Vitamin C in Post-cardiac Arrest
Vitamin C in Post-cardiac Arrest
Only half of the patients suffering from cardiac arrest arrive at the hospital alive. Of
 these survivors, more than 50% will still die or remain severely disabled. During cardiac
 arrest ischemia causes damage to the vital organs, especially the brain. When with return of
 spontaneous circulation oxygen is re-offered to the ischemic organs, massive amounts of
 reactive oxygen species (ROS) are produced. These ROS can further increase the damage to the
 myocardium and brain (reperfusion injury). Vitamin C is the primary circulating antioxidant.
 It scavenges free radicals and reduces the production of ROS. In a recent study we
 demonstrated that vitamin C plasma levels are deficient in ~60% of the patients after cardiac
 arrest, probably due to massive consumption. Vitamin C deficiency reduces the protection
 against oxidative stress. Intravenous supplementation is needed to restore deficiency and the
 antioxidative effect of vitamin C is much more potent if it is administered in a
 supraphysiological dose (≥ 3 g per day). Its strong antioxidative effect may reduce damage to
 the circulation and to brain, heart and other organs. Beneficial effects of high dose i.v.
 vitamin C after cardiac arrest have been demonstrated in preclinical studies, but not in
 patients.

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

 Objectives:

 -  To determine whether an early high dose i.v. vitamin C can improve organ function,
 especially neurological outcome, in patients after cardiac arrest

 -  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.
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.
Inclusion Criteria:

 -  An out-of-hospital cardiac arrest with return of spontaneous circulation

 -  Ventricular fibrillation or ventricular tachycardia as first registered cardiac rhythm

 -  Glasgow Coma Scale (GCS)-score ≤8.

 Exclusion Criteria:

 -  Patients with pre-existent terminal renal insufficiency

 -  Known glucose 6-phosphate dehydrogenase deficiency (risk of hemolysis)

 -  History of urolithiasis, oxalate nephropathy or hemochromatosis

 -  Treatment limitations.