Randomized Trial of Three Anticonvulsant Medications for Status Epilepticus

Kapur, Jaideep; Elm, Jordan; Chamberlain, James M.; Barsan, William G.; Cloyd, James C.; Lowenstein, Daniel H.; Shinnar, Shlomo; Conwit, Robin; Meinzer, Caitlyn; Cock, Hannah R.; Fountain, Nathan B.; Connor, Jason T.; Silbergleit, Robert

doi:10.1056/nejmoa1905795

Cited by 396 publications

(397 citation statements)

References 18 publications

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“…Primary endpoint was absence of clinically evident seizures and improved responsiveness at 60 min. No significant difference regarding efficacy or safety were seen, including similar response to levetiracetam (47%), fosphenytoin (45%), and valproic acid (46%) [138]. These results corroborate further, that there are no major differences between these three medications during the second line therapy phase.…”

Section: Second-line Therapy (Established Status Epilepticus [Se])supporting

confidence: 63%

Pharmacotherapy for Pediatric Convulsive Status Epilepticus

2019

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Convulsive status epilepticus (CSE) is one of the most common pediatric neurological emergencies. Ongoing seizure activity is a dynamic process and may be associated with progressive impairment of gamma-aminobutyric acid (GABA)-mediated inhibition due to rapid internalization of GABA A receptors. Further hyperexcitability may be caused by AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) and NMDA (N-methyl-d-aspartic acid) receptors moving from subsynaptic sites to the synaptic membrane. Receptor trafficking during prolonged seizures may contribute to difficulties treating seizures of longer duration and may provide some of the pathophysiological underpinnings of established and refractory SE (RSE). Simultaneously, a practice change toward more rapid initiation of first-line benzodiazepine (BZD) treatment and faster escalation to second-line non-BZD treatment for established SE is in progress. Early administration of the recommended BZD dose is suggested. For second-line treatment, non-BZD anti-seizure medications (ASMs) include valproate, fosphenytoin, or levetiracetam, among others, and at this point there is no clear evidence that any one of these options is better than the others. If seizures continue after second-line ASMs, RSE is manifested. RSE treatment consists of bolus doses and titration of continuous infusions under continuous electro-encephalography (EEG) guidance until electrographic seizure cessation or burst-suppression. Ultimately, etiological workup and related treatment of CSE, including broad spectrum immunotherapies as clinically indicated, is crucial. A potential therapeutic approach for future studies may entail consideration of interventions that may accelerate diagnosis and treatment of SE, as well as rational and early polytherapy based on synergism between ASMs by utilizing medications targeting different mechanisms of epileptogenesis and epileptogenicity.

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Section: Second-line Therapy (Established Status Epilepticus [Se])supporting

confidence: 63%

Pharmacotherapy for Pediatric Convulsive Status Epilepticus

2019

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“…Because most RCTs are frequentist, trial reports that use Bayesian statistics will be unfamiliar to many readers, impeding understanding and dissemination. However, Bayesian trials and analyses are becoming considerably more common, which should reduce this problem (30,(77)(78)(79).…”

Section: Discussionmentioning

confidence: 99%

The REMAP-CAP (Randomized Embedded Multifactorial Adaptive Platform for Community-acquired Pneumonia) Study. Rationale and Design

et al. 2020

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There is broad interest in improved methods to generate robust evidence regarding best practice, especially in settings where patient conditions are heterogenous and require multiple concomitant therapies. Here, we present the rationale and design of a large, international trial that combines features of adaptive platform trials with pragmatic point-of-care trials to determine best treatment strategies for patients admitted to an intensive care unit with severe community-acquired pneumonia (CAP). The trial uses a novel design entitled a randomized embedded multifactorial adaptive platform (REMAP). The design has 5 key features: i.) randomization, allowing robust causal inference; ii.) embedding of study procedures into routine care processes, facilitating enrollment, trial efficiency, and generalizability; iii.) a multifactorial statistical model comparing multiple interventions across multiple patient subgroups; iv.) response-adaptive randomization with preferential assignment to those interventions that appear most favorable, and v.) a platform structured to permit continuous, potentially perpetual enrollment beyond the evaluation of the initial treatments. The trial randomizes patients to multiple interventions within 4 treatment domains: antibiotics, antiviral therapy for influenza, host immunomodulation with extended macrolide therapy, and alternative corticosteroid regimens, representing 240 treatment regimens. The trial generates estimates of superiority, inferiority and equivalence between regimens on the primary outcome of 90-day mortality, stratified by presence or absence of concomitant shock and proven or suspected influenza infection. The trial will also compare ventilatory and oxygenation strategies and has capacity to address additional questions rapidly during pandemic respiratory infections.

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“…pregnancy or breastfeeding, comorbid medical problems and medication factors, e.g. tolerability (Alick & Doyle, 2018;Anderson, 2020;Kapur et al, 2019;Má laga et al, 2019). Many of the medicines used for treatment are not completely safe for each patient and, additionally, a discernible resistance to some available drugs has been observed (Sander, 2003;Zaccara et al, 2007;Perucca & ISSN 2053-2296 # 2020 International Union of Crystallography Gilliam, 2012).…”

Section: Introductionmentioning

confidence: 99%

The conformational analyses of 2-amino-N-[2-(dimethylphenoxy)ethyl]propan-1-ol derivatives in different environments

Nitek¹,

Kania²,

Marona³

et al. 2020

Acta Crystallogr C

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Four crystal structures of 2-amino-N-(dimethylphenoxyethyl)propan-1-ol derivatives, characterized by X-ray diffraction analysis, are reported. The free base (R,S)-2-amino-N-[2-(2,3-dimethylphenoxy)ethyl]propan-1-ol, C13H21NO2, 1, crystallizes in the space group P21/n, with two independent molecules in the asymmetric unit. The hydrochloride, (S)-N-[2-(2,6-dimethylphenoxy)ethyl]-1-hydroxypropan-2-aminium chloride, C13H22NO2 +·Cl−, 2c, crystallizes in the space group P21, with one cation and one chloride anion in the asymmetric unit. The asymmetric unit of two salts of 2-picolinic acid, namely, (R,S)-N-[2-(2,3-dimethylphenoxy)ethyl]-1-hydroxypropan-2-aminium pyridine-2-carboxylate, C13H22NO2 +·C6H4NO2 −, 1p, and (R)-N-[2-(2,6-dimethylphenoxy)ethyl]-1-hydroxypropan-2-aminium pyridine-2-carboxylate, C13H22NO2 +·C6H4NO2 −, 2p, consists of one cation and one 2-picolinate anion. Salt 1p crystallizes in the triclinic centrosymmetric space group P-1, while salt 2p crystallizes in the space group P41212. The conformations of the amine fragments are contrasted and that of 2p is found to have an unusual antiperiplanar arrangement about the ether group. The crystal packing of 1 and 2c is dominated by hydrogen-bonded chains, while the structures of the 2-picolinate salts have hydrogen-bonded rings as the major features. In both salts with 2-picolinic acid, the specific R 1 2(5) hydrogen-bonding motif is observed. Structural studies have been enriched by the generation of fingerprint plots derived from Hirshfeld surfaces.

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Randomized Trial of Three Anticonvulsant Medications for Status Epilepticus

Cited by 396 publications

References 18 publications

Pharmacotherapy for Pediatric Convulsive Status Epilepticus

Pharmacotherapy for Pediatric Convulsive Status Epilepticus

The REMAP-CAP (Randomized Embedded Multifactorial Adaptive Platform for Community-acquired Pneumonia) Study. Rationale and Design

The conformational analyses of 2-amino-N-[2-(dimethylphenoxy)ethyl]propan-1-ol derivatives in different environments

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