Dosing vitamin C in critically ill patients with special attention to renal replacement therapy: a narrative review

Vitamin C has anti-oxidant, anti-inflammatory, and immune-enhancing capacities, and acts as a cofactor for the synthesis of collagen, cortisol, catecholamines, and vasopressin [1]. Plasma vitamin C concentrations frequently flirt with scurvy levels in septic, trauma, and burn patients, after major surgery, and in any condition characterized by overwhelming systemic oxidative and inflammatory stress [2]. Diminished intake, increased consumption, and reduced recycling all contribute to this vitamin C deficiency. In line with its biological modulator functions and continued depletion in severe disease, restoring normal circulating vitamin C levels is thought to improve hemodynamics [3], limit organ failure, and benefit survival of critically ill patients. Promising results have been reported in small cohorts of patients receiving a repletion dose of vitamin C in combination with vitamin E. High-dose intravenous (IV) vitamin C significantly reduced fluid requirements, weight gain, and wound edema and improved renal and pulmonary function in the acute phase after burn injury [4]. Vitamin C infusion, alone [5‐7] or in combination with thiamine and hydrocortisone [8], reduced biomarkers of inflammation and endothelial injury and had a positive impact on shock reversal, recovery from organ failure, and survival in severe sepsis and septic shock in a landmark before after trial [8], but not in the most recent vitamins trial which randomized septic shock patients to the above-mentioned cocktail or to hydrocortisone alone [9]. Apart from the hydrocortisone in all control patients, the vitamins trial differs from the before–after trial by a later timing of vitamin C (median more than 24 h after admission), and by less comorbidity. The value of early high-dose IV vitamin C treatment in ischemia/reperfusion injury has been extensively documented in animal experiments [10], but requires confirmation in clinical trials. Altogether, evidence on vitamin C supplementation is still fragmentary or inconclusive and does not support a widespread use in critically ill patients [11, 12]. For instance, regarding the CITRUS-ALI study which is widely quoted and promoted as a negative study; in actuality it is a double-positive study [13]. Indeed, the authors have recalculated the Sequential Organ Failure Assessment (SOFA) score as several errors did occur like for instance imputing the SOFA score prior to death in those patients who died prior to 96 h [5]. This reanalysis demonstrates a significant difference in SOFA scores between the two groups at 96 h and this reanalysis should be published soon [13]. Nevertheless, adjuvant vitamin C therapy holds particular promise in sepsis because of its apparent involvement in sepsis-related pathophysiological processes and the remarkably positive results in small clinical studies. A large number of randomized controlled trials (RCTs) are currently recruiting patients with sepsis and septic shock [14] to assess the benefit of vitamin C alone or in combination with hydrocortisone and thiamine.

The recommended daily dietary intake of vitamin C in healthy individuals is approximately 100 mg and produces plasma vitamin C levels between 60 and 100 µmol/L [15]. Vitamin C dosing in critically ill patients, however, is still an issue under debate. Also, it is unclear whether the dosing strategy should attempt to achieve normal or supraphysiologic (up to 1000 µmol/L) plasma vitamin C levels.

Some items pertaining to vitamin C dosing are known. First, intravenous (IV) dosing is crucial. Enteral uptake is unpredictable and may be seriously limited because the enteral transporter is satiable [1] and gut function often is impaired during critical illness. Second, high vitamin C doses (2–3 g/day) must be administered to restore plasma concentrations to normal [16, 17] and sustained therapy is needed to prevent reoccurrence of hypovitaminosis [17]. Third, a very high dose (100–200 mg/kg/day) is required to obtain supranormal plasma concentrations [4, 17]. Studies which showed beneficial effects on biological and clinical outcome parameters used very high vitamin C doses (66 mg/kg/h or 1584 mg/kg/day) on the first day of admission in burn patients [4] and 3 g, 6 g or 200 mg/kg daily in septic or trauma patients [5‐8].

In a recent animal study, 24 adult male Wistar rats were randomly distributed into three groups: Group I received sevoflurane only, whereas Groups II and III additionally received moderate (150 mg/kg) and high (300 mg/kg) doses of ascorbic acid. The study found a dose-dependent reduction of acute tubular necrosis in the ascorbic acid group [29]. In patients with severe sepsis and septic shock treated with colistin according to a modified pharmacokinetics–pharmacodynamics (PK/PD)-based dosing strategy, Dalfino et al. identified baseline renal impairment and older age as strong predictors of AKI occurrence. Concomitant administration of ascorbic acid markedly reduced AKI risk [30]. In the before–after study of Marik, less patients received RRT for AKI in the group receiving ascorbic acid (in combination with hydrocortisone and thiamine) [8].

Significant toxicity of high-dose vitamin C has not been reported in published clinical trials. However, in view of a potential increase in vitamin C supplementation in critical illness, vigilance remains imperative.

Some potential side-effects must be emphasized:

Important side-effects of vitamin C are not reported in any of the mentioned controlled trials, also not in the most recent VITAMIN randomized trial [9]. Furthermore, vitamin C has been evaluated for treating atrial fibrillation in RCTs after cardiac surgery [39]. Meta-analyses also evaluated adverse events. They concluded that vitamin C was safe [40], although meta-analyses upon vitamin C should be taken with caution as recently shown [41].

Vitamin C is closely involved in pathophysiological processes related to ischemia–reperfusion, immunomodulation, and inflammation. Critical illness leads to a rapid exhaustion of vitamin C stores. Adjuvant therapy with vitamin C has been shown to mitigate organ injury in burn, sepsis, and post-cardiac surgery patients. The optimal dosing strategy in critically ill patients is unknown and a most effective or specific pathology-related dosing schedule remains to be established. However, at least 2–3 g IV vitamin C must be supplemented daily during the acute phase to normalize plasma concentrations. Preliminary clinical experience suggests that high-dose vitamin C therapy (≥ 6 g daily) in the acute phase is associated with better outcome and no significant toxicity. The promising results of adjuvant high-dose vitamin C alone or in combination with thiamine and hydrocortisone are currently being evaluated in large RCTs.

Scarce available data remain inconclusive regarding dose adjustments during RRT. However, vitamin C dosing during CRRT should probably not exceed the dose administered to critically ill patients not on CRRT, though this hypothesis needs to be confirmed in RCTs. Low plasma concentration can be expected during RRT for a prolonged time period due to persistent extracorporeal removal and metabolic loss due to circuit-induced oxidative stress accentuating the need for further pharmacokinetic and dose–response studies in the setting of CRRT. However, a dosage of about 1 g twice daily may be needed to obtain normal plasma concentration during RRT.