By Drayton Hammond, PharmD, MSc, FCCM
Clinical Pharmacy Specialist, Adult Critical Care, Rush University Medical Center, Chicago
Dr. Hammond reports no financial relationships relevant to this field of study.
Sepsis remains a major healthcare problem associated with significant morbidity and mortality.1 Standard septic shock therapies include fluid resuscitation, antimicrobials, and vasopressors.2 Roles for hydrocortisone, ascorbic acid (vitamin C), and thiamine (HAT therapy) as potential adjuvants remain controversial.3-18
The reduced form of vitamin C, ascorbate, affects both cellular regulation and immune system function.19,20 It acts as an antioxidant and free radical scavenger to improve microvascular and macrovascular function, reduce endothelial permeability, regulate macrophage function, and decrease cellular apoptosis.19-21 Vitamin C is an essential co-factor for catecholamine and vasopressin synthesis and may be depleted in critically ill patients.22,23
VITAMIN C AND HAT THERAPY EFFICACY
Several randomized controlled trials (RCTs) and observational studies have evaluated vitamin C alone or as part of HAT therapy in sepsis and septic shock.3-18 Only two RCTs reported positive mortality outcomes.13,15 The VITAMINS trial compared HAT therapy (n = 109) vs. hydrocortisone (n = 107) alongside usual care in septic shock.16 No differences in mortality, median time alive, or vasopressor-free days up to day 7 were found between the groups. Two recently published RCTs, the Combined treatment with HYdrocortisone, Vitamin C, and Thiamine for the Treatment of Sepsis and Septic Shock (HYVCTTSSS) trial and the Outcomes of metabolic Resuscitation using Ascorbic acid, thiamiNe, and Glucocorticoids in the Early treatment of Sepsis (ORANGES) trial, failed to demonstrate mortality benefit with vitamin C.17,18 HYVCTTSSS was terminated early because of a significantly higher incidence of severe hypernatremia with HAT therapy.17 However, data from 80 enrolled patients did not demonstrate a mortality benefit at 28 days (27.5% vs. 35%, P = 0.47). The subgroup of patients diagnosed with sepsis within 48 hours had lower mortality compared to placebo (13.6% vs. 47.6%, P = 0.02).
The ORANGES trial (n = 137) evaluated HAT therapy in patients diagnosed with sepsis or septic shock within 12 hours from hospital admission.18 The primary endpoint was updated after patient enrollment from hospital mortality to resolution of shock and change in Sequential Organ Failure Assessment (SOFA) score at 96 hours from baseline. The authors reported a significant reduction in duration of vasopressor use in patients who received HAT therapy (27 ± 22 vs. 53 ± 38 hours, P < 0.001) but no difference in intensive care unit (ICU) (9% vs. 14%, P = 0.37) and hospital mortality (16.4% vs. 19%, P = 0.65) compared to placebo. Both HYVCTSSS and ORANGES did not control for hydrocortisone use between groups, which potentially could have confounded these outcomes.
The second largest multicenter, placebo-controlled RCT, CITRIS-ALI (n = 167), randomized septic patients with acute respiratory distress syndrome (ARDS) to vitamin C (50 mg/kg intravenous [IV] every six hours) or placebo for 96 hours.15 Even though there was no difference in the co-primary endpoint of change in SOFA score, serum C-reactive protein, and thrombomodulin at 96 hours from baseline, the 28-day mortality was lower in the vitamin C group (29.8% vs. 46.3%, 95% confidence interval [CI], between-group difference 2% to 31%, P = 0.03).15 However, the mortality analyses did not account for multiple comparisons.
Eight observational studies have evaluated mortality, and only three of these studies reported positive mortality findings.3-10
Resolution of Organ Failure
The presumed protective effect of vitamin C on organ function also has been evaluated in both observational studies and RCTs.3-8,12-18 Only three out of seven RCTs that assessed improvement in organ function (i.e., improvement in SOFA scores or need for renal replacement therapy) reported greater improvement with vitamin C. However, these significant improvements should be interpreted cautiously, since these were secondary endpoints assessed without adjustment for multiple comparisons. Only one observational study assessed this endpoint and observed that patients who received vitamin C had a greater change in SOFA scores at 72 hours (4.8 ± 2.4 vs. 0.9 ± 2.7, P < 0.001).3
VITAMIN C TIME TO INITIATION IN SEPTIC SHOCK
The effect of time to initiation of vitamin C therapy on outcomes remains controversial. In patients with septic shock, early vitamin C administration may prevent over-resuscitation and subsequent negative sequelae.24-26 Marik et al evaluated patients who received vitamin C within 24 hours of ICU admission and showed a decrease in hospital mortality with vitamin C.3 HYVCTTSSS found a 34% improvement in mortality in a predefined subgroup analysis of patients with sepsis within 48 hours (n = 22).17 These findings were not replicated in other RCTs.4,5,16
In the VITAMINS trial, the median time from meeting Sepsis-3 criteria to vitamin C initiation in the intervention group was 12.1 hours (IQR, 5.7-19.0 hours).16 Despite all patients receiving vitamin C within 24 hours of sepsis diagnosis, no mortality benefit was detected. ORANGES recruited patients within 12 hours of development of septic shock, and patients received their first dose of the study treatment between three and 14 hours (mean, 9.9 ± 4.5 hours). Again, there was no observed difference in mortality.18 Although the proposed mechanisms of benefit for vitamin C in septic shock support early administration, the differences in timing of vitamin C and outcomes in many RCTs make deciphering optimal timing of vitamin C initiation difficult.
PATIENT POPULATIONS THAT MAY BENEFIT FROM HIGH-DOSE VITAMIN C
Currently, clinical equipoise exists regarding high-dose vitamin C use in sepsis and septic shock, both with and without the use of other metabolic resuscitation agents, because of variable findings and methodological quality in RCTs and studies.3-18 However, there may be specific patient populations for whom beneficial outcomes are more likely.
Severity of Critical Illness
Patients in the Marik study were less severely ill than those in the VITAMINS trial.3,16 Patients in both received similar HAT therapy regimens, although some patients enrolled in the VITAMINS trial had therapy initiated beyond the first 24 hours of ICU admission, and Marik et al did not describe time to receipt of HAT therapy.3,16 Patients in the VITAMINS trial were randomized after being on IV vasopressors for at least two hours, whereas only 46% of patients in the Marik et al study were on IV vasopressors at baseline. Additionally, baseline lactate values were lower in the Marik et al study (mean 2.7 mmol/L ± 1.5 vs. median 4.2 mmol/L; IQR, 2.8-5.9]).3,16 The benefit seen in the Marik study may have been more profound because of the increased likelihood of recovery in these less severely ill patients. However, vitamin C has shown mortality benefit in more severely ill patients in an observational before-and-after study.8 In a subgroup analysis of this study, vitamin C was significantly associated with lower in-hospital mortality in patients with SOFA scores > 10 points (adjusted odds ratio [OR], 0.53; 95% CI, 0.29-0.97, P = 0.03) and baseline albumin level < 3.0 mg/dL (adjusted OR, 0.53; 95% CI, 0.30-0.93, P = 0.02).8
Acute Respiratory Distress Syndrome in Sepsis
The CITRIS-ALI trial randomized patients with sepsis who developed ARDS to high-dose vitamin C (50 mg/kg IV every six hours for four days) or placebo.15 Two-thirds of patients were in shock at enrollment, and two-thirds of patients received corticosteroids. Although the primary outcome, change in SOFA score, was similar between groups, an exploratory secondary outcome of 28-day mortality was lower in patients randomized to vitamin C (29.8% vs. 46.3%, P = 0.03). Because mortality also was lower on day 4 after the trial intervention was completed (4% vs. 23%), this survivorship bias could have affected other short-term outcomes (e.g., change in SOFA score). Further trial data in ARDS that is powered to determine a potentially moderate mortality benefit is necessary before vitamin C can be confidently recommended in these patients.
SAFETY CONCERNS WITH VITAMIN C AND THIAMINE
Although few safety events and adverse events have been reported in studies, vitamin C is not a benign therapy. Adverse effects are rare, but they may include oxalate nephropathy, hypernatremia, fictitious hyperglycemia, and hemolysis in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency.27
Vitamin C is metabolized into oxalate, which binds with calcium to form a precipitate in renal tubules that can cause acute and chronic tubular injury, interstitial fibrosis, and renal failure.28 Doses of 10 g carried an increased risk of oxalate crystal formation.29 At least five cases of oxalate nephropathy have been reported in patients receiving IV vitamin C.27
Prior to the HYVCTTSSS trial, there have been five reported cases of hypernatremia with IV vitamin C administration. Hypernatremia can occur with large doses of vitamin C because marketed products of IV vitamin C are sodium ascorbate.27 The HYVCTTSSS trial was terminated early because of the incidence of severe hypernatremia (> 160 mmol/L) in addition to ineffectiveness of the treatment.17 Thirteen patients in the treatment group compared with three patients in the placebo group experienced severe hypernatremia (relative risk [RR] 4.43; 95% CI, 1.34-14.1; P = 0.05).
Vitamin C also may cause fictitious hyperglycemia.30 This is because of an interaction with the mechanism of some point-of-care blood glucose machines that use glucose dehydrogenase-pyrroloquinoline quinone amperometric methods.30 When vitamin C is oxidized at the electrode surface, it causes more electron production that potentiates a larger current, causing interference with glucose biosensors.31
G6PD deficiency is an exclusion criterion in many of the ongoing trials for vitamin C because of the potential risk of hemolysis with very high doses (> 60 g).32 However, doses used in the protocols for sepsis (up to 6 g/day) should not achieve blood concentrations typical of causing harm.33
The role of vitamin C in sepsis has been evaluated in observational and randomized controlled trials. Vitamin C produces early reductions in pro-inflammatory mediators and slows the progression of endothelial injury in patients with severe sepsis. There is inconsistency in the vitamin C dosing regimens used in clinical trials, making it challenging to draw definitive conclusions on its role in sepsis. In general, vitamin C appears to be safe. However, patients should be monitored for nephropathy and glucose monitoring errors when high-dose vitamin C is administered. Overall, there is insufficient evidence to support the routine use of vitamin C in sepsis. Future studies are warranted to identify subgroups of sepsis patients that may benefit from vitamin C therapy.
- Gaieski DF, Edwards JM, Kallan MJ, Carr BG. Benchmarking the incidence and mortality of severe sepsis in the United States. Crit Care Med 2013;41:1167-1174.
- Rhodes A, Evans LE, Alhazzani W, et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Crit Care Med 2017;45:486-552.
- Marik PE, Khangoora V, Rivera R, et al. Hydrocortisone, vitamin C, and thiamine for the treatment of severe sepsis and septic shock: A retrospective before-after study. Chest 2017;151:1229-1238.
- Ahn JH, Oh DK, Huh JW, et al. Vitamin C alone does not improve treatment outcomes in mechanically ventilated patients with severe sepsis or septic shock: A retrospective cohort study. J Thorac Dis 2019;11:1562-1570.
- Litwak JJ, Cho N, Nguyen HB, et al. Vitamin C, hydrocortisone, and thiamine for the treatment of severe sepsis and septic shock: A retrospective analysis of real-world application. J Clin Med 2019;8:478.
- Mitchell AB, Ryan TE, Gillion AR, et al. Vitamin C and thiamine for sepsis and septic shock. Am J Med 2020;133:635-638.
- Sadaka F, Grady J, Organti N, et al. Ascorbic acid, thiamine, and steroids in septic shock: Propensity matched analysis. J Intensive Care Med 2019. doi:10.1177/0885066619864541. [Online ahead of print].
- Shin TG, Kim YJ, Ryoo SM, et al. Early vitamin C and thiamine administration to patients with septic shock in emergency departments: Propensity score-based analysis of a before-and-after cohort study. J Clin Med 2019;8:102.
- Byerly S, Parreco JP, Soe-Lin H, et al. Vitamin C and thiamine are associated with lower mortality in sepsis. J Trauma Acute Care Surg 2020;89:111-117.
- Coloretti I, Biagioni E, Venturelli S, et al. Adjunctive therapy with vitamin C and thiamine in patients treated with steroids for refractory septic shock: A propensity matched before-after, case-control study. J Crit Care 2020;59:37-41.
- Galley HF, Howdle PD, Walker BE, Webster NR. The effects of intravenous antioxidants in patients with septic shock. Free Radic Biol Med 1997;23:768-774.
- Fowler AA 3rd, Syed AA, Knowlson S, et al. Phase I safety trial of intravenous ascorbic acid in patients with severe sepsis. J Transl Med 2014;12:32.
- Zabet MH, Mohammadi M, Ramezani M, Khalili H. Effect of high-dose Ascorbic acid on vasopressor’s requirement in septic shock. J Res Pharm Pract 2016;5:94.
- Nabil Habib T, Ahmed I. Early adjuvant intravenous vitamin C treatment in septic shock may resolve the vasopressor dependence. Int J Microbiol Adv Immunol 2017;5:77-81.
- Fowler AA 3rd, Truwit JD, Hite RD, 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 tailure: The CITRIS-ALI randomized clinical trial. JAMA 2019;322:1261-1270.
- Fujii T, Luethi N, Young PJ, 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 2020;323:423-431.
- Chang P, Liao Y, Guan J, et al. Combined treatment with hydrocortisone, vitamin C, and thiamine for sepsis and septic shock: A randomized controlled trial. Chest 2020;158:174-182.
- Iglesias J, Vassallo AV, Patel VV, et al. Outcomes of metabolic resuscitation using ascorbic acid, thiamine, and glucocorticoids in the early treatment of sepsis: The ORANGES trial. 2020;158:164-173.
- Moskowitz A, Andersen LW, Huang DT, et al. Ascorbic acid, corticosteroids, and thiamine in sepsis: A review of the biologic rationale and the present state of clinical evaluation. Crit Care 2018;22:283.
- Wilson JX. Mechanism of action of vitamin C in sepsis: Ascorbate modulates redox signaling in endothelium. BioFactors 2009;35:5-13.
- Oudemans-van Straaten HM, Spoelstra-de Man AM, de Waard MC. Vitamin C revisited. Crit Care 2014;18:460.
- Cárcamo JM, Pedraza A, Bórquez-Ojeda O, Golde DW. Vitamin C suppresses TNF alpha-induced NF kappa B activation by inhibiting I kappa B alpha phosphorylation. Biochemistry 2002;41:12995-13002.
- Carr AC, Shaw GM, Fowler AA, Natarajan R. Ascorbate-dependent vasopressor synthesis: A rationale for vitamin C administration in severe sepsis and septic shock? Crit Care 2015;19:418.
- Sadaka F, Juarez M, Naydenov S, O’Brien J. Fluid resuscitation in septic shock: The effect of increasing fluid balance on mortality. J Intensive Care Med 2014;29:213-217.
- Boyd JH, Forbes J, Nakada TA, et al. Fluid resuscitation in septic shock: A positive fluid balance and elevated central venous pressure are associated with increased mortality. Crit Care Med 2011;39:259-265.
- Alsous F, Khamiees M, DeGirolamo A, et al. Negative fluid balance predicts survival in patients with septic shock: A retrospective pilot study. Chest 2000;117:1749-1754.
- Yanase F, Fujii T, Naorungroj T, et al. Harm of IV high-dose vitamin C therapy in adult patients: A scoping review. Crit Care Med 2020;48:e620-e628.
- Knight J, Madduma-Liyanage K, Mobley JA, et al. Ascorbic acid intake and oxalate synthesis. Urolithiasis 2016;44:289-297.
- de Grooth HJ, Manubulu-Choo WP, Zandvliet AS, et al. Vitamin C pharmacokinetics in critically ill patients: A randomized trial of four IV regimens. Chest 2018;153:1368-1377.
- Kahn SA, Lentz CW. Fictitious hyperglycemia: Point-of-care glucose measurement is inaccurate during high-dose vitamin C infusion for burn shock resuscitation. J Burn Care Res 2015;36:e67-e71.
- Ceriotti F, Kaczmarek E, Guerra E, et al. Comparative performance assessment of point-of-care testing devices for measuring glucose and ketones at the patient bedside. J Diabetes Sci Technol 2015;9:268-277.
- Campbell GD Jr, Steinberg MH, Bower JD. Letter: Ascorbic acid-induced hemolysis in G-6-PD deficiency. Ann Intern Med 1975;82:810.
- Marik PE. Is intravenous vitamin C contraindicated in patients with G6PD deficiency? Crit Care 2019;23:109.