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

Abstract

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 | 199 REDDY Et al.

Combination of antiseizure medications phenobarbital, ketamine, and midazolam reduces soman‐induced epileptogenesis and brain pathology in rats

“…In mice exposed to a seizure‐inducing dose of soman, a low dose of phenobarbital monotherapy (20 mg/kg) resulted in a delay in onset to SRS but did not reduce neuropathology. 41 Higher doses of phenobarbital as evaluated against DFP in rats 17 , 18 or combination of lower doses of phenobarbital with other antiseizure medications as used in the current study may be needed to improve neuroprotection. These findings demonstrate the efficacy of combining subanesthetic doses of antiseizure medications in reducing cholinergic‐induced SE and epileptogenesis.…”

“… 16 Similar dose‐response effects of phenobarbital as an adjunct to midazolam were observed following exposure to the pesticide diisopropyl fluorophosphate (DFP). 17 , 18 The latter studies, however, did not investigate the effect of phenobarbital adjunct treatment on epileptogenesis and neuronal cell death at an endpoint longer than 24 or 72 hours. The antiseizure effects of phenobarbital occur in other seizure models, including maximal electroshock, picrotoxin, and electrical hippocampal stimulation.…”

Refractory and Super-Refractory Status Epilepticus in Nerve Agent-Poisoned Rats Following Application of Standard Clinical Treatment Guidelines

“…This is further reason to avoid iterative benzodiazepine administration, as time spent waiting for benzodiazepines to fail may reduce the efficacy of more promising therapies. PHB and VPA were chosen for comparison because, in addition to their frequent use against benzodiazepine-refractory SE, PHB and derivatives of VPA have previously been shown to terminate organophosphate-induced SE (White et al, 2012;Shekh-Ahmad et al, 2013, 2015Bar-Klein et al, 2014;Haines et al, 2019;Jackson et al, 2019;Reddy et al, 2020;Spampanato et al, 2020). It is also possible that other common second-line antiseizure drugs like FOS and LEV would provide greater benefit against NA-induced SE.…”

Allopregnanolone and perampanel as adjuncts to midazolam for treating diisopropylfluorophosphate‐induced status epilepticus in rats

“…We have found through power spectral analysis in the frequency domain that EEG power is increased during DFP seizures within frequency bands encompassed within the 1‐ to 40‐Hz range of frequencies. A similar range of frequencies has been used to assess drug effects on DFP seizures by others 4,58,59 . It was desirable to eliminate higher frequencies, which may represent electrical noise and other artifacts, including muscle movement 60 .…”

“…A similar range of frequencies has been used to assess drug effects on DFP seizures by others. 4,58,59 It was desirable to eliminate higher frequencies, which may represent electrical noise and other artifacts, including muscle movement. 60 Rats were allowed to move freely in the monitoring system during recordings.…”