Vitamin C in Post-cardiac Arrest (VITaCCA)

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.

Vitamin C depletion.

This overpowering oxidative stress during PCAS can quickly exhaust body stores of vitamin C due to massive cellular consumption and reduced regeneration. We have shown that vitamin C plasma concentrations were decreased by more than 50% compared to healthy volunteers already on the first day after cardiac arrest. After 3 days plasma concentrations further declined and more than half the patients were deficient. Low vitamin C levels were associated with multiple organ dysfunction (higher Sequential Organ Failure Assessment (SOFA) scores) and mortality. Other studies, though investigating septic and not post cardiac arrest patients, also show markedly depressed vitamin C levels on the day of admittance (~ 10 and 6 µmol/l) and an association between low vitamin C levels and multiple organ failure.

However, these deficient vitamin C levels in critically ill patients often will go unnoticed. Due to the complexity and cost of its laboratory measurement plasma levels are not available in daily practice. In addition, the vitamin C content of enteral nutrition is assumed to be sufficient. However, current nutrition protocols (even with immune enhanced nutrition) fail to normalise vitamin C levels. These low plasma levels are likely to reflect real deficiency, since they are accompanied by scorbutic intracellular leucocyte vitamin C levels as well. Even with iv vitamin C dosages up to 1 g per day vitamin C depletion persists.

(Pre) clinical studies.

Multiple preclinical experiments support the potential beneficial effect of high-dose iv vitamin C post cardiac arrest. In a rat cardiac arrest model vitamin C administration immediately after return of spontaneous circulation (ROSC) improved survival rate and neurological outcome and decreased myocardial damage. In organ-specific ischemia-reperfusion models of kidney, liver and skeletal muscle iv vitamin C ameliorated respectively renal structure and function, bile flow and cholate secretion and muscle function.

Up to now no clinical study specifically addressed the post cardiac arrest population, but several controlled studies in critically ill patients showed favourable results. In critically ill surgical patients 3 g iv vitamin C per day reduced pulmonary morbidity, new organ failure, duration of ICU/hospital stay and mortality. In burn patients very high dose iv vitamin (66 mg/kg/hr) reduced fluid requirements, body weight gain and respiratory dysfunction. In a recent pilot trial of patients with severe sepsis vitamin C both 50 mg/kg/day and 200 mg/kg/day caused earlier recovery from organ failure with reduction of the pro-inflammatory biomarkers. In a before and after study of patients with septic shock high dose iv vitamin C combined with iv thiamine and stress dose steroids substantially accelerated shock reversal and improved survival. Two studies in critically ill patients administering respectively 2.7 g/day and 1.5 g/day showed no clinical benefit. These different results might be explained by difference in timing (relatively late) and route of administration (enteral). None of the clinical studies reported negative results of vitamin C .

Safety of high dose vitamin C.

Up to now, no adverse events due to high-dose vitamin C have been reported even with extremely high dosing schedules. Theoretical risks comprise acidosis, a paradoxal pro-oxidative effect in case of iron overload, and oxalate kidney stones. In critically ill patients with sepsis 200 mg/kg/day and in cancer patients even megadoses up to 1500 mg/kg iv vitamin C three times weekly were tolerated without significant side effects. Neither these studies, nor studies in healthy volunteers reported acidosis. Vitamin C can reduce catalytic metals such as Fe2+ and Cu2+ with adverse, pro-oxidative effects in patients with hemochromatosis. These patients are excluded in most studies and will also be excluded in our study. High dose vitamin C increases urinary oxalate excretion. However, oxalate nephrocalcinosis and calcium oxalate stones take months to years to develop and none of the studies with short-term vitamin C administration reported kidney stone formation.

The investigators hypothesize that vitamin C reduces organ damage, especially cerebral injury, if administered for a short period as a high iv dose during the very early phase of reperfusion after cardiac arrest.

Primary 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 Objectives:

• 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.