TRAUMATIC BRAIN INJURY SEIZURE PROPHYLAXIS MAJOR SEAN MEREDITH - - PowerPoint PPT Presentation
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
The American Pharmacist Association is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. 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.”
Target Audience: Pharmacists and Pharmacist Technicians ACPE#: 0202-0000-18-224-L01-P/T Activity Type: Knowledge-based
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
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
Case Background Guidelines/Evidence Pharmacokinetics of phenytoin Key points
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
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, O2Sat 99% PMHx: unknown Allergies: unknown Home meds: unknown
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
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?
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
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 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
Otherwise healthy adults with TBI
AEDs
Placebo
(within 7 days)
(after 7 days)
anticonvulsants and seizures (limited to English language, humans and randomized controlled trials)
referenced in MA, review article and guidelines
6 results 6 results 2 included 2 included
1- Not blinded/random 1- VPA PK 1- MgSO4 1- Subgroup analysis 1- Not blinded/random 1- VPA PK 1- MgSO4 1- Subgroup analysis
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
IIa)
There is insufficient evidence to recommend levetiracetam over phenytoin regarding
efficacy in preventing early PTS and toxicity (Level IIa)
MA, 10 RCT, n= 2326
P
People of all ages diagnosed with acute TBI
I
Any conventional AED (carbamazepine, phenytoin, valproate, oxcarbazepine, lamotrigine, levetiracetam, topiramate)
seizure
C
Other pharmacological agent, placebo or usual care
ARR 8.9%, NNT= 11
R, DB, PC, ITT, n=404
P
Pts >16 y/o with severe injury, at least one of: cortical contusion visible on CT , subdural, epidural or intracerebral hematoma, depressed skull fracture, penetrating head wound, seizure within 24 hours of injury, or GCS ≤ 10
I
40-80 μmol/L (10-20 mg/L) and free 3-6 μmol/L (0.75-1.5 mg/L) x 12 months
C
Placebo x 12 months
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
ARR 10.6%, NNT= 9
p> 0.2 at 12 and 24 months
Variable Phenytoin Placebo RR P value ARR (% ) NNH
Mortality (day 8) 14% 15% 0.93 NR N/A N/A Mortality (1 year) 22% 20% 1.1 NR N/A N/A Stop due to rash 8% 2% 4 < 0.01
16
R, DB, ITT, n=379 P
Pts > 14 y/o with a qualifying traumatic injury, at least one of: immediate PTS, depressed skull fracture, penetrating brain injury, CT evidence of cortical contusion, subdural, epidural or intracerebral hematoma
I
C
Valproate 1 month n= 120 Valproate 6 months n= 127 Phenytoin 1 week 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
Variable Phenytoin Valproate 1 month Valproate 6 months RR P value
Early seizure 1.5% 4.5% 2.9 (0.7-13.3) 0.14 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
group and study was stopped by Data and Safety Monitoring Board. Decision to stop study occurred after planned sample size attained
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
Phenytoin concentrations
averaged at least target range for 91% of patients during first week
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
R, SB, n= 52 P
Pts > 17 y/o with TBI or subarachnoid hemorrhage admitted less than 24 hours prior to randomization, GCS 3-8 (inclusive), or GCS motor score of 5 or less and abnormal CT scan showing intracranial pathology, hemodynamically stable with SBP ≥ 90 mmHg, at least one reactive pupil
I
C
therapeutic serum levels of 10-20 μg/ml (40-80 μmol/L)
Levetiracetam n= 34 Phenytoin n=18
Age 44 35 Male (%) 76.5 72.2 TBI (%) 88.2 88.9 GCS in emerg 5 4 Mean phenytoin levels day 2/day 6 17.7 μg/ml (70.8 μmol/L)/15.2 μg/ml (60.8 μmol/L)
Variable Levetiracetam Phenytoin RR P value ARR (% ) NNT/NNH
Early Seizure 14.7% 16.7% 0.88 1.0 N/A N/A Death 41.2% 22.2% 1.85 0.227 N/A N/A Worsened neurological status 17.6% 50% 0.35 0.024 32.4 3 GI problem 2.9% 22.2% 0.13 0.043 N/A N/A
Surviving patients only (levetiracetam n=20, phenytoin n=14) Lower Disability Rating Scale (DRS) at 3/6 months with levetiracetam
p= 0.006/0.037
Higher Glasgow Outcome Scale Extended (GOSE) at 6 months with
levetiracetam p= 0.016
Vd: 0.6-0.7 L/kg Heavily protein bound Metabolism: Dose dependent and saturable, Michaelis-Menten, pharmacokinetics Half life dependent upon serum concentration SS occurs in 7-10 days Reason for LD for seizure prophylaxis Excreted in the urine (<5% unchanged) Inducer of CYP 2B6, 2C19, 3A4, PGP Interacts with everything… Lowers serum concentrations
Narrow therapeutic index medication Target trough range: 40-80 μmol/L (10-20 mg/L) Affected by albumin and renal function Total = measured phenytoin/((adjustment X albumin) + 0.1) Adjustment 0.2, 0.1 if Clcr < 20 ml/min Can also do free levels When do TDM? 1-2 hours post LD MD TDM in the studies ranged from daily to being conducted on days 2 and 6
Is post traumatic seizure prophylaxis indicated? If yes, which agent and dose? Phenytoin 20 mg/kg IV LD 1.5 g (estimated 75 kg) IV phenytoin LD administered at 1815 MD 150 mg IV q8h How long should treatment last? No benefit beyond 7 days What would be target trough level, if applicable? 40-80 μmol/L (10-20 mg/L)
Phenytoin most studied for post TBI seizure prophylaxis Prevention of early PTS, but no benefits for late PTS No mortality benefit Valproate increased morality signal compared to phenytoin Levetiracetam potentially has long term benefits No TDM required! More, better designed, trials required Phenytoin narrow therapeutic index drug that requires TDM Pharmacists active role in treatment plan Perfect opportunity for pharmaceutical care!!!
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