High-dose ascorbic acid burn resuscitation

Overview

High-dose ascorbic acid is one of the antioxidant adjuncts proposed to limit the fluid burden of burn resuscitation. Severe burns increase endothelial permeability, producing systemic capillary leak and massive fluid shifts into the extravascular space ^[37]. Use of high-dose vitamin C has become a popular approach to limit fluid resuscitation volumes and edema formation, and the antioxidant has been adopted in many burn centers as an adjunct to resuscitation ^[21][25]. The clinical appeal is mechanistic and economic: vitamin C is a cheap, strong, multifaceted antioxidant that is especially robust for resuscitation of the circulation ^[11].

The evidence arc is unusual. A consistent fluid-sparing signal runs from experimental burn models through one widely cited human randomized trial, yet the harder outcomes that matter most, mortality and ventilator days, have not been confirmed, and the most recent clinical data are mixed ^[12][17][36]. Newer monitoring approaches and alternative strategies to crystalloid alone, including high-dose ascorbic acid, have had mixed results in limiting fluid creep, and clear demonstration of outcome improvement remains elusive ^[12]. Against this backdrop the 2024 American Burn Association (ABA) Clinical Practice Guidelines on Burn Shock Resuscitation state that they are unable to make any recommendation on the use of high-dose vitamin C as an adjunct during acute burn shock resuscitation ^[1]. This page covers the antioxidant rationale, dosing and the fluid-sparing evidence, clinical outcomes, the safety controversies, and the open evidence gaps that keep the adjunct unsettled.

Physiologic Rationale

Burn trauma is associated with inflammatory events that release free radicals, promoting oxidative stress and subsequent tissue damage ^[32]. Enhanced free radical production is paralleled by impaired antioxidant defenses, indicated by burn-related decreases in superoxide dismutase, catalase, glutathione, alpha-tocopherol, and ascorbic acid levels ^[8]. Reduced plasma ascorbate is a hallmark of oxidative stress and occurs in severe burns alongside sepsis, trauma, and other critical illness ^[9]. Cellular oxidative stress is a critical step in burn-mediated injury, and antioxidant strategies that either inhibit free radical formation or scavenge free radicals may provide organ protection ^[8].

The proposed mechanism connects this oxidative cascade to capillary leak. High-dose vitamin C can prevent or restore microcirculatory flow impairment by inhibiting NADPH-oxidase and inducible nitric oxide synthase activation, augmenting tetrahydrobiopterin, preventing uncoupling of oxidative phosphorylation, decreasing formation of superoxide and peroxynitrite, and directly scavenging superoxide ^[11]. It can also restore vascular responsiveness to vasoconstrictors and preserve the endothelial barrier by maintaining occludin phosphorylation and preventing apoptosis ^[11]. Supraphysiologic ascorbate concentrations, achievable only by parenteral administration, restore nitric oxide bioavailability and endothelial function in vitro ^[9][38]. Because of limited oral bioavailability and rapid clearance ^[38], the intravenous route appears to be the only way to deliver the doses required for a clinical effect ^[10].

Experimental work links these mechanisms to measurable reductions in microvascular leak. In a canine model, high-dose vitamin C diminished early postburn lipid peroxidation and reduced microvascular leakage of fluid and protein, with lower postburn lymph malondialdehyde and less than half the increase in protein flux seen without treatment ^[6][7]. In thermally injured rats, high-dose vitamin C attenuated the strongly negative interstitial fluid hydrostatic pressure that develops in burned dermis and reduced edema as measured by tissue water content ^[34]. In a rat burn-plasma-transfer model, a bolus of 66 mg/kg followed by 33 mg/kg/h reduced microvascular barrier dysfunction to sham-burn levels, whereas half that dose had no significant effect, identifying a dose threshold for the antileak effect ^[35].

Dosing and Administration

The regimen with the strongest human data is a continuous intravenous infusion of 66 mg/kg/h over the first 24 hours after injury. In the landmark single-center randomized study by Tanaka and colleagues in patients with burns of more than 30% total body surface area, this dose attenuated postburn lipid peroxidation and reduced resuscitation fluid volume requirements and edema generation; ascorbic acid was infused during the initial 24-hour study period ^[2]. Several later burn-center protocols adopted the same 66 mg/kg/h rate, in some cases as an 18-hour infusion ^[25][26].

Dosing has been studied across a wide range. A high-dose-versus-low-dose comparison in severely burned adults contrasted 66 mg/kg/h for 24 hours with a low-dose regimen of 3.5 g/day; ascorbic acid plasma levels were elevated roughly 10-fold in the low-dose group and 150-fold in the high-dose group at 24 hours ^[16]. A nationwide cohort defined high-dose therapy as a dosage in excess of 10 g, or in excess of 24 g, within 2 days of admission ^[18]. Retrospective comparisons have also used scheduled intermittent intravenous dosing, such as 1250 mg every 6 hours for 72 hours against a 500 mg oral comparator ^[33]. Animal data established that the antioxidant effect is dose-dependent up to a ceiling: in third-degree burns in guinea pigs, a 340 mg/kg/day regimen was effective while 170 mg/kg/day was less so and 680 mg/kg/day was no more beneficial ^[4].

The reproducible pharmacodynamic effect across these regimens is fluid-sparing. With adjuvant high-dose vitamin C, experimental groups reduced the 24-hour resuscitation volume from 4 mL/kg/%burn to roughly 1 mL/kg/%burn while maintaining adequate cardiac output ^[3][4]. In burn-injured sheep, continuous high-dose vitamin C infusion reduced net fluid balance by about 30% at 6 hours and about 50% at 48 hours compared with lactated Ringer's alone, while increasing plasma total antioxidant potential roughly 25-fold ^[5]. A systematic review of acute burn edema found that continuous administration of vitamin C reduced local wound edema and systemic fluid retention with large effect sizes ^[14].

Outcomes

The outcome most consistently supported is reduction of resuscitation fluid volume in the first 24 hours. In the Tanaka randomized study, 24-hour total fluid infusion volumes were 5.5 mL/kg/%burn in the control group versus 3.0 mL/kg/%burn in the ascorbic acid group; treated patients gained 9.2% of pretreatment weight versus 17.8% in controls, and burned-tissue water content was lower ^[2]. The same trial reported a longer duration of mechanical ventilation in controls (21.3 days) than in the ascorbic acid group (12.1 days), with lower serum malondialdehyde and a higher oxygenation ratio in treated patients, although heart rate, mean arterial pressure, central venous pressure, and urine output were equivalent between groups ^[2]. A best-evidence emergency-medicine review concluded that preliminary evidence suggests vitamin C can reduce the volume required for fluid resuscitation, improve wound healing, and reduce ventilation requirements in patients with severe burns ^[15].

Retrospective and cohort data partly reinforce and partly temper this picture. In a retrospective review by Kahn and colleagues, patients given 66 mg/kg/h had lower 24-hour fluid requirements (5.3 vs 7.1 mL/kg/%TBSA) and higher urine output (1.5 vs 1.0 mL/kg/h) than lactated Ringer's controls, with no difference in pneumonia, renal failure, or mortality ^[13]. A Japanese nationwide cohort found that high-dose vitamin C therapy was associated with reduced in-hospital mortality (risk ratio 0.79) when used at a minimum threshold of 10 g within the first 2 days of admission, although the association did not hold under a higher 24-g threshold ^[18]. A high-dose-versus-low-dose adult trial found a significant reduction in colloid fluid requirements with high-dose therapy but comparable hemodynamic and secondary clinical outcomes between groups ^[16].

Negative and equivocal signals run alongside. A retrospective study by Lin and colleagues found that high-dose ascorbic acid, while potentially reducing inflammation and fluid requirements, may not improve meaningful outcomes such as ventilator requirements, ventilator-associated pneumonia, or mortality, with no significant difference in ventilator-associated pneumonia (29% vs 14%) or mortality (26% vs 23%) ^[17]. A study by Flores and colleagues found that high-dose ascorbic acid decreased only the initial 24-hour fluid requirements (3.06 vs 4.32 mL/kg/%TBSA) but not total fluid intake over 72 hours, with no significant differences in organ-failure scores, complications, or mortality ^[19]. The state-of-the-science assessment is that improvements in clinical outcome have not been convincingly demonstrated ^[21].

Complications and Safety

The safety profile is the principal brake on broader adoption. The most clinically immediate problem is glucometer interference. All patients in one series demonstrated falsely elevated point-of-care glucose values during and immediately after the infusion period, with discrepancies ranging from 10 to 200 mg/dL ^[25]. A paired-measurement study found mean point-of-care glucose (225 mg/dL) significantly higher than laboratory glucose (138 mg/dL) during high-dose infusion, with the discrepancy resolving once the infusion ended ^[26]. Treating an erroneously high glucose value with insulin is potentially dangerous and could lead to iatrogenic hypoglycemia and seizures, and the authors of these studies concluded that point-of-care glucose monitoring is best avoided during and after vitamin C therapy ^[25][26]. Glucose-meter chemistry matters, because anemia and high-dose ascorbic acid both negatively affect glucose-monitoring-system accuracy and tight glycemic control in burn patients ^[27].

Renal injury is the most serious concern. Both high-dose and low-dose vitamin C have been shown to cause secondary calcium-oxalate nephropathy, worsen acute kidney injury, and delay renal recovery in non-burn patients, and the first case series in burn patients identified calcium-oxalate nephropathy after high-dose therapy ^[22]. A case of megadose vitamin C through alternative medicine produced biopsy-proven calcium-oxalate crystal nephropathy requiring permanent renal replacement therapy, illustrating the nephrotoxic potential of toxic doses ^[24]. In a major-burn cohort, resuscitation with high-dose vitamin C was independently associated with more frequent early acute kidney injury ^[23].

A vasopressor signal has also emerged. In a study of vasopressor use during acute burn resuscitation, patients given high-dose vitamin C more often required vasopressors (69% vs 17%), and multivariate and propensity analyses found high-dose vitamin C independently associated with greater vasopressor use, although the authors noted this needs formal evaluation in a large randomized study ^[28]. Vitamin C is among the agents listed in the management of vasoplegic syndrome, the low-resistance resistant hypotension that complicates burns and other critical illness ^[29]. Set against these signals, several reports describe limited adverse effects: a high-dose-versus-low-dose adult trial found high-dose therapy was not associated with a significantly increased risk of any complication, and the Kahn retrospective review reported that vitamin C can be used without an increased risk of renal failure ^[16][13]. Two recent large randomized trials of high-dose vitamin C in sepsis and COVID-19 showed signs of harm, sharpening caution about extrapolating benefit from small burn cohorts ^[30].

Special Considerations

Practice patterns vary widely, and at least one center has reversed course. In 2018 an adult burn center updated its resuscitation guideline to remove high-dose ascorbic acid therapy, lower the 24-hour fluid estimate from 4 to 2 mL/kg/%TBSA, and optimize colloid guidance; the revised protocol achieved significantly lower 24-hour resuscitation volumes (2.94 mL/kg/%TBSA, down from 3.74 before revision) without an increase in adverse safety events, mechanical-ventilation duration, or mortality ^[20]. This experience indicates that the fluid-creep problem the adjunct targets can be addressed by a lower starting crystalloid rate and disciplined colloid use without the antioxidant ^[20].

Timing and dose remain individualized. Vitamin C given as early as possible after the injurious event appears most effective, consistent with its proposed role in intervening early in the oxidant cascade ^[11]. Across the literature, mixed results on the most effective dose and method of administration persist, and reviewers call for center-level protocols and confirmatory trials before any standardized regimen can be recommended ^[33][31].

Controversies and Evidence Gaps

No multicenter confirmation of the landmark trial. A quarter century after the Tanaka randomized study, high-dose ascorbic acid has been investigated in only a small number of clinical studies, and improvements in clinical outcome have not been convincingly demonstrated ^[21]. The systematic review that found large fluid-sparing effects also flagged that each review outcome was based on a small single-facility study, and that future research must focus on multicenter trials ^[14]. An RCT comparing high-dose vitamin C as an adjunct to crystalloid against crystalloid alone has been called urgently required ^[21].

Fluid-sparing versus outcome benefit. The reduction in early fluid volume is reproducible, but whether it translates into fewer ventilator days or lower mortality is unsettled. The Tanaka trial reported shorter ventilation ^[2], the Japanese cohort reported a dose-dependent mortality association ^[18], yet the Lin and Flores studies found no outcome benefit and no reduction in total fluid intake beyond the first 24 hours ^[17][19]. Reviewers note that alternative resuscitation strategies including high-dose ascorbic acid have had mixed results in limiting fluid creep, and clear outcome improvement remains elusive ^[12].

Safety as a live constraint. The osmotic-diuresis, oxalate-nephropathy, acute-kidney-injury, and vasopressor signals are not fully reconciled with the reports describing limited adverse effects, and concerns persist surrounding induction of osmotic diuresis leading to intravascular volume depletion ^[21][22][28]. Whether short-course high-dose infusion carries the oxalate risk seen with chronic or megadose exposure is not resolved within the burn population ^[22][24].

Pharmacokinetics before pivotal trials. Recent integrative reviews argue that a better understanding of the vitamin's pharmacokinetics and pharmacodynamics is a first requirement before embarking on well-powered, well-designed clinical trials ^[36]. Open questions include optimal timing, since early versus late administration are likely distinct, and duration of therapy, where withdrawal-induced injury is possible ^[30]. Until these gaps close, the 2024 ABA guideline's inability to issue a recommendation reflects the state of the evidence rather than a verdict on the adjunct ^[1].

References

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