Dual Anti-glutamate Therapy in Super-refractory Status Epilepticus After Cardiac Arrest

Study Overview
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Brief Summary
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Status epilepticus (SE) is found in 20-30% of patients in coma after cardiac arrest, is often refractory to medical therapy and is considered a negative prognostic factor. Intensity and duration of treatment of refractory and super-refractory post-anoxic SE pose the ethical dilemma between futility of treatments and, conversely, their premature suspension. A recent study by the Epilepsy Center of the San Gerardo Hospital has shown that patients with super-refractory post-anoxic SE and favorable prognostic indicators can achieve a good functional outcome in more than 40% of cases, if treated with intensive and protracted therapy. However, there is profound uncertainty about the best combination of antiseizure medications and anesthetics to use in this condition. A combined anti-glutamatergic therapy with ketamine (anti-NMDA receptor) and perampanel (anti-AMPA receptor), aimed at counteracting the excitotoxicity linked to global cerebral ischemia, could be particularly effective in the treatment of super-refractory SE with post-anoxic etiology. Preliminary results in the first 26 patients treated in the Coordinating Center of the project indicate that this therapy appears safe and highly effective (80% SE resolution, 40% good neurological outcome). The aim of the SUPER-CAT study is to investigate the efficacy and safety of combined therapy with ketamine and perampanel (dual anti-glutamatergic therapy) in patients with post-anoxic super-refractory status epilepticus, compared to other therapies, using a multi-centre, retrospective, cohort study design.

Detailed Description
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Status epilepticus (SE) is found in 20-30% of patients in a coma after cardiac arrest, is frequently refractory to medical therapy and is usually considered a poor prognostic factor. The intensity and duration of treatment for post-anoxic refractory and super-refractory SE remains a highly controversial issue, posing the ethical dilemma between futility and premature discontinuation of care. Although the TELSTAR randomized clinical trial demonstrated the futility of aggressive treatment in post-anoxic patients with generalized periodic pattern, the question remains open about the benefit of aggressive therapy in post-anoxic patients with SE properly defined according to the Salzburg criteria. The latest guidelines of the European Resuscitation Council recommend the use of electroencephalogram (EEG) both for the neurological prognosis and for the diagnosis of post-cardiac arrest epileptic seizures, define the highly malignant EEG patterns (which do not include status epilepticus; while generalized periodic pattern and suppressed background are included) and recommend treatment of seizures with first-line antiepileptic therapy (levetiracetam or valproate), while there are no recommendations regarding second-line antiepileptic therapy. The same guidelines recommend a multi-modal approach, using different indicators (brainstem reflexes, somatosensory evoked potentials, EEG patterns, neuron-specific enolase [NSE] levels and neuroimaging) to arrive at the formulation of the neurological prognosis. A favorable neurological outcome is present in <15% of post-anoxic SE cases after moderate intensity treatment. A recent study by the Epilepsy Center of the San Gerardo Hospital ASST Monza on a prospective cohort of 166 consecutive patients with cardiac arrest showed that patients with refractory post-anoxic SE and favorable prognostic indicators can achieve a good functional outcome (CPC 1-2) in > 40% of cases, if treated aggressively and prolonged with second-line anti-epileptic and anesthetic therapy. However, there is profound uncertainty about the best combination of antiseizure medications and anesthetics to use in this condition. A pilot study of the Epilepsy Center of the San Gerardo ASST Monza hospital has shown an efficacy of 75% of anti-glutamatergic therapy with oral load of perampanel (anti-AMPA receptor), combined with different types of anesthetics (including ketamine, anti -NMDA receptor), in 8 patients with super-refractory post-anoxic SE. All patients included in this series presented the main favorable prognostic indicators (presence of brainstem reflexes, presence of N20 cortical evoked potentials, absence of generalized periodic pattern) and in 60% of cases (5 out of 8 cases) a neuroimaging with mild anoxic damage. The clinical outcome was favorable, with the achievement of functional independence in 50% of cases (4 cases out of 8) after 3 months. A dual anti-glutamatergic therapy, performed by combining ketamine and perampanel could contrast in a particularly effective way the excitotoxicity linked to the global cerebral ischemia, favoring the resolution of the super-refractory SE and improving the global outcome of the post-cardiac arrest patient. Preliminary results in the first 26 post-anoxic super-refractory SE patients treated in the project Coordinating Center indicate that a dual anti-glutamatergic therapy with ketamine and perampanel appears highly effective (81% SE resolution; 41% good neurological outcome after 6 months) and without significant side effects. The selection of these patients was made on the basis of the multi-modal prognostic indicators described above, in accordance with the current guidelines on neurological prognosis. The aim of the SUPER-CAT study is to evaluate the efficacy and safety of combined therapy with ketamine and perampanel (dual anti-glutamatergic therapy) in patients with super-refractory SE of post-anoxic aetiology, compared to other therapies, using a multi-centre, retrospective, cohort study design. The study will be conducted thanks to the collaboration of the Intensive Care and Resuscitation Units and the Epilepsy Centers of 9 Italian hospitals, with the epidemiological-statistical coordination of the Mario Negri Institute for Pharmacological Research in Milan. Patients with super-refractory status epilepticus after in-hospital or out-of-hospital cardio-circulatory arrest will be enrolled. The results of the study will allow to compare the feasibility, efficacy and safety of dual anti-glutamate therapy with ketamine and perampanel in super-refractory post-anoxic SE compared to other anti-epileptic and anesthetic therapies used in normal clinical practice. If clinically relevant, these results will lay the foundations for the development of a subsequent randomized clinical trial. The study has a retrospective observational design, therefore no interventions or modifications in conventional diagnostic and therapeutic procedures will be carried out.

Official Title
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SUPER-refractory Status Epilepticus After Cardiac Arrest: a Multicenter, Retrospective, Cohort Study of Dual Anti-glutamate Therapy With Ketamine and Perampanel

Conditions
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Status Epilepticus, Cardiac Arrest

Intervention / Treatment
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* Drug: Ketamine
* Drug: Any anti-epileptic and anesthetic therapy, excluding Ketamine and Perampanel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: age ≥ 18 years patients in coma after cardio-circulatory arrest (CCA) admitted to the Intensive Care Unit and treated with target temperature management (TTM) for the first 24 hours initiation of continuous electroencephalographic (cEEG) monitoring within 24-36 hours of CCA diagnosis of super-refractory status epilepticus, relapsed after the first cycle of anesthetics (lasting > 24 hours) and antiepileptic therapy, defined according to the international Salzburg criteria9 presence of pupillary reflex present bilaterally presence of N20 cortical response present bilaterally Exclusion Criteria: EEG with periodic pattern (generalized periodic discharges; GPDs) status epilepticus resolved after the first cycle of anesthetics + antiepileptics pregnant women

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Dual anti-glutamate therapy (DUAL)<br>Patients who received ketamine as a continuous i.v. for 3 days (induction dose 1.5-3 mg/kg, followed by maintenance dose 2-10 mg/kg/h; dose adjustment according to EEG target of ketamine pattern) + oral perampanel via nasogastric tube for 5 days (12 mg if weight > 60 kg; 9 mg if weight 50-60 kg; 6 mg if weight < 50 kg), followed by gradual dose reduction according to clinical evolution. | Drug: Ketamine<br>* Dual anti-glutamatergic therapy (DUAL) intervention group: patients who received ketamine as a continuous i.v. for 3 days (induction dose 1.5-3 mg/kg, followed by maintenance dose 2-10 mg/kg/h; dose adjustment according to EEG target of ketamine pattern) + oral perampanel via nasogastric tube for 5 days (12 mg if weight > 60 kg; 9 mg if weight 50-60 kg; 6 mg if weight < 50 kg), followed by gradual reduction according to clinical evolution.<br>* Other names: Perampanel;|
| Control (OTHERS)<br>Patients who received any antiseizure and anesthetic therapy according to usual clinical practice, excluding the two anti-glutamate drugs ketamine and perampanel. | Drug: Any anti-epileptic and anesthetic therapy, excluding Ketamine and Perampanel<br>* Any antiseizure and anesthetic therapy according to usual clinical practice, excluding the two anti-glutamate drugs Ketamine and Perampanel<br>* Other names: Levetiracetam, Valproate, Phenytoin, Lacosamide, Topiramate, Propofol, Midazolam, Thiopental;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of patients with resolution of status epilepticus | Number of patients with resolution of status epilepticus, not followed by relapse and without the use of additional antiepileptic drugs, evaluated over the entire period of stay in the Intensive Care Unit, in the two groups DUAL versus OTHERS | Over the entire period of stay in the Intensive Care Unit (up to 30 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of patients with with time-locked resolution of status epilepticus | Number of patients with with resolution of status epilepticus 5 days after the start of therapy, not followed by relapse and without the use of additional antiepileptic drugs (only in the DUAL group) | first 5 days after start of therapy | 
| Number of patients with early favorable neurological outcome | Number of patients with early favorable neurological outcome, defined as the patient's awakening (up to command execution) during the stay in the Intensive Care Unit | Over the entire period of stay in the Intensive Care Unit (up to 30 days) | 
| Number of patients with favorable long-term neurological outcome | Number of patients with favorable long-term neurological outcome, defined by a modified Rankin scale score ≤ 2 at 6 months (minimum score 0, maximum score 6; lower scores indicate better outcomes) | 6 months after cardiac arrest | 
| mortality in intensive care | mortality in intensive care | Over the entire period of stay in the Intensive Care Unit (up to 30 days) | 
| mortality at 6 months | mortality at 6 months | 6 months after cardiac arrest | 
| cumulative probability of resolution of status epilepticus | incidence of the occurrence of resolution of status epilepticus, taking into account death as competing risk (cumulative incidence function) | Over the entire period of stay in the Intensive Care Unit (up to 30 days) | 
| Number of patients with abnormal cholestasis indices | Number of patients with abnormal cholestasis indices (GT-gamma > 3 times the upper limit of normal) | Over the entire period of stay in the Intensive Care Unit (up to 30 days) | 
| Number of patients with third degree atrioventricular block or cardiac arrest recurrence | Number of patients with third degree atrioventricular block or cardiac arrest recurrence | Over the entire period of stay in the Intensive Care Unit (up to 30 days) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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super-refractory, prognostic indicators, perampanel, ketamine