Early high-dose vitamin C in post-cardiac arrest syndrome (VITaCCA): study protocol for a randomized, double-blind, multi-center, placebo-controlled trial

Sander Rozemeijer,Harm-Jan De Grooth,Corstiaan A Den Uil,Roel Vink,Bas Van Den Bogaard,Armand R J Girbes,Arthur R H Van Zanten,Thijs C D Rettig,Heleen M Oudemans-Van Straaten,Angélique M E De Man,Paul W G Elbers,Rob J Bosman,Eric A Dubois,Evert-Jan Wils

doi:10.1186/s13063-021-05483-3

Abstract

BackgroundHigh-dose intravenous vitamin C directly scavenges and decreases the production of harmful reactive oxygen species (ROS) generated during ischemia/reperfusion after a cardiac arrest. The aim of this study is to investigate whether short-term treatment with a supplementary or very high-dose intravenous vitamin C reduces organ failure in post-cardiac arrest patients.MethodsThis is a double-blind, multi-center, randomized placebo-controlled trial conducted in 7 intensive care units (ICUs) in The Netherlands. A total of 270 patients with cardiac arrest and return of spontaneous circulation will be randomly assigned to three groups of 90 patients (1:1:1 ratio, stratified by site and age). Patients will intravenously receive a placebo, a supplementation dose of 3 g of vitamin C or a pharmacological dose of 10 g of vitamin C per day for 96 h. The primary endpoint is organ failure at 96 h as measured by the Resuscitation-Sequential Organ Failure Assessment (R-SOFA) score at 96 h minus the baseline score (delta R-SOFA). Secondary endpoints are a neurological outcome, mortality, length of ICU and hospital stay, myocardial injury, vasopressor support, lung injury score, ventilator-free days, renal function, ICU-acquired weakness, delirium, oxidative stress parameters, and plasma vitamin C concentrations.DiscussionVitamin C supplementation is safe and preclinical studies have shown beneficial effects of high-dose IV vitamin C in cardiac arrest models. This is the first RCT to assess the clinical effect of intravenous vitamin C on organ dysfunction in critically ill patients after cardiac arrest.Trial registrationClinicalTrials.gov NCT03509662. Registered on April 26, 2018. https://clinicaltrials.gov/ct2/show/NCT03509662European Clinical Trials Database (EudraCT): 2017-004318-25. Registered on June 8, 2018. https://www.clinicaltrialsregister.eu/ctr-search/trial/2017-004318-25/NL

Highlights

High-dose intravenous vitamin C directly scavenges and decreases the production of harmful reactive oxygen species (ROS) generated during ischemia/reperfusion after a cardiac arrest
vitamin C in post-cardiac arrest syndrome (VITaCCA) is the first double-blind, multi-center, randomized placebo-controlled trial to compare the effects of early high-dose vitamin C on organ dysfunction in patients after cardiac arrest
The optimal dosing for intravenous vitamin C in the context of critical illness is still unknown and may depend on the patients’ comorbid condition, on the severity of the acute disease, and on the subsequent degree of oxidative stress

Summary

Introduction

High-dose intravenous vitamin C directly scavenges and decreases the production of harmful reactive oxygen species (ROS) generated during ischemia/reperfusion after a cardiac arrest. Intravenous treatment with high-dose vitamin C may improve the clinical outcome of post-cardiac arrest patients with ROSC (return of spontaneous circulation), because reactive oxygen species (ROS), generated during the systemic ischemic-reperfusion response, contribute to organ damage and death [1, 2]. Vitamin C directly scavenges free radicals, repairs oxidized scavengers such as glutathione, and reduces the production of ROS [3]. As a result, it may reduce ischemia/reperfusion injury. Intravenous supplementation is required to restore the deficiency [11,12,13,14] or to achieve higher plasma concentrations [12]

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