2 page summary on scientific paper on neurological drug comparison.

1. Neurocrit Care (2010) 12:165–172
DOI 10.1007/s12028-009-9304-y
ORIGINAL ARTICLE
Prospective, Randomized, Single-Blinded Comparative Trial
of Intravenous Levetiracetam Versus Phenytoin for Seizure
Prophylaxis
Jerzy P. Szaflarski • Kiranpal S. Sangha •
Christopher J. Lindsell • Lori A. Shutter
Published online: 7 November 2009
Ó Humana Press Inc. 2009
Abstract received IV load with either LEV or fosphenytoin followed
Background Anti-epileptic drugs are commonly used for by standard IV doses of LEV or PHT. Doses were adjusted
seizure prophylaxis after neurological injury. We per- to maintain therapeutic serum PHT concentrations or if
formed a study comparing intravenous (IV) levetiracetam patients had seizures. Continuous EEG (cEEG) monitoring
(LEV) to IV phenytoin (PHT) for seizure prophylaxis after was performed for the initial 72 h; outcome data were
neurological injury. collected.
Methods In this prospective, single-center, randomized, Results A total of 52 patients were randomized
single-blinded comparative trial of LEV versus PHT (2:1 (LEV = 34; PHT = 18); 89% with sTBI. When control-
ratio) in patients with severe traumatic brain injury (sTBI) ling for baseline severity, LEV patients experienced better
or subarachnoid hemorrhage (NCT00618436) patients long-term outcomes than those on PHT; the Disability
Rating Scale score was lower at 3 months (P = 0.042) and
the Glasgow Outcomes Scale score was higher at 6 months
J. P. Szaflarski (&) Á L. A. Shutter
(P = 0.039). There were no differences between groups in
Department of Neurology, University of Cincinnati Academic
Health Center, 260 Stetson Street, Rm. 2350, Cincinnati, seizure occurrence during cEEG (LEV 5/34 vs. PHT 3/18;
OH 45267-0525, USA P = 1.0) or at 6 months (LEV 1/20 vs. PHT 0/14;
e-mail: jerzy.szaflarski@uc.edu P = 1.0), mortality (LEV 14/34 vs. PHT 4/18; P = 0.227).
There were no differences in side effects between groups
J. P. Szaflarski
Cincinnati Epilepsy Center at the University Hospital, (all P > 0.15) except for a lower frequency of worsened
Cincinnati, OH, USA neurological status (P = 0.024), and gastrointestinal
problems (P = 0.043) in LEV-treated patients.
J. P. Szaflarski Á L. A. Shutter
Conclusions This study of LEV versus PHT for seizure
The University of Cincinnati Neuroscience Institute, Cincinnati,
OH, USA prevention in the NSICU showed improved long-term
`
outcomes of LEV-treated patients vis-a-vis PHT-treated
K. S. Sangha patients. LEV appears to be an alternative to PHT for
Department of Pharmacy Services, The University Hospital,
seizure prophylaxis in this setting.
Cincinnati, OH, USA
K. S. Sangha Keywords Levetiracetam Á Phenytoin Á Fosphenytoin Á
James L. Winkle College of Pharmacy, University of Cincinnati, Seizure prevention Á ICU Á SAH Á TBI Á
Cincinnati, OH, USA
Long-term outcomes Á GCS Á GOS Á DRS
C. J. Lindsell
Department of Emergency Medicine, University of Cincinnati
Academic Health Center, Cincinnati, OH, USA Introduction
L. A. Shutter
Department of Neurosurgery, University of Cincinnati Academic Seizures in the setting of acute brain injury are common;
Health Center, Cincinnati, OH, USA the chance of seizure occurrence depends, in part, on the

2. 166 Neurocrit Care (2010) 12:165–172
severity of neurological injury [1]. Approximately 8.4% Methods
of patients with subarachnoid hemorrhage have overt
seizures within the first 24 h of presentation and the Subject Recruitment, Screening and the Informed
combined incidence of covert (as detected by EEG) and Consent Process
overt seizures in patients with traumatic brain injury (TBI)
or subarachnoid hemorrhage (SAH) may reach 25–50% This study was approved by the Institutional Review
[2–6]. As a consequence of seizures in the acute setting Boards at the University of Cincinnati and The University
there is an increase in secondary injuries including Hospital. The study was registered with www.Clinical
aneurysmal rupture or re-rupture, intermittent, and sus- Trials.gov, Identifier: NCT00618436. Subjects were iden-
tained increased intracranial pressure, hypoxia, physical tified by the neuro-intensive care physicians from patients
injury, and death. Any of these complications may admitted to the Neuroscience ICU (NSICU). Screening
adversely affect the neurological status of patients with procedures included a complete medical history, details of
brain injury and worsen their clinical outcome. Finally, the precipitating event, physical examinations, complete
early seizures may be predictive of subsequent epilepsy baseline and ongoing vital sign assessments, neurological
development [7, 8]. The prevalence of post-traumatic epi- evaluations, laboratory results, and diagnostic imaging
lepsy (approximately 6% of all epilepsies), the awareness of performed. Screening assessments were performed by the
the high incidence of seizures after neurological injury and clinician involved in the care of the patient to determine
the contribution of seizures to secondary injury suggest the subject eligibility criteria, especially GCS or Hunt–Hess
use of prophylactic anti-epileptic drugs (AEDs) in this diagnosis.
setting [9]. Inclusion criteria for enrollment included: (1) traumatic
Currently, the American Academy of Neurology sup- brain injury or subarachnoid hemorrhage admitted to the
ports the use of phenytoin (PHT) in the setting of acute hospital less than 24 h prior to randomization; (2) GCS score
traumatic brain injury for seizure prevention [10]. But, 3–8 (inclusive), or GCS motor score of 5 or less and abnor-
PHT carries high chance of potential side effects, medi- mal admission CT scan showing intracranial pathology; (3)
cation interactions, and potential harmful reactions hemodynamically stable with a systolic BP C90 mmHg; (4)
including anticonvulsant hypersensitivity syndrome, rash at least one reactive pupil; (5) C17 years of age; and (6)
or Stevens–Johnson syndrome, tissue necrosis complicat- signed informed consent and HIPAA authorization for
ing medication extravasation, and purple glove syndrome. research form. Exclusion criteria for enrollment included:
Therefore, better treatment options than PHT are needed. (1) no venous access; (2) spinal cord injury; (3) history of or
Oral and, more recently, intravenous (IV) levetiracetam CT confirmation of previous brain injury such as brain
(LEV) have been studied in open-label trials or in a ret- tumor, cerebral infarct, or spontaneous intracerebral hem-
rospective fashion in the acute care setting [11–16]. For orrhage; (4) hemodynamically unstable; (5) suspected
example, we recently completed a review of 379 patients anoxic events; (6) other peripheral trauma likely to result in
who received AEDs for seizure prophylaxis in the NSICU liver failure; (7) age less than 17 years of age; (8) known
setting [16]. We have shown that when PHT was used prior hypersensitivity to any anticonvulsant; (9) any treatment,
to the NSICU admission, it was frequently replaced during condition, or injury that contraindicated treatment with LEV
the ICU stay with LEV monotherapy (P < 0.001) and that or PHT; and (10) inability to obtain signed informed consent
patients treated with LEV monotherapy when compared to and HIPAA authorization for research.
other AEDs had lower complication rates and shorter
NSICU stays. Our results suggested that LEV may be a
desirable alternative to PHT. Based on our experiences General Design
with IV LEV, we designed a standardized seizure pro-
phylaxis protocol for patients with severe TBI and high This investigator initiated trial was originally designed to
grade SAH using IV LEV. This prospective, randomized enroll 52 patients with SAH and 52 patients with severe
single-blinded study compares patients treated with IV traumatic brain injury (sTBI), but recruitment and funding
LEV to those treated with PHT as prophylactic AEDs in issues prompted a change in design to focus on sTBI and
the NSICU setting. The primary objective was to compare stop enrollment at 52 patients. Randomization occurred as
the safety of LEV in critically ill NSICU patients to the soon as possible and up to 24 h after admission in the
safety of PHT, which is currently the most commonly used NSICU and was done at a 2:1 ratio of LEV to PHT; sub-
agent. The secondary objectives were to compare the rate jects were randomized and treatment group was assigned
of clinically evident and sub-clinical seizures, and to by the pharmacy. Once enrolled, cEEG was initiated and
compare long-term outcomes between patients treated with continued for up to 72 h. The study electrophysiologist
LEV and those treated with PHT. (J. P. Szaflarski) was blinded to the group assignment or

3. Neurocrit Care (2010) 12:165–172 167
diagnosis and reported results of the EEGs to the PI (L. A. service at University Hospital. The project coordinator was
Shutter) on a daily basis. The managing physicians were notified about the randomization and authorized dispensing
partially blinded in that they were not aware of which the appropriate medication based on the physician’s order.
group the patient was randomized into, but PHT levels The investigational pharmacy service maintained records
could be reviewed in the hospital laboratory computer. The of the receipt and distribution of medications used in this
managing physicians were also unblinded to treatment clinical trial to provide drug accountability.
group if seizures occurred in order to optimize treatment.
All patients were treated with the standard of care for Safety and Efficacy Monitoring
TBI or SAH per NSICU protocols. TBI management pro-
tocols followed the Guidelines for Management of Severe Safety
Traumatic Brain Injury [17]. SAH management protocols
were based on treatment algorithms developed with the The primary outcome measure was the incidence of clinical
Neurosurgery Department’s Cerebrovascular Service at the adverse events. Patients were evaluated daily during the
University Hospital. AED management used standardized hospital stay for seizures, fever, neurological changes, car-
doses at the time of initiation, with adjustments in the diovascular, hematologic and dermatologic abnormalities,
dosing performed by the study pharmacist (K. S. Sangha) liver failure, renal failure, and death. Each adverse event was
to maintain therapeutic levels of PHT. In the event of classified by the PI as attributable or possibly attributable to
seizures the study medication doses were escalated per the study drug versus other adverse events (unlikely related to
protocol until the maximum recommended dose was the study drug, unrelated to the study drug, or unknown).
reached. Maximum recommended doses were defined by a Serious adverse events for this study were defined as those that
measured therapeutic level of 20 lg/dl for PHT, and resulted in death, prolonged hospitalization, life threatening
1500 mg IV BID for LEV. Failure to suppress seizure events, persistent or significant disability, or is an important
activity once at maximum dose resulted in the addition of medical event that may not be immediately life threatening or
PHT to the current LEV dose or addition of LEV to the result in death or hospitalization but based upon appropriate
current PHT dose. If this regimen did not provide benefit, medical judgment may have jeopardized the subject, or may
treatment with other AEDs was initiated. Any other con- require medical or surgical intervention to prevent one of the
comitant medication and treatment required as the standard other outcomes listed in the definitions above.
of care for patient treatment were continued. All concurrent
drugs given and treatments provided were documented, Efficacy
including dates of administration and reason for use.
The secondary endpoints were seizure frequency and long-
Treatment with Study Medications term outcomes (seizures, Glasgow Outcomes Scale-
Extended (GOSE), Disability Rating Scale (DRS)). All
The PHT group received a loading dose of fos-PHT 20 mg/ patients were monitored on continuous EEG (cEEG) for
kg PE IV, maximum of 2000 mg, given over 60 min and 72 h or until awake and following commands. Since over
was then started on a PHT maintenance dose (5 mg/kg/day, 50% of initial seizure activity in these patients consists of
rounded to nearest 100 mg dose, IV every 12 h given over subclinical non-convulsive seizures, as observed in a
15 min). PHT serum levels were checked on days 2 and 6 number of studies [6, 18, 19] and about 93% of these
after randomization and dosing was adjusted by the phar- seizures occur within the first 2 days of admission to the
macist as needed to maintain therapeutic serum levels of ICU, we stopped cEEG as patients awakened, or by 72 h
10–20 lg/dl. The LEV group received a loading dose of after admission if there were no seizures.
20 mg/kg IV, rounded to the nearest 250 mg over 60 min
then started on maintenance dose (1000 mg, IV every 12 h Outcome Measures
given over 15 min) as prophylaxis. LEV dose was adjusted
as needed for therapeutic effect up to 1500 mg every 12 h The clinical research coordinator remained blinded to patient
(3000 mg/day) as maximum dose if seizures occurred. study medication and conducted all outcome assessments.
Patients were maintained on study medications for 7 days. Data dictionary with explicit, pre-specified data definitions
If there were no seizures at that time (clinical or sub- was used. Neurological outcomes were assessed using the
clinical), study medication was discontinued. Intravenous GOSE and DRS at time of hospital discharge and again at 3
medications were used for the entire 7 days. and 6 months after admission. Seizure frequency, any
Study medication was supplied by the study sponsor adverse events, prescribed medications, and a Resource
(LEV) or by the investigators (fos-PHT and PHT) and Utilization Questionnaire were also documented at the 3 and
stored and dispensed by the investigational pharmacy 6 month follow-up.

4. 168 Neurocrit Care (2010) 12:165–172
Statistical Analyses Table 1 Characteristics of subjects in the study grouped by study
arm
Initially, the two groups were characterized using descriptive PHT LEV P value
statistics. Medians and ranges are used for continuous vari-
N = 18 N = 34
ables, frequencies, and percentages are used for categorical
variables. Comparisons between groups were based on Demographics
Fisher’s Exact tests for categorical variables or a Mann– Age 35 18–80 44 17–75 0.802
Whitney U-test for continuous variables. Generalized linear Male 13 72.2 26 76.5 0.747
models were used to test for differences between groups Female 5 27.8 8 23.5
adjusted for confounding factors. Statistical analyses were Diagnosis
conducted using SPSS version 17.0 (SPSS Inc., Chicago, IL). SAH 2 11.1 4 11.8 1.000
TBI 16 88.9 30 88.2
GCS
Results On scene
Eyes 1 1–4 1 1–4 0.917
Demographic data of the 52 enrolled patients are presented Verbal 1 1–4 1 1–5 0.643
in Table 1. A total of 18 patients were enrolled in the PHT Motor 2 1–6 1 1–6 0.777
arm and 34 in the LEV arm; and 88.5% were diagnosed Total 4 3–14 5 3–15 0.718
with sTBI. There were no differences in PHT verus LEV In emergency department
groups in baseline characteristics, including GCS at Eyes 1 1–4 1 1–4 0.801
admission (4 vs. 5; P = 0.42), GCS at 24 h (3 vs. 3; Verbal 1 1–5 1 1–5 0.645
P = 0.99), and interventions performed (all P > 0.5). Motor 2 1–6 2 1–6 0.376
There were no differences in early seizure occurrence
Total 4 3–15 5 3–14 0.419
between the PHT versus LEV groups (3/18 vs. 5/34;
Best in first 24 h
P = 1.0, respectively) or death (4/18 vs. 14/34; P = 0.227).
Eyes 1 1–4 2 1–4 0.090
The patients death were evaluated in detail. An early death
Verbal 1 1–5 1 1–5 0.527
attributed to the injury itself occurred in six patients (PHT 2/
Motor 5 3–6 5 1–6 0.277
18 vs. LEV 4/34; P = 0.150); in the other cases families
Total 8 5–15 9 3–15 0.301
decided to withdraw care early (within 30 days after injury)
Worst in first 24 h
in five patients (PHT 0/18 vs. LEV 5/34; P = 1.00) and late
Eyes 1 1–3 1 1–3 0.221
(1–6 months after injury) in seven patients (PHT 2/18 vs.
Verbal 1 1–4 1 1–5 0.449
LEV 5/34; P = 1.00) based on quality of life issues. The
Motor 1 1–6 1 1–6 0.938
seizures that occurred were all non-convulsive in nature.
Total 3 3–12 3 3–14 0.991
The overall duration of PHT treatment was 7 (3–7) days
vs. 7 (1–7) days with LEV (P = 0.969). There were no Interventions
differences in PHT versus LEV groups in other short- and ICP monitor 15 83.3 29 85.3 1.000
long-term outcomes including GCS at 7 days (6 vs. 7; Licox 14 77.8 22 64.7 0.529
P = 0.58) and GOS at discharge (2 vs. 2; P = 0.33), Craniotomy 6 33.3 14 41.2 0.766
3 months (3 vs. 3; P = 0.61), and 6 months (3 vs. 3; Hematoma evacuation 4 22.2 9 26.5 1.000
P = 0.89; Table 2). There were no differences between Decompression 3 16.7 9 26.5 0.507
PHT and LEV groups in the occurrence of fever, increased Data are given as median and range or frequency and percent.
intracranial pressure (ICP), stroke, hypotension, arrhyth- P values were from Fisher’s Exact tests or Mann–Whitney U-tests as
mia, thrombocytopenia/coagulation abnormalities, liver appropriate; GCS Glasgow Coma Scale, SAH subarachnoid hemor-
rhage, TBI traumatic brain injury, ICP intracranial pressure
abnormalities, renal abnormalities, or early death (all
P > 0.15). LEV-treated patients experienced worsening
neurological status less frequently (P = 0.024) and had surviving patients treated with LEV experienced better
less gastrointestinal problems (P = 0.043); there was outcomes than surviving patients treated with PHT
tendency toward lower incidence of anemia in patients including lower DRS at 3 and 6 months (P = 0.006 and
treated with PHT (P = 0.076). In the PHT group, the mean P = 0.037, respectively) and higher GOSE at 6 months
PHT serum concentrations were 17.7 mcg/ml on day 2 and (P = 0.016). Finally, after adjusting for GCS at admission,
15.2 mcg/ml on day 6. there were no differences in DRS at discharge (P = 0.472),
Tables 3 and 4 show the characteristics of patients who but at 3 months, the DRS was 5.2 points lower (95%CI
survived in each study arm, and their outcomes. Overall, 0.2–10.3) among those treated with LEV compared with

5. Neurocrit Care (2010) 12:165–172 169
Table 2 Outcomes and complication data for 52 patients with trau- Table 3 Characteristics of surviving patients in the two study groups
matic brain injury or subarachnoid hemorrhage enrolled in the study
PHT LEV P value
PHT LEV P value
N = 14 N = 20
N = 18 N = 34
Demographics
Injury Severity Scale 27 16–50 28 9–50 0.953 Age 30 18–80 39 18–66 0.904
GCS, day 7 6 3–15 7 3–15 0.581 Male 10 71.4 16 80.0 0.689
GCS, discharge 10 3–15 10 5–5 0.617 Female 4 28.6 4 20.0
GOSE, discharge 2 1–3 2 1–4 0.334 Diagnosis
DRS discharge 23 7–30 24 7–30 0.547 SAH 2 14.3 2 10.0 1.000
GOSE 3 months 3 1–5 3 1–7 0.612 TBI 12 85.7 18 90.0
DRS 3 months 13 5–30 15 0–30 0.959 GCS
GOSE 6 months 3 1–7 3 1–8 0.892 On scene
DRS 6 months 9 0–30 17 0–30 0.787 Eyes 1 1–4 1 1–4 0.647
Fever 10 55.6 18 52.9 1.000 Verbal 1 1–4 1 1–5 0.434
Increased intracranial pressure 8 44.4 13 38.2 0.769 Motor 1 1–6 5 1–6 0.183
Stroke 3 16.7 7 20.6 1.000 Total 2 3–14 7 3–14 0.121
Worsen neurologic status 9 50.0 6 17.6 0.024 In emergency department
Hypotension 2 11.1 7 20.6 0.470 Eyes 1 1–4 1 1–4 0.622
Cardiac arrhythmia 6 33.3 14 41.2 0.766 Verbal 1 1–5 1 1–5 0.489
Anemia 4 22.2 17 50.0 0.076 Motor 2 1–6 5 1–6 0.170
Platelets low 3 16.7 5 14.7 1.000 Total 4 3–15 7 3–14 0.183
Coagulation deficits 1 5.6 2 5.9 1.000 Best in first 24 h
Dermatological 0 0.0 0 0.0 – Eyes 1 1–4 3 1–4 0.022
Liver function tests 0 0.0 2 5.9 0.538 Verbal 1 1–5 1 1–5 0.413
Renal 1 5.6 2 5.9 1.000 Motor 5 3–6 6 3–6 0.027
Gastrointestinal 4 22.2 1 2.9 0.043 Total 7 5–15 10 5–15 0.036
Early death 2 11.1 4 11.8 0.150 Worst in first 24 h
Care withdrawn early 0 0.0 5 14.7 1.000 Eyes 1 1–3 1 1–3 0.872
Care withdrawn late 2 11.1 5 14.7 1.000 Verbal 1 1–4 1 1–5 0.928
Length of stay 15 4–31 14 3–49 0.616 Motor 2 1–6 2 1–6 0.439
AED duration 7 3–7 7 1–7 0.969 Total 4 3–12 5 3–14 0.341
Seizures at follow–up 0 0.0 1 5.3 1.000 Interventions
AED, 3 months 3 21.4 4 21.1 1.000 ICP monitor 12 85.7 15 75.0 0.672
AED, 6 months 2 18.2 2 13.3 1.000 Licox 11 78.6 12 60.0 0.295
GCS Glasgow Coma Scale, GOSE Glasgow Outcomes Scale-Exten- Craniotomy 5 35.7 7 365.0 1.000
ded, DRS Disability Rating Scale Hematoma evacuation 3 21.4 4 20.0 1.000
Decompression 2 14.3 5 25.0 0.672
those treated with PHT (P = 0.042). At 6 months, the
difference was 3.7 points (95%CI -1.0 to 8.5), but this was
not statistically significant (P = 0.118). The GOSE was that LEV is at least as safe as PHT when used for seizure
not different at discharge or 3 months, but at 6 months it prevention in the NSICU setting, and that the short- and
was 1.5 points higher for those treated with LEV compared long-term outcome measures favor the use of LEV. This
with those treated with PHT (95%CI 0.1–3.0; P = 0.039). includes significantly better side-effects profile of LEV
There was no difference in overall seizure control between (less worsening of neurological status and less gastroin-
study arms (3/14 vs. 3/20; P = 1.000). testinal problems) when compared to PHT and significantly
improved outcomes at 3 and 6 months including higher
GOSE and lower DRS in the LEV-treated patients.
Discussion Phenytoin is an established standard AED in the setting of
acute traumatic brain injury. In fact, the American Academy
This first randomized, single-blinded trial of treatment with of Neurology suggests using PHT for seizure prevention in
LEV versus PHT in patients with sTBI and/or SAH shows the first 7 days after traumatic brain injury [10]. But, the

6. 170 Neurocrit Care (2010) 12:165–172
Table 4 Outcomes and complication data for surviving patients only patients with LEV in the setting of TBI and/or SAH pro-
PHT LEV P value
vides long-term benefits over PHT. We note that while the
baseline characteristics of both groups including severity of
N = 14 N = 20 injury are similar (as demonstrated by similar GCS scores
Injury Severity Scale 26 16–50 28 9–38 0.439 in the first 24 h and at discharge), two different measures of
GCS, day 7 6 3–15 10 4–15 0.138 long-term outcome, the GOSE and DRS, at 3 and 6 months
GCS, discharge 10 3–15 11 6–15 0.396 favor LEV as the AED of choice in this setting. We
GOSE, discharge 3 2–3 3 2–4 0.545 speculate that the better neurological outcomes seen here
DRS discharge 22 7–29 22 7–26 0.436 may afford patients treated with LEV higher chance of
GOSE 3 months 3 2–5 4 2–7 0.107 return to the society as productive members.
DRS 3 months 11 5–23 5 0–23 0.006 LEV is known to potently suppress seizures in animal
GOSE 6 months 3 3–7 5 3–8 0.016
models of both, focal and secondary generalized epilepsies
DRS 6 months 6 0–20 3 0–17 0.037
[21–23]. Further, pretreatment with LEV can prevent or
delay the development of kindled seizures [23, 24]. In
Fever 7 50.0 9 45.0 1.000
addition, LEV has been shown to be neuroprotective in
Increased intracranial pressure 6 42.9 4 20.0 0.252
animal models of brain injury [25, 26]. Because of that
Stroke 2 14.3 0 0.0 0.162
suppressive effect on seizures the results of our trial are not
Worsen neurologic status 6 42.9 1 5.0 0.012
surprising. Surprising, though, is the fact that we were able
Hypotension 0 0.0 3 15.0 0.251
to show results favoring LEV in this setting despite rela-
Cardiac arrhythmia 3 21.4 8 40.0 0.295
tively small number of patients enrolled in the trial. Pre-
Anemia 3 21.4 8 40.0 0.295
clinical studies support our findings and raise the possi-
Platelets low 1 7.1 2 10.0 1.000
bility that patients at high risk for seizure development may
Coagulation deficits 1 7.1 2 10.0 1.000
benefit from prophylactic use of LEV instead of PHT
Dermatological 0 0.0 0 0.0 –
during periods of acute brain insult, i.e., invasive neuro-
Liver function tests 0 0.0 0 0.0 –
surgical procedures, trauma, stroke, subarachnoid, or
Renal 0 0.0 0 0.0 – intracerebral hemorrhage. Further, the results of our study
Gastrointestinal 3 21.4 1 5.0 0.283 suggest that a randomized, double-blind trial of LEV in this
Early death 0 0.0 0 0.0 – setting evaluating short- and long-term outcomes is war-
Care withdrawn early 0 0.0 0 0.0 – ranted in order to evaluate the neuroprotective and anti-
Care withdrawn late 0 0.0 0 0.0 – epileptogenic effects of this AED in humans.
Length of stay 15 4–31 13 7–28 0.545 Our single-blinded trial used cEEG for the monitoring
AED duration 7 3–7 7 6–7 0.602 of possible subclinical (covert) seizures in the enrolled
Seizures at follow-up 0 0.0 1 5.6 1.000 patients. Continuous EEG monitoring has been used to
AED, 3 months 3 21.4 3 16.7 1.000 determine the incidence of early seizures and for prog-
AED, 6 months 2 18.2 2 13.3 1.000 nostication in patients admitted to the NSICU, and is
considered to be the new standard of care in this setting
[2, 27]. Knowledge of the EEG characteristics is known to
availability of newer AEDs questions the use of PHT as the affect treatment and predict outcome [28, 29]. In one of
first line AED in this setting; some even suggest that it may the first studies of EEG utility for the detection of non-
be reasonable to use LEV instead of PHT for seizure pro- convulsive seizures and status epilepticus in the ICU
phylaxis in the setting of intracranial surgery and NSICU setting, Privitera et al. [30] found that out of 198 cases
management [13, 20]. LEV has been used in the NSICU with altered consciousness but no clinical convulsions, 74
setting for several years now and numerous studies have (37%) showed EEG and clinical evidence of definite or
reported on oral as well as IV use of this medication for the probable nontonic–clonic seizures or status epilepticus. In
treatment or prevention of seizures in this setting. However, a study of critically ill patients admitted to a neurological
existing studies of LEV safety and efficacy in the NSICU ICU setting, 19% of the patients monitored with cEEG
setting are limited by their methodology, relying either on had seizures, of which 92% had no overt clinical signs of
retrospective chart review or an open-label design [11–16]. seizure activity; 88% seizures detected in the first 24 and
Therefore, previous studies do not provide strong evidence 93% in the first 48 h [18]. Although the incidence of
that LEV affords better short- and long-term outcomes when seizures in our study is somewhat lower (8/52; 15%), this
compared to other treatments. is likely related to the fact that patients in our study were
In the present study, we compared in a blinded and selected based on the presence of severe TBI and not
randomized fashion these two AEDs to show that treating based on the suspicion that they may or may not be

7. Neurocrit Care (2010) 12:165–172 171
having seizures. Our study is therefore likely more Conclusions
reflective of clinical practice, where prophylactic treat-
ments are not given on suspicion of seizure occurrence, This single-blinded, randomized study of LEV versus PHT
but to prevent seizure occurrence among all patients; the in the NSICU setting showed that patients treated with
minor discrepancy in the detected seizure incidence is `
PHT vis-a-vis LEV have the same outcomes in respect to
expected in this instance. death or seizures, but LEV results in less undesirable side
Studies using intermittent or cEEG recordings have effects and better long-term outcomes as measured with
clearly documented high incidence of subclinical seizures GOSE and DRS. Therefore, LEV may be a suitable alter-
in sTBI/SAH patient population [6, 18, 19, 30]. In native to PHT in seizure prevention in patients with sTBI
patients with sTBI, studies have confirmed that early or SAH in the NSICU setting.
PHT use (up to 7 days post-TBI) reduces the risk of
early seizures (relative risk reduction: 0.37, 95%CI Acknowledgments This study was supported by a grant from UCB
Inc., Principal Investigator: Lori A. Shutter, MD. This study was
0.18–0.74); similar short-term effect was observed in a presented in part at the Neurocritical Care Society Meetings in 2008
single trial of carbamazepine [10]. Availability and and 2009. Data Safety Monitoring Board included Drs. Andrew
administration of IV AEDs is especially relevant for the Ringer, MD (Department of Neurosurgery) and Michael D. Privitera,
critically ill patients with altered levels of consciousness. MD (Department of Neurology).
Traditionally, medications such as phenytoin, phenobar- Disclosure of Conflicts of Interest Jerzy P. Szaflarski, MD, PhD
bital, and valproic acid have been used because of well- has received grant support from the American Academy of Neurol-
defined and easily monitored therapeutic drug levels, and ogy, Davis Phinney Foundation/Sunflower Revolution, National
the availability of the IV formulations. Unfortunately Institutes of Health, UCB Pharma Inc., and The University Research
Council at the University of Cincinnati. He has served as a paid
liver toxicity, hypotension, hematologic abnormalities, consultant and/or speaker for Abbott Laboratories, American Acad-
drug interactions, and sedation are only a few of the emy of Neurology, Pfizer and UCB, Inc. Kiranpal S. Sangha,
many adverse effects of these agents that can become Pharm.D—has nothing to disclose. Christopher J. Lindsell, PhD—has
problematic in critically ill patients. Availability of received grant support from Abbott POC. Lori A. Shutter, MD has
received grant support for the Department of Defense, National
newer prophylactic medications that could be easily Institute of Health, and UCB Pharma, Inc. She has served as a paid
initiated with fewer side effects could be beneficial in consultant and/or speaker for Integra Lifesciences and the Brain
this patient population. Because of the high frequency of Trauma Foundation.
clinical and subclinical seizures in this setting, sTBI
presents an ideal human target for further investigations
of AEDs such as LEV in prevention of seizures and
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