Clinical Pharmacology of First- and Second-Line Treatments of Convulsive Status Epilepticus

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Clinical Pharmacology of First- and Second-Line Treatments of Convulsive Status Epilepticus

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Convulsive status epilepticus (SE) is a serious neurological disorder characterized by abnormally prolonged seizures or multiple discrete seizures lasting more than five minutes between which there is incomplete recovery of consciousness. SE must be treated rapidly to avoid long term consequences such as neuronal loss and brain damage. While benzodiazepines including lorazepam (LZP), midazolam (MDZ) and diazepam (DZP) are recommended as first-line treatments of SE and have been shown to be safe and effective3–5, their failure rate ranges from 25-55%. Fosphenytoin (FOS), levetiracetam (LEV) and valproic acid (VPA) are commonly used as second-line treatments; however, until recently there were no randomized controlled studies to guide the selection of one drug over the others. The Established Status Epilepticus Treatment Trial (ESETT) was a multicenter, blinded, randomized study to determine the most and/or the least effective therapy among FOS, LEV and VPA for the treatment of benzodiazepine-refractory generalized convulsive SE. The primary outcome of ESETT was clinical cessation of seizures and improved responsiveness at 60 minutes after the start of study drug infusion without additional antiseizure medications. The overarching objective of my dissertation work is to address two unmet needs related to better utilization of the available first- and second-line treatments of generalized convulsive SE using data collected as a part of ESETT. While evidence-based guidelines provide guidance on the use of benzodiazepines as initial therapy including which benzodiazepine to administer, time of administration relative to onset of SE, and the dose and route of administration based on the patient’s weight; smaller studies have found that these guidelines are often not implemented in practice. Further, underdosing is a prognostic factor for refractoriness of SE and poor outcomes. Specific aim one of my research was to perform a comprehensive characterization of benzodiazepine use as first-line treatment in a large cohort of adults and children with convulsive SE who failed treatment and progressed to established SE. I hypothesized that benzodiazepines as first-line treatment of SE are not appropriately used in practice despite the availability of evidence-based guidelines. The benzodiazepine dosing patterns were described using pre-enrollment data from 478 patients with convulsive SE enrolled at 57 centers across the United States in ESETT. The results showed that most of the DZP administrations were given by caregivers prior to emergency medical services (EMS) arrival by the rectal route and a majority of these met guideline-recommendations. On the other hand, > 85% of MDZ doses, mostly administered by EMS personnel using the intramuscular (IM) or intravenous (IV) routes, and > 75% of LZP doses, most of which were administered using the IV route in the emergency department (ED) setting, were lower than guideline recommendations. Following an interim analysis, additional training was provided to study teams at participating sites designed to increase the awareness of appropriate benzodiazepine dosing. However, these educational efforts did not improve the pattern of underdosing overall or specifically in the ED. Further, it took a median of 27 minutes to administer the first dose of benzodiazepine after the onset of SE and a median of six minutes more to receive the cumulative adequate dose of benzodiazepines after the first dose. Delays in treatment may be one of the reasons why these patients failed first-line therapy. Introduction of newer, easy-to-use benzodiazepine formulations like IN DZP (Valtoco®) and IN MDZ (Nayzilam®), updating EMS protocols to reflect the current guidelines, availability of rapidly interpreted electroencephalography in the EMS and ED settings, regular training of EMS and ED personnel, and routine follow-up of practice patterns for quality assurance may improve the dosing patterns and, potentially, reduce benzodiazepine failure rates. Lastly, the association of benzodiazepine doses was tested with the ESETT primary outcome (clinical seizure cessation with improved responsiveness at 60 minutes after the administration of second-line treatment) using logistic regression. Higher cumulative doses of benzodiazepines were not significantly associated with higher likelihood of treatment success. Taken together, these results suggest that the recommended treatment must be administered as a single full dose as early as possible after the onset of SE. Specific aim two was to evaluate whether fixed dosing affects efficacy of second-line therapies. Weight-based dosing capped at 75 kg was used in ESETT for FOS, LEV and VPA. While development of a drug exposure-response relationship is the approach that I intended to use, the study was stopped early because of futility. Consequently, only a small number of pharmacokinetic samples were collected, which was insufficient to develop the models needed to perform the analysis. As an alternative, the association of weight, weight-normalized dose, treatment, and sex with primary outcome success in ESETT was tested. I hypothesized that patients weighing > 75 kg who received the capped doses of ESETT drugs would have lower drug exposure and would be more likely to be non-responders as compared to those weighing ≤ 75 kg. However, capping the dose at 75 kg did not significantly affect the likelihood of primary outcome success in ESETT. However, future studies measuring drug concentrations and including heavier individuals with higher body mass index are needed to confirm these findings. We were interested in measuring early exposure of the drug because rapid response desired with an emergent therapy is driven by the early exposure at the site of action. While a reliable estimate of early exposure is required to develop the exposure-response relationship to guide therapy, collecting early pharmacokinetic samples in an ED is challenging. Using ESETT and the ESETT drugs as a motivational example, I conducted a pharmacokinetic simulation study to evaluate the predictive performance of using two early plasma concentrations and a population pharmacokinetic modeling approach to estimate early drug exposure. The performance of the population pharmacokinetics approach was compared with standard non-compartmental analysis (NCA). I hypothesized that the estimates of early exposure obtained using the population pharmacokinetic approach will be closer to the true value as compared to those obtained using standard NCA. Using prior published pharmacokinetic models and two concentration measures in the first two hours post drug administration, I found that early drug exposure can be estimated with reasonable precision. Further, the performance of the population pharmacokinetic approach was found to be significantly superior as compared to a standard NCA approach. This approach can be applied in other emergent conditions or situations where early drug exposure may be of interest. The results from ESETT showed that there was no difference in the efficacy of FOS, LEV and VPA for the treatment of benzodiazepine-refractory SE in adults and children. Based on these results, I hypothesized that LEV will most likely be the second-line treatment of choice as it is easier to administer, has a better overall safety profile with fewer side effects and is the most cost-effective drug among the three. While the safety profiles for the three drugs were generally similar in ESETT, rate of endotracheal intubation with FOS was significantly higher in children. Further, the response rates for second-line treatments in ESETT were approximately 50%, indicating that there is a clear unmet need in this area for better therapies. Among the available treatment options, ketamine, which is an N-methyl-D-aspartate (NMDA) receptor antagonist, might be a potential alternative. As a future direction, I designed a prospective, multicenter, randomized, double-blind study of ketamine for the treatment of convulsive SE in the ED. Using data from ESETT, my research work suggests that the currently available therapies for initial treatment of convulsive SE can be better utilized to improve outcomes in patients. Further, my research indicates that that there is little reason to think that higher doses of FOS, LEV and VPA will result in greater response rates. Hence, the conduct of controlled clinical trials of other antiseizure medications for benzodiazepine-refractory SE is warranted. This work also provides valuable information to facilitate the design and conduct of a future study for the treatment of convulsive SE in an ED setting.


University of Minnesota Ph.D. dissertation. August 2020. Major: Experimental & Clinical Pharmacology. Advisors: Lisa Coles, Angela Birnbaum. 1 computer file (PDF); xvi, 199 pages.

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Sathe, Abhishek Gopal. (2020). Clinical Pharmacology of First- and Second-Line Treatments of Convulsive Status Epilepticus. Retrieved from the University Digital Conservancy,

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