Pilot trial of high-dose vitamin C in critically ill COVID-19 patients

Abstract

Background: Few specific medications have been proven effective for the treatment of patients with severe coronavirus disease 2019 (COVID-19). Here, we tested whether high-dose vitamin C infusion was effective for severe COVID-19.

Methods: This randomized, controlled, clinical trial was performed at 3 hospitals in Hubei, China. Patients with confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in the ICU were randomly assigned in as 1:1 ratio to either the high-dose intravenous vitamin C (HDIVC) or the placebo. HDIVC group received 12 g of vitamin C/50 ml every 12 h for 7 days at a rate of 12 ml/hour, and the placebo group received bacteriostatic water for injection in the same way within 48 h of arrival to ICU. The primary outcome was invasive mechanical ventilation-free days in 28 days (IMVFD28). Secondary outcomes were 28-day mortality, organ failure (Sequential Organ Failure Assessment (SOFA) score), and inflammation progression (interleukin-6).

Results: Only 56 critical COVID-19 patients were ultimately recruited due to the early control of the outbreak. There was no difference in IMVFD28 between two groups (26.0 [9.0-28.0] in HDIVC vs 22.0 [8.50-28.0] in control, p = 0.57). HDIVC failed to reduce 28-day mortality (P = 0.27). During the 7-day treatment period, patients in the HDIVC group had a steady rise in the PaO₂/FiO₂ (day 7: 229 vs. 151 mmHg, 95% CI 33 to 122, P = 0.01), which was not observed in the control group. IL-6 in the HDIVC group was lower than that in the control group (19.42 vs. 158.00; 95% CI -301.72 to -29.79; P = 0.04) on day 7.

Conclusion: This pilot trial showed that HDIVC failed to improve IMVFD28, but might show a potential signal of benefit in oxygenation for critically ill patients with COVID-19 improving PaO2/FiO2 even though.

Keywords: Coronavirus disease 2019; High-dose intravenous vitamin C; Severe acute respiratory syndrome coronavirus 2.

Fig. 1

Flowchart of patients. HDIVC high-dose intravenous vitamin C

Fig. 2

The IMVFD28 in high-dose intravenous vitamin C and placebo group. The IMVFD28 was 26.0 days[9.0–28.0] in HDIVC, and 22.0 days[8.5–28.0] in placebo group, but this difference was not statistically significant (P = 0.57, CI 4.8[-4.7 to 7.2]). IMV invasive mechanical ventilation, HDIVC high-dose intravenous vitamin C

Fig. 3

The 28-day mortality from randomization (day 1) to day 28. a Kaplan–Meier analysis was used to estimate the 28-day mortality, and survival curves were compared with the Wilcoxon test (P = 0.27) among patients with COVID-19. Cox regression was used for multiple comparisons (P = 0.31, HR, 0.50 [95% CI 0.2 to 1.8]). b Kaplan–Meier analysis was used to estimate the 28-day mortality and survival curves were compared with the Wilcoxon test (P = 0.06) among severe COVID-19 patients (baseline SOFA score ≥ 3). Cox regression was used as multiple comparisons (P = 0.07, HR, 0.32 [95% CI 0.10–1.06]). HDIVC high-dose intravenous vitamin C, COVID-19 coronavirus disease 2019, SOFA Sequential Organ Failure Assessment

Fig. 4

P/F and SOFA scores following high-dose intravenous vitamin C treatment. a The bars show the standard deviation (SD) of the mean. The P/F in both groups was approximately 200 at enrollment. After initiation of treatment, there was a steady rise in the P/F in the HDIVC group and a decline in the P/F in the placebo group (day 3: 217 vs. 189, 95% CI -34 to 90, P = 0.37; day 7: 229 vs. 151, 95% CI 33 to 122, P = 0.01). b △7 of P/F means the difference between the value from Day1 to Day7. Boxes represent the median and interquartile range (25th and 75th percentiles), and whiskers represent the range of values. The delta P/F ratio showed a different result in two groups (20.0 ± 96.68 vs. -51.88 ± 150.72, P = 0.04, 41.02 (5.92–172.45)). △7 was calculated by the difference between the value from Day 1 to Day 7. c The bars showed the interquartile range (IQR) of the median. There was no difference in the initial Sequential Organ Failure Assessment (SOFA) scores of the 2 groups at baseline (vitamin C vs placebo, median, 3.5[3.0–6.8] vs 2.0 [3.0–5.0]). After 7-day treatment, the median of SOFA score increased from 2.0 to 6.0 in the placebo group and slightly decreased from 3.5 to 3.0 in the HDIVC group, but there was no difference between the 2 groups. d △7 of SOFA scores means the difference between the value from Day1 to Day7. Boxes represent the median and interquartile range (25th and 75th percentiles), and whiskers represent the range of values. The delta SOFA scores showed no significant difference in two groups (0.0[-2.75-1.0] vs. 0.0[-1.0-3.5], P = 0.25, CI -1.35(-3.04-0.34)). △7 was calculated by the difference between the value from Day 1 to Day 7. HDIVC high-dose intravenous vitamin C, SOFA Sequential Organ Failure Assessment, P/F PaO₂/FiO₂COVID-19 coronavirus disease 2019