Starting ketamine for neuroprotection earlier than its current use as an anesthetic/antiepileptic drug late in refractory status epilepticus

Fujikawa, Denson G.

doi:10.1111/epi.14676

Cited by 38 publications

(35 citation statements)

References 41 publications

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“… 37 Fujikawa recommended that KET be started early in the sequence of treatments for RSE because it acts as a neuroprotectant against glutamate-induced widespread neuronal necrosis (despite ongoing ictal discharges) in animal models of SE. 38 It also interacts with opioid, monoaminergic, muscarinic, and nicotinic receptor ion channels ( l -calcium and sodium channels) and modulates some cytokines. 37 Additionally, KET may reduce the neuroinflammation, which may contribute to the refractoriness of SE.…”

Section: Resultsmentioning

confidence: 99%

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Treatment of Refractory Convulsive Status Epilepticus: A Comprehensive Review by the American Epilepsy Society Treatments Committee

et al. 2020

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Purpose: Established tonic–clonic status epilepticus (SE) does not stop in one-third of patients when treated with an intravenous (IV) benzodiazepine bolus followed by a loading dose of a second antiseizure medication (ASM). These patients have refractory status epilepticus (RSE) and a high risk of morbidity and death. For patients with convulsive refractory status epilepticus (CRSE), we sought to determine the strength of evidence for 8 parenteral ASMs used as third-line treatment in stopping clinical CRSE. Methods: A structured literature search (MEDLINE, Embase, CENTRAL, CINAHL) was performed to identify original studies on the treatment of CRSE in children and adults using IV brivaracetam, ketamine, lacosamide, levetiracetam (LEV), midazolam (MDZ), pentobarbital (PTB; and thiopental), propofol (PRO), and valproic acid (VPA). Adrenocorticotropic hormone (ACTH), corticosteroids, intravenous immunoglobulin (IVIg), magnesium sulfate, and pyridoxine were added to determine the effectiveness in treating hard-to-control seizures in special circumstances. Studies were evaluated by predefined criteria and were classified by strength of evidence in stopping clinical CRSE (either as the last ASM added or compared to another ASM) according to the 2017 American Academy of Neurology process. Results: No studies exist on the use of ACTH, corticosteroids, or IVIg for the treatment of CRSE. Small series and case reports exist on the use of these agents in the treatment of RSE of suspected immune etiology, severe epileptic encephalopathies, and rare epilepsy syndromes. For adults with CRSE, insufficient evidence exists on the effectiveness of brivaracetam (level U; 4 class IV studies). For children and adults with CRSE, insufficient evidence exists on the effectiveness of ketamine (level U; 25 class IV studies). For children and adults with CRSE, it is possible that lacosamide is effective at stopping RSE (level C; 2 class III, 14 class IV studies). For children with CRSE, insufficient evidence exists that LEV and VPA are equally effective (level U, 1 class III study). For adults with CRSE, insufficient evidence exists to support the effectiveness of LEV (level U; 2 class IV studies). Magnesium sulfate may be effective in the treatment of eclampsia, but there are only case reports of its use for CRSE. For children with CRSE, insufficient evidence exists to support either that MDZ and diazepam infusions are equally effective (level U; 1 class III study) or that MDZ infusion and PTB are equally effective (level U; 1 class III study). For adults with CRSE, insufficient evidence exists to support either that MDZ infusion and PRO are equally effective (level U; 1 class III study) or that low-dose and high-dose MDZ infusions are equally effective (level U; 1 class III study). For children and adults with CRSE, insufficient evidence exists to support that MDZ is effective as the last drug added (level U; 29 class IV studies). For adults with CRSE, insufficient evidence exists to support that PTB and PRO are equally effective (level U; 1 class III study). For adults and children with CRSE, insufficient evidence exists to support that PTB is effective as the last ASM added (level U; 42 class IV studies). For CRSE, insufficient evidence exists to support that PRO is effective as the last ASM used (level U; 26 class IV studies). No pediatric-only studies exist on the use of PRO for CRSE, and many guidelines do not recommend its use in children aged <16 years. Pyridoxine-dependent and pyridoxine-responsive epilepsies should be considered in children presenting between birth and age 3 years with refractory seizures and no imaging lesion or other acquired cause of seizures. For children with CRSE, insufficient evidence exists that VPA and diazepam infusion are equally effective (level U, 1 class III study). No class I to III studies have been reported in adults treated with VPA for CRSE. In comparison, for children and adults with established convulsive SE (ie, not RSE), after an initial benzodiazepine, it is likely that loading doses of LEV 60 mg/kg, VPA 40 mg/kg, and fosphenytoin 20 mg PE/kg are equally effective at stopping SE (level B, 1 class I study). Conclusions: Mostly insufficient evidence exists on the efficacy of stopping clinical CRSE using brivaracetam, lacosamide, LEV, valproate, ketamine, MDZ, PTB, and PRO either as the last ASM or compared to others of these drugs. Adrenocorticotropic hormone, IVIg, corticosteroids, magnesium sulfate, and pyridoxine have been used in special situations but have not been studied for CRSE. For the treatment of established convulsive SE (ie, not RSE), LEV, VPA, and fosphenytoin are likely equally effective, but whether this is also true for CRSE is unknown. Triple-masked, randomized controlled trials are needed to compare the effectiveness of parenteral anesthetizing and nonanesthetizing ASMs in the treatment of CRSE.

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Section: Resultsmentioning

confidence: 99%

“…Fujikawa notes that KET should be avoided in neonates and in women during the third trimester owing to evidence that it increases neuronal apoptosis in rats during these stages of infant development. 38 …”

Section: Resultsmentioning

confidence: 99%

Treatment of Refractory Convulsive Status Epilepticus: A Comprehensive Review by the American Epilepsy Society Treatments Committee

et al. 2020

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“…This mitigation program is only available to patients through a restricted distribution program at certified healthcare facilities where the healthcare provider can carefully monitor the patient. The anesthetic ketamine, which is being proposed as anticonvulsant for refractory SE, may have similar limitations as phenobarbital 54 . In addition, the potential biological variability including sex differences in the protective effect of phenobarbital warrant further scrutiny 55 .…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2020

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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.

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“…ere are clear benefits to early administration of ketamine for SE, including limiting the adverse events from polypharmacy and avoiding intubation [178], and earlier administration of ketamine for SE and RSE has been advocated [174,178,181]. Furthermore, early administration of ketamine may prevent neuronal necrosis, making it a useful medication to use early on in SE [182].…”

Section: Seizuresmentioning

confidence: 99%

A Review of Nonanesthetic Uses of Ketamine

Pribish

Wood

Kalava

2020

Anesthesiology Research and Practice

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Ketamine, a nonselective NMDA receptor antagonist, is used widely in medicine as an anesthetic agent. However, ketamine’s mechanisms of action lead to widespread physiological effects, some of which are now coming to the forefront of research for the treatment of diverse medical disorders. This paper aims at reviewing recent data on key nonanesthetic uses of ketamine in the current literature. MEDLINE, CINAHL, and Google Scholar databases were queried to find articles related to ketamine in the treatment of depression, pain syndromes including acute pain, chronic pain, and headache, neurologic applications including neuroprotection and seizures, and alcohol and substance use disorders. It can be concluded that ketamine has a potential role in the treatment of all of these conditions. However, research in this area is still in its early stages, and larger studies are required to evaluate ketamine’s efficacy for nonanesthetic purposes in the general population.

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Starting ketamine for neuroprotection earlier than its current use as an anesthetic/antiepileptic drug late in refractory status epilepticus

Cited by 38 publications

References 41 publications

Treatment of Refractory Convulsive Status Epilepticus: A Comprehensive Review by the American Epilepsy Society Treatments Committee

Treatment of Refractory Convulsive Status Epilepticus: A Comprehensive Review by the American Epilepsy Society Treatments Committee

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

A Review of Nonanesthetic Uses of Ketamine

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