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

Mortality

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

CONCLUSION

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. 

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