple glove syndrome

Valproic acid 20-40 mg/kg IV (max 3000 mg/dose, max rate 6 mg/kg/min)

Hyperammonemia

Levetiracetam 60 mg/kg (max 4500 mg/dose, max rate 5 mg/kg/min)

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 high-dose 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

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: 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)

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Shake It Up: Seizure Prophylaxis and Status Epilepticus Management

Emily Yarborough, PharmD PGY2 Critical Care Pharmacy Resident January 4, 2018