Early high-dose vitamin C in post-cardiac arrest syndrome.

INTERVENTION: Product Name: Ascorbic acid 1.5 gr/50 ml and 5 gr/50 ml Product Code: 1.5 gr and 5 gr Pharmaceutical Form: Solution for injection/infusion INN or Proposed INN: Ascorbic acid Other descriptive name: ASCORBIC ACID PH EUR Concentration unit: mg/ml milligram(s)/millilitre Concentration type: range Concentration number: 30‐100 Pharmaceutical form of the placebo: Infusion Route of administration of the placebo: Intravenous use Pharmaceutical form of the placebo: Injection Route of administration of the placebo: Intravenous use CONDITION: Patients admitted to the Intensive Care after out‐of‐hospital cardiac arrest with return of spontaneous circulation, ventricular fibrillation or ventricular tachycardia as first registered cardiac rhythm and EMV‐score =8 ; MedDRA version: 20.0 Level: PT Classification code 10078202 Term: Post cardiac arrest syndrome System Organ Class: 10029205 ‐ Nervous system disorders Therapeutic area: Diseases [C] ‐ Cardiovascular Diseases [C14] PRIMARY OUTCOME: ; Main Objective: ‐ To determine whether an early high dose i.v. vitamin C can improve organ function, especially neurological outcome, in patients after cardiac arrest; ; Secondary Objective: ‐ To explore the optimal dosing regimen for high dose i.v. vitamin C; ‐ To investigate in vitro the difference in effect of plasma obtained from post cardiac arrest patients treated with placebo, 3 gr/day or 10 gr/day vitamin C on endothelial cell viability and underlying oxidative pathways.; Primary end point(s): We will determine organ failure at 96 hours measured by the delta (?) Sequential Organ Failure Assessment (SOFA) score. ?SOFA score is defined as the difference between SOFA admission and SOFA at 96 hour. Death at 96‐hours will be counted as the maximum SOFA score (24 points). Timepoint(s) of evaluation of this end point: After 96 hours INCLUSION CRITERIA: Patients suffering an out‐of‐hospital cardiac arrest with return of spontaneous circulation, ventricular fibrillation or ventricular tachycardia as first registered cardiac rhythm and EMV‐score =8 will be included. Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18‐64 years) yes F.1.2.1 Number of subjects for this age range 200 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 340 SECONDARY OUTCOME: ; Secondary end point(s): As secondary outcomes we will investigate: neurological outcome (Maximal Glasgow Coma Score at 96‐h and after weaning of sedation; Cerebral Performance Categories scale, Modified Rankin Scale, extended Glasgow Outcome Scale and Short Form‐36 at 90 and 180 days, neuron‐specific enolase day 1, 2 and 3); clinical parameters (IC‐ and hospital stay, 28‐day and 90‐day mortality), organ injury (myocardial injury measured by troponin and CK‐MB (maximum day 1), lung injury score, ventilation time, renal function, need of renal replacement therapy, IC‐acquired weakness (Medical Research Council score), delirium (CAM‐ICU score), oxidative stress parameters (such as F2‐isoprostanes) and vitamin C plasma concentrations.; If the necessary funding will be obtained, we will investigate the differential dynamic response to post‐cardiac arrest in patients randomized to vitamin C or placebo via simultaneous measurement and integration of the metabolome, transcriptome and the genome.; In vitro experiments:; To determine the different effect of 3 or 10 gram vitamin C or placebo on the underlying oxidative pathways we will investigate how plasma obtained from the trial patients affects cultured human systemic microvascular endothelial cells with regard to endothelial cell viability, ROS production intracellular vitamin C concentrations, NADPH‐oxidase expression, p47Phox expression, endothelial barrier function and mitochondrial respiratory chain function.; Timepoint(s) of evaluation of this end point: After 96 hours and at the end of ICU‐stay. Neurological outcome will also be evaluated after 90 days and after 180 days.