Szaflarski, J (2010) Neutocrit Care

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Szaflarski, J (2010) Neutocrit Care

  1. 1. Neurocrit Care (2010) 12:165–172 DOI 10.1007/s12028-009-9304-y ORIGINAL ARTICLEProspective, Randomized, Single-Blinded Comparative Trialof Intravenous Levetiracetam Versus Phenytoin for SeizureProphylaxisJerzy P. Szaflarski • Kiranpal S. Sangha •Christopher J. Lindsell • Lori A. ShutterPublished online: 7 November 2009Ó Humana Press Inc. 2009Abstract received IV load with either LEV or fosphenytoin followedBackground Anti-epileptic drugs are commonly used for by standard IV doses of LEV or PHT. Doses were adjustedseizure prophylaxis after neurological injury. We per- to maintain therapeutic serum PHT concentrations or ifformed 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 wereneurological injury. collected.Methods In this prospective, single-center, randomized, Results A total of 52 patients were randomizedsingle-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 betteror 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 monthsJ. P. Szaflarski (&) Á L. A. Shutter (P = 0.039). There were no differences between groups inDepartment of Neurology, University of Cincinnati AcademicHealth 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 groupsJ. P. SzaflarskiCincinnati Epilepsy Center at the University Hospital, (all P > 0.15) except for a lower frequency of worsenedCincinnati, 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 seizureThe 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-treatedK. S. Sangha patients. LEV appears to be an alternative to PHT forDepartment of Pharmacy Services, The University Hospital, seizure prophylaxis in this setting.Cincinnati, OH, USAK. S. Sangha Keywords Levetiracetam Á Phenytoin Á Fosphenytoin ÁJames L. Winkle College of Pharmacy, University of Cincinnati, Seizure prevention Á ICU Á SAH Á TBI ÁCincinnati, OH, USA Long-term outcomes Á GCS Á GOS Á DRSC. J. LindsellDepartment of Emergency Medicine, University of CincinnatiAcademic Health Center, Cincinnati, OH, USA IntroductionL. A. ShutterDepartment 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. 2. 166 Neurocrit Care (2010) 12:165–172severity of neurological injury [1]. Approximately 8.4% Methodsof patients with subarachnoid hemorrhage have overtseizures within the first 24 h of presentation and the Subject Recruitment, Screening and the Informedcombined incidence of covert (as detected by EEG) and Consent Processovert 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 Universitythere is an increase in secondary injuries including Hospital. The study was registered with www.Clinicalaneurysmal 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 patientsinjury, and death. Any of these complications may admitted to the Neuroscience ICU (NSICU). Screeningadversely affect the neurological status of patients with procedures included a complete medical history, details ofbrain injury and worsen their clinical outcome. Finally, the precipitating event, physical examinations, completeearly seizures may be predictive of subsequent epilepsy baseline and ongoing vital sign assessments, neurologicaldevelopment [7, 8]. The prevalence of post-traumatic epi- evaluations, laboratory results, and diagnostic imaginglepsy (approximately 6% of all epilepsies), the awareness of performed. Screening assessments were performed by thethe high incidence of seizures after neurological injury and clinician involved in the care of the patient to determinethe contribution of seizures to secondary injury suggest the subject eligibility criteria, especially GCS or Hunt–Hessuse 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 theports the use of phenytoin (PHT) in the setting of acute hospital less than 24 h prior to randomization; (2) GCS scoretraumatic 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 foring 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 orOral 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) suspectedexample, we recently completed a review of 379 patients anoxic events; (6) other peripheral trauma likely to result inwho received AEDs for seizure prophylaxis in the NSICU liver failure; (7) age less than 17 years of age; (8) knownsetting [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 LEVthe ICU stay with LEV monotherapy (P < 0.001) and that or PHT; and (10) inability to obtain signed informed consentpatients treated with LEV monotherapy when compared to and HIPAA authorization for research.other AEDs had lower complication rates and shorterNSICU stays. Our results suggested that LEV may be adesirable alternative to PHT. Based on our experiences General Designwith IV LEV, we designed a standardized seizure pro-phylaxis protocol for patients with severe TBI and high This investigator initiated trial was originally designed tograde SAH using IV LEV. This prospective, randomized enroll 52 patients with SAH and 52 patients with severesingle-blinded study compares patients treated with IV traumatic brain injury (sTBI), but recruitment and fundingLEV to those treated with PHT as prophylactic AEDs in issues prompted a change in design to focus on sTBI andthe NSICU setting. The primary objective was to compare stop enrollment at 52 patients. Randomization occurred asthe safety of LEV in critically ill NSICU patients to the soon as possible and up to 24 h after admission in thesafety 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 assignedof clinically evident and sub-clinical seizures, and to by the pharmacy. Once enrolled, cEEG was initiated andcompare long-term outcomes between patients treated with continued for up to 72 h. The study electrophysiologistLEV and those treated with PHT. (J. P. Szaflarski) was blinded to the group assignment or
  3. 3. Neurocrit Care (2010) 12:165–172 167diagnosis and reported results of the EEGs to the PI (L. A. service at University Hospital. The project coordinator wasShutter) on a daily basis. The managing physicians were notified about the randomization and authorized dispensingpartially 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 recordscould be reviewed in the hospital laboratory computer. The of the receipt and distribution of medications used in thismanaging 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 MonitoringTBI or SAH per NSICU protocols. TBI management pro-tocols followed the Guidelines for Management of Severe SafetyTraumatic Brain Injury [17]. SAH management protocolswere based on treatment algorithms developed with the The primary outcome measure was the incidence of clinicalNeurosurgery Department’s Cerebrovascular Service at the adverse events. Patients were evaluated daily during theUniversity 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 wasto maintain therapeutic levels of PHT. In the event of classified by the PI as attributable or possibly attributable toseizures the study medication doses were escalated per the study drug versus other adverse events (unlikely related toprotocol 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 thatmeasured therapeutic level of 20 lg/dl for PHT, and resulted in death, prolonged hospitalization, life threatening1500 mg IV BID for LEV. Failure to suppress seizure events, persistent or significant disability, or is an importantactivity once at maximum dose resulted in the addition of medical event that may not be immediately life threatening orPHT to the current LEV dose or addition of LEV to the result in death or hospitalization but based upon appropriatecurrent PHT dose. If this regimen did not provide benefit, medical judgment may have jeopardized the subject, or maytreatment with other AEDs was initiated. Any other con- require medical or surgical intervention to prevent one of thecomitant medication and treatment required as the standard other outcomes listed in the definitions above.of care for patient treatment were continued. All concurrentdrugs given and treatments provided were documented, Efficacyincluding 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)). AllThe PHT group received a loading dose of fos-PHT 20 mg/ patients were monitored on continuous EEG (cEEG) forkg PE IV, maximum of 2000 mg, given over 60 min and 72 h or until awake and following commands. Since overwas then started on a PHT maintenance dose (5 mg/kg/day, 50% of initial seizure activity in these patients consists ofrounded to nearest 100 mg dose, IV every 12 h given over subclinical non-convulsive seizures, as observed in a15 min). PHT serum levels were checked on days 2 and 6 number of studies [6, 18, 19] and about 93% of theseafter randomization and dosing was adjusted by the phar- seizures occur within the first 2 days of admission to themacist as needed to maintain therapeutic serum levels of ICU, we stopped cEEG as patients awakened, or by 72 h10–20 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 minthen started on maintenance dose (1000 mg, IV every 12 h Outcome Measuresgiven over 15 min) as prophylaxis. LEV dose was adjustedas 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 definitionsIf there were no seizures at that time (clinical or sub- was used. Neurological outcomes were assessed using theclinical), study medication was discontinued. Intravenous GOSE and DRS at time of hospital discharge and again at 3medications 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 andstored and dispensed by the investigational pharmacy 6 month follow-up.
  4. 4. 168 Neurocrit Care (2010) 12:165–172Statistical Analyses Table 1 Characteristics of subjects in the study grouped by study armInitially, the two groups were characterized using descriptive PHT LEV P valuestatistics. Medians and ranges are used for continuous vari- N = 18 N = 34ables, frequencies, and percentages are used for categoricalvariables. Comparisons between groups were based on DemographicsFisher’s Exact tests for categorical variables or a Mann– Age 35 18–80 44 17–75 0.802Whitney U-test for continuous variables. Generalized linear Male 13 72.2 26 76.5 0.747models were used to test for differences between groups Female 5 27.8 8 23.5adjusted for confounding factors. Statistical analyses were Diagnosisconducted 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 GCSResults On scene Eyes 1 1–4 1 1–4 0.917Demographic data of the 52 enrolled patients are presented Verbal 1 1–4 1 1–5 0.643in Table 1. A total of 18 patients were enrolled in the PHT Motor 2 1–6 1 1–6 0.777arm and 34 in the LEV arm; and 88.5% were diagnosed Total 4 3–14 5 3–15 0.718with sTBI. There were no differences in PHT verus LEV In emergency departmentgroups in baseline characteristics, including GCS at Eyes 1 1–4 1 1–4 0.801admission (4 vs. 5; P = 0.42), GCS at 24 h (3 vs. 3; Verbal 1 1–5 1 1–5 0.645P = 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 0.419between the PHT versus LEV groups (3/18 vs. 5/34; Best in first 24 hP = 1.0, respectively) or death (4/18 vs. 14/34; P = 0.227). Eyes 1 1–4 2 1–4 0.090The patients death were evaluated in detail. An early death Verbal 1 1–5 1 1–5 0.527attributed to the injury itself occurred in six patients (PHT 2/ Motor 5 3–6 5 1–6 0.27718 vs. LEV 4/34; P = 0.150); in the other cases families Total 8 5–15 9 3–15 0.301decided to withdraw care early (within 30 days after injury) Worst in first 24 hin 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 0.449LEV 5/34; P = 1.00) based on quality of life issues. The Motor 1 1–6 1 1–6 0.938seizures 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) daysvs. 7 (1–7) days with LEV (P = 0.969). There were no Interventionsdifferences in PHT versus LEV groups in other short- and ICP monitor 15 83.3 29 85.3 1.000long-term outcomes including GCS at 7 days (6 vs. 7; Licox 14 77.8 22 64.7 0.529P = 0.58) and GOS at discharge (2 vs. 2; P = 0.33), Craniotomy 6 33.3 14 41.2 0.7663 months (3 vs. 3; P = 0.61), and 6 months (3 vs. 3; Hematoma evacuation 4 22.2 9 26.5 1.000P = 0.89; Table 2). There were no differences between Decompression 3 16.7 9 26.5 0.507PHT 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 asmia, thrombocytopenia/coagulation abnormalities, liver appropriate; GCS Glasgow Coma Scale, SAH subarachnoid hemor- rhage, TBI traumatic brain injury, ICP intracranial pressureabnormalities, renal abnormalities, or early death (allP > 0.15). LEV-treated patients experienced worseningneurological status less frequently (P = 0.024) and had surviving patients treated with LEV experienced betterless gastrointestinal problems (P = 0.043); there was outcomes than surviving patients treated with PHTtendency toward lower incidence of anemia in patients including lower DRS at 3 and 6 months (P = 0.006 andtreated with PHT (P = 0.076). In the PHT group, the mean P = 0.037, respectively) and higher GOSE at 6 monthsPHT 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%CIsurvived in each study arm, and their outcomes. Overall, 0.2–10.3) among those treated with LEV compared with
  5. 5. Neurocrit Care (2010) 12:165–172 169Table 2 Outcomes and complication data for 52 patients with trau- Table 3 Characteristics of surviving patients in the two study groupsmatic 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 DemographicsInjury Severity Scale 27 16–50 28 9–50 0.953 Age 30 18–80 39 18–66 0.904GCS, day 7 6 3–15 7 3–15 0.581 Male 10 71.4 16 80.0 0.689GCS, discharge 10 3–15 10 5–5 0.617 Female 4 28.6 4 20.0GOSE, discharge 2 1–3 2 1–4 0.334 DiagnosisDRS discharge 23 7–30 24 7–30 0.547 SAH 2 14.3 2 10.0 1.000GOSE 3 months 3 1–5 3 1–7 0.612 TBI 12 85.7 18 90.0DRS 3 months 13 5–30 15 0–30 0.959 GCSGOSE 6 months 3 1–7 3 1–8 0.892 On sceneDRS 6 months 9 0–30 17 0–30 0.787 Eyes 1 1–4 1 1–4 0.647Fever 10 55.6 18 52.9 1.000 Verbal 1 1–4 1 1–5 0.434Increased intracranial pressure 8 44.4 13 38.2 0.769 Motor 1 1–6 5 1–6 0.183Stroke 3 16.7 7 20.6 1.000 Total 2 3–14 7 3–14 0.121Worsen neurologic status 9 50.0 6 17.6 0.024 In emergency departmentHypotension 2 11.1 7 20.6 0.470 Eyes 1 1–4 1 1–4 0.622Cardiac arrhythmia 6 33.3 14 41.2 0.766 Verbal 1 1–5 1 1–5 0.489Anemia 4 22.2 17 50.0 0.076 Motor 2 1–6 5 1–6 0.170Platelets low 3 16.7 5 14.7 1.000 Total 4 3–15 7 3–14 0.183Coagulation deficits 1 5.6 2 5.9 1.000 Best in first 24 hDermatological 0 0.0 0 0.0 – Eyes 1 1–4 3 1–4 0.022Liver function tests 0 0.0 2 5.9 0.538 Verbal 1 1–5 1 1–5 0.413Renal 1 5.6 2 5.9 1.000 Motor 5 3–6 6 3–6 0.027Gastrointestinal 4 22.2 1 2.9 0.043 Total 7 5–15 10 5–15 0.036Early death 2 11.1 4 11.8 0.150 Worst in first 24 hCare withdrawn early 0 0.0 5 14.7 1.000 Eyes 1 1–3 1 1–3 0.872Care withdrawn late 2 11.1 5 14.7 1.000 Verbal 1 1–4 1 1–5 0.928Length of stay 15 4–31 14 3–49 0.616 Motor 2 1–6 2 1–6 0.439AED duration 7 3–7 7 1–7 0.969 Total 4 3–12 5 3–14 0.341Seizures at follow–up 0 0.0 1 5.3 1.000 InterventionsAED, 3 months 3 21.4 4 21.1 1.000 ICP monitor 12 85.7 15 75.0 0.672AED, 6 months 2 18.2 2 13.3 1.000 Licox 11 78.6 12 60.0 0.295GCS Glasgow Coma Scale, GOSE Glasgow Outcomes Scale-Exten- Craniotomy 5 35.7 7 365.0 1.000ded, DRS Disability Rating Scale Hematoma evacuation 3 21.4 4 20.0 1.000 Decompression 2 14.3 5 25.0 0.672those treated with PHT (P = 0.042). At 6 months, thedifference was 3.7 points (95%CI -1.0 to 8.5), but this wasnot statistically significant (P = 0.118). The GOSE was that LEV is at least as safe as PHT when used for seizurenot different at discharge or 3 months, but at 6 months it prevention in the NSICU setting, and that the short- andwas 1.5 points higher for those treated with LEV compared long-term outcome measures favor the use of LEV. Thiswith those treated with PHT (95%CI 0.1–3.0; P = 0.039). includes significantly better side-effects profile of LEVThere 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 AcademyThis first randomized, single-blinded trial of treatment with of Neurology suggests using PHT for seizure prevention inLEV versus PHT in patients with sTBI and/or SAH shows the first 7 days after traumatic brain injury [10]. But, the
  6. 6. 170 Neurocrit Care (2010) 12:165–172Table 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 scoresInjury Severity Scale 26 16–50 28 9–38 0.439 in the first 24 h and at discharge), two different measures ofGCS, day 7 6 3–15 10 4–15 0.138 long-term outcome, the GOSE and DRS, at 3 and 6 monthsGCS, discharge 10 3–15 11 6–15 0.396 favor LEV as the AED of choice in this setting. WeGOSE, discharge 3 2–3 3 2–4 0.545 speculate that the better neurological outcomes seen hereDRS discharge 22 7–29 22 7–26 0.436 may afford patients treated with LEV higher chance ofGOSE 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 animalGOSE 6 months 3 3–7 5 3–8 0.016 models of both, focal and secondary generalized epilepsiesDRS 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]. InFever 7 50.0 9 45.0 1.000 addition, LEV has been shown to be neuroprotective inIncreased intracranial pressure 6 42.9 4 20.0 0.252 animal models of brain injury [25, 26]. Because of thatStroke 2 14.3 0 0.0 0.162 suppressive effect on seizures the results of our trial are notWorsen neurologic status 6 42.9 1 5.0 0.012 surprising. Surprising, though, is the fact that we were ableHypotension 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 mayCoagulation deficits 1 7.1 2 10.0 1.000 benefit from prophylactic use of LEV instead of PHTDermatological 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, orRenal 0 0.0 0 0.0 – intracerebral hemorrhage. Further, the results of our studyGastrointestinal 3 21.4 1 5.0 0.283 suggest that a randomized, double-blind trial of LEV in thisEarly 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 monitoringAED duration 7 3–7 7 6–7 0.602 of possible subclinical (covert) seizures in the enrolledSeizures at follow-up 0 0.0 1 5.6 1.000 patients. Continuous EEG monitoring has been used toAED, 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 toavailability of newer AEDs questions the use of PHT as the affect treatment and predict outcome [28, 29]. In one offirst 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 ICUphylaxis in the setting of intracranial surgery and NSICU setting, Privitera et al. [30] found that out of 198 casesmanagement [13, 20]. LEV has been used in the NSICU with altered consciousness but no clinical convulsions, 74setting for several years now and numerous studies have (37%) showed EEG and clinical evidence of definite orreported on oral as well as IV use of this medication for the probable nontonic–clonic seizures or status epilepticus. Intreatment or prevention of seizures in this setting. However, a study of critically ill patients admitted to a neurologicalexisting studies of LEV safety and efficacy in the NSICU ICU setting, 19% of the patients monitored with cEEGsetting are limited by their methodology, relying either on had seizures, of which 92% had no overt clinical signs ofretrospective chart review or an open-label design [11–16]. seizure activity; 88% seizures detected in the first 24 andTherefore, previous studies do not provide strong evidence 93% in the first 48 h [18]. Although the incidence ofthat LEV affords better short- and long-term outcomes when seizures in our study is somewhat lower (8/52; 15%), thiscompared 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 notrandomized fashion these two AEDs to show that treating based on the suspicion that they may or may not be
  7. 7. Neurocrit Care (2010) 12:165–172 171having seizures. Our study is therefore likely more Conclusionsreflective of clinical practice, where prophylactic treat-ments are not given on suspicion of seizure occurrence, This single-blinded, randomized study of LEV versus PHTbut to prevent seizure occurrence among all patients; the in the NSICU setting showed that patients treated withminor discrepancy in the detected seizure incidence is ` PHT vis-a-vis LEV have the same outcomes in respect toexpected 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 withclearly 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 sTBIpatients with sTBI, studies have confirmed that early or SAH in the NSICU setting.PHT use (up to 7 days post-TBI) reduces the risk ofearly 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 was0.18–0.74); similar short-term effect was observed in a presented in part at the Neurocritical Care Society Meetings in 2008single trial of carbamazepine [10]. Availability and and 2009. Data Safety Monitoring Board included Drs. Andrewadministration 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, PhDbital, 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, Nationalthe 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 paidliver 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—hasproblematic 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, Nationalnewer prophylactic medications that could be easily Institute of Health, and UCB Pharma, Inc. She has served as a paidinitiated with fewer side effects could be beneficial in consultant and/or speaker for Integra Lifesciences and the Brainthis patient population. Because of the high frequency of Trauma Foundation.clinical and subclinical seizures in this setting, sTBIpresents an ideal human target for further investigationsof AEDs such as LEV in prevention of seizures andepilepsy and the use of cEEG appears to be indicated in Referencesthis setting as many seizures may go unnoticed in theseverely compromised NSICU patients. 1. Hesdorffer D. Risk factors. In: Engel J, Pedley T, editors. Epi- Limitations of this study should be noted. While the lepsy: a comprehensive textbook. Philadelphia: Wolters Kluwer, Lippincott–Raven Publishers; 2007. p. 57–63.cEEG interpretation was provided by a physician blinded 2. Claassen J, Hirsch LJ, Frontera JA, et al. Prognostic significanceto group assignment, the clinicians managing the patients of continuous EEG monitoring in patients with poor-grade sub-were not always blinded to the treatment. Therefore, arachnoid hemorrhage. Neurocrit Care. 2006;4:103–12.although unlikely, we cannot exclude the possibility that 3. Claassen J, Jette N, Chum F, et al. Electrographic seizures and periodic discharges after intracerebral hemorrhage. Neurology.some of the group differences are due to the biases of the 2007;69:1356–65.clinicians managing the critically ill patients. Second, the 4. Lowenstein DH. Epilepsy after head injury: an overview. Epi-statistical analyses have not been adjusted for multiple lepsia. 2009;50(Suppl 2):4–9.comparisons. Given the number of statistical tests, it is 5. Szaflarski JP, Rackley AY, Kleindorfer DO, et al. 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