Vitamin C in Post-cardiac Arrest (VITaCCA)

Gelderse Vallei Hospital, Sint Franciscus Gasthuis, Tergooiziekenhuizen, Amphia Hospital, Erasmus Medical Center, Noordwest Ziekenhuisgroep, Maasstad Hospital, OLVG

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.

In this multicentre, placebo controlled double-blind randomized clinical trial patients will be recruited from the Intensive Care Units of 8 hospitals. 270 comatose patients suffering an out-of-hospital cardiac arrest with ventricular fibrillation/tachycardia as first registered cardiac rhythm and EMV-score ≤8 will be included. As soon as possible patients will be randomly allocated to one of 3 treatment groups of 90 patients each and vitamin C or placebo will be started for 96 hours. Group 1 will be treated with placebo, group 2 with 2 times a day a bolus of 1.5 gr vitamin C and group 3 with 2 times a day a bolus of 5 gr vitamin C. All patients will receive thiamine 200 mg q 12 hourly for 4 days to limit the conversion of vitamin C to oxalate.

Group 1 will be treated with placebos for 4 days. All patients will receive Thiamine 200 mg q 12 hourly for 4 days to limit the conversion of vitamin C to oxalate

Group 2 will be treated with 1.5 gr Vitamin C b.i.d. (3 gr/day) for 4 days. All patients will receive Thiamine 200 mg q 12 hourly for 4 days to limit the conversion of vitamin C to oxalate

Group 3 will be treated with 5 gr Vitamin C b.i.d. (10 gr/day) for 4 days. All patients will receive Thiamine 200 mg q 12 hourly for 4 days to limit the conversion of vitamin C to oxalate

Vitamine C will be administered intravenously as ascorbic acid (ascorbinezuur CF 100 mg/ml, Centrafarm BV, Etten Leur, Netherlands).

All patients will receive thiamine 200 mg q 12 hourly for 4 days to limit the conversion of vitamin C to oxalate.

ΔSOFA score is defined as the difference between SOFA admission and SOFA at 96 hours (46). Death at 96-hours will be counted as the maximum SOFA score (24 points).

Neurological outcome. The Glasgow Coma Scale (GCS) is the most common scoring system used to describe the level of consciousness. The GCS measures the following functions: Eye opening (E): 4 = spontaneous, 3 = to sound, 2 = to pressure, 1 = none. Verbal response (V): 5 = orientated, 4 = confused, 3 = words, but not coherent, 2 = sounds, but no words, 1 = none. Motor response (M): 6 = obeys command, 5 = localizing, 4 = normal flexion, 3 = abnormal flexion, 2 = extension, 1 = none.

Neurological outcome after cardiac arrest. CPC 1: Good cerebral performance (normal life) CPC 2: Moderate cerebral disability (disability but independent) CPC 3: Severe cerebral disability (conscious but disabled and dependent) CPC 4: Coma or vegetative state (unconscious) CPC 5: Brain death

Neurological outcome. The modified Rankin Scale (mRS) is a commonly used scale for measuring the degree of disability or dependence in the daily activities of people who have suffered a stroke or other causes of neurological disability. The scale runs from 0-6, running from perfect health without symptoms to death. 0 - No symptoms. - No significant disability. Able to carry out all usual activities, despite some symptoms. - Slight disability. Able to look after own affairs without assistance, but unable to carry out all previous activities. - Moderate disability. Requires some help, but able to walk unassisted. - Moderately severe disability. Unable to attend to own bodily needs without assistance, and unable to walk unassisted. - Severe disability. Requires constant nursing care and attention, bedridden, incontinent. - Dead.

Neurological outcome. The Glasgow Outcome Scale (GOS) is a global scale for functional outcome that rates patient status into one of five categories: Dead, Vegetative State, Severe Disability, Moderate Disability or Good Recovery. The Extended GOS (GOSE) provides more detailed categorization into eight categories by subdividing the categories of severe disability, moderate disability and good recovery into a lower and upper category: the scale runs from 1-8. Death Vegetative state Lower severe disability Upper severe disability Lower moderate disability Upper moderate disability Lower good recovery Upper good recovery.

The total length of IC-stay will be determined from the date of ICU admission until the patient is discharged from the Intensive Care Unit or the date of death from any cause, assessed up to 1 year after the first day of admission.

The total length of hospital-stay will be determined from the date of ICU admission until the patient is discharged from the hospital or the date of death from any cause assessed up to 1 year after the first day of admission.

When the patient is discharged from the Intensive Care or when the patient past away, the total duration of vasopressor support will be determined, assessed up to 1 year after the first day of admission.

Total ventilation time during ICU stay will be determined when the patient is discharged from the ICU or when the patient past away from any cause, assessed up to 1 year after the first day of admission.

eGFR will be measured daily till discharge from the ICU, assessed up to 1 year after the first day of admission.

Serum creatinine will be measured daily till discharge from the ICU, assessed up to 1 year after the first day of admission.

Need of renal replacement therapy during hospital admission will be determined at hospital discharge, assessed up to 1 year after the first day of admission.

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.

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