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Background: Drug pharmacokinetics (PK) are altered in neurocritically ill patients, and optimal levetiracetam dosing for seizure prophylaxis is unknown., Objective: This study evaluates levetiracetam PK in critically ill patients with severe traumatic brain injury (sTBI) receiving intravenous levetiracetam 1000 mg every 8 (LEV8) to 12 (LEV12) hours for seizure prophylaxis., Methods: This prospective, open-label study was conducted at a level 1 trauma, academic, quaternary care center. Patients with sTBI receiving seizure prophylaxis with LEV8 or LEV12 were eligible for enrollment. Five sequential, steady-state, postdose serum levetiracetam concentrations were obtained. Non-compartmental analysis (NCA) and compartmental approaches were employed for estimating pharmacokinetic parameters and projecting steady-state trough concentrations. Pharmacokinetic parameters were compared between LEV8 and LEV12 patients. Monte Carlo simulations (MCS) were performed to determine probability of target trough attainment (PTA) of 6 to 20 mg/L. A secondary analysis evaluated PTA for weight-tiered levetiracetam dosing., Results: Ten male patients (5 LEV8; 5 LEV12) were included. The NCA-based systemic clearance and elimination half-life were 5.3 ± 1.2 L/h and 4.8 ± 0.64 hours. A one-compartment model provided a higher steady-state trough concentration for the LEV8 group compared with the LEV12 group (13.7 ± 4.3 mg/L vs 6.3 ± 1.7 mg/L; P = 0.008). Monte Carlo simulations predicted regimens of 500 mg every 6 hours, 1000 mg every 8 hours, and 2000 mg every 12 hours achieved therapeutic target attainment. Weight-tiered dosing regimens achieved therapeutic target attainment using a 75 kg breakpoint., Conclusion and Relevance: Neurocritically ill patients exhibit rapid levetiracetam clearance resulting in a short elimination half-life. Findings of this study suggest regimens of levetiracetam 500 mg every 6 hours, 1000 mg every 8 hours, or 2000 mg every 12 hours may be required for optimal therapeutic target attainment. Patient weight of 75 kg may serve as a breakpoint for weight-guided dosing to optimize levetiracetam therapeutic target attainment for seizure prophylaxis., Competing Interests: Declaration of Conflicting InterestsThe authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: B.F. received honoraria from UCB Pharma and serves on the scientific advisory boards for Marinus Pharmaceuticals, Inc and SAGE Therapeutics. He receives research funding from the National Institutes of Health, US Department of Defense, and National Science Foundation and is the site principal investigator for studies funded by Biogen, Inc and Marinus Pharmaceuticals, Inc. B.F. has no relevant conflicts of interest to this research. L.B.N. conducts traumatic brain injury–related research funded by grants to the University of Cincinnati College of Medicine from Abbott Laboratories and Biogen, Inc. L.B.N. has no relevant conflicts of interest to this research.

Objectives: Generalized periodic discharges (GPDs) are associated with nonconvulsive seizures. Triphasic waves (TWs), a subtype of GPDs, have been described in relation to metabolic encephalopathy and not felt to be associated with seizures. We sought to establish the consistency of use of this descriptive term and its association with seizures., Methods: 11 experts in continuous EEG monitoring scored 20 cEEG samples containing GPDs using Standardized Critical Care EEG Terminology. In the absence of patient information, the inter-rater agreement (IRA) for EEG descriptors including TWs was assessed along with raters' clinical EEG interpretation and compared with actual patient information., Results: The IRA for 'generalized' and 'periodic' was near-perfect (kappa=0.81), but fair for 'triphasic' (kappa=0.33). Patients with TWs were as likely to develop seizures as those without (25% vs 26%, N.S.) and surprisingly, patients with TWs were less likely to have toxic-metabolic encephalopathy than those without TWs (55% vs 79%, p<0.01)., Conclusions: While IRA for the terms "generalized" and "periodic" is high, it is only fair for TWs. EEG interpreted as TWs presents similar risk for seizures as GPDs without triphasic appearance. GPDs are commonly associated with metabolic encephalopathy, but 'triphasic' appearance is not predictive., Significance: Conventional association of 'triphasic waves' with specific clinical conditions may lead to inaccurate EEG interpretation., (Copyright © 2015 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.)

Objective: Generalized periodic discharges are increasingly recognized on continuous EEG monitoring, but their relationship to seizures and prognosis remains unclear., Methods: All adults with generalized periodic discharges from 1996 to 2006 were matched 1:1 to controls by age, etiology, and level of consciousness. Overall, 200 patients with generalized periodic discharges were matched to 200 controls., Results: Mean age was 66 years (range 18-96); 56% were comatose. Presenting illnesses included acute brain injury (44%), acute systemic illness (38%), cardiac arrest (15%), and epilepsy (3%). A total of 46% of patients with generalized periodic discharges had a seizure during their hospital stay (almost half were focal), vs 34% of controls (p = 0.014). Convulsive seizures were seen in a third of both groups. A total of 27% of patients with generalized periodic discharges had nonconvulsive seizures, vs 8% of controls (p < 0.001); 22% of patients with generalized periodic discharges had nonconvulsive status epilepticus, vs 7% of controls (p < 0.001). In both groups, approximately half died or were in a vegetative state, one-third had severe disability, and one-fifth had moderate to no disability. Excluding cardiac arrest patients, generalized periodic discharges were associated with increased mortality on univariate analysis (36.8% vs 26.9%; p = 0.049). Multivariate predictors of worse outcome were cardiac arrest, coma, nonconvulsive status epilepticus, and sepsis, but not generalized periodic discharges., Conclusion: Generalized periodic discharges were strongly associated with nonconvulsive seizures and nonconvulsive status epilepticus. While nonconvulsive status epilepticus was independently associated with worse outcome, generalized periodic discharges were not after matching for age, etiology, and level of consciousness.

Seizures and status epilepticus are epilepsy emergencies with high morbidity and mortality. Early treatment is crucial, and the identification of an underlying etiology informs both continued treatment and prognosis. Many patients have underdiagnosed nonconvulsive seizures or nonconvulsive status epilepticus, particularly the comatose or critically ill. Timely EEG can be useful for diagnosis, management, optimizing treatment response, and determining prognosis in these patients. Refractory conditions can be quite complicated with limited evidence-based guidance, but treatment should not be restricted by nihilism even in the most prolonged cases, especially if there is not widespread irreversible brain injury., (Copyright © 2012 Elsevier Inc. All rights reserved.)