Early High-dose Vitamin C in Post-cardiac Arrest Syndrome

Problem definition.

In Europe, each day more than 1000 patients suffer from cardiac arrest. Despite improvement of medical technologies mortality is still very high, around 75 - 80%. Of the patients who initially survive to Intensive Care Unit (ICU) admission, more than 50% still dies or remains severely disabled due to the post cardiac arrest syndrome (PCAS). Crucial in this syndrome is the overwhelming oxidative stress, which is caused by systemic ischemia/reperfusion injury and leads to destruction of endothelial function with cardiovascular failure and brain damage. Besides targeted temperature management, we have no effective therapy to improve prognosis. The levels of our primary circulating antioxidant, vitamin C, are markedly depressed after cardiac arrest. Early, high dose intravenous (iv) vitamin C administration can boost the body's antioxidant defence, and could be a new promising therapeutic intervention to improve clinical outcome by limiting oxidative damage.

Rationale high dose vitamin C.

Vitamin C administration is often wrongly considered as complementary or even alternative medicine, which does not do justice to the strong scientific base of the pleiotropic antioxidative effects of high-dose iv (not enteral!) vitamin C administration as demonstrated in multiple preclinical and clinical studies. With enteral supplementation maximally tolerated dosages cannot achieve plasma levels of > 250 µmol/l due to limited absorption. In critically ill patients, enteral supplementation even cannot restore deficiency due to the acutely increased requirements. Iv vitamin C administration generates much higher plasma levels, thus yielding more and more potent antioxidative effects. The underlying pathophysiological mechanisms are well elucidated. High plasma levels of vitamin C not only limit the generation of reactive oxygen species (ROS), repair other oxidized scavengers such as glutathione and modulate numerous enzyme reactions, but can also act as a direct radical scavenger. In addition, vitamin C maintains nitric oxide mediated endothelial integrity and vasomotor control. Furthermore, vitamin C is a cofactor in several biosynthetic pathways, such as collagen, catecholamines and peptide hormones. Deficiency will decrease there formation. Vitamin C can thereby recover endogenous vasopressor synthesis and improve wound healing.

Post cardiac arrest huge amounts of ROS are generated by various pathways. The main source of ROS are the mitochondria due to uncoupling of oxidative phosphorylation. In addition, ROS are produced by upregulated enzymes such as NADPH oxidase or during oxidation of catecholamines. When unopposed these ROS can damage virtually every biomolecule and cause severe endothelial dysfunction. This has been demonstrated in vitro: plasma derived from patients after cardiac arrest induced massive cell death of cultured endothelial cells due to pro-oxidant stress and deterioration of anti-oxidant defenses. Cell death was highest immediately after admission to the ICU.