Clinical Research Directory

Ketamine add-on Therapy for Established Status Epilepticus Treatment Trial (KESETT)

The goal of this clinical trial is to determine if treatment of patients with two doses of ketamine plus levetiracetam versus levetiracetam alone leads to more effective control of status epilepticus.

Improving Status Epilepticus Treatment Times

This is a stepped-wedge cluster randomized effectiveness-implementation hybrid study aimed at determining the effect of dissemination of a QI bundle on the time to treatment of SE among hospitalized, non-critically ill children. The primary study endpoint is to decrease the time from the SE diagnosis to treatment with the first dose of a benzodiazepine (BZD) as measured during hospitalization, which will decrease chances of morbidity and mortality.

Augmented Renal Clearance in Neurocritical Care

Stroke, severe brain injury, uncontrolled seizures and brain infections are the most common life-threatening neurological illnesses in the world with an estimated combined annual hospital management cost of up to 44 billion dollars. Seizures and infections are common complications following acute neurological illnesses and contribute significantly to poor outcomes if not promptly treated with appropriately dosed anti-seizure medications and antibiotics, respectively. Limited research suggested that many of those patients present with a phenomenon called augmented renal clearance (ARC) or, in other words, enhanced kidney function. ARC may have a significant influence on how medications are removed from the body potentially resulting in insufficient doses and treatment failure. Therefore, patients with ARC require higher medication doses; however, ARC is largely undetected using kidney assessment methods currently used in practice. In addition, it is not clear how medications should be dosed in those with ARC. The majority of ARC research has not focused on patients with life-threatening neurological illnesses. Thus, clinicians are likely under-dosing vital medications in those patients, and completely unaware. There is an immediate need to address the gap in knowledge. Therefore, this research aims to characterize the phenomenon of ARC in patients with life-threatening neurological illnesses through identifying the frequency, duration, contributing factors and clinical impact of ARC. Adult patients admitted to the neurosciences intensive care unit for life-threatening neurological illnesses will be enrolled in the study. Urine and blood samples wil be collected from participants to determine the presence of ARC and identify its contributing factors. In addition, blood samples will be collected from participants treated with select antibiotics and anti-seizure medications to determine their concentration and propose dose adjustment in those with ARC. This research is expected to improve the care of patients with life-threatening neurological illnesses through efficient identification and monitoring of patients exhibiting ARC facilitating timely medication dosage optimization. Furthermore, recommendations of optimal doses of commonly used medications in patients with ARC would improve the likelihood of treatment success with potential to improve patients' health and wellbeing.

Targeted Hypothermia Versus Targeted Normothermia After Convulsive Refractory Status Epilepticus

The HYBERNATUS-II study is a phase-III, open-label, randomized controlled trial in patients with convulsive refractory SE receiving mechanical ventilation. Patients are allocated at random to either early targeted hypothermia for 24 hours or targeted normothermia at the acute phase of ICU management. This trial is a superiority multicentric trial and patients will be randomized in a 1:1 ratio using an electronic Cas Report Form. Before any examination or intervention related to the study may be carried out, the investigator must obtain the freely given, informed and written consent of the participant, or of his/her substitute decision maker (family member, close relative or legal representative) where applicable. However, eligible subjects are unconscious and inherently not able to consent. Two situations of inclusion are therefore envisaged: \- In case a substitute decision maker is present or contactable: a freely given, informed and written consent of the substitute decision maker will be performed. \- In case a substitute decision maker is not present or contactable in the inclusion time frame, the patient may be included through a process of differed consent. Substitute decision maker will be informed as soon as possible and a freely given, informed and written pursuit consent will be performed. In all cases, the patient will have to confirm his participation to the study through a freely given, informed and written pursuit consent as soon as their condition allows it. If the patient is under curatorship, the pursuit consent may be given based on his or her own decision. If the patient is under guardianship, the written guardian's consent will also be required. Individuals liable to participate in studies stipulated in line 1° of article L. 1121-1 of the Code de la Santé Publique (French Public Health Code) benefit from a preliminary medical examination adapted to the study. Patients will be included after informed consent as soon as possible once they satisfied all eligibility criteria. The inclusion window is until 3.5 hours (210 minutes) after convulsive SE onset. Consecutive eligible patients will be included and randomly allocated in a 1:1 ratio to one of the two procedure groups. Randomization and concealment will be ensured by using a secure, computer-generated, interactive, response system accessible via the Internet available at each study centre 24H/24. Randomization list will be prepared by an independent statistician who will not be in charge of the analysis. Randomization lists will be generated by a dedicated computer program, with randomly varying sized blocks, and stratified as follows: according to sites, previous history of epilepsy \[yes or not\], and results of brain imaging \[Abnormal Brain Imaging or not\]. Each investigator will be able to access the randomization site using a personal password. Randomization will be carried out after checking of the inclusion criteria and the absence of exclusion criteria and after obtaining a written and informed consent or according to the emergency procedure by the principal investigator or a physician representing the investigator before the person is enrolled in the study of each centre involved in the study. Each patient will be assigned a unique identification number. An inclusion confirmation will be sent by email to the investigator specifying the allocated procedure arm. Patients will be randomly allocated to one of the two study procedure groups. The two groups will differ only in the administration of early targeted hypothermia for 24 hours or targeted normothermia at the acute phase of ICU management. All other treatment will be standardized in the two groups. Targeted Hypothermia group : Implementation of allocation arm is started within 30 min after randomization.The objective is to lower the core body temperature to 33°C \[32-34°C\] rapidly after randomization then to maintain this temperature for 24 hours. The management in the targeted hypothermia group will include the following. Targeted normothermia group. Implementation of allocation arm is started within 30 min after randomization. The objective of the control group is to ensure normothermia 37° \[36.5-37.5°C\] for 72 hours after randomization. Antipyretic treatments will be given in case of a core temperature higher than 37.8°C. In case of failure, cooling with a surface non-invasive loop-feedback TTM device associating pads directly adhering to the patient's skin (Artic Sun TM provided by the study, similar in all participating centers) will be initiated with a target temperature of 37° \[36.5-37.5°C\]. No active warming will be provided for patients in the normothermia group who had a spontaneous body temperature below 36.5°C. Patients included in the study will be followed until the 90th day after inclusion. The duration of the participation will therefore be 3 months for each patient.

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

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.

Simulation Trial of Telemedical Support for Paramedics

In the United States, the current standard of prehospital (i.e. outside of hospitals) emergency care for children with life-threatening illnesses in the community includes remote physician support for paramedics providing life-saving therapy while transporting the child to the hospital. Most prehospital emergency medical services (EMS) agencies use radio-based (audio only) communication between paramedics and physicians to augment this care. However, this communication strategy is inherently limited as the remote physician cannot visualize the patient for accurate assessment and to direct treatment. The purpose of this pilot randomized controlled trial (RCT) is to evaluate whether use of a 2-way audiovisual connection with a pediatric emergency medicine expert (intervention = "telemedical support") will improve the quality of care provided by paramedics to infant simulator mannequins with life threatening illness (respiratory failure). Paramedics receiving real-time telemedical support by a pediatric expert may provide better care due to decreased cognitive burden, critical action checking, protocol verification, and error correction. Because real pediatric life-threatening illnesses are rare, high stakes events and involve a vulnerable population (children), this RCT will test the effect of the intervention on paramedic performance in simulated cases of pediatric medical emergencies. The two specific aims for this research are: * Aim 1: To test the intervention efficacy by determining if there is a measurable difference in the frequency of serious safety events between study groups * Aim 2: To compare two safety event detection methods, medical record review, and video review

PeRampanel fOr Status ePilEpticus pRophylaxis Post-cardiac Arrest

Brain injury is the main cause of death and disability for patients surviving cardiac arrest resuscitation and seizures are diagnosed in up to a third of these patients. The investigators are proposing a pilot randomized placebo-controlled clinical trial to evaluate the safety and feasibility of perampanel use for post-cardiac arrest status epilepticus (PCARSE) prevention after cardiac arrest.

Improving Outcomes for Patients With Life-Threatening Neurologic Illness

Background: While the intensive care of patients with life-threatening brain illnesses has advanced tremendously, a large number of therapies are still without proper scientific support. This can be partly explained by the fact that mechanisms of initial brain injury are still not well understood. Why additional neurological injury occurs during a patient's stay in the NeuroCritical Care Unit (NCCU) despite current best, evidence-based clinical practices, is also not well understood. However, over the past decade, better tools have become available to measure and monitor the impact of our clinical care on the rapidly changing physiology and chemistry of the injured brain. Some of these tools are CT, MRI, ultrasound, and catheter-based technology measuring blood flow and metabolism. These tools have enabled earlier detection of injury and complications and newer therapeutic strategies. Purpose: Examine disease pathways common to all brain injuries seen in the University of Maryland's 22-bed NCCU. Life-threatening neurological illnesses cared for in the NCCU include massive stroke, bleeding in and around the brain (subarachnoid hemorrhage, intracerebral hemorrhage, subdural hemorrhage, intraventricular hemorrhage), brain tumors, difficult to control seizures, neurologic infections, nerve and muscle diseases (such as myasthenia gravis or Guillain-Barre Syndrome), and spinal cord disorders among others. Many NCCU patients are comatose or paralyzed and may suffer injuries in other parts of the body as well. This effort will require the creation of a robust clinical database for the capture of data including patient characteristics (age, sex), clinical characteristics, medical treatments, surgical interventions, physiological data (such as vital signs, cerebral blood flow, intracranial pressure, cerebral oximetry, etc), laboratory data, and standard-of-care diagnostic studies such as electroencephalography (EEG), ultrasound, CT, MRI, and angiograms. Similar databases exist at other major centers for neurocritical care and have been instrumental to the identification of characteristics both predictive of and associated with outcomes of patients long after their stay in the NCCU. In addition, the samples collected will be included in the University of Maryland Medicine (UMM) Biorepository which is a shared resource to enable biomedical research by University of Maryland faculty.

De-identified UNMH EEG Corpus Database Creation With Fully De-identified Clinical Information

This proposal outlines the steps required for the creation of a pilot database of EEG recordings and de-identified medical records from patients internally referred within the UNMH Comprehensive Epilepsy Center. The UNMH EEG Corpus would be the first database of its kind. Other public databases contain either patient EEG signals or medical records, but without both kinds of information, it is impossible to relate pre-treatment neurobiomarkers with post-treatment prognosis. The database will also contain information that can improve seizure localization based off of scalp and intracranial EEG, and the requisite data for the creation of algorithms that forecast seizure activity; a development that could ultimately lead to novel responsive neural stimulation procedures that suppress seizures before they begin.

Lacosamide Intravenous Injection for Emergency Termination of Status Epilepticus

Status epilepticus (SE) is an acute and critical form of neurological and systemic diseases involving multiple clinical disciplines, with an annual incidence of (20-73) per 100,000 people and a clinical case fatality rate of 20%. Although there are many causes of SE, the primary goal of treatment is to terminate the seizures quickly, and timely and standardized treatment can reduce mortality and improve prognosis. The prognosis is closely related to the duration of the episode, and the longer the episode, the worse the prognosis. If seizures of convulsive status epilepticus persist for more than 10 minutes and are not provided with optimal therapeutic intervention, serious adverse outcomes and even death are likely to occur. How to effectively terminate status epilepticus and actively find effective, reliable and safe treatment options is a key research problem at present. Due to critical illness, limited treatment options, and poor prognosis, new treatments are urgently needed to terminate persistent epileptic activity. Lacosamide (LCM) is a third-generation new antiepileptic drug, which was approved in 2008 for the additive treatment of patients aged 16 years and older with focal seizures, with or without generalized seizures. In 2017, it was extended to patients over 4 years of age. Lacosamide is an anticonvulsant drug with a new dual mechanism of action: first, lacosamide antagonizes the glycine site of N-methyl-D-aspartate (NMDA) receptor; Second, lacosamide selectively acts on the slow inactivation of sodium channels and prolongs the inactivation time of sodium channels, which can more effectively reduce sodium influx and reduce the excitability of neurons, so as to achieve the purpose of treating epilepsy. Lacosamide exhibits linear pharmacokinetics, high oral bioavailability, protein binding of \< 15%, rapid and almost complete absorption in a single oral dose, and maximum plasma concentrations within 1 to 4 hours. A number of randomized controlled clinical studies and real-world studies abroad have shown that lacosamide can significantly improve the effective rate and seizure-free rate of epilepsy control, and it is well tolerated and has fewer adverse reactions. The 2022 Chinese Expert Consensus on the Diagnosis and Treatment of Post-stroke Epilepsy recommended lacosamide injection as a first-line drug for non-convulsive status epilepticus after stroke, and the Chinese Expert Consensus on the Diagnosis and Treatment of Status Epilepticus in Children (2022) recommended that lacosamide be considered as an additive treatment for refractory convulsive status epilepticus in children \> 60 minutes . There is a lack of clinical research data on the efficacy and safety of intravenous bolus lacosamide for status epilepticus, including convulsive status epilepticus and non-convulsive epilepticus.

buRst-supprESsion TO Stop Refractory Status Epilepticus Post-cardiac Arrest

RESTORE is a randomized clinical trial investigating the safety and feasibility of using EEG treatment targets (burst suppression vs. seizure suppression) for post-cardiac arrest refractory status epilepticus treatment.

EEG Monitoring for Refractory Status Epilepticus

This is a prospective randomized study to investigate the yield of continuous electroencephalogram (cEEG), as a diagnostic tool in intensive care unit (ICU), for patients with refractory status epilepticus (RSE) and the contribution of this test to the patient final outcome, compared with standard medical care. Specifically, the hypothesis is that the use of cEEG for patients with RSE will significantly reduce the length of in-hospital stay, mortality, and subsequent complications (such as infections or pressure ulcers). It is also predicted that quality of life will be higher following cEEG at 0, 3, 6 and 12 months after discharge. As there are currently no data available from previous studies assessing the impact of cEEG on markers of the final clinical outcome in patients with RSE, this study is going to start as a feasibility study, aiming to obtain initial data for the primary outcome measure, in order to perform a sample size calculation for a larger future trial. The pilot study will also assess the integrity of the study protocol, specifically the recruitment process and the consent procedure, and also determine the necessary costs for running a cEEG service in ICU for patients with RSE

Study of Pathophysiology of Status Epilepticus and Dysimmune Encephalitis

COLETTE is an interventional study for which blood, cerebrospinal fluid and post-mortem tissues are collected in patients with status epilepticus or epilepsy associated to dysimmune encephalitis as well as in control patients, to better understand the pathophysiology of these severe epileptic disorders.

The Role of Imaging in the Diagnosis, Management and Prognosis of Possible Non-convulsive Status Epilepticus

The investigators propose a prospective study of 20 control subjects and 180 consecutive patients with possible non-convulsive status epilepticus (NCSE). The investigators will obtain three functional images of the brain: 1. Fluorodeoxyglucose positron emission tomography (FDG-PET) 2. Perfusion (and structural) magnetic resonance (MR) images 3. Computed tomography (CT) perfusion. Brain hypermetabolism/hyperperfusion is a strong argument to confirm a diagnosis of non-convulsive status epilepticus. The aim is to determine which of the three functional imaging techniques is the most sensitive and easy to obtain in the detection of hypermetabolism/hyperperfusion. The investigators will determine which EEG patterns are associated with hypermetabolism/perfusion. The investigators will further study and describe the management with antiseizure medication and outcome of the group with possible non-convulsive status epilepticus WITH hypermetabolism/hyperperfusion versus the group with possible non-convulsive status epilpticus WITHOUT hypermetabolism/hyperperfusion. The investigators will make recommendations for an imaging protocol in possible NCSE for widespread use. The aim is to offer guidelines to incorporate imaging in the diagnosis, management and prognosis of NCSE in patients with the ictal-interictal continuum.

Exogenous Ketone Esters for Refractory Status Epileptics

This study aims to investigate the efficacy of add-on exogenous ketone esters for the treatment of children with refractory generalized convulsive status epilepticus

Patient-reported Outcome and Patient-reported Experience After Status Epilepticus

Status epilepticus (SE) is a common life-threatening neurological emergency in which prolonged or multiple closely spaced seizures can result in long-term impairments. SE remains associated with considerable mortality and morbidity, with little progress over the last three decades. The proportion of patients who die in the hospital is about 20% overall and 40% in patients with refractory SE. Morbidity is more difficult to evaluate, as adverse effects of SE are often difficult to differentiate from those attributed to the cause of SE. Our experience suggests that nearly 50% of patients may experience long-term functional impairments. The precise description of the consequences of these functional impairments and their impact on quality of life after SE requiring intensive care management has been little studied. Indeed, if cognitive, physical and mental impairments are now identified in the populations of patients who required intensive care under the term postresuscitation syndrome (PICS), neuronal lesions consecutive to the SE itselfor to its cause could be responsible for these different functional alterations. Thus, the following have been described: (i) cognitive disorders in the areas of attention, executive functions and verbal fluency, visual and working memory disorders, but also spatio-temporal disorders; (ii) physical disorders such as the so-called post-resuscitation polyneuromyopathy; and (iii) mental disorders such as anxiety disorders, depressive states or those related to post-traumatic stress. Assessment and characterization of patient-reported outcomes is essential to complement the holistic assessment of clinically relevant outcomes from the patient's perspective. The POSEIDON study was a cross-sectional collection of PROs and HR-QOL components, and associated with patient functional outcomes, in those who required ICU management for status epilepticus. We propose here to continue the description of potential alterations after a subsequent ME, namely a longitudinal study (POSEIDON 2) which will also include the evaluation of patient-reported experience (PREMS) and the measurement of family burden.

The STatus Epilepticus Prognosis Study

The goal of this study is to improve the prognosis of patients who present with Status Epilepticus (SE). In the first part of this study, the investigators aim to find better markers of good and poor outcomes of SE patients while in the ICU. The objective is to measure the levels of brain protein micro-particles that are detectable in blood samples. The investigators seek to determine whether elevated levels of micro-particles in the bloodstream in SE patients can be used to predict the eventual outcome of survivors. The goal of the second part of the study is to evaluate long-term cognitive outcomes in survivors of SE To date, there is no reliable information to inform what cognitive recovery is like for survivors of SE after ICU discharge. The objective is to use the Creyos cognitive testing platform to assess different domains of cognitive function for up to 1 year after SE onset. Patients who have pre-existing epilepsy but have not had status epilepticus will serve as patient controls for the cognitive testing portion of this study. The third part of this study will evaluate brain changes in survivors of refractory SE. To date, there are no known studies that document to what extent the anatomy of the brain changes following SE. The objective is to characterize these changes by conducting two brain research scans 6 months apart. Patients will be invited to Robart\&#39;s Research Institute for a scan 1-3 months and 6-8 months (6 months apart) after refractory SE to measure structural and functional changes in the brain throughout the recovery process.

Rapid-Response EEG in Children With Suspected Status Epilepticus

Seizures are common in children (\~350 per 100,000 patients per year) and require immediate medical attention. If the seizure is prolonged (\> 5 minutes) it is called status epilepticus and delayed treatment leads to higher risk in drug resistance and brain injury. The current standard of care for children admitted to the ICU with established or suspected status epilepticus is to start a conventional continuous EEG study that helps diagnosing seizures by typical electro graphic patterns. It takes on average 4 hours to start and another two hours to obtain a reading by epileptologists. This is far beyond the time window of starting an EEG study (60 minutes) as recommended by the neurocritical care society. In adult ICUs, point of care "Rapid Response EEG" are becoming a new standard of care and our ICU adopted this practice in 2020. It can be easily placed by the ICU staff rather than a specifically trained EEG technician but has a lower resolution due to fewer leads (10 vs. 20). The purpose of this study is to determine wether and by how much time RR-EEG yields faster preliminary EEG reports that the previously available conventional EEG (cEEG) and wether the detection of electro graphic seizures is comparable. This is a retrospective cohort study following patients who are admitted to the PICU and are placed on either cEEG or RR-EEG for status epilepticus.

The Efficacy and Safety of Levetiracetam Versus Fosphenytoin in Convulsive Status Epilepticus

Status epilepticus (SE) is an emergency, life-threatening medical condition that may cause irreversible cerebral damage. Therefore, the rapid and secure cessation of seizures and resuscitation is crucial. Potent gamma-aminobutyric acid agonists, including benzodiazepines, are recommended as first-line treatments. For the complete cessation of SE and prevention of recurrence, long-acting antiepileptic drugs (e.g.- FPHT) are also required as second-line treatments along with short-acting benzodiazepines. Intravenous fosphenytoin (FPHT) is associated with fewer adverse events such as life-threatening arrhythmia, cardiac arrest, hypotension, and allergic reactions. Levetiracetam (LEV), is considered to be effective for SE with less serious adverse events including dizziness, somnolence, headache, and transient agitation, but there have been no reports of arrhythmias, hypotension, Stevens-Johnson syndrome, or hepatotoxicity. Preceding studies show that levetiracetam is similarly effective and associated with fewer adverse effects than those of fosphenytoin. Few trials have compared the effectiveness and safety of levetiracetam (LEV) and fosphenytoin (FHP) for status epilepticus worldwide. Moreover, genetic variation is likely to play a crucial role in the development of adverse drug reactions (ADRs) including drug resistance. By far, no study has yet been conducted addressing the issue of efficacy and safety between levetiracetam (LEV) and fosphenytoin (FHP) in status epilepticus in the context of the Bangladeshi population. A comparative study of the efficacy and safety of levetiracetam (LEV) and fosphenytoin (FHP) will be expected to give more confidence for the use of the drug. Considering this the study aims to assess the safety and efficacy of levetiracetam (LEV) and fosphenytoin (FHP) in status epilepticus. This study finding has an implication in the treatment protocol which will be beneficial for the patients and physicians as well. Furthermore, it will give input to the policymaker for developing new guidelines regarding status epilepticus management and also encourage future research.

Sustained Effort Network for Treatment of Status Epilepticus/European Academy of Neurology Registry on Refractory Status Epilepticus (SENSE-II/AROUSE)

SENSE-II/AROUSE is a prospective, multicenter registry for patients treated for SE. The primary objective is to document patients and SE characteristics, treatment modalities, EEG features, and outcome of consecutive adults admitted fir SE treatment in each of the participating centers and to identify predictors of outcome and refractoriness.

Status Epilepticus in the Critically Ill Patients

Convulsive and Non Convulsive Status Epilepticus (SE) and Pseudo Status Epilepticus prospective registry. Data collection using a standardized form : demographic data and data related to the SE, including circumstances of onset, dates and times of onset and of seizure control, on-scene clinical findings, clinical features of the seizures, pre-hospital and hospital care providers, timing of antiepileptic and supportive treatments, results of etiological investigations, cause of SE, type and dosage of antiepileptic drugs. Dates and times of EEG monitoring, EEG results. Outcomes including vital status and Glasgow Outcome Scale score at ICU and hospital discharge, day-90 and 1-year after SE and determined based on data in the ICU and/or neurologist charts and/or patients phone interview.