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Phenobarbital as alternate anticonvulsant for organophosphate‐induced benzodiazepine‐refractory status epilepticus and neuronal injury

OBJECTIVE: Organophosphates (OPs) such as diisopropylfluorophosphate (DFP) and soman are lethal chemical agents that can produce seizures, refractory status epilepticus (SE), and brain damage. There are few optimal treatments for late or refractory SE. Phenobarbital is a second‐line drug for SE, usu...

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Autores principales: Reddy, Doodipala Samba, Perumal, Dheepthi, Golub, Victoria, Habib, Andy, Kuruba, Ramkumar, Wu, Xin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7278559/
https://www.ncbi.nlm.nih.gov/pubmed/32524045
http://dx.doi.org/10.1002/epi4.12389
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author Reddy, Doodipala Samba
Perumal, Dheepthi
Golub, Victoria
Habib, Andy
Kuruba, Ramkumar
Wu, Xin
author_facet Reddy, Doodipala Samba
Perumal, Dheepthi
Golub, Victoria
Habib, Andy
Kuruba, Ramkumar
Wu, Xin
author_sort Reddy, Doodipala Samba
collection PubMed
description OBJECTIVE: Organophosphates (OPs) such as diisopropylfluorophosphate (DFP) and soman are lethal chemical agents that can produce seizures, refractory status epilepticus (SE), and brain damage. There are few optimal treatments for late or refractory SE. Phenobarbital is a second‐line drug for SE, usually after lorazepam, diazepam, or midazolam have failed to stop SE. Practically, 40 minutes or less is often necessary for first responders to arrive and assist in a chemical incident. However, it remains unclear whether administration of phenobarbital 40 minutes after OP intoxication is still effective. Here, we investigated the efficacy of phenobarbital treatment at 40 minutes postexposure to OP intoxication. METHODS: Acute refractory SE was induced in rats by DFP injection as per a standard paradigm. After 40 minutes, subjects were given phenobarbital intramuscularly (30‐100 mg/kg) and progression of seizure activity was monitored by video‐EEG recording. The extent of brain damage was assessed 3 days after DFP injections by neuropathology analysis of neurodegeneration and neuronal injury by unbiased stereology. RESULTS: Phenobarbital produced a dose‐dependent seizure protection. A substantial decrease in SE was evident at 30 and 60 mg/kg, and a complete seizure termination was noted at 100 mg/kg within 40 minutes after treatment. Neuropathology findings showed significant neuroprotection in 100 mg/kg cohorts in brain regions associated with SE. Although higher doses resulted in greater protection against refractory SE and neuronal damage, they did not positively correlate with improved survival rate. Moreover, phenobarbital caused serious adverse effects including anesthetic or comatose state and even death. SIGNIFICANCE: Phenobarbital appears as an alternate anticonvulsant for OP‐induced refractive SE in hospital settings. A careful risk‐benefit analysis is required because of negative outcomes on survival and cardio‐respiratory function. However, the need for sophisticated support and critical monitoring in hospital may preclude its use as medical countermeasure in mass casualty situations.
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spelling pubmed-72785592020-06-09 Phenobarbital as alternate anticonvulsant for organophosphate‐induced benzodiazepine‐refractory status epilepticus and neuronal injury Reddy, Doodipala Samba Perumal, Dheepthi Golub, Victoria Habib, Andy Kuruba, Ramkumar Wu, Xin Epilepsia Open Full‐length Original Research OBJECTIVE: Organophosphates (OPs) such as diisopropylfluorophosphate (DFP) and soman are lethal chemical agents that can produce seizures, refractory status epilepticus (SE), and brain damage. There are few optimal treatments for late or refractory SE. Phenobarbital is a second‐line drug for SE, usually after lorazepam, diazepam, or midazolam have failed to stop SE. Practically, 40 minutes or less is often necessary for first responders to arrive and assist in a chemical incident. However, it remains unclear whether administration of phenobarbital 40 minutes after OP intoxication is still effective. Here, we investigated the efficacy of phenobarbital treatment at 40 minutes postexposure to OP intoxication. METHODS: Acute refractory SE was induced in rats by DFP injection as per a standard paradigm. After 40 minutes, subjects were given phenobarbital intramuscularly (30‐100 mg/kg) and progression of seizure activity was monitored by video‐EEG recording. The extent of brain damage was assessed 3 days after DFP injections by neuropathology analysis of neurodegeneration and neuronal injury by unbiased stereology. RESULTS: Phenobarbital produced a dose‐dependent seizure protection. A substantial decrease in SE was evident at 30 and 60 mg/kg, and a complete seizure termination was noted at 100 mg/kg within 40 minutes after treatment. Neuropathology findings showed significant neuroprotection in 100 mg/kg cohorts in brain regions associated with SE. Although higher doses resulted in greater protection against refractory SE and neuronal damage, they did not positively correlate with improved survival rate. Moreover, phenobarbital caused serious adverse effects including anesthetic or comatose state and even death. SIGNIFICANCE: Phenobarbital appears as an alternate anticonvulsant for OP‐induced refractive SE in hospital settings. A careful risk‐benefit analysis is required because of negative outcomes on survival and cardio‐respiratory function. However, the need for sophisticated support and critical monitoring in hospital may preclude its use as medical countermeasure in mass casualty situations. John Wiley and Sons Inc. 2020-04-14 /pmc/articles/PMC7278559/ /pubmed/32524045 http://dx.doi.org/10.1002/epi4.12389 Text en © 2020 The Authors. Epilepsia Open published by Wiley Periodicals Inc. on behalf of International League Against Epilepsy. This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Full‐length Original Research
Reddy, Doodipala Samba
Perumal, Dheepthi
Golub, Victoria
Habib, Andy
Kuruba, Ramkumar
Wu, Xin
Phenobarbital as alternate anticonvulsant for organophosphate‐induced benzodiazepine‐refractory status epilepticus and neuronal injury
title Phenobarbital as alternate anticonvulsant for organophosphate‐induced benzodiazepine‐refractory status epilepticus and neuronal injury
title_full Phenobarbital as alternate anticonvulsant for organophosphate‐induced benzodiazepine‐refractory status epilepticus and neuronal injury
title_fullStr Phenobarbital as alternate anticonvulsant for organophosphate‐induced benzodiazepine‐refractory status epilepticus and neuronal injury
title_full_unstemmed Phenobarbital as alternate anticonvulsant for organophosphate‐induced benzodiazepine‐refractory status epilepticus and neuronal injury
title_short Phenobarbital as alternate anticonvulsant for organophosphate‐induced benzodiazepine‐refractory status epilepticus and neuronal injury
title_sort phenobarbital as alternate anticonvulsant for organophosphate‐induced benzodiazepine‐refractory status epilepticus and neuronal injury
topic Full‐length Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7278559/
https://www.ncbi.nlm.nih.gov/pubmed/32524045
http://dx.doi.org/10.1002/epi4.12389
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