Introduction
Vitamin C is a water-soluble vitamin with a variety of antioxidant,
1 anti-inflammatory,
2 and microvascular
3 effects. Widely used in over-the-counter formulations for the common cold and general well-being,
4 in recent years, there has been an expanding role for the use of vitamin C in the hospital setting. Although the overall prevalence of hypovitaminosis C is around 7.1% in the general population,
5 up to 47.3% of undifferentiated hospitalized patients are deficient in vitamin C.
6
Vitamin C levels are known to be decreased in critical illness
7–10 and are associated with severity of illness.
7,11 Although vitamin C requirements are greater in this population due to increased oxidative stress,
12 levels may be restored to normal,
8,13 or even brought to supra-normal,
14 with parenteral supplementation.
Supplemental vitamin C has shown promise in both animal models of sepsis
3,15–21 and human trials in the intensive care unit (ICU) setting.
22–31 Although a simple vitamin, a variety of biological mechanisms have been postulated to account for the beneficial actions of vitamin C in the context of sepsis and organ failure. These include the prevention and restoration of micro-circulatory flow impairment due to reactive oxygen species, the preservation of vascular responsiveness to vasoconstrictors, the preservation of endothelial barrier function, and augmentation of anti-bacterial defense, leading to an overall mitigation of organ injury and dysfunction in critically ill patients.
32
However, the largest studies with the most promising results have investigated vitamin C as part of combination (“cocktail”) therapies administered together with vitamin E or thiamine plus hydrocortisone.
31 The last study is particularly impressive, demonstrating a substantial (8.5% versus 40.4%) reduction in mortality as well as decreased Sequential Organ Failure Assessment (SOFA) scores and length of vasopressor support compared to controls, but it is unclear which, if any, of the three constituents was responsible for these effects, obscuring the true effect of vitamin C. Furthermore, questions have been raised regarding the methodology of this study with respect to its small sample size, lack of randomization, and retrospective design.
33
Few studies have focused specifically on the benefits of isolated administration of vitamin C in critically ill patients. Generally, these studies have been small and have yielded few conclusive results, and a comprehensive synthesis of the data has not been conducted heretofore. Hence, we aim in this review to provide a comprehensive meta-analysis of all studies involving isolated vitamin C administration in critically ill patients and to examine the effects upon overall mortality in addition to common clinical parameters in this setting, such as vasopressor requirements, the duration of mechanical ventilation, and resuscitation fluid requirements.
Discussion
Although several meta-analyses have explored the effect of combination antioxidants in critical illness, our study is the first to focus exclusively on the role of vitamin C. The main results from our analysis of five studies are that vitamin C administration is not associated with decreased mortality but is associated with decreased vasopressor requirements and duration of mechanical ventilation.
Vitamin C is an essential cofactor for the production of endogenous vasopressors.
83 Through its actions on tyrosine hydroxylase, the rate-limiting enzyme of catecholamine synthesis,
84,85 and its role as a cofactor for dopamine β-hydroxylase,
86 vitamin C is involved in the biosynthesis of norepinephrine at physiologic concentrations.
84 Vitamin C also acts as a cofactor for peptidylglycine α-amidating monooxygenase (PAM),
87 an enzyme that catalyzes the formation of arginine vasopressin.
88 On the basis of these observations, Carr et al.
89 hypothesized that “the administration of high-dose ascorbate in conditions of hypovitaminosis C (e.g. severe sepsis and septic shock) may support the endogenous synthesis of these vasoactive compounds and thus ameliorate the need for exogenously administered vasopressors.”
It is noteworthy that, although we were able to demonstrate decreased vasopressor requirements and trends toward reduced fluid resuscitation needs and increased urine output, we did not find an overall difference in mortality. One possible reason for this discrepancy is the variance in baseline patient characteristics across the included studies. In general, the studies which did not demonstrate a numerically less mortality rate in the treatment group featured patients with relatively less severe hemodynamic derangements upon study commencement. In Tanaka et al.’s
22 study, the average mean arterial pressure of enrolled patients was around 90 mm Hg, and all deaths occurred after the 96-h fluid resuscitation phase, by which time plasma vitamin C levels in the treatment group had already declined to match controls. In Kahn et al.’s study, only 4 of 17 patients in the treatment group required vasopressors compared to 9 of 16 controls. The authors note that “because one group had more than 50% more patients on vasopressors, the results would have been misleading.” In Ferrón-Celma et al.’s
23 study, only 5 of 20 patients even required vasopressor support. Conversely, Zabet et al.
26 did demonstrate decreased mortality with vitamin C administration, but the average mean arterial pressure (MAP) upon enrollment was under 70 mm Hg. Taken together, these observations support the hypothesis that vitamin C indeed exerts a vasopressor sparing effect, but the magnitude of this effect may depend upon the initial need for vasopressor support. The benefits of
supplemental vitamin C would be expected to be more pronounced in those with refractory vasopressor-dependent shock compared to patients with stable hemodynamics with little or no need for vasopressor support, and this difference in expected benefit might explain the difference in mortality among the analyzed studies. A similar line of reasoning applied to the VASST (Vasopressin and Septic Shock) trial, where the administration of supplemental vasopressin reduced the need for norepinephrine support without affecting mortality; the authors therein speculated that the reason for this was due to the high average MAP of enrolled patients (72–73 mm Hg).
90
The significance of the decreased requirements for mechanical ventilation is unknown, as is the question of whether this is actually reflective of a real improvement in pulmonary status. Across all studies, only Tanaka et al.
22 demonstrated an improvement in any parameter of pulmonary function (increased PaO2/FiO2 ratio in the treatment group), but the average duration of mechanical ventilation in the treatment group was 12.1 days, far longer than the initial 24-h period of vitamin C administration. Furthermore, it is unclear whether this effect is dependent upon a decreased need for resuscitation fluids and hence a concomitant reduction in the incidence and severity of pulmonary edema or is an independent effect upon the lung parenchyma. Animal research has demonstrated that vitamin C exerts a protective effect upon the pulmonary tissues in both ischemia–reperfusion
91 and lipopolysaccharide-induced models of lung injury
15,92,93 through a variety of mechanisms, including increased alveolar fluid clearance, enhanced epithelial barrier function, and the attenuation of pro-inflammatory and pro-coagulant states accompanying sepsis.
94 The same group has reported encouraging results in a recent series of case reports in the setting of acute respiratory distress syndrome (ARDS)
79–81 and has recently concluded a phase II multicenter trial investigating Vitamin C Infusion for Treatment in Sepsis Induced Acute Lung Injury (CITRIS-ALI, NCT02106975).
95 This study should further clarify the possible role of vitamin C in the treatment of acute lung injury and ARDS.
The optimal dose and target plasma concentration of vitamin C in the setting of critical illness are unknown. The recommended daily oral dose in healthy subjects needed to maintain normal plasma levels above 50 µmol/L is 95–110 mg/day.
96 However, physiological requirements are increased during times of increased oxidative stress and metabolic turnover,
12 and plasma levels have been found to be correspondingly lower in the ICU population.
7 Intravenous dosing has been shown to produce higher plasma concentrations than oral administration
97 due to saturable intestinal absorption,
98 and 3 g/day is required to maintain plasma levels in the normal range in ICU patients.
8
The five studies included in this meta-analysis featured doses as low as 450 mg/day
23 to 1584 mg/kg/day,
22,24 a 250-fold difference in a 70 kg subject. The difference in dosages given may result in differing effects. As previously mentioned, vitamin C is an essential cofactor for the production of endogenous vasopressors.
83 It has been suggested that vitamin C is released from the adrenal cortex in response to adrenocorticotropic hormone (ACTH) to ensure that “norepinephrine synthesis [in the medulla] always proceeds at maximum velocity (Vmax).”
99 Indeed, this study noted that vitamin C levels in the adrenal veins of patients with hyperaldosteronism who were administered ACTH were found to be 176 ± 71 μmol/L, over four times higher than concentrations within plasma. The authors speculated that this allows vitamin C to act locally as a paracrine mediator to stimulate norepinephrine and epinephrine synthesis. If the Carr hypothesis
89 is correct, and given the suppression of corticotropin and the overall dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis during critical illness,
100,101 it can be surmised that the minimum plasma concentration of vitamin C required in critical illness to support endogenous norepinephrine synthesis should be at least as great as the maximum intraadrenal concentration needed for this function in healthy controls. Analogous reasoning with hypophyseal vein concentrations can be extended for endogenous vasopressin synthesis in the setting of sepsis-related endocrine dysfunction. This level might be slightly higher given the higher pituitary concentrations of vitamin C.
102
In the Fowler study, patients administered “low-dose” vitamin C at 50 mg/kg/24 h achieved an average steady-state plasma concentration of 331 μmol/L,
25 above what would be expected to support endogenous norepinephrine synthesis. However, there was a further reduction in SOFA scores among patients given a higher dose of vitamin C at 200 mg/kg/24 h. Patients in this latter group achieved an average steady-state plasma concentration of 3082 μmol/L. This may suggest additional, non-hemodynamic benefits at higher, supra-physiologic doses, possibly through the antioxidant, anti-inflammatory, and microvascular actions of vitamin C, and these may be responsible for the aforementioned pulmonary benefits. Furthermore, serum levels of C-reactive protein,
25 procalcitonin,
25 poly(ADP-ribose) polymerase,
23 and malondialdehyde
22 were decreased in the intervention groups across multiple studies. Several of these markers of cellular damage have been found to correlate with organ failure beyond the cardiovascular and pulmonary systems, suggesting an overall bodily cytoprotective effect in the context of systemic inflammation.
103,104
High-dose intravenous vitamin C is generally regarded as safe even in gram doses.
105 No significant side effects were reported across any of these five studies. Nevertheless, caution should be exercised in patients with renal impairment.
106 Although rare, oxalate nephropathy has been documented in burn patients using the same 66 mg/kg/h dose used in the Tanaka and Kahn studies.
107 Patients with glucose 6-phosphate dehydrogenase deficiency and paroxysmal nocturnal hemoglobinuria should be excluded from treatment due to the risk of intravascular hemolysis.
13 Although not studied in the critically ill population, potential pro-oxidant effects are largely of academic interest only and do not appear to be of concern in noncancerous cells.
108 Interestingly, one recent study in the outpatient setting suggests that intravenous vitamin C administered at gram doses may cause an acute decrease in MAP of around 7 mm Hg.
109 Although this effect was limited to patients with prehypertension at baseline, vitamin C does indeed have acute vasodilatory properties;
110 whether this may precipitate a paradoxical collapse in hemodynamic function in the setting of critical illness is unknown.
A major strength of this meta-analysis is that we investigated only the administration of isolated vitamin C on clinical outcomes in the critically ill, as opposed to vitamin C in combination with other agents as part of an antioxidant cocktail, the effects of which cannot be attributed properly to any particular agent. Also, a varied mix of medical, surgical, and burn patients were included, and each study contributed relatively equally in weight.
This meta-analysis has several weaknesses that should be kept in mind. First, only five studies were included due to the paucity of research on isolated vitamin C administration. Study sizes were small, with the largest study consisting of only 37 subjects, the doses used between studies was disparate, and the risk of bias was generally judged to be uncertain or high. Sample sizes for secondary outcomes were even sparser. Heterogeneity among the studies and the patient populations therein was not insignificant. In particular, mortality data had to be taken from the longest available time point in each study due to the non-uniform duration of follow-up across studies. In addition, through the inclusion of patients across many diverse settings, the gain in statistical power resulting therefrom must be weighed against the weakening association between the fixed intervention and the growing list of conditions, all under the umbrella of “critical illness,” on which the agent acts in thematic relation to. Whereas the mechanisms by which vitamin C exerts its actions have been studied mostly on animal models of sepsis and septic shock, such pathways may not pertain in likewise fashion to the hypovolemic shock of burn patients; the inclusion of the latter population and the application of meta-analytic techniques thereto may result in a conclusion that dilutes or otherwise obfuscates the effects of vitamin C when applied only to sepsis. One study utilized a dose of vitamin C far below the others, and this was not adjusted for patient weight;
23 however, the exclusion of this study did not affect the primary outcome of mortality. Finally, focusing on the isolated administration of vitamin C ignores any summative or synergistic benefits to be had when used in combination with other agents. Without even knowing the specific nature of vitamin C, it does seem a priori implausible that a single substance would have a substantial effect upon a parameter as global as mortality given the complex biochemical and pathophysiological milieu of critical illness. Many essential vitamin and mineral deficiencies can occur in this setting, including iron, selenium,
111 magnesium,
112 thiamine,
113 and vitamin D,
114 and repletion of several of these may be required before substantial clinical improvements are seen.
In view of these deficiencies in the primary literature, this meta-analysis should be considered as an orienting endeavor to guide future studies. Indeed, further trials are in various stages of completion in this area, exploring the role of vitamin C within the context of acute lung injury,
95 severe sepsis,
115,116 and septic shock.
117,118 In addition, spurred by the promising results of the Marik study, trials are underway to explore the effects of vitamin C combined with thiamine and hydrocortisone.
119–123 Taken together, these studies should elucidate both the role of isolated vitamin C and its synergistic effects.