Vitamin C in sepsis: end of the debate?

Introduction

Oxidative stress is one of the key pathophysiological mechanisms that mediate sepsis-related tissue injury.1 In ischemia-reperfusion injury and septic shock, there is enhanced generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS), as part of the biological defense mechanism.2 However, excessive ROS activity can be harmful and normally controlled by counterregulatory antioxidant mechanisms. However, the massive surge of ROS that often occurs in sepsis results in the overwhelming of the antioxidant defense mechanisms. Excessive ROS activity causes injury to proteins, lipids, and nucleic acids, resulting in endothelial injury, cellular and organ dysfunction.3

ROS: pathophysiological mechanisms of injury in sepsis

Uncontrolled ROS activity leads to endothelial dysfunction in ischemia-reperfusion injury and sepsis. This triggers damage to the endothelial glycocalyx and cell membranes with disruption of tight intercellular junctions, resulting in increased capillary permeability.4

Endothelial nitric oxide (eNO) is crucial in maintaining the patency of blood vessels through its vasodilator effect. The vasodilator effect of eNO is mediated through cyclic guanosine monophosphate by activation of soluble guanyl-cyclase.5Besides, eNO inhibits platelet aggregation and adhesion of activated platelets and leukocytes, thus maintaining vascular patency.6 Unopposed ROS activity leads to inhibition of eNOS synthetase, with reduced production of eNO and thereby, loss of its vasodilator effect. The loss of the endothelial vasodilator response attenuates the effect of vasoconstrictor agents. Furthermore, reduced levels of eNO lead to adhesion of leukocytes and platelets besides triggering inflammation and coagulation. Vasodilatation-induced hypotension, capillary leak, and blockage of microcirculatory blood flow ensue, leading to worsening hypoxia.

Ascorbate, the redox product of vitamin C, ameliorates oxidative stress in endothelial cells through inhibition of the production of ROS, including superoxide, hydrogen peroxide, and peroxynitrite.7 Ascorbate may also scavenge peroxides at high doses and increase the bioavailability of eNO. Through the generation of eNO by stimulation of eNOS, ascorbate may also tighten the endothelial barrier, thereby decreasing endothelial permeability. Ascorbate may also inhibit apoptosis 8 and promote the generation of endothelial progenitor cells.9 Ascorbate-mediated inhibition of ROS may attenuate ischemia-reperfusion injury to the myocardium, thereby reducing the incidence of myocardial stunning and arrhythmias.10

The antioxidant effect of Vitamin C in sepsis 

Vitamin C, by its antioxidant effect, may ameliorate tissue injury triggered by oxidative stress.11  Preclinical studies have demonstrated the putative benefits of vitamin C in reversing the pathophysiological changes observed in sepsis. Vitamin C may improve the response to vasopressor agents.12 Besides, it may augment the endothelial barrier function by mitigating the increase in vascular permeability,13 thereby enhancing microvascular blood flow.14 Humans are unable to synthesize vitamin C,15 and levels are often low in critically ill patients.16 Hence, biological plausibility suggests that vitamin C supplementation in critically ill septic patients may be beneficial.

Vitamin C in sepsis: clinical studies 

Considering the plausibility of clinical benefit from its antioxidant effect, several recent clinical trials have evaluated clinical outcomes using variable doses of vitamin C in patients with sepsis. Vitamin C has been administered as monotherapy or as combination therapy with thiamine and hydrocortisone. 

High-dose vitamin C

The LOVIT study was carried out in 35 medical-surgical ICUs in Canada, France, and New Zealand.17 This study included patients who had suspected or proven infection and were on vasopressor support. In the intervention arm, vitamin C, 50 mg/kg was administered 6 hourly, intravenously, for 96 hours for a maximum of 16 doses. The control group received matching placebo. Thiamine and glucocorticoids were administered based on clinician judgment. The vitamin C group included 429 patients, and the control group, 434 patients. The primary outcome, a composite of death or persistent organ dysfunction at 28 days, was significantly higher in the vitamin C compared to the control group (44.5% vs. 38.5%; risk ratio: 1.21; 95% CI, 1.04 to 1.40; P = 0.01). Among the secondary outcomes, there was no significant difference in the individual components of the composite primary outcome –mortality or persisting organ dysfunction at 28 days. The median organ dysfunction-free days was also not significantly different between groups. The SOFA scores at specific time intervals from days 1–28, 6-month survival, and health-related quality of life were also similar between the two groups. This study clearly demonstrated a lack of beneficial effect, and possible harm from the use of high-dose vitamin C in patients with severe sepsis. 

Vitamin C in patients with sepsis and acute respiratory distress syndrome (ARDS)

The CITRIS-ALI trial randomized 167 patients with sepsis and ARDS to receive vitamin C 50 mg/kg/6 hours intravenously or placebo for 96 hours.18 The change in the mean modified SOFA scores from baseline to 96 hours were similar between the two groups. The C-reactive protein and thrombomodulin levels were also similar at 168 hours. On exploratory analysis without adjustment for multiple comparisons, the 28-day mortality was significantly lower in the vitamin C group (29.8% vs. 46.3%; p = 0.03). 

Vitamin C as part of combination therapy 

Marik et al. performed an electronic health record-based, retrospective, before-after study to evaluate the efficacy of treatment with a cocktail including vitamin C, thiamine, and hydrocortisone in patients with septic shock.19  During a 7-month period, consecutive patients with severe sepsis or septic shock and a procalcitonin level ≥2 ng/ml were administered vitamin C 1.5 g/hours, hydrocortisone 50 mg/6 hours, and thiamine 200 mg/12 hours. Vasopressors were administered to target a mean arterial pressure of 65 mm Hg. The control group included consecutive patients with severe sepsis or septic shock admitted during a 7-month period preceding the intervention. During the control period, no patient received thiamine or vitamin C as part of therapy. Forty-seven patients were included in each group. The hospital mortality was significantly lower in the treatment group (8.5% vs. 40.4%, P <0.001). On propensity-adjusted analysis, the odds ratio for mortality with the vitamin C cocktail was 0.13 (95% CI, 0.04-0.48; P = 0.002). The mean duration of vasopressor support was also significantly shorter in the intervention arm (18.3 vs. 54.9 hours, P = 0.001). This observational study suggested possible benefits with a combination of vitamin C, thiamine, and hydrocortisone in patients with septic shock; the authors suggested further controlled trials to confirm the findings of their study.

Against the background of the Marik et al. study, the VITAMINS trial evaluated the effect of a cocktail including vitamin C, thiamine, and hydrocortisone in patients with septic shock.20 The eligibility criteria included a primary diagnosis of septic shock with an acute increase in the SOFA score by at least two points, a lactate level >2 mmol/l, and the requirement for vasopressor support for at least 2 hours prior to enrollment. The combination of intravenous vitamin C 1.5 g/6 hours, hydrocortisone 50 mg/6 hours, and thiamine 200 mg/12 hours was compared to a control group that received hydrocortisone 50 mg/6 hours alone. This multicenter RCT was conducted across 10 ICUs in Australia, New Zealand, and Brazil. In the primary analysis, 107 patients were included in the intervention arm; 104 were included in the control arm.

The primary outcome, the duration of time alive and vasopressor-free until day 7 was not significantly different between the two groups [intervention group: 122.1 (76.3–145.4 hours) vs. control group: 124.6 (82.1–147.0 hours, P = 0.83)]. Among the secondary outcomes, there was no significant difference between groups in the 28-, 90-day, ICU, or hospital mortality. The duration of vasopressor-free days, mechanical ventilation-free days, and renal replacement-free days were also similar between the two groups. The SOFA decreased by day 3 in both groups; the decrease was marginally greater in the intervention group. This study demonstrated that the combination of vitamin C, thiamine, and hydrocortisone did not lead to a more rapid resolution of septic shock compared to hydrocortisone alone.

The vitamin C cocktail was evaluated among patients with sepsis in the VICTAS trial.21 Patients with cardiovascular or respiratory dysfunction due to suspected infection were included. In the intervention arm, patients received intravenous vitamin C 1.5 g, thiamine 100 mg, and hydrocortisone 50 mg, 6 hourly for up to 96 hours. The treatment was commenced within 4 hours of randomization. Matching placebos were administered in the control group. The trial was designed to include up to 2000 patients; however, it was prematurely stopped after the enrolment of 501 patients due to a lack of continued funding. The intervention group included 252 patients in the primary analysis, with 249 patients in the control group. The primary outcome, the ventilator- and vasopressor-free days in the first 30 days following randomization was not significantly different between groups [intervention: 25 days (0-29 days) vs. control: 26 days (0-28 days), p = 0.85]. The 30-day mortality was also similar between the intervention and the control groups (22% vs. 24%). This study, although terminated early, did not reveal any difference in clinical outcomes with the use of the vitamin C cocktail in patients with sepsis with respiratory or cardiovascular dysfunction.

The findings of the South Korean, multicenter ATESS RCT, were similar.22 Patients in septic shock were randomized to receive intravenous vitamin C 50 mg/kg (maximum dose of 6 g/day) and thiamine 200 mg 12 hourly for 48 hours or placebo. Among the 111 patients enrolled, 53 were included in the intervention group and 58 in the control group. Vasopressin infusion and hydrocortisone 200 mg/day were administered in patients who required high-dose norepinephrine. The primary outcome was Δ SOFA, the difference between the baseline and 72-hour SOFA scores. No significant difference was observed in the Δ SOFA at 72 hours between the intervention and the control groups [3, (− 1 to 5) vs. 3, (0–4), P = 0.96]. Predefined secondary outcomes, including the 7-, 28-, 90-day, hospital, and ICU mortality were also similar between the two groups. The occurrence of shock reversal was also similar.

Metanalysis of vitamin C in sepsis 

Agarwal et al. performed a meta-analysis of RCTs that evaluated the effect of vitamin C as monotherapy or combination therapy among hospitalized patients with severe infection.23 The authors identified 41 RCTs including 4915 patients eligible for inclusion. Low-quality evidence suggested that vitamin C may reduce in-hospital, 30-day, and early mortality. However, on sensitivity analysis that included only published trials that were blinded with a low risk of bias, the impact of vitamin C was nonsignificant. All the trials that evaluated the 90-day mortality were at low risk of bias and revealed higher mortality with vitamin C administration. There was no evidence of benefit among subgroups of patients related to cointerventions (monotherapy vs. combination therapy), the dose administered, or the type of infection. Overall, there was no evidence of improved survival in this meta-analysis.

Key points

  • Oxidative stress arising from the generation of excessive ROS may be a key trigger of sepsis-induced organ dysfunction 
  • Vitamin C evokes robust antioxidant mechanisms and may mitigate the impact of oxidative stress in sepsis 
  • Besides enhancing the response to vasopressor agents through an increase in the synthesis of eNO, vitamin C may also augment endothelial barrier function and reduce vascular permeability
  • Preclinical studies had demonstrated putative benefits of vitamin C in reversing the pathophysiological changes observed in sepsis; this led to several clinical trials that explored possible clinical benefit from vitamin C administration either alone or in combination with thiamine and hydrocortisone in patients with sepsis
  • An early observational study by Marik et al. revealed reduced hospital mortality and a shorter duration of vasopressor support in patients with septic shock who were administered a cocktail of vitamin C, thiamine, and hydrocortisone
  • Subsequently, several RCTs have evaluated the benefit of vitamin C alone or in combination in patients with sepsis; however, no evidence of clinical benefit has been observed
  • The composite outcome of death or persistent organ dysfunction at 28 days was significantly higher with a high-dose vitamin C cocktail in the LOVIT study, the largest RCT so far on this topic 
  • Based on the available evidence, there is no suggestion of benefit with vitamin C therapy, either alone or in combination, in patients with severe sepsis and septic shock 

References

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2.         De Backer, D., Orbegozo Cortes, D., Donadello, K. & Vincent, J.-L. Pathophysiology of microcirculatory dysfunction and the pathogenesis of septic shock. Virulence 5, 73–79 (2014).

3.         Biesalski, H. K. & McGregor, G. P. Antioxidant therapy in critical care–is the microcirculation the primary target? Crit Care Med 35, S577-583 (2007).

4.         Burke-Gaffney, A. & Evans, T. W. Lest we forget the endothelial glycocalyx in sepsis. Crit Care 16, 121 (2012).

5.         Hellsten, Y., Nyberg, M., Jensen, L. G. & Mortensen, S. P. Vasodilator interactions in skeletal muscle blood flow regulation. J Physiol 590, 6297–6305 (2012).

6.         Cyr, A. R., Huckaby, L. V., Shiva, S. S. & Zuckerbraun, B. S. Nitric Oxide and Endothelial Dysfunction. Crit Care Clin 36, 307–321 (2020).

7.         Wilson, J. X. & Wu, F. Vitamin C in sepsis. Subcell Biochem 56, 67–83 (2012).

8.         Haendeler, J., Zeiher, A. M. & Dimmeler, S. Vitamin C and E prevent lipopolysaccharide-induced apoptosis in human endothelial cells by modulation of Bcl-2 and Bax. Eur J Pharmacol 317, 407–411 (1996).

9.         Fiorito, C. et al. Antioxidants increase number of progenitor endothelial cells through multiple gene expression pathways. Free Radic Res 42, 754–762 (2008).

10.       Valls, N. et al. Amelioration of persistent left ventricular function impairment through increased plasma ascorbate levels following myocardial infarction. Redox Report 21, 75–83 (2016).

11.       Amrein, K., Oudemans-van Straaten, H. M. & Berger, M. M. Vitamin therapy in critically ill patients: focus on thiamine, vitamin C, and vitamin D. Intensive Care Med 44, 1940–1944 (2018).

12.       Armour, J., Tyml, K., Lidington, D. & Wilson, J. X. Ascorbate prevents microvascular dysfunction in the skeletal muscle of the septic rat. J Appl Physiol (1985) 90, 795–803 (2001).

13.       Han, M. et al. Ascorbate protects endothelial barrier function during septic insult: Role of protein phosphatase type 2A. Free Radic Biol Med 48, 128–135 (2010).

14.       Tyml, K., Li, F. & Wilson, J. X. Septic impairment of capillary blood flow requires nicotinamide adenine dinucleotide phosphate oxidase but not nitric oxide synthase and is rapidly reversed by ascorbate through an endothelial nitric oxide synthase-dependent mechanism. Crit Care Med 36, 2355–2362 (2008).

15.       Drouin, G., Godin, J.-R. & Pagé, B. The Genetics of Vitamin C Loss in Vertebrates. Curr Genomics 12, 371–378 (2011).

16.       Carr, A. C. et al. Hypovitaminosis C and vitamin C deficiency in critically ill patients despite recommended enteral and parenteral intakes. Critical Care 21, 300 (2017).

17.       Lamontagne, F. et al. Intravenous Vitamin C in Adults with Sepsis in the Intensive Care Unit. N Engl J Med 386, 2387–2398 (2022).

18.       Fowler, A. A. et al. Effect of Vitamin C Infusion on Organ Failure and Biomarkers of Inflammation and Vascular Injury in Patients With Sepsis and Severe Acute Respiratory Failure: The CITRIS-ALI Randomized Clinical Trial. JAMA322, 1261 (2019).

19.       Marik, P. E., Khangoora, V., Rivera, R., Hooper, M. H. & Catravas, J. Hydrocortisone, Vitamin C, and Thiamine for the Treatment of Severe Sepsis and Septic Shock: A Retrospective Before-After Study. Chest 151, 1229–1238 (2017).

20.       Fujii, T. et al. Effect of Vitamin C, Hydrocortisone, and Thiamine vs Hydrocortisone Alone on Time Alive and Free of Vasopressor Support Among Patients With Septic Shock: The VITAMINS Randomized Clinical Trial. JAMA 323, 423 (2020).

21.       Sevransky, J. E. et al. Effect of Vitamin C, Thiamine, and Hydrocortisone on Ventilator- and Vasopressor-Free Days in Patients With Sepsis: The VICTAS Randomized Clinical Trial. JAMA 325, 742 (2021).

22.       Hwang, S. Y. et al. Combination therapy of vitamin C and thiamine for septic shock: a multi-centre, double-blinded randomized, controlled study. Intensive Care Med 46, 2015–2025 (2020).

23.       Agarwal, A. et al. Parenteral Vitamin C in Patients with Severe Infection: A Systematic Review. NEJM Evidence(2022) doi:10.1056/EVIDoa2200105.

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