Current Controversies in Sepsis Management

Stephanie R. Moss, MD; Hallie C. Prescott, MD, MSc


Semin Respir Crit Care Med. 2019;40(5):594-603. 

In This Article

Vitamin C in Sepsis

In recent years, there has been interest in evaluating the ability of vitamin C to attenuate sepsis-related organ dysfunction and mortality.[51] During critical illness, such as trauma, ischemia/reperfusion, and sepsis, cytokine release and reactive oxygen species lead to oxidative stress and tissue injury.[52,53] This can be mitigated by antioxidants such as vitamin C, but vitamin C levels are low in most patients with septic shock.[54] In animal models, vitamin C supplementation attenuated sepsis-related organ dysfunction,[55–57] and so there has been increasing interest in testing vitamin C supplementation in clinical practice. Vitamin C has a good safety profile in numerous patient populations,[57–60] although increased oxalate levels (via endogenous conversion) have been reported in some patients with standard supplementation levels (2,000 mg/day), which can increase risk of renal stone formation, particularly among men.[61,62] Also, there have been case reports of renal failure in patients who receive very high doses (e.g., 45 g/day) of vitamin C.[63,64]

Several studies have evaluated vitamin C supplementation in trauma and burn populations. In one study of a critically ill surgical population, 595 patients (91% trauma patients) were randomized to vitamin C supplementation versus standard care, and the vitamin C arm had lower rates of multiorgan failure, shorter duration of mechanical ventilation, and shorter ICU length of stay.[65] A large retrospective observational study of 4,294 trauma patients found a 28% relative risk reduction in mortality, and decreased length of stay with an antioxidant protocol including vitamin C.[66] Two small studies, one randomized and one observational, of burn patients in Japan found that high-dose vitamin C infusion (66 mg/kg/h for 24 hours) was associated with decreased fluid requirements and increased urine output, without an increase in renal dysfunction.[60,67]

With respect to sepsis management, a small (n = 24) phase I randomized placebo-controlled clinical trial assessed safety and tolerability of vitamin C (at 50 and 200 mg/kg/day dosings) in a medical ICU population with severe sepsis.[68] There were no adverse events with vitamin C, and reductions in SOFA score, procalcitonin, and C-reactive protein compared with controls. In a more recent randomized study in a surgical population with septic shock, patients randomized to vitamin C required lower doses and shorter duration of vasopressor therapy.[69] The proposed mechanism for this effect is that vitamin C acts as a cofactor for endogenous norepinephrine and vasopressin synthesis.[70]

In a recent publication in Chest, Marik et al performed a retrospective pre/postclinical study comparing patients treated with IV vitamin C (1.5 g every 6 hours), hydrocortisone (50 mg every 6 hours), and thiamine (200 mg every 12 hours) to matched patients treated with standard practice.[71] This particular three-drug regimen was prescribed because prior literature suggests that glucocorticoids have a synergistic effect with vitamin C in regard to antioxidant and anti-inflammatory activity.[71] Thiamine was added because thiamine deficiency has been associated with increased mortality in sepsis.[72] Moreover, thiamine deficiency increases the conversion of glyoxylate to oxalate;[73] therefore it was hypothesized that thiamine supplementation would minimize any risk of oxalate deposition conferred by the vitamin C itself.[71]

The study included a total of 94 patients split evenly between control and experimental groups. Control patients received hydrocortisone based on provider discretion (60% were treated with hydrocortisone). Patients treated with the vitamin C protocol had dramatically lower mortality—an 87% relative reduction and 32% absolute reduction in in-hospital mortality relative to the matched controls. In addition, vitamin C-treated patients had a shorter duration of vasopressor-dependent shock, a faster clearance of procalcitonin, and a lower rate of renal replacement (despite concerns about oxalate deposition in acute kidney injury with vitamin C therapy).[71]

The results from Marik et al are on one hand exciting. Vitamin C, thiamine, and hydrocortisone are inexpensive, widely available, and could be readily implemented at scale, even in lower resource settings. However, it was a small, single-center, nonrandomized study with historical controls. These factors limit the generalizability of the findings. Moreover, the effect size is implausibly large. Two recent reviews of vitamin C therapy in sepsis conclude that there is insufficient evidence to recommend changes to clinical practice.[53,57] Rather, the results of Marik et al must be replicated in a prospective, multicenter RCT before vitamin C should be used in standard practice. Fortunately, several trials are underway. The VICTAS trial is multicenter, placebo-controlled and double-blinded, with a goal recruitment of 2,000 subjects from 40 medical centers in the United States (NCT #03509350).[74] Meanwhile the Australian and New Zealand Intensive Care Society is conducting a randomized, open-label trial called VITAMINS (NCT # 03333278).[75]