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VITAMIN C - A Love Story

Vitamin C in Critical Illness

 |  Rob Mac Sweeney

Schematic image of small fruit pieces in a syringe

Image: Shutterstock | Medical-R

Vitamin C – A Love Story

Every generation of clinicians inherits a remedy that seems to promise more than mere biology should allow. For our forebears at sea it was citrus, the difference between life and death on a latish eighteenth‑century deck. For late‑twentieth‑century dreamers it was Linus Pauling’s crystalline faith in ascorbate. And for many of us in critical care over the last decade, vitamin C became that rare thing—an old molecule with a new mystique. This is the love story of an idea, told with trials, tempering, and the tug of evidence.

Act I — Sailors, Scurvy, and the First “Randomised” Trial

James Lind’s famous 1747 comparison of citrus versus other cures for scurvy is often cast as the first randomised clinical trial, though the assignment was not truly randomised in a modern sense. Still, Lind’s method—comparing like with like, varying one thing—was revolutionary. His sailors receiving oranges and lemons recovered rapidly; those given cider, vinegar, seawater, or elixirs did not. The experiment seeded a clinical tradition: disciplined comparison over anecdote, physiology tempered by proof.1

Act II — Pauling’s Promise

Two centuries later, double Nobel laureate Linus Pauling argued that vitamin C could prevent colds and improve well‑being, catalysing a popular fascination that has barely dimmed. Pauling’s claims outran the data, but he was right about one thing: ascorbate biology is astonishingly rich, extending from co‑factor roles in catecholamine synthesis to redox buffering under stress.2 Interest spilled into oncology, where the National Cancer Institute still maintains a sober review of intravenous vitamin C as adjunct therapy—promising hypotheses, mixed human data, unresolved questions of dose and delivery.3

Critical care would soon claim its own chapter. Ascorbate participates in dopamine β‑hydroxylase–mediated conversion of dopamine to noradrenaline, supports endothelial function, and scavenges reactive species—physiological hooks tailor‑made for the catecholamine‑hungry, oxidant‑rich milieu of septic shock.4

Act III — The Spark: an ICU Before–After and the CCR Stage

In early 2017, Marik and colleagues published a single‑centre before–after study in Chest (47 patients per epoch) suggesting that hydrocortisone, vitamin C, and thiamine dramatically reduced hospital mortality in severe sepsis/septic shock (8.5% vs 40.4%; adjusted odds of death 0.13, 95% CI 0.04–0.48).5 The story then stepped onto the Critical Care Reviews stage in Belfast, where Marik’s 2017 CCR talk captured global imagination and scepticism in equal measure.6

Within two years, Fowler et al. reported CITRIS‑ALI, a multicentre RCT of septic patients with ARDS randomised to high‑dose vitamin C (50 mg/kg every 6 h for 96 h) or placebo. The three primary endpoints—change in SOFA, CRP, and thrombomodulin at 96 h—were negative. A nominally lower 28‑day mortality emerged among those receiving vitamin C (secondary outcome), but the trial was not adjusted for multiplicity; the authors correctly counselled caution.7

Then came randomisation of the Marik “cocktail” itself. The VITAMINS trial, led by Fujii and colleagues and presented live57 at CCR20, compared hydrocortisone+vitamin C+thiamine to hydrocortisone alone in septic shock. The primary outcome—hours alive and vasopressor‑free at 7 days—did not differ (median 122.1 vs 124.6 h; difference −2.5 h, 95% CI −10.0 to 5.1).8 In the same era, ACTS (n=200) found no reduction in change in SOFA at 72 h (between‑group difference −0.8, 95% CI −1.7 to 0.2) and a neutral signal for mortality (HR 1.3, 95% CI 0.8–2.2).9 VICTAS (n=501) was halted for funding/time, with no difference in ventilator‑/vasopressor‑free days at 30 days (median 25 vs 26; difference −0.2 days, 95% CI −3.5 to 3.8).10 ATESS, a meticulous Korean RCT, similarly returned neutral findings.11

Finally, the LOVIT trial, reported in NEJM, asked a sobering question: might vitamin C be harmful in the sickest? In 872 adults with sepsis on vasopressors, high‑dose vitamin C (50 mg/kg q6h for 96 h) increased the composite of death or persistent organ dysfunction at day 28 compared with placebo (44.5% vs 38.5%; absolute difference 6.0 percentage points, 95% CI 0.8–11.2; RR 1.21, 95% CI 1.04–1.40).12

By 2023, a careful meta‑analysis of intravenous vitamin C monotherapy in critically ill adults concluded that pooled effects on mortality were null, with heterogeneity but no convincing signal to treat outside trials.13

An important aside on controversy

In March 2022, media coverage reported statistical allegations that the original 2017 before–after study might rely on fraudulent data; these were not peer‑reviewed, were contested by the authors, and—critically—the Chest paper remains published without retraction or an expression of concern.14,5 Whatever one’s view, the allegation episode further emphasised the need to privilege neutral, well‑conducted RCTs over dramatic observational findings.

Interlude — The Antioxidant Paradox: When Vitamin C Turns Pro‑oxidant

It is tempting to focus only on potential benefit when an intervention is physiologically sensible. But redox biology is not a one‑way street, and so too for ascorbate. At pharmacological plasma concentrations achievable only by intravenous infusion, ascorbate can reduce transition metals (e.g., Fe3+→Fe2+), catalysing Fenton chemistry and generating hydrogen peroxide (H2O2) in extracellular fluid; elegant in vivo work in animals and humans has demonstrated measurable ascorbate radicals and H2O2 generation under these conditions.15 Contemporary reviews likewise frame ascorbate as a compound with “two faces”—antioxidant at physiological concentrations, potentially pro‑oxidant at millimolar levels depending on catalytic metal availability and compartmentalisation.16

Why does this matter in the ICU? Because sepsis is an iron‑rich, inflamed, dysregulated state. A therapy capable of donating electrons and spawning H2O2 might—counter‑intuitively—exacerbate oxidative injury or alter microvascular signalling in susceptible tissues. Add practical risks such as oxalate nephropathy (vitamin C is metabolised to oxalate) and analytical artefact (interference with some point‑of‑care glucose meters), and the case for balance is compelling. Biopsy‑proven oxalate nephropathy has been described after high‑dose intravenous vitamin C in severely ill patients, including two COVID‑19 cases (AKI with calcium oxalate deposition) and additional series during the pandemic period.17,18 High ascorbate levels can also produce spurious hyperglycaemia on certain glucose dehydrogenase–based point‑of‑care meters, particularly in renal impairment—risking inappropriate insulin and hypoglycaemia if laboratories are not used for confirmation.19,20

Therapeutic deliberation demands symmetry: opportunity is necessary but not sufficient; one must weigh plausible harm with equal seriousness before embracing a therapy at scale. Vitamin C embodies that duty of balance.

Mechanisms of Action — How Might Vitamin C Work?

If our romance with vitamin C began with sailors and was rekindled by sepsis, the molecular script is no less dramatic. In endothelium—the organ that lines the vascular tree—ascorbate concentrates via SVCT transporters, augments nitric oxide signalling, and stabilises the permeability barrier under inflammatory stress.21 One well‑defined route is through tetrahydrobiopterin (BH4) biology: ascorbate increases intracellular BH4, recoupling endothelial nitric oxide synthase (eNOS) and restoring physiologic NO generation when oxidative stress would otherwise tilt the enzyme towards superoxide.22,23,24

Vitamin C is also a classical co‑factor for several Fe2+/2‑oxoglutarate–dependent hydroxylases. That includes prolyl and lysyl hydroxylases in collagen biosynthesis—basic to vascular integrity and wound strength—and the two carnitine biosynthetic hydroxylases that help sustain mitochondrial fatty‑acid entry during stress.25,26 At the neurohumoral interface, ascorbate enables peptidylglycine α‑amidating monooxygenase (PAM) to convert glycine‑extended precursors into amidated hormones (e.g., vasopressin‑family peptides), and supports catecholamine synthesis via dopamine β‑hydroxylase—mechanisms that sit naturally with shock physiology.27,4

Beyond classical enzymology, ascorbate modulates hypoxia and gene regulation. As a reducing co‑factor for prolyl‑hydroxylases that target HIF‑α, ascorbate promotes HIF degradation and may temper hypoxia‑inflammation crosstalk; it also enhances TET/JmjC dioxygenases that drive active DNA and histone demethylation—pathways reported to be ascorbate‑sensitive in immune and epithelial cells.28,29

Immunologically, vitamin C accumulates in neutrophils, supports chemotaxis and phagocytosis, and may modulate NET formation; deficiency impairs several of these functions in vivo.30 At the microvascular level, animal and cellular models show improved capillary perfusion, reduced leak, and preservation of junctional proteins during inflammatory stress—effects that map to inhibition of NADPH oxidase signalling and protection of tight‑junction phosphorylation states.31,32,33,34

Vitamin C mechanisms of action

Figure 1. Mechanisms of action of vitamin C in critical illness. Selected supporting sources: 21,22,23,24,25,26,27,28,29,30,31,32,33,34

Potential Benefits and Harms — The Balance Sheet

Placed against this mechanistic canvas, what might we hope for—and fear—in the ICU? Potential benefits include improved microvascular perfusion and endothelial barrier stability, which are repeatedly observed in preclinical sepsis and ischaemia‑reperfusion models;31,32,33 anti‑inflammatory signalling via NF‑κB inhibition;36 and vasopressor‑sparing effects suggested by a small RCT in surgical septic shock.35 In burns, early high‑dose vitamin C reduced resuscitation volumes in a single‑centre trial, though contemporary generalisability is limited.43 Yet across modern ICU RCTs the signal for hard outcomes has been neutral or worse—CITRIS‑ALI’s secondary mortality finding aside—underscoring the chasm between mechanism and effect.7,12,13

Potential harms track the “two faces” of ascorbate: pro‑oxidant chemistry (ascorbate radical/H2O2 generation at millimolar concentrations),15,16 oxalate nephropathy,17,18 spurious hyperglycaemia on some glucose meters,19,20 and, in patients with G6PD deficiency, case‑reported haemolysis and even methaemoglobinaemia with high‑dose infusions.37,38 Sodium‑ascorbate “mega‑dose” strategies also carry a sodium load; hypernatraemia has been observed in pilot work and mandates vigilance.39

Potential benefits and harms of Vitamin C

Figure 2. Potential benefits and potential harms of vitamin C in critical illness (schematic). Selected supporting sources:31,32,33,35,36,7,12,13,15,16,17,18,19,20,37,38,39

Act IV — Why Didn’t Sepsis Yield?

The neutral and adverse results are not mysterious when read alongside pathophysiology and trial method. First, corticosteroids are effective adjuncts in some septic shock phenotypes; in two pivotal trials, steroids were common or mandated in the control condition (VITAMINS: hydrocortisone alone; VICTAS: ~32% open-label), and in ACTS they were permitted but used in a minority (~14%)—all of which could blunt any incremental signal from adding vitamin C or thiamine.8,9,10 Second, timing is everything in sepsis trials: redox‑sensitive pathways may be most modifiable very early—before organ injury is entrenched—yet many participants were randomised after shock physiology had been present for hours.7,12,13 Third, dosing and pharmacokinetics are non‑trivial. Oral vitamin C saturates intestinal transporters, whereas intravenous dosing can achieve plasma levels differing by orders of magnitude; bio‑distribution, renal handling, and the redox milieu vary widely across patients.13

Guideline panels have moved accordingly: the 2021 Surviving Sepsis Campaign issued a weak recommendation against routine IV vitamin C in sepsis/septic shock outside clinical trials, based on low‑certainty evidence and the absence of proven benefit.40

A discreet word on dose

Language around dose is often loose, so here is a pragmatic taxonomy used in the ICU literature. At nutritional intakes typical of a balanced diet—about 75 mg per day for women and 90 mg per day for men—vitamin C absorption from the gut is highly efficient, exceeding 80%, and plasma concentrations stabilise around 60 µmol/L. These intakes represent the physiological range, meeting metabolic requirements for enzyme co-factors and antioxidant recycling.

When oral supplementation increases total intake into the hundreds of milligrams per day, absorption efficiency begins to fall, but plasma levels rise modestly toward a plateau of ≈70–80 µmol/L. This defines the ordinary supplementary range, beyond which higher oral doses yield little further increase because intestinal transporters and renal handling become saturated.

At intakes above about 1 g per day, less than half of the vitamin C is absorbed, and plasma concentrations cannot rise appreciably further. Only intravenous administration bypasses these limitations, producing transient millimolar plasma concentrations—orders of magnitude higher than those achievable by oral intake.41 

“High‑dose” IV regimens in sepsis trials commonly delivered 6–16 g/day (e.g., 50 mg/kg every 6 h for 96 h, as in CITRIS‑ALI and LOVIT).7,12 “Mega‑dose” has been used for doses ≥30 g/day, explored in preclinical work and small translational studies for profound vasoplegia; the biological rationale (including potential pro‑oxidant signalling) is provocative but unproven in sepsis.42

Act V — Beyond Sepsis: Other Critical‑Care Frontiers

Critical care has trialled vitamin C outside sepsis, notably in burns. An older, single‑centre trial suggested reduced fluid requirements with high‑dose vitamin C in major burns, but external validity and modern care differences limit generalisability.43 Nutritional science, for its part, reminds us how quickly deficiency develops in the critically ill—plasma vitamin C concentrations can fall to “latent scurvy” ranges—without proving that supraphysiological replacement improves outcomes.41

Act VI — The CCR Thread: From Belfast to Melbourne

Vitamin C’s modern arc has run through CCR. Marik’s lecture at CCR17 lit the fuse on a decade of trials.6 The field pivoted at CCR20 when the VITAMINS RCT debuted live to thousands of clinicians worldwide, with transparent debate and an immediate editorial response.8 LOVIT’s carefully executed design then reframed our priors by suggesting harm at the high‑dose end of common sepsis regimens.12

Act VII — Circling Back: High‑Dose, Then Mega‑dose?

Even as sepsis trials cooled enthusiasm, some investigators asked whether vitamin C might work under different biological circumstances, or at doses high enough to change its mechanism of action. Preclinical and early translational work has explored “mega‑dose” sodium ascorbate to reverse vasoplegia—pharmacology that courts the very pro‑oxidant properties cautioned above. The hypothesis is as bold as it is contentious: could a burst of controlled extracellular H2O2 signal vascular reset in shock? The answer awaits rigorous human RCTs focused on patient‑centred outcomes, not surrogate kinetics.42

Interest has not waned. A recent pilot, double‑blind, randomised trial tested a mega‑dose sodium ascorbate regimen in septic shock (60 g over 6 h), reporting physiological signals (greater cumulative urine output; faster vasopressor reduction) but no significant difference in the 24‑h primary endpoint; the study was prospectively registered.39,44 Beyond the ICU enrolment window, an emergency‑department RCT (C‑EASIE) randomised 292 patients with sepsis or septic shock to early IV vitamin C (1.5 g q6h for 4 days) vs placebo and was neutral; its registration underscores the discipline of public protocols.45,46 Additional registrations illustrate ongoing exploration, including a high‑dose vitamin C study in septic shock and a multicentre megadose programme.47,48 In post–cardiac arrest care, protocols alongside VITaCCA—for example, the VICEPAC programme—are evaluating high‑dose regimens in out‑of‑hospital cardiac arrest with shock.49 A multicentre feasibility RCT of megadose sodium ascorbate in early septic shock is also registered in ANZCTR (MEGA SCORES), reflecting the field’s methodical next steps.50

In burns, a large international multicentre trial (VICToRY) is evaluating high‑dose intravenous vitamin C (approximately 200 mg/kg/day for 96 hours) on a composite of persistent organ dysfunction and death; Canadian centres are among the recruiting sites, and details are available via registration and sponsor pages.51,52

Finale — Post–Cardiac Arrest Syndrome: VITaCCA

Ischaemia–reperfusion after cardiac arrest is a redox storm distinct from the immune dyscrasia of sepsis. That difference underpins VITaCCA, a multicentre, randomised, double‑blind, placebo‑controlled trial in the Netherlands testing whether early high‑dose vitamin C improves organ dysfunction in post‑cardiac arrest syndrome. The protocol compares two IV dosing strategies—approximately 3 g/day (“supplementary”) and 10 g/day (“pharmacological”) for 96 h—against placebo, with 270 patients planned and SOFA‑based endpoints, plus detailed safety and PK/PD sampling.53,54,55

There is a poetic symmetry here. The vitamin that rewrote maritime medicine became our modern ICU muse. We tested it earnestly in sepsis and learned hard things about dose, timing, and harm. Now, in a different pathophysiological theatre, we may yet learn more. CCR Down Under in Melbourne (9–10 December 2025) will host the VITaCCA results56—completing a circle that began with CCR17 and ran through VITAMINS and LOVIT.

Will VITaCCA rescue the romance or write the epilogue? The physiology is plausible, the trial is tight, and the moment is CCR’s. Let’s meet in Melbourne to find out.

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