Refractory Status Epilepticus Treatment Study

Study Overview
=================
Brief Summary
-----------------
Identify the most effective dose of valproic acid when used in combination with phenytoin for treatment of patients with refractory status epilepticus, which allow a better clinical course and prognosis of the disease.

Detailed Description
-----------------
Phase III Clinical trial, to identify the most effective dose of valproic acid (20mg/kg bolus, 1mg/kg/h maintenance vs 40mg/kg bolus, 2mg/kg/h maintenance) in combination with phenytoin, in patients with refractory status epilepticus. Multicenter clinical trial, single-blind, prospective, randomized 1:1 assignment.

Official Title
-----------------
Refractory Status Epilepticus: Plasmatic Levels Monitorization Utility

Conditions
-----------------
Grand Mal Status Epilepticus, Non-convulsive Status Epilepticus

Intervention / Treatment
-----------------
* Drug: valproic acid (VPA)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patients ≥ 18 years of age who meet the diagnosis of EER seizure, and previously they have been treated according to the clinical protocol at our center status (Diazepam 10mg Clonazepam 1mg and Phenytoin or iv at a dose of 20mg/kg in case persistence of the clinic): -Present seizures for at least 30 minutes without regaining awareness among them. Patients ≥ 18 years of age who meet the diagnosis of nonconvulsive EER, and previously they have been treated according to the clinical protocol at our center status (Diazepam 10mg Clonazepam 1mg and Phenytoin or iv at a dose of 20mg/kg in case persistence of the clinic): After submitting an EER seizures that yield clinically performed an EEG that shows SE electricity. Evidence of a non-convulsive SE to perform an EEG of a patient admitted for any cause, either by filing seizures, altered mental status, or any other cause, and to persist after the treatment administered previously discussed. Patients in whom it has obtained the written informed consent by the representative and/or patient, as the case Exclusion Criteria: Patients with severe cerebral anoxia, when the first EEG evidences a pattern of flare-suppression. Patients who registers PLEDs (periodic epileptic lateralaized Discharges) without clinical seizure activity association to register or without electrical crises. Patients < 18 years of age. Patients in whom there is diagnostic doubt (eg non-convulsive status among and encephalopathy). Pregnant or breastfeeding. Patients with allergy to phenytoin, hydantoin or hypersensitivity to sodium valproate Patients with porphyria Patients with severe liver disease or dysfunction. Patients with heart block or second and third grade sinus bradycardia.
Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: 40mg/kg intial valproate bolus<br>Patient receives a 40mg/kg valproate bolus with a maintenance of 1mg/kg/h, after benzodiazepine + phenytoin administration | Drug: valproic acid (VPA)<br>* Best dosage at the initial bolus of VPA in patient with satatus epilepticus refractarius (after benzodiazepine + phenytoin treatment)<br>* Other names: Status Epilepticus Refractarius;|
| Active Comparator: 20mg/Kg intial bolus valproate<br>Patient receives a 20mg/kg valproate bolus with a maintenance of 1mg/kg/h, after benzodiazepine + phenytoin administration | Drug: valproic acid (VPA)<br>* Best dosage at the initial bolus of VPA in patient with satatus epilepticus refractarius (after benzodiazepine + phenytoin treatment)<br>* Other names: Status Epilepticus Refractarius;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| status epilepticus resolution | After 48h treatment administration the status epilepticus has to be solved without any other antiepileptic medications | after 48h treatment administration | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Estimation of pharmacokinetic parameters of valproate (VPA) and phenytoin (PHT) | Estimation of pharmacokinetic parameters of VPA (Cl: clearance, Vd: volume of distribution) and PHT (Vmax: maximum speed of metabolism and Km: plasma concentration at which the rate of metabolism is half the maximum) | During 48h post valproate administration | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
refractory status epilepticus, valproic acid, phenytoin, benzodiazepines, Valproic acid initial dosage in status treatment