Clinical trial NCT05756621: Dual Anti-glutamate Therapy in Super-refractory Status Epilepticus After Cardiac Arrest
Official title: SUPER-refractory Status Epilepticus After Cardiac Arrest: a Multicenter, Retrospective, Cohort Study of Dual Anti-glutamate Therapy with Ketamine and Perampanel
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Status Epilepticus
Cardiac Arrest
Keywords: super-refractory
prognostic indicators
perampanel
ketamine
Lead sponsor: University of Milano Bicocca
Sponsor class: OTHER
Collaborators: name: Azienda Ospedaliera San Gerardo di Monza
name: Azienda Ospedaliero-Universitaria di Modena
name: Azienda Ospedaliera Universitaria Integrata Verona
name: Ospedale Centrale Bolzano
name: Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia
name: Azienda Ospedaliero-Universitaria Careggi
name: Azienda Ospedaliero-Universitaria di Parma
name: Santa Chiara Hospital
name: Ospedale M. Bufalini Cesena
name: Azienda Ospedaliera Brotzu
name: Istituto Di Ricerche Farmacologiche Mario Negri
First posted: 2023-03-06
Enrollment: 80
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: RETROSPECTIVE
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

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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Number of patients with resolution of status epilepticus
timeFrame: Over the entire period of stay in the Intensive Care Unit (up to 30 days)
Secondary outcomes:
measure: Number of patients with with time-locked resolution of status epilepticus
timeFrame: first 5 days after start of therapy
measure: Number of patients with early favorable neurological outcome
timeFrame: Over the entire period of stay in the Intensive Care Unit (up to 30 days)
measure: Number of patients with favorable long-term neurological outcome
timeFrame: 6 months after cardiac arrest
measure: mortality in intensive care
timeFrame: Over the entire period of stay in the Intensive Care Unit (up to 30 days)
measure: mortality at 6 months
timeFrame: 6 months after cardiac arrest
measure: cumulative probability of resolution of status epilepticus
timeFrame: Over the entire period of stay in the Intensive Care Unit (up to 30 days)
measure: Number of patients with abnormal cholestasis indices
timeFrame: Over the entire period of stay in the Intensive Care Unit (up to 30 days)
measure: Number of patients with third degree atrioventricular block or cardiac arrest recurrence
timeFrame: Over the entire period of stay in the Intensive Care Unit (up to 30 days)
Other outcomes:
Locations:
city: Brescia
country: Italy
facility: ASST Spedali Civili Brescia
state: BS
city: Bolzano
country: Italy
facility: Ospedale Centrale di Bolzano
state: BZ
city: Cagliari
country: Italy
facility: Ospedale G. Brotzu
state: CA
city: Cesena
country: Italy
facility: Ospedale M. Bufalini
state: FC
city: Firenze
country: Italy
facility: AOU Careggi
state: FI
city: Monza
country: Italy
facility: Fondazione IRCCS San Gerardo dei Tintori Monza
state: MB
city: Modena
country: Italy
facility: Azienda Ospedaliero-Universitaria di Modena
state: MO
city: Parma
country: Italy
facility: Azienda Ospedaliero-Universitaria di Parma
state: PR
city: Trento
country: Italy
facility: Ospedale Santa Chiara Trento
state: TN
city: Verona
country: Italy
facility: Azienda Ospedaliero-Universitaria Integrata di Verona
state: VR
Study officials:
affiliation: University of Milano Bicocca
name: Simone Beretta, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Fondazione IRCCS Gerardo dei Tintori Monza
name: Matteo Pozzi, MD
role: STUDY_CHAIR
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citation: 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.
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