TRAUMATIC BRAIN INJURY SEIZURE PROPHYLAXIS MAJOR SEAN MEREDITH BSCH, BSP, PHARM D, CD ROYAL CANADIAN MEDICAL SERVICE
CPE Information and Disclosures Sean Meredith declares no conflicts of interest, real or apparent, and no financial interests in any company, product, or service mentioned in this program, including grants, employment, gifts, stock holdings, and honoraria.” The American Pharmacist Association is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education.
CPE Information Target Audience: Pharmacists and Pharmacist Technicians ACPE#: 0202-0000-18-224-L01-P/T Activity Type: Knowledge-based
Learning Objectives At the completion of this activity, Pharmacists will be able to: Explain the severity of a traumatic brain injury (TBI) based on the Glasgow Coma Scale (GCS) List the risk factors for early Post Traumatic Seizure (PTS) Recognize the most effective and safe Anti Epileptic Drug (AED) following a TBI for preventing PTS based on primary literature State the most effective duration of AED treatment following a TBI for preventing PTS based on primary literature Identify the therapeutic drug range for phenytoin
Learning Objectives At the completion of this activity, Pharmacy Technicians will be able to: State the incidence of PTS in patients that have experienced a TBI List the risk factors for early PTS Identify the therapeutic drug range for phenytoin
Outline Case Background Guidelines/Evidence Pharmacokinetics of phenytoin Key points
Case ID: 29 y/o soldier c/c: GSW to left occipital region of skull, no exit wound HPI: Injured at 1645 GCS 13 initially at CCP, decreased to 8 and intubated Received ketamine, fentanyl, TXA, mannitol, ertapenem, rocuronium, 2 units pRBC on scene/in transit
Case O/E at the Role 2 at 1750: GCS 10T (E4, V1T, M5 (left movement only)) Pupils PERL 2mm P 92 BPM, BP 131/81mmHg, O 2 Sat 99% PMHx: unknown Allergies: unknown Home meds: unknown
Case At the Role 2 Sedation Ketamine: 190 mg intermittently administered as well as infusion started at 1807 at 1.2 mg/kg/hr. Discontinued at 1844 Fentanyl: 600 μg intermittently administered as well as infusion started at 1825 at 100 μg/hr (titrated up as ketamine reduced) Midazolam: 6 mg intermittently administered as well as infusion started at 1840 at 3 mg/hr Td X-ray: skull fracture No CT available
Self-Assessment Questions Based on the case: Is post traumatic seizure prophylaxis indicated? If yes, which agent and dose? How long should treatment last? What would be target trough level, if applicable?
BACKGROUND
Epidemiology 1,2 1.7 M experience TBI/year in US 275,000 admitted to hospital 75% considered mild 5-7% experience PTS 20-25% pts have subclinical seizures detected on EEG TBI from combat on the rise Occurrence in veterans significantly higher than general population From 2005-07, 28-31% transferred to Walter Reed Medical Centre had brain related injuries
Pathophysiology 3,4 Mechanism of TBI Caused by blunt force trauma to the brain Diffuse brain damage from acceleration/deceleration/rotation resulting in diffuse axonal injury and brain swelling Outcomes from TBI Primary insult- triggers cascade of events leading to cell death Secondary insult- damage that occurs to neurons as a result of physiological response to initial injury
TBI Severity 1,2 TBI severity based upon GCS score on admission Severe GCS ≤ 8 LOC, amnesia 12-24 hours, depressed skull fracture, brain contusion or intracranial hematoma Moderate 9-13 Mild 14-15
Risk Factors for Early and Late PTS 1
GUIDELINES/EVIDENCE
Clinical Question Otherwise healthy adults with TBI P I AEDs C Placebo O • Reduce proportion of patients that experience early seizures (within 7 days) • Reduce proportion of patients that experience late seizures (after 7 days) • Reduce mortality from any cause • Reduce proportion of patients that experience treatment related A/E
Search Strategy • Ovid MEDLINE: Brain injuries and 6 results 6 results anticonvulsants and seizures (limited to English language, humans and randomized controlled trials) 1- Not blinded/random 1- Not blinded/random • Similar search for MA 1- VPA PK 1- VPA PK 1- MgSO 4 1- MgSO 4 • One study obtained that was 1- Subgroup analysis 1- Subgroup analysis referenced in MA, review article and guidelines 2 included 2 included
AANS Guidelines 2,5 2007 Prophylactic use of phenytoin or valproate is not recommended for preventing late PTS (Level II) Anticonvulsants are indicated to decrease the incidence of early PTS (within 7 days of injury). However, early PTS is not associated with worse outcomes (Level II) 2016 No change for late PTS (Level IIa) Phenytoin is recommended to decrease incidence of early PTS (within 7 days of injury), when the overall benefit is felt to outweigh the complications associated with such treatment. However, early PTS have not been associated with worse outcomes (Level IIa) There is insufficient evidence to recommend levetiracetam over phenytoin regarding efficacy in preventing early PTS and toxicity (Level IIa)
Thompson et al 2015 6 MA, 10 RCT, n= 2326 People of all ages diagnosed with acute TBI P Any conventional AED (carbamazepine, phenytoin, valproate, oxcarbazepine, I lamotrigine, levetiracetam, topiramate) - Administered medication post injury but prior to first post traumatic seizure Other pharmacological agent, placebo or usual care C
Early Seizure 6 ARR 8.9%, NNT= 11
Late Seizure 6
Mortality 6
Adverse Effects 6
Temkin et al 1990 7 R, DB, PC, ITT, n=404 Pts >16 y/o with severe injury, at least one of: cortical contusion visible on CT , P subdural, epidural or intracerebral hematoma, depressed skull fracture, penetrating head wound, seizure within 24 hours of injury, or GCS ≤ 10 -Anticipated likelihood of seizure ≥ 20% - Phenytoin IV LD 20 mg/kg I - LD of drug required within 24 hours of injury - MD determined by phenytoin levels targeting total 40-80 μ mol/L (10-20 mg/L) and free 3-6 μ mol/L (0.75-1.5 mg/L) x 12 months Placebo x 12 months C
Patient Characteristics 7 Phenytoin n= 208 Placebo n= 196 Age 34 ± 18 34 ± 17 Sex (% male) 78 75 Automobile (%) 34 31 Motorcycle (%) 18 19 Pedestrian (%) 13 12 Fall (%) 15 15 Assault, fight, suicide attempt (%) 14 11 Other (%) 6 11 GCS ≤ 10 (%) 60 67
Early Seizure 7 ARR 10.6%, NNT= 9
Late Seizure 7 p> 0.2 at 12 and 24 months
Results 7 Variable Phenytoin Placebo RR P value ARR (% ) NNH Mortality 14% 15% 0.93 NR N/A N/A (day 8) Mortality 22% 20% 1.1 NR N/A N/A (1 year) Stop due 8% 2% 4 < 0.01 -6 16 to rash
Phenytoin Levels 7
Temkin et al 1999 8 R, DB, ITT, n=379 Pts > 14 y/o with a qualifying traumatic injury, at least one of: immediate PTS, depressed skull P fracture, penetrating brain injury, CT evidence of cortical contusion, subdural, epidural or intracerebral hematoma - LD required within 24 hours after injury - Phenytoin IV LD 20 mg/kg I - MD beginning at 5 mg/kg/d in two divided doses - Target 40-80 μ mol/L (10-20 μ g/ml) - 1/3 study population one week treatment duration with phenytoin - Valproate IV LD 20 mg/kg C - Initial MD 15 mg/kg/d in four divided doses - Target 277-693 μ mol/L (40-100 μ g/ml) - 1/3 study population one month treatment duration with valproate - 1/3 study population six month treatment duration with valproate
Patient Characteristics 8 Valproate Valproate Phenytoin 1 month 6 months 1 week n= 120 n= 127 n= 132 Age 40 ± 19 36 ± 16 36 ± 16 Gender (% male) 84 77 84 Automobile (%) 34 28 29 Motorcycle (%) 4 7 7 Pedestrian/bike (%) 10 12 15 Fall (%) 23 24 16 Struck, shot, stab (%) 24 24 28 GCS (mean) 11.6 ± 3.6 11.1 ± 3.8 11.7 ± 3.8
Results 8 Variable Phenytoin Valproate Valproate RR P value 1 month 6 months Early 1.5% 4.5% 2.9 (0.7-13.3) 0.14 seizure Late seizure NR NR 1.4 (0.8-2.4) 0.27 Mortality 7.2% 13.4% 2.0 (0.9-4.1) 0.07 • Early safety analyses showed mortality to be significantly higher for valproate group and study was stopped by Data and Safety Monitoring Board. Decision to stop study occurred after planned sample size attained
Adverse Effects 8 Attributable to study meds: Neutropenia in 14 year old girl on valproate. Returned to normal two months after medication stopped Rash in 51 year old woman on phenytoin. Responded to prednisone and hydroxyzine Lab values for liver fxn and coagulation performed five times during 6 month trial: Platelets significantly lower in valproate arms p= 0.0001 – 0.03 ALT 3 x ULN occurred more frequently in phenytoin arm p= 0.002
Drug Levels 8 Phenytoin concentrations averaged at least target range for 91% of patients during first week of tmt Mean valproate concentrations were at, or above, target range for 97%, 90% and 85% of patients at 1 week, 1 month and 6 months respectively
Valproate IV Only Available SAP in Canada
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