Dual Anti-glutamate Therapy in Super-refractory Status Epilepticus After Cardiac Arrest (SUPER-CAT)

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

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.

Study Overview

• Status: Recruiting
• Conditions: Cardiac Arrest; Status Epilepticus
• Intervention / Treatment: Drug: Ketamine; Drug: Any anti-epileptic and anesthetic therapy, excluding Ketamine and Perampanel

Detailed Description

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.

• Study Type: Observational
• Enrollment (Estimated): 80

Contacts and Locations

• Study Contact: Name: Simone Beretta, MD, PhD; Phone Number: 00390392333568; Email: simone.beretta@unimib.it

Study Locations

• Italy
  • BS
    • Brescia, BS, Italy
      • Recruiting
      • ASST Spedali Civili Brescia
      • Contact: Laura Broglio
  • BZ
    • Bolzano, BZ, Italy
      • Not yet recruiting
      • Ospedale Centrale di Bolzano
      • Contact: Igor Florio
  • CA
    • Cagliari, CA, Italy
      • Not yet recruiting
      • Ospedale G. Brotzu
      • Contact: Marta Corona, MD
  • FC
    • Cesena, FC, Italy
      • Not yet recruiting
      • Ospedale M. Bufalini
      • Contact: Marco Longoni, MD
  • FI
    • Firenze, FI, Italy
      • Not yet recruiting
      • AOU Careggi
      • Contact: Antonello Grippo, MD
  • MB
    • Monza, MB, Italy, 20900
      • Recruiting
      • Fondazione IRCCS San Gerardo dei Tintori Monza
      • Contact: Simone Beretta, MD, PhD; Phone Number: +390392333568; Email: simone.beretta@unimib.it
  • MO
    • Modena, MO, Italy
      • Not yet recruiting
      • Azienda Ospedaliero-Universitaria di Modena
      • Contact: Stefano Meletti, MD, PhD
  • PR
    • Parma, PR, Italy
      • Not yet recruiting
      • Azienda Ospedaliero-Universitaria di Parma
      • Contact: Lucia Zinno
  • TN
    • Trento, TN, Italy
      • Recruiting
      • Ospedale Santa Chiara Trento
      • Contact: Stefania Filipponi, MD
  • VR
    • Verona, VR, Italy
      • Not yet recruiting
      • Azienda Ospedaliero-Universitaria Integrata di Verona
      • Contact: Marilena Casartelli, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Patients with super-refractory status epilepticus after cardiac arrest, admitted to the Intensive Care Unit, with continuous EEG monitoring, presence of first-line favorable prognostic indicators (pupillary reflexes and N20 cortical responses bilaterally; absence of periodic EEG pattern).

Outcomes will be also analyzed for the following pre-defined population:

"Patients with favorable prognostic indicators": patients presenting 5 or more of the following: 1) presence of a pupillary reflex bilaterally; (2) presence of corneal reflex bilaterally; (3) presence of N20 cortical response bilaterally; (4) NSE <68 ng/mL at 24-72 hours from ACC; (5) absence of periodic EEG patterns (GPDs); (6) absence of severe anoxic brain damage on neuroimaging

Description

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

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Dual anti-glutamate therapy (DUAL); 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; "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.; Other Names: Perampanel
Control (OTHERS); 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; Any antiseizure and anesthetic therapy according to usual clinical practice, excluding the two anti-glutamate drugs Ketamine and Perampanel; Other Names: Levetiracetam, Valproate, Phenytoin, Lacosamide, Topiramate, Propofol, Midazolam, Thiopental

What is the study measuring?

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)

Collaborators and Investigators

• Sponsor: University of Milano Bicocca
• Collaborators: Azienda Ospedaliera Universitaria Integrata Verona; Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia; Istituto Di Ricerche Farmacologiche Mario Negri; Azienda Ospedaliero-Universitaria di Parma; Azienda Ospedaliero-Universitaria di Modena; Azienda Ospedaliero-Universitaria Careggi; Santa Chiara Hospital; Azienda Ospedaliera San Gerardo di Monza; Azienda Ospedaliera Brotzu; Ospedale M. Bufalini Cesena; Ospedale Centrale Bolzano
• Investigators: Principal Investigator: Simone Beretta, MD, PhD, University of Milano Bicocca; Study Chair: Matteo Pozzi, MD, Fondazione IRCCS Gerardo dei Tintori Monza

Publications and helpful links

General Publications

• Mani R, Schmitt SE, Mazer M, Putt ME, Gaieski DF. The frequency and timing of epileptiform activity on continuous electroencephalogram in comatose post-cardiac arrest syndrome patients treated with therapeutic hypothermia. Resuscitation. 2012 Jul;83(7):840-7. doi: 10.1016/j.resuscitation.2012.02.015. Epub 2012 Feb 23.
• Lybeck A, Friberg H, Aneman A, Hassager C, Horn J, Kjaergaard J, Kuiper M, Nielsen N, Ullen S, Wise MP, Westhall E, Cronberg T; TTM-trial Investigators. Prognostic significance of clinical seizures after cardiac arrest and target temperature management. Resuscitation. 2017 May;114:146-151. doi: 10.1016/j.resuscitation.2017.01.017. Epub 2017 Feb 3.
• Cronberg T. Should Postanoxic Status Epilepticus Be Treated Agressively? Yes! J Clin Neurophysiol. 2015 Dec;32(6):449-51. doi: 10.1097/WNP.0000000000000209.
• Dragancea I, Wise MP, Al-Subaie N, Cranshaw J, Friberg H, Glover G, Pellis T, Rylance R, Walden A, Nielsen N, Cronberg T; TTM trial investigators. Protocol-driven neurological prognostication and withdrawal of life-sustaining therapy after cardiac arrest and targeted temperature management. Resuscitation. 2017 Aug;117:50-57. doi: 10.1016/j.resuscitation.2017.05.014. Epub 2017 May 12.
• Ruijter BJ, Keijzer HM, Tjepkema-Cloostermans MC, Blans MJ, Beishuizen A, Tromp SC, Scholten E, Horn J, van Rootselaar AF, Admiraal MM, van den Bergh WM, Elting JJ, Foudraine NA, Kornips FHM, van Kranen-Mastenbroek VHJM, Rouhl RPW, Thomeer EC, Moudrous W, Nijhuis FAP, Booij SJ, Hoedemaekers CWE, Doorduin J, Taccone FS, van der Palen J, van Putten MJAM, Hofmeijer J; TELSTAR Investigators. Treating Rhythmic and Periodic EEG Patterns in Comatose Survivors of Cardiac Arrest. N Engl J Med. 2022 Feb 24;386(8):724-734. doi: 10.1056/NEJMoa2115998.
• Leitinger M, Trinka E, Gardella E, Rohracher A, Kalss G, Qerama E, Hofler J, Hess A, Zimmermann G, Kuchukhidze G, Dobesberger J, Langthaler PB, Beniczky S. Diagnostic accuracy of the Salzburg EEG criteria for non-convulsive status epilepticus: a retrospective study. Lancet Neurol. 2016 Sep;15(10):1054-62. doi: 10.1016/S1474-4422(16)30137-5. Epub 2016 Aug 8.
• Nolan JP, Sandroni C, Bottiger BW, Cariou A, Cronberg T, Friberg H, Genbrugge C, Haywood K, Lilja G, Moulaert VRM, Nikolaou N, Mariero Olasveengen T, Skrifvars MB, Taccone F, Soar J. European Resuscitation Council and European Society of Intensive Care Medicine Guidelines 2021: Post-resuscitation care. Resuscitation. 2021 Apr;161:220-269. doi: 10.1016/j.resuscitation.2021.02.012. Epub 2021 Mar 24. Erratum In: Resuscitation. 2021 Oct;167:109-110.
• Dragancea I, Backman S, Westhall E, Rundgren M, Friberg H, Cronberg T. Outcome following postanoxic status epilepticus in patients with targeted temperature management after cardiac arrest. Epilepsy Behav. 2015 Aug;49:173-7. doi: 10.1016/j.yebeh.2015.04.043. Epub 2015 Jun 24.
• Beretta S, Coppo A, Bianchi E, Zanchi C, Carone D, Stabile A, Padovano G, Sulmina E, Grassi A, Bogliun G, Foti G, Ferrarese C, Pesenti A, Beghi E, Avalli L. Neurologic outcome of postanoxic refractory status epilepticus after aggressive treatment. Neurology. 2018 Dec 4;91(23):e2153-e2162. doi: 10.1212/WNL.0000000000006615. Epub 2018 Oct 31.
• Beretta S, Padovano G, Stabile A, Coppo A, Bogliun G, Avalli L, Ferrarese C. Efficacy and safety of perampanel oral loading in postanoxic super-refractory status epilepticus: A pilot study. Epilepsia. 2018 Oct;59 Suppl 2:243-248. doi: 10.1111/epi.14492. Epub 2018 Aug 29.

Study record dates

Study Major Dates

• Study Start (Actual): January 15, 2022
• Primary Completion (Estimated): June 30, 2024
• Study Completion (Estimated): September 30, 2024

Study Registration Dates

• First Submitted: February 17, 2023
• First Submitted That Met QC Criteria: March 1, 2023
• First Posted (Actual): March 6, 2023

Study Record Updates

• Last Update Posted (Estimated): January 1, 2024
• Last Update Submitted That Met QC Criteria: December 29, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Keywords: ketamine; perampanel; super-refractory; prognostic indicators
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Nervous System Diseases; Neurologic Manifestations; Seizures; Heart Arrest; Status Epilepticus; Hypoglycemic Agents; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Anesthetics, Dissociative; Anesthetics, Intravenous; Anesthetics, General; Excitatory Amino Acid Antagonists; Excitatory Amino Acid Agents; Tranquilizing Agents; Psychotropic Drugs; Membrane Transport Modulators; Hypnotics and Sedatives; Adjuvants, Anesthesia; Anti-Anxiety Agents; GABA Modulators; GABA Agents; Voltage-Gated Sodium Channel Blockers; Sodium Channel Blockers; Cytochrome P-450 CYP1A2 Inducers; Cytochrome P-450 Enzyme Inducers; Nootropic Agents; Ketamine; Anesthetics; Midazolam; Propofol; Lacosamide; Anticonvulsants; Levetiracetam; Topiramate; Phenytoin; Thiopental
• Other Study ID Numbers: SUPER-CAT

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No