Propofol–ketamine combination therapy for effective control of super-refractory status epilepticus

Sabharwal, Vivek; Ramsay, Eugene; Martinez, Raisa C.; Shumate, Rachel; Khan, Fawad; Dave, Hina; Iwuchukwu, Ifeanyi; McGrade, Harold

doi:10.1016/j.yebeh.2015.07.040

Cited by 54 publications

(66 citation statements)

References 4 publications

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“…The termination rate in our case series with ( S )-KET is largely in line with the results of case series using the racemic mixture [31, 33]. Only one recently published case series reported an outstanding resolution rate of 91 % [32]. The authors of this study explained their high success rate with the early administration of KET and/or propofol (within 24–48 h).…”

Section: Discussionsupporting

confidence: 88%

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(S)-Ketamine in Refractory and Super-Refractory Status Epilepticus: A Retrospective Study

et al. 2016

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ObjectiveThe aim was to describe the safety and efficacy of (S)-ketamine [(S)-KET] in a series of patients with refractory and super-refractory status epilepticus (RSE and SRSE) in a specialized neurological intensive care unit (NICU).MethodsWe retrospectively analyzed the data of patients with RSE and SRSE treated with (S)-KET in the NICU, Salzburg, Austria, from 2011 to 2015. Data collection included demographic features, clinical presentation, diagnosis, electroencephalogram (EEG) data, anticonvulsant treatment, timing, and duration of treatment with (S)-KET. Outcomes were seizure control and death.ResultsA total of 42 patients (14 women) with RSE and SRSE were treated with (S)-KET. The median duration of status epilepticus (SE) was 10 days [first quartile (Q1) 5.0, Q3 21.0]; the median latency from SE onset to the first administration of (S)-KET was 3 days (Q1 2.0, Q3 6.8). Prior to (S)-KET administration, patients had received a median of two (Q1 2.0, Q3 3.0) anesthetics and three (Q1 2.0, Q3 4.0) antiepileptic drugs. Forty percent of patients (17/42) received propofol: 65 % prior to (S)-KET; 35 % at the same time with (S)-KET. Seven patients received a median bolus of (S)-KET of 200 mg (Q1 200, Q3 250) followed by a continuous infusion, while 35 started with a continuous infusion (maximum rate median 2.55 mg/kg/h; Q1 2.09, Q3 3.22). In 64 % of patients (27/42), (S)-KET was the last drug before SE cessation; in five patients, it was given with propofol at the same time. Median duration of administration was 4 days (Q1 2.0, Q3 6.8). Overall (S)-KET treatment was well tolerated, adverse effects were not observed, and overall mortality was 45.2 %.ConclusionsTreatment of SRSE in adult patients with (S)-KET led to resolution of status in 64 %. No adverse events were found, indicating a favorable safety profile.

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Section: Discussionsupporting

confidence: 88%

“…Our doses of the continuous infusions were quite similar to the doses of other studies with the racemic mixture of KET [31, 33], whereas our median maximum dose (median 2.55, Q1 2.09, Q3 3.22) was low compared with the studies with intravenous KET where maximum rates of 10.5 mg/kg/h were applied [32]. …”

Section: Discussionsupporting

confidence: 75%

(S)-Ketamine in Refractory and Super-Refractory Status Epilepticus: A Retrospective Study

et al. 2016

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“…This is in agreement with our hypothesis that correcting the consequences of GABA A R and NMDAR trafficking would stop benzodiazepine‐refractory SE, but does not prove that hypothesis, since ketamine has several mechanisms of action in addition to NMDAR channel blockage . Clinical and experimental studies suggest that ketamine administration can control refractory SE, and its combination with propofol is effective in controlling super‐refractory SE in patients . A combination of diazepam and phenobarbital (with the anticholinergic scopolamine) has also been reported to stop refractory SE and to prevent CA1 damage in a lower dose lithium–pilocarpine model of SE .…”

Section: Discussionsupporting

confidence: 69%

Midazolam–ketamine dual therapy stops cholinergic status epilepticus and reduces Morris water maze deficits

et al. 2016

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SUMMARY Objective Pharmacoresistance remains an unsolved therapeutic challenge in status epilepticus (SE) and in cholinergic SE induced by nerve agent intoxication. SE triggers a rapid internalization of synaptic GABAA receptors and externalization of NMDA receptors that may explain the loss of potency of standard anti-epileptic drugs (AED). We hypothesized that a drug combination aimed at correcting the consequences of receptor trafficking would reduce SE severity and its long-term consequences. Methods A severe model of SE was induced in adult Sprague-Dawley rats with a high dose of lithium and pilocarpine. The GABAA receptor agonist midazolam, the NMDA receptor antagonist ketamine and/or the AED valproate were injected 40 min after SE onset in combination or as monotherapy. Measures of SE severity were the primary outcome. Secondary outcomes were acute neuronal injury, spontaneous recurrent seizures (SRS), and Morris water maze (MWM) deficits. Results Midazolam-ketamine dual therapy was more efficient than double-dose midazolam or ketamine monotherapy or than valproate-midazolam or valproate-ketamine dual therapy in reducing several parameters of SE severity, suggesting a synergistic mechanism. In addition, midazolam-ketamine dual therapy reduced SE-induced acute neuronal injury, epileptogenesis and MWM deficits. Significance This study showed that a treatment aimed at correcting maladaptive GABAA receptor and NMDA receptor trafficking can stop SE and reduce its long-term consequences. Early Midazolam-ketamine dual therapy may be superior to monotherapy in the treatment of benzodiazepine-refractory SE.

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“…Beyond BSP, similar considerations may be relevant to patients with other persistently abnormal electroencephalographic activity patterns that are linked to increased metabolic demand, including refractory seizures or sustained rhythmic and periodic epileptiform discharges . In addition, recent studies have shown that super‐refractory status epilepticus, as seen in Patient 1, may remit with the use of ketamine, another NMDA‐antagonist agent . Lastly, ketogenic diet is increasingly used as an effective treatment for refractory seizures in adults, another treatment modality thought to alter metabolic substrate availability even though the basic underlying mechanism is not completely understood …”

Section: Discussionmentioning

confidence: 99%

“…65 In addition, recent studies have shown that super-refractory status epilepticus, as seen in Patient 1, may remit with the use of ketamine, another NMDAantagonist agent. 66,67 Lastly, ketogenic diet is increasingly used as an effective treatment for refractory seizures in adults, 68 another treatment modality thought to alter metabolic substrate availability even though the basic underlying mechanism is not completely understood. 69,70 Perhaps most importantly, our findings in conjunction with emerging clinical trials of neuroimaging markers of structural integrity in post-cardiac arrest comatose patients 17,18 also support the broad use of structural imaging protocols (including MRIs) in such patients.…”

Section: Discussionmentioning

confidence: 99%

Independent Functional Outcomes after Prolonged Coma following Cardiac Arrest: A Mechanistic Hypothesis

Forgács

Devinsky

Schiff

2020

Annals of Neurology

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Objective Survivors of prolonged (>2 weeks) post–cardiac arrest (CA) coma are expected to remain permanently disabled. We aimed to investigate 3 outlier patients who ultimately achieved independent functional outcomes after prolonged post‐CA coma to identify electroencephalographic (EEG) markers of their recovery potential. For validation purposes, we also aimed to evaluate these markers in an independent cohort of post‐CA patients. Methods We identified 3 patients with late recovery from coma (17–37 days) following CA who recovered to functionally independent behavioral levels. We performed spectral power analyses of available EEGs during prominent burst suppression patterns (BSP) present in all 3 patients. Using identical methods, we also assessed the relationship of intraburst spectral power and outcomes in a prospectively enrolled cohort of post‐CA patients. We performed chart reviews of common clinical, imaging, and EEG prognostic variables and clinical outcomes for all patients. Results All 3 patients with late recovery from coma lacked evidence of overwhelming cortical injury but demonstrated prominent BSP on EEG. Spectral analyses revealed a prominent theta (~4–7Hz) feature dominating the bursts during BSP in these patients. In the prospective cohort, similar intraburst theta spectral features were evident in patients with favorable outcomes; patients with BSP and unfavorable outcomes showed either no features, transient burst features, or decreasing intraburst frequencies with time. Interpretation BSP with theta (~4–7Hz) peak intraburst spectral power after CA may index a recovery potential. We discuss our results in the context of optimizing metabolic substrate availability and stimulating the corticothalamic system during recovery from prolonged post‐CA coma. ANN NEUROL 2020;87:618–632

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Propofol–ketamine combination therapy for effective control of super-refractory status epilepticus

Cited by 54 publications

References 4 publications

(S)-Ketamine in Refractory and Super-Refractory Status Epilepticus: A Retrospective Study

(S)-Ketamine in Refractory and Super-Refractory Status Epilepticus: A Retrospective Study

Midazolam–ketamine dual therapy stops cholinergic status epilepticus and reduces Morris water maze deficits

Independent Functional Outcomes after Prolonged Coma following Cardiac Arrest: A Mechanistic Hypothesis

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