Vitamin C in Critical Illness: Drug Therapy, Not Just Nutrition

Few molecules have ridden a more dramatic rollercoaster through modern medicine than vitamin C, and few have inspired sharper disagreement at the bedside of the critically ill. Now an international group of intensive-care specialists from Belgium, Switzerland, Germany and the Netherlands is asking clinicians and researchers to draw a line that decades of hype have blurred: the line between vitamin C as a drug and vitamin C as a nutrient. Writing as a correspondence published on 7 July in the journal Intensive Care Medicine, Anne-Françoise Rousseau of the University Hospital of Liège and her co-authors argue that the wave of large randomized trials testing gram-scale intravenous vitamin C in sepsis, cardiac arrest and severe burns must not be mistaken for a verdict on vitamin C as an essential micronutrient. Confusing the two, they warn, risks corrupting both the science and the everyday nutritional care of patients at their most vulnerable.

The commentary appears alongside the publication of the VITaCCA randomized clinical trial, a study led from the Netherlands that tested whether early high-dose vitamin C could improve outcomes after out-of-hospital cardiac arrest — one of the most devastating emergencies an intensive care unit faces, in which the heart stops before help arrives and the brain is starved of oxygen. It also weighs the VICTORY trial, published in JAMA, which evaluated high-dose intravenous vitamin C against mortality and organ dysfunction in severe burn injury. Together with the 2022 LOVIT trial in adults with sepsis, these studies complete a trilogy of rigorous tests of the pharmacotherapy hypothesis: that megadoses of ascorbate, delivered directly into the bloodstream, could blunt the self-destructive inflammatory chemistry of acute critical illness. In the authors’ reading, that hypothesis has now been tested on its own terms — and the verdict applies to the drug, not to the nutrient.

The megadose idea has deep roots and a familiar arc. Scurvy, the wasting illness of vitamin C deficiency, haunted long sea voyages for centuries before the Scottish naval surgeon James Lind showed in the 1740s that citrus could prevent it — one of the first controlled treatment comparisons in medical history. For the next two hundred years, vitamin C was understood exactly as physiology dictates: a small daily quantity, measured in tens of milligrams, whose absence unravels collagen, healing and blood vessel integrity. The modern pharmacological era began when researchers reframed ascorbate as a radical-scavenging drug for acute disease rather than a dietary staple. Small observational series in septic patients — including protocols that combined vitamin C with thiamine and hydrocortisone — reported striking improvements in organ function and survival, and enthusiasm raced through the world’s intensive care units faster than the evidence could travel. The field then did what rigorous medicine must do: it launched large, placebo-controlled, multicenter randomized trials.

The biological rationale was never frivolous, because ascorbate sits at the center of human biochemistry. Humans cannot synthesize the molecule at all: the gene for L-gulonolactone oxidase, the final enzyme of the synthesis pathway, became defunct in our primate ancestors tens of millions of years ago, making vitamin C a mandatory dietary component. Once in the body, ascorbate acts as the principal water-soluble antioxidant, donating electrons to neutralize reactive oxygen species and helping regenerate the lipid-soluble antioxidant vitamin E in cell membranes. It is also an obligatory cofactor for a family of metal-dependent enzymes: the prolyl and lysyl hydroxylases that mature collagen, the enzymes that assemble carnitine for shuttling fatty acids into mitochondria, dopamine β-hydroxylase, which produces the catecholamine hormones of the stress response, and the hydroxylases that regulate hypoxia-inducible factor, a master switch of cellular adaptation to low oxygen. Critical illness attacks precisely these systems.

Sepsis, cardiac arrest and major burns unleash torrents of reactive oxygen species from activated immune cells and damaged mitochondria; ischemia followed by reperfusion multiplies the oxidative burden; the endothelial lining of blood vessels, rich in ascorbate-dependent chemistry, is stripped and inflamed. Against this backdrop, physicians have repeatedly observed that plasma ascorbate concentrations collapse in the sickest patients within hours to days of admission. Consumption outpaces supply, inflamed and fluid-loaded kidneys clear the water-soluble vitamin faster, tissue redistribution dilutes it, and dietary intake ceases because patients cannot eat. Low levels have been repeatedly associated in observational studies with organ failure and death, and surveys of intensive care populations have found a substantial fraction of patients at concentrations compatible with frank deficiency — the biochemical range of scurvy — despite never having missed a meal before falling ill. Replenishing those stores looks like elementary physiology. And it is exactly here that Rousseau and colleagues plant their conceptual flag: restoring physiologic blood levels so ordinary enzyme chemistry can run is nutrition; injecting grams to create extraordinary chemical conditions is pharmacotherapy.

The distinction is written into the pharmacokinetics. Swallowed vitamin C crosses the gut wall through sodium-dependent transporters whose capacity saturates quickly, so the fraction absorbed falls as the dose rises — no amount of oral supplementation can reproduce the concentrations achieved by infusion. Intravenous administration bypasses this gate and drives plasma concentrations ten- to a hundred-fold above the physiologic range. But the excess is fleeting: once plasma levels exceed the renal threshold, the kidneys switch from conserving ascorbate to excreting it, and the surplus of a gram-scale bolus is largely eliminated within hours. High-dose protocols therefore produce brief supraphysiologic spikes followed by rapid washout — exposure profiles characteristic of an investigational drug, not of a nutrient maintaining steady-state tissue saturation. Proponents counter that the spikes are the point, since only at such concentrations can ascorbate act as a direct antioxidant in the vascular compartment. Skeptics answer that the same exposures carry recognized risks, including an oxalate load on kidneys already injured by shock.

The randomized evidence has now tested the drug hypothesis in three of intensive care’s most lethal syndromes. In 2022, Lamontagne and colleagues reported in the New England Journal of Medicine that intravenous vitamin C in adults with sepsis produced no benefit on a composite of death and persistent organ dysfunction, with the data leaning toward possible harm — a result that startled a field primed by smaller, promising studies. The VICTORY investigators then posed the same question in severe burn injury, where hypermetabolism and open wounds had made antioxidants especially attractive, and the VITaCCA investigators posed it in out-of-hospital cardiac arrest, where reoxygenation of starved tissues was expected to amplify oxidative injury to the heart and brain. In the authors’ assessment of this accumulating record, pharmacologic vitamin C, in the doses and regimens actually tested, has not emerged as a therapy that changes survival or organ outcomes. Notably, the appeal comes partly from insiders: co-author Christian Stoppe of University Hospital Würzburg is a VICTORY investigator, and co-author Angélique de Man of Amsterdam UMC is a senior author of VITaCCA — scientists re-examining a field they helped build.

But closing the pharmacotherapy file, the authors insist, must not be confused with closing the nutritional one. Vitamin C remains an indispensable element of nutrition therapy in the ICU, as codified in the ESPEN micronutrient guideline published in 2022 by a team that includes co-author Mette Berger of Lausanne, and in the ESPEN-endorsed recommendations for nutritional therapy in major burns that Rousseau and Berger co-authored in 2013. In burn care the nutrient’s roles are concrete and physical: collagen cross-linking beneath healing grafts, antioxidant defense of the endangered microcirculation, immune competence in a patient whose defenses are literally burned away with the skin. Nutritional dosing — delivered enterally or parenterally alongside the full spectrum of other micronutrients — aims to correct deficiency and maintain physiologic concentrations, not to create pharmacologic peaks. By the authors’ logic, the failure of the megadose trials makes that corrective task more important, not less, because the deficiency it addresses was never in dispute and because patients with burns, sepsis and cardiac arrest deplete the vitamin fastest.

The danger of conflation runs in both directions. If clinicians hear “vitamin C trials failed” and conclude that micronutrient supplementation is fringe science, critically ill patients may be stripped of a cheap, physiologically justified component of care, with consequences ranging from delayed wound closure to overt deficiency disease. Conversely, if nutritional supplementation is marketed as if it were the drug therapy tested in the trials, expectations inflate, and every disappointing result erodes confidence in micronutrient care as a whole. The correspondence calls for precision in vocabulary and in practice: screen for and correct actual deficiencies, individualize provision in burns, sepsis and cardiac arrest, and reserve the language of pharmacotherapy — with its demands for dose-finding studies, efficacy trials and formal safety evaluation — for interventions that are genuinely drug-like. High-dose ascorbate is not nutrition multiplied by ten; it is a different intervention carrying a different evidence burden.

The correspondence, which the authors published without external funding, lands as more than a technical footnote to two trials. It is a lesson in how medicine metabolizes enthusiasm: a nutrient became a drug candidate, the drug was tested properly, and the distinction between the two identities is now the most valuable thing left on the table. Vitamin C the pharmacological bet on oxidative stress has not paid off in sepsis, burns or cardiac arrest. Vitamin C the nutrient remains the raw material for collagen, catecholamines and antioxidant defense that no critically ill patient can live without, and its provision belongs to the unglamorous, evidence-based discipline of nutrition therapy. Rousseau and colleagues’ message to the intensive-care community is blunt: mourn the drug if you must, but keep feeding the nutrient. In resuscitation bays and burn units, where the difference between deficiency and adequacy is measured in wounds that will not close, keeping the two apart may matter as much as any megadose ever did.