Early high-dose vitamin C in post-cardiac arrest syndrome.

Only half of the patients suffering from cardiac arrest arrive at the hospital
alive. Of these survivors, 50% will still die or remain severely disabled.
During cardiac arrest ischemia causes damge 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 increase the damage to the myocardium and brain (reperfusion
injury). Vitamin C is the primary circulating antioxidant. It can scavenge free
radical and reduce 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. These deficient levels
reduce the protection against oxidative stress. Patients with decreased vitamin
C levels had more organ dysfunction and a worse survival. Vitamin C deficiency
will often remain unnoticed, because this complicated and expensive laboratory
measurement will not be routinely available. The antioxidative effect of
vitamin C is much more potent if it is administered intravenously in a higher,
supraphysiological dose (>= 3 gr per day). Its strong antioxidative effect may
reduce damage 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.

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.

In this multicentre, placebo controlled double-blind randomized clinical trial
patients will be recruited from the Intensive Care Units of: VU University
Medical Centre, Noordwest Ziekenhuisgroep, Gelderse Vallei Hospital, Franciscus
Gasthuis & Vlietland, Tergooiziekenhuizen, the Amphia Hospital, the Erasmus
Medical Centre, OLVG Oost and the Maasstad Hospital.

As soon as possible (ultimately < 5 hours after ROSC) after their arrival at
the Emergency Department, patients will be randomly allocated to one of 3
treatment groups of 120 (90 evaluable) 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. After
these 4 days the overwhelming oxidative stress and associated organ damage will
have settled down and vitamin C levels will be restored. Vitamin C
administration will then be lowered to standard nutritional dose to allow the
physiological signaling and repair function of low concentrations of ROS. All
patients will receive thiamine 200 mg q 12 hourly for 4 days to limit the
conversion of vitamin C to oxalate.

A total of 100 ml blood will be taken during a period of four days from an
arterial line which is routinely present for monitoring. The patient will not
notice the blood sampling. He/she will notice the collection of urine samples,
because all patients have a bladder catheter.

The risk of potential side effects of high dose vitamin C is very small. There
is a small risk of formation of oxalate crystals in the urine. Formation of
kidney stones of oxalate crystals has only been observed after prolonged intake
of high dose vitamin C. In addition, renal function of all patients at our ICU
is monitored routinely by daily determination of serum creatinine, estimated
Glomerular Filtration Rate (eGFR) and fluid balance. Diuresis is monitored
hourly. When indicated, an urine sediment analysis or echography of the kidneys
will be carried out. Vitamin C can exert pro-oxidatieve effects. Pro-oxidative
effects are mostly observed at low dose vitamin C and in patients with
hemochromatosis. In this study patients will receive high doses and patients
with hemochromatosis will be excluded. Therefore, we will expect less oxidative
stress. Sometimes high-dose i.v. vitamin C can lead to factitious hyperglycemia
when measured with point-of-care devices, mostly at dosages much higher than
used in our study. We will measure blood glucoses during the period of vitamin
C administration by blood gas analysis or in the central laboratory.