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

NCT05756621 | Recruiting

• 1 other identifier: SUPER-CAT
• Study Type: observational
• Target: 80
• Locations: 1 country
• Sites: 10

Brief Summary

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.

Conditions

Status Epilepticus; Cardiac Arrest

Keywords

super-refractory; prognostic indicators; perampanel; ketamine

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (8)

• Number of patients with with time-locked resolution of status epilepticus

  first 5 days after start of therapy

• Number of patients with early favorable neurological outcome

  Over the entire period of stay in the Intensive Care Unit (up to 30 days)

• Number of patients with favorable long-term neurological outcome

  6 months after cardiac arrest

• mortality in intensive care

  Over the entire period of stay in the Intensive Care Unit (up to 30 days)

• mortality at 6 months

  6 months after cardiac arrest

Study Arms (2)

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

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

Interventions

Ketamine DRUG

"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.

Also known as: Perampanel

Dual anti-glutamate therapy (DUAL)

Any anti-epileptic and anesthetic therapy, excluding Ketamine and Perampanel DRUG

Any antiseizure and anesthetic therapy according to usual clinical practice, excluding the two anti-glutamate drugs Ketamine and Perampanel

Also known as: Levetiracetam, Valproate, Phenytoin, Lacosamide, Topiramate, Propofol, Midazolam, Thiopental

Control (OTHERS)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• 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

You may qualify if:

• 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

You may not qualify if:

• EEG with periodic pattern (generalized periodic discharges; GPDs)
• status epilepticus resolved after the first cycle of anesthetics + antiepileptics
• pregnant women

Sponsors & Collaborators

• University of Milano Bicocca: lead
• Azienda Ospedaliera San Gerardo di Monza: collaborator
• Azienda Ospedaliero-Universitaria di Modena: collaborator
• Azienda Ospedaliera Universitaria Integrata Verona: collaborator
• Ospedale Centrale Bolzano: collaborator
• Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia: collaborator
• Azienda Ospedaliero-Universitaria Careggi: collaborator
• Azienda Ospedaliero-Universitaria di Parma: collaborator
• Santa Chiara Hospital: collaborator
• Ospedale M. Bufalini Cesena: collaborator
• Azienda Ospedaliera Brotzu: collaborator
• Istituto Di Ricerche Farmacologiche Mario Negri: collaborator

Study Sites (10)

ASST Spedali Civili Brescia

Brescia, BS, Italy

RECRUITING

Ospedale Centrale di Bolzano

Bolzano, BZ, Italy

NOT YET RECRUITING

Ospedale G. Brotzu

Cagliari, CA, Italy

NOT YET RECRUITING

Ospedale M. Bufalini

Cesena, FC, Italy

NOT YET RECRUITING

AOU Careggi

Florence, FI, Italy

NOT YET RECRUITING

Fondazione IRCCS San Gerardo dei Tintori Monza

Monza, MB, 20900, Italy

RECRUITING

Azienda Ospedaliero-Universitaria di Modena

Modena, MO, Italy

NOT YET RECRUITING

Azienda Ospedaliero-Universitaria di Parma

Parma, PR, Italy

NOT YET RECRUITING

Ospedale Santa Chiara Trento

Trento, TN, Italy

RECRUITING

Azienda Ospedaliero-Universitaria Integrata di Verona

Verona, VR, Italy

NOT YET RECRUITING

Related Publications (10)

• 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.

  PMID: 22366352 BACKGROUND

• 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.

  PMID: 28163232 BACKGROUND

• Cronberg T. Should Postanoxic Status Epilepticus Be Treated Agressively? Yes! J Clin Neurophysiol. 2015 Dec;32(6):449-51. doi: 10.1097/WNP.0000000000000209.

  PMID: 26629753 BACKGROUND

• 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.

  PMID: 28506865 BACKGROUND

• 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.

  PMID: 35196426 BACKGROUND

• 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.

  PMID: 27571157 BACKGROUND

• 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.

  PMID: 33773827 BACKGROUND

• 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.

  PMID: 26117526 BACKGROUND

• 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.

  PMID: 30381366 BACKGROUND

• 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.

  PMID: 30159874 BACKGROUND

MeSH Terms

Conditions

Status Epilepticus; Heart Arrest

Interventions

Ketamine; perampanel; Levetiracetam; Valproic Acid; Phenytoin; Lacosamide; Topiramate; Propofol; Midazolam; Thiopental

Condition Hierarchy (Ancestors)

Seizures; Neurologic Manifestations; Nervous System Diseases; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Heart Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Cyclohexanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Acetamides; Amides; Acetates; Acids, Acyclic; Carboxylic Acids; Pyrrolidinones; Pyrrolidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Pentanoic Acids; Valerates; Fatty Acids, Volatile; Fatty Acids; Lipids; Hydantoins; Imidazolidines; Imidazoles; Azoles; Fructose; Hexoses; Monosaccharides; Sugars; Carbohydrates; Ketoses; Phenols; Benzene Derivatives; Hydrocarbons, Aromatic; Benzodiazepines; Benzazepines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Thiobarbiturates; Barbiturates; Pyrimidinones; Pyrimidines

Study Officials

• Simone Beretta, MD, PhD

  University of Milano Bicocca

  PRINCIPAL INVESTIGATOR

• Matteo Pozzi, MD

  Fondazione IRCCS Gerardo dei Tintori Monza

  STUDY CHAIR

Central Study Contacts

Simone Beretta, MD, PhD

CONTACT

00390392333568; simone.beretta@unimib.it

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: RETROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 17, 2023
• First Posted: March 6, 2023
• Study Start: January 15, 2022
• Primary Completion: September 30, 2025
• Study Completion: September 30, 2025
• Last Updated: July 29, 2025

Record last verified: 2025-07

Locations

IT (10)