Intravenous vitamin C monotherapy in critically ill patients: a systematic review and meta-analysis of randomized controlled trials with trial sequential analysis

Abstract

Background A recent landmark randomized controlled trial (RCT) in septic patients demonstrated an increased risk of death and persistent organ dysfunction with intravenous Vitamin C (IVVC) monotherapy, which represents a disparate result from previous systematic reviews and meta-analyses (SRMA). We performed an updated SRMA of IVVC monotherapy to summarize and explore heterogeneity across current trials and conduct trial sequential analysis (TSA) to guard against type-I or type-II statistical errors. Methods RCTs evaluating IVVC in adult critically ill patients were included. Four databases were searched from inception to 22 June 2022 without language restrictions. The primary outcome was overall mortality. Random effect meta-analysis was performed to estimate the pooled risk ratio. TSA for mortality was performed using the DerSimonian–Laird random effect model, alpha 5%, beta 10%, and relative risk reduction (RRR) of 30%, 25%, and 20%. Results We included 16 RCTs (n = 2130). IVVC monotherapy is associated with significant reduction in overall mortality [risk ratio (RR) 0.73, 95% confidence interval (CI) 0.60–0.89; p = 0.002; I2 = 42%]. This finding is supported by TSA using RRR of 30% and 25%, and sensitivity analysis using fixed-effect meta-analysis. However, the certainty of our mortality finding was rated low using GRADE due to the serious risk of bias and inconsistency. In a priori subgroup analyses, we found no differences between single vs multicenter, higher (≥ 10,000 mg/day) vs lower dose and sepsis vs non-sepsis trials. Post-hoc, we found no differences in subgroup analysis of earlier (< 24 h) vs delayed treatment, longer (> 4 days) vs shorter treatment duration, and low vs other risk of bias studies. IVVC may have the greatest benefit in trials that enrolled patients above (i.e., > 37.5%; RR 0.65, 95% CI 0.54–0.79) vs below (i.e., ≤ 37.5%; RR 0.89, 95% CI 0.68–1.16) median control group mortality (test for subgroup differences: p = 0.06), and TSA supported this. Conclusions IVVC monotherapy may be associated with mortality benefits in critically ill patients, particularly in patients with a high risk of dying. Given the low certainty of evidence, this potentially life-saving therapy warrants further studies to identify the optimal timing, dosage, treatment duration, and patient population that will benefit most from IVVC monotherapy. PROSPERO Registration ID: CRD42022323880. Registered 7th May 2022.

Highlights in the clinical nutrition literature: A critical appraisal of current research

“…Further analysis of the Sequential Organ Failure Assessment score, inflammatory biomarkers, hypoglycemia, stage 3 acute kidney injury, 6‐month survival, health‐related quality of life, or safety outcomes showed no significant difference between the study intervention and placebo groups. In addition to a meta‐analysis by the LOVIT investigators 6 , another updated meta‐analysis including the LOVIT study still indicated a survival benefit, particularly in those patients with higher degree of mortaility 7 . Taken together, existing evidence including the results of the LOVIT trial indicates that the role of vitamin C in patients with sepsis is limited.…”

Intravenous vitamin C therapy in adult patients with sepsis: A rapid practice guideline

“…Our results are comparable to those of other recently published systematic reviews. Three of recent systematic reviews showed reduction in overall mortality with vitamin C mono‐ or combination‐therapy, but certainty of evidence was evaluated as very low, 6 low, 2 or moderate 4 . Other studies did not find firm evidence for a difference in mortality 1,3,5 .…”

“…Given its antioxidant properties, researchers hypothesize that vitamin C may attenuate the systemic response to infection that results in organ failure and poor patient outcomes in sepsis. Few interventions in the critically ill population have gained as much attention as vitamin C, with at least six systematic reviews published during the last year alone 1–6 …”

“…Few interventions in the critically ill population have gained as much attention as vitamin C, with at least six systematic reviews published during the last year alone. [1][2][3][4][5][6] Despite a proliferation of studies, vitamin C's effect on the outcomes of patients with sepsis has been unclear. Studies have reached contradictory results, with recent high-quality trials not confirming previously described benefits of vitamin C. [7][8][9][10] Moreover, the largest study published to date suggested harm from vitamin C in the composite outcome of death or persistent organ dysfunction.…”

Vitamin C in critical illness: end of the story or still a place?

“…Interestingly, the authors suggested harmful effects, whereas the respective analyzed data (five RCTs, 1722 patients) did not support this finding [28 ▪▪ ]. Most recently, Lee et al published their SRMA with 16 RCTs (2130 patients), including the RCTs mentioned above [29 ▪▪ ]. They showed a significantly reduced overall mortality in patients receiving vitamin C monotherapy.…”