Parenteral Vitamin C in Patients with Severe Infection: A Systematic Review

BACKGROUND: Inflammation and oxidative damage caused by severe infections may be attenuated by vitamin C. METHODS: We conducted a systematic review of randomized controlled trials (RCTs) of parenteral vitamin C as combined therapy or monotherapy versus no parenteral vitamin C administered to adults hospitalized with severe infection. The primary outcome was mortality. We performed random-effects meta-analyses and assessed certainty in effect estimates. RESULTS: Of 1547 citations, 41 RCTs (n = 4915 patients) were eligible for inclusion. Low-certainty evidence suggested that vitamin C may reduce in-hospital mortality (21 RCTs, 2762 patients; risk ratio, 0.88 [95% confidence interval (CI), 0.73 to 1.06]), 30-day mortality (24 RCTs, 3436 patients; risk ratio, 0.83 [95% CI, 0.71 to 0.98]), and early mortality (before hospital discharge or 30 days; 34 RCTs, 4366 patients; risk ratio, 0.80 [95% CI, 0.68 to 0.93]). Effects were attenuated in sensitivity analyses limited to published blinded trials at low risk-of-bias (in-hospital mortality: risk ratio, 1.07 [95% CI, 0.92 to 1.24], moderate certainty; 30-day mortality: risk ratio, 0.88 [95% CI, 0.71 to 1.10], low certainty; and early mortality: risk ratio, 0.88 [95% CI, 0.73 to 1.06], low certainty). For 90-day mortality, all trials had low risk-of-bias; moderate-certainty evidence suggested harm (five RCTs, 1722 patients; risk ratio, 1.07 [95% CI, 0.94 to 1.21]). Moderate-certainty evidence suggested an increased risk of hypoglycemia (risk ratio, 1.20 [95% CI, 0.69 to 2.08]). Effects on other secondary outcomes were mixed and informed by low-certainty evidence. No credible subgroup effects were observed for mortality related to cointerventions (monotherapy vs. combined therapy), dose, or type of infection (Covid-19 vs. other). CONCLUSIONS: Overall, evidence from RCTs does not establish a survival benefit for vitamin C in patients with severe infection. (PROSPERO number, CRD42020209187.)