Publication

• Title: Early high-dose vitamin C for out-of-hospital cardiac arrest: the VITaCCA randomized clinical trial
• Acronym: VITaCCA
• Year: 2026
• Journal published in: Intensive Care Medicine
• Citation: Rozemeijer S, Dubois EA, de Grooth HJ, den Uil CA, Rettig TCD, Rijpstra TA, et al. Early high-dose vitamin C for out-of-hospital cardiac arrest: the VITaCCA randomized clinical trial. Intensive Care Med. 2026.

Context & Rationale

• Background

  Post-cardiac arrest syndrome is a global ischaemia–reperfusion injury state characterised by myocardial stunning, endothelial injury, brain injury, vasoplegia, systemic inflammation, and multi-organ dysfunction. The VITaCCA protocol framed early high-dose intravenous vitamin C as a biologically plausible antioxidant strategy in a patient group with a clearly timed reperfusion insult.¹
• Background

  The trial was built on the observation that vitamin C concentrations fall rapidly after cardiac arrest, probably through consumption during oxidative stress. Prior pharmacokinetic work suggested that approximately 2–3 g/day restores plasma concentrations, whereas 10 g/day produces supraphysiological concentrations.
• Background

  Before VITaCCA, post-arrest clinical evidence was thin: one before-and-after study of thiamine plus vitamin C did not show improved neurological outcome, and a small pilot randomised trial of 3 g/day vitamin C was inconclusive for neuron-specific enolase.
• Research Question/Hypothesis

  Does early intravenous vitamin C, given as either a supplementation dose of 3 g/day or a pharmacological dose of 10 g/day for 96 hours, reduce organ dysfunction after comatose shockable out-of-hospital cardiac arrest compared with placebo?
• Why This Matters

  Vitamin C is cheap, widely available, and mechanistically attractive, but ICU vitamin C biology is complex. ESPEN guidance separated physiological micronutrient replacement from unselected pharmacological high-dose treatment, and VITaCCA directly tested both concepts in a homogeneous reperfusion-injury population.²

Design & Methods

• Research Question: Whether early 3 g/day or 10 g/day intravenous vitamin C improves the 96-hour change in resuscitation-SOFA score after shockable out-of-hospital cardiac arrest, compared with placebo.
• Study Type: Phase 2, multicentre, double-blind, randomised, placebo-controlled, three-arm trial conducted in six Dutch ICUs.
• Population:
  • Adults aged ≥18 years.
  • Out-of-hospital cardiac arrest with return of spontaneous circulation.
  • Initial shockable rhythm: ventricular fibrillation, pulseless ventricular tachycardia, or automated external defibrillator shock advised.
  • Comatose after ROSC, with Glasgow Coma Scale ≤8.
  • First study dose had to be feasible within 5 hours after ROSC.
  • Key exclusions were terminal renal insufficiency or renal replacement therapy, known glucose-6-phosphate dehydrogenase deficiency, history of urolithiasis, oxalate nephropathy or haemochromatosis, and treatment limitations at randomisation.
  • Deferred proxy consent was sought within 72 hours after ICU admission; patients who died before consent could be obtained within 72 hours remained included.
• Intervention:
  • 3 g/day arm: L-ascorbic acid 1.5 g intravenously every 12 hours for 96 hours or until ICU discharge.
  • 10 g/day arm: L-ascorbic acid 5 g intravenously every 12 hours for 96 hours or until ICU discharge.
  • Study medication was diluted in 50 mL 0.9% sodium chloride, prepared in amber-coloured syringes with orange infusion lines, and infused over 15 minutes.
  • All patients received thiamine 200 mg intravenously every 12 hours for 4 days or until ICU discharge, intended to limit oxalate generation.
• Comparison:
  • Placebo was 50 mL 0.9% sodium chloride every 12 hours for 96 hours or until ICU discharge.
  • Post-arrest care, targeted temperature management, prognostication, and withdrawal decisions followed contemporary national and international guidance.
  • Thiamine was administered in the placebo arm as well, so the isolated variable was vitamin C dose, not thiamine exposure.
• Blinding: Patients, bedside clinicians, nurses, investigators, outcome assessors, and analysts remained blinded until the primary analysis had been performed with treatment arms coded as A, B, and C.
• Statistics: A total of 270 patients, 90 per arm, was targeted to detect a 2.0-point difference in 96-hour change in R-SOFA score, assuming SD 3.5, 90% power, two-sided alpha 0.01, and 10% loss after randomisation. The primary analysis was a modified intention-to-treat analysis using a linear mixed model with random intercept for site and adjustment for baseline R-SOFA and age.
• Follow-Up Period: Primary outcome at 96 hours; mortality and neurological outcomes at 28 and 180 days.

Key Results

This trial was not stopped early. It completed recruitment and follow-up; a prespecified blinded interim safety analysis focused on mortality was performed mid-study without trial termination.

• The 3 g/day supplementation dose did not improve organ dysfunction or clinical outcomes compared with placebo.
• The 10 g/day pharmacological dose was associated with less improvement in R-SOFA and concordant harm signals across early mortality, myocardial injury, kidney replacement therapy, neurological outcome, and SAEs.
• The findings are best interpreted as a phase 2 efficacy-futility and safety signal, not as a definitive mortality trial.

Internal Validity

• Randomisation and Allocation: Allocation was computer-generated, 1:1:1, stratified by site and age ≤66 versus >66 years, with permuted blocks of 6. Randomisation was performed by pharmacy staff or nurses not involved in direct clinical care, supporting allocation concealment.
• Blinding: Blinding was robust: syringes and infusion lines were masked, study medication was prepared by unblinded personnel, and patients, clinicians, nurses, researchers, and analysts were blinded until after blinded primary analyses had been completed.
• Drop-out and Exclusions: Of 383 randomised patients, 368 received at least one dose and entered the safety analysis. The full analysis population contained 291 patients, and the primary modified intention-to-treat population contained 273 patients. Eighteen treated patients were excluded from the primary efficacy analysis because the first dose was administered >5 hours after ROSC or because inclusion criteria were not met.
• Deferred Consent: Seventy-seven treated patients were withdrawn after at least one scheduled dose because deferred consent was not obtained or was withdrawn. This is ethically inherent to emergency research but creates a meaningful attrition mechanism.
• Baseline Characteristics: Groups were broadly balanced, with mean age 63 years, 84% male, high rates of witnessed arrest and bystander CPR, and median time from arrest to sustained ROSC of 15–16 minutes. The 10 g group had numerically more chronic kidney disease, more ST-elevation myocardial infarction, lower first pH, higher lactate, and slightly longer arrest-to-CPR time, which may have contributed to the harm signal.
• Protocol Adherence: Patients received a mean of 6 (SD 2) infusions in each arm. Premature study-treatment discontinuation occurred in 10 placebo patients, 7 patients in the 3 g group, and 4 patients in the 10 g group, mostly because of ICU-to-ICU transfer.
• Timing: The first dose was delivered early for an ICU trial: mean time from ROSC to first dose was 3 h 35 min in placebo, 3 h 23 min in the 3 g group, and 3 h 28 min in the 10 g group. This was still after the immediate reperfusion burst of reactive oxygen species, which occurs within minutes.
• Dose: Separation of vitamin C exposure was clear by design: 0 g/day, 3 g/day, and 10 g/day for 96 hours. However, vitamin C status was not used for enrolment or dose adjustment, and plasma vitamin C, oxidative stress, and oxalate analyses were not part of the primary report.
• Separation of the Variable of Interest: The main contrast was vitamin C dose on a common thiamine background. All groups received thiamine 200 mg every 12 hours, so the trial cannot answer whether thiamine itself has benefit or harm after cardiac arrest.
• Outcome Assessment: The primary endpoint was complete for all mITT patients. R-SOFA is mostly objective, but the CNS component, death assignment, and post-arrest prognostication are intrinsically linked to sedation, coma recovery, and withdrawal-of-life-sustaining-treatment decisions.
• Statistical Rigor: The trial used a published protocol, a final SAP before unblinding, a blinded primary analysis before treatment allocation was revealed, and prespecified sensitivity analyses. However, observed R-SOFA variability, SD 5.7–7.6, exceeded the assumed SD 3.5, and secondary outcomes were not protected against multiplicity.
• Key Sensitivity Analyses: The full analysis population was consistent with the primary analysis: 10 g vs placebo +2.5 R-SOFA points; 95% CI 0.6 to 4.5; P=0.01. Adjustment for time to sustained ROSC and first pH attenuated the overall P value to 0.095, although 10 g vs placebo remained +2.1 points; 95% CI 0.2 to 4.0; P=0.03. Excluding patients who died before 96 hours attenuated the primary signal, underscoring the influence of early death.
• Heterogeneity: Age modified the primary treatment effect, with older age associated with less R-SOFA improvement in both vitamin C groups compared with placebo; interaction P=0.03. First measured pH did not modify effect; interaction P=0.55.

Conclusion on Internal Validity: Internal validity is moderate-to-strong. The trial was well blinded, well randomised, and rigorously analysed, but the phase 2 sample size, substantial deferred-consent attrition, early-death dependence of the primary endpoint, baseline numerical imbalances, and multiplicity across secondary outcomes mean that the harm signal should be treated as serious and coherent rather than definitive proof of mortality harm.

External Validity

• Population Representativeness: The trial applies best to adult comatose survivors of shockable out-of-hospital cardiac arrest admitted to ICU after ROSC, without immediate treatment limitations or major contraindications to vitamin C.
• Important Exclusions: The results do not directly apply to non-shockable arrest, in-hospital cardiac arrest, awake post-arrest patients, paediatric patients, patients already receiving renal replacement therapy, known G6PD deficiency, haemochromatosis, oxalate nephropathy, recent stone disease, or patients with early treatment-limitation decisions.
• Healthcare Setting: Conduct in Dutch ICUs with guideline-based post-resuscitation care supports applicability to similar high-income critical care systems, but not necessarily to systems with different prehospital logistics, prognostication practices, temperature-management protocols, or ICU transfer pathways.
• Intervention Generalisability: VITaCCA tested L-ascorbic acid 3 g/day or 10 g/day started a mean of 3.5 hours after ROSC. It does not test prehospital administration, sodium ascorbate, longer treatment, lower enteral replacement, biomarker-guided replacement, or different co-interventions.

Conclusion on External Validity: External validity is good for the selected shockable OHCA ICU population and poor for broader cardiac-arrest phenotypes. The results strongly discourage routine 10 g/day L-ascorbic acid after shockable OHCA, but they do not close every possible question about targeted repletion in documented deficiency.

Strengths & Limitations

• Strengths:
  • First substantial double-blind randomised trial of vitamin C in comatose post-cardiac arrest patients.
  • Highly plausible reperfusion-injury biology tested in a relatively homogeneous population with known timing of ROSC.
  • Three-arm design separated supplementation-dose from pharmacological-dose vitamin C.
  • Early administration compared with most sepsis vitamin C trials.
  • Complete primary outcome ascertainment.
  • Blinded analysis before unmasking, with prespecified sensitivity and subgroup analyses.
• Limitations:
  • Phase 2 trial, not powered for mortality or uncommon safety events.
  • Deferred-consent process excluded 77 treated patients from efficacy analysis, introducing possible attrition bias.
  • Observed R-SOFA variability exceeded assumptions used for the sample-size calculation.
  • Primary endpoint was strongly influenced by early deaths because death at 96 hours was assigned maximum R-SOFA score.
  • Secondary outcome and safety signals were multiple, not multiplicity-adjusted, and sometimes had missing data after transfers.
  • No primary report of plasma vitamin C concentrations, oxidative-stress markers, or oxalate outcomes.
  • 10 g group had small baseline numerical imbalances in illness severity and renal/cardiac risk.

Interpretation & Why It Matters

• Clinical practice

  VITaCCA provides no support for routine intravenous vitamin C after shockable OHCA. The 10 g/day regimen should be avoided outside carefully justified research, and the 3 g/day repletion-dose strategy should not be assumed beneficial in this population.
• Mechanistic implication

  The trial challenges the assumption that more antioxidant exposure is better during early reperfusion. Reactive oxygen species are not purely injurious; they also contribute to signalling, repair, immune function, and vascular adaptation.
• Dose implication

  The dose-response pattern is clinically important: placebo performed best, 3 g/day was intermediate, and 10 g/day was worst for several outcomes. This argues against empiric pharmacological vitamin C dosing in undifferentiated critical illness.
• Trial-design implication

  Future trials should avoid assuming class benefit, should measure baseline vitamin C status and redox biology, should predefine safety mechanisms including oxalate and renal injury, and should use endpoints less dominated by early death when exploring organ dysfunction.

Controversies & Other Evidence

• Endpoint controversy: Assigning death at 96 hours the maximum R-SOFA score was a defensible worst-rank solution to informative censoring, but it makes the primary outcome highly sensitive to early mortality. When deaths before 96 hours were excluded, the difference between groups became smaller.
• Timing controversy: Mean first-dose timing of 3 h 29 min after ROSC was early for ICU research but late relative to the immediate oxidative burst after reperfusion. This may explain absence of benefit, but it does not explain the consistent direction of harm with 10 g/day.
• Formulation controversy: VITaCCA, LOVIT, LOVIT-COVID/REMAP-CAP, and VICTORY used ascorbic acid rather than sodium ascorbate. Whether sodium ascorbate has different haemodynamic, acid-base, renal, or redox effects remains unanswered.
• Supplementation controversy: The 3 g/day arm was intended to normalise vitamin C concentrations, yet it did not improve outcomes. This challenges routine supplementation after cardiac arrest even before considering pharmacological dosing.

• Across contemporary high-quality ICU trials, the direction of evidence has moved away from empiric high-dose intravenous vitamin C.
• The most concerning pattern is the convergence of harm or futility signals across sepsis, COVID-19, cardiac arrest, and burns, rather than any single trial in isolation.
• Remaining research questions should focus on documented deficiency, lower-dose replacement, formulation, timing, and mechanistically enriched subgroups—not routine pharmacological dosing.

Summary

• VITaCCA randomised 273 comatose shockable OHCA patients in the primary mITT analysis to placebo, 3 g/day vitamin C, or 10 g/day vitamin C for 96 hours.
• The primary outcome favoured placebo: R-SOFA improved by −3.2 points with placebo, −2.3 with 3 g/day, and −0.8 with 10 g/day; 10 g vs placebo difference +2.5 points; 95% CI 0.5 to 4.5; P=0.01.
• The 3 g/day supplementation dose did not improve organ dysfunction or patient-centred outcomes.
• The 10 g/day dose was associated with higher troponin T, more renal replacement therapy, worse CPC-defined neurological outcome, more early deaths, and more SAEs.
• VITaCCA aligns with LOVIT, LOVIT-COVID/REMAP-CAP, and VICTORY in weakening the case for routine high-dose intravenous vitamin C in ICU practice.

Overall Takeaway

VITaCCA is an important mechanistic and clinical safety trial rather than a definitive phase 3 mortality trial. In a biologically attractive post-arrest reperfusion population, vitamin C did not improve organ dysfunction, 3 g/day did not show supplementation benefit, and 10 g/day produced a coherent harm signal that should change bedside behaviour and trial design.

Bibliography

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