Table 2.
Studies in critical illness using vitamin C in combination therapy
| Study/design | Patient, n (intervention/control) | Protocol | Important clinical outcomes |
|---|---|---|---|
| Nathens et al. (2002);33 RCT | Critically ill surgical patients, n = 595 (301/294) | VitC and alpha-tocopherol vs. placebo; VitC 1000 mg q8 h until discharge from ICU or 28 days (whichever was shorter) | Decreased multiple organ failure, reduction of TNF-α, IL-1β, IL-6; decreased ICU and hospital stay, and increased ventilator-free days in the treatment arm |
| Marik et al. (2017);27 before–after retrospective | Severe sepsis or septic shock and PCT >2 ng/mL; n = 94 (47/47 | HAT therapy (HCT 50 mg q6 h × 7 d; VitC 1.5 g IV q6 h × 4 days or until ICU discharge, thiamine 200 mg q12 × 4 d) vs. control | Mortality reduction; 8.5% mortality in treatment arm vs. 40.4% in control arm, p < 0.001; median 72 h PCT, SOFA scores, vasopressor requirements decreased in the treatment arm |
| Fujii et al. (2020) VITAMINS trial;36 RCT | Septic shock, n = 211 (107/104) | HAT therapy (identical to Marik) vs. hydrocortisone alone | No difference in 28- or 90-day mortality or vasopressor-free days |
| Moskowitz et al. (2020) ACTS trial;37 RCT | Septic shock, n = 205 (103/102) | HAT therapy vs. placebo; HCT 50 mg, VitC 1.5 g IV, thiamine 100 mg q6 4 d | No difference in SOFA score over 72 h, the incidence of kidney failure, 30-day mortality |
| Iglesias et al. (2020) ORANGES trial;40 RCT | Sepsis and septic shock; n = 137 (68/69) | HAT therapy (identical to Marik) vs. placebo | Vasopressor time (resolution of shock) reduced in HAT arm (27 ± 22 vs. 53 ± 38 h, p < 0.001); no significant differences ICU and hospital mortality, ICU and hospital LOS, ventilator-free days, and PCT |
| Chang et al. (2020) HYVCTTSSS trial;39 RCT | Sepsis and septic shock; n = 80 (40/40) | HAT therapy (identical to Marik) vs. placebo | Terminated early (underpowered). No mortality benefit. Improvement of 72-h change in SOFA score (p = 0.02). Treatment group > incidents of hypernatremia (p = 0.005). In prespecified subgroup analysis, patients in the treatment subgroup diagnosed with sepsis within 48 h showed lower mortality than the control subgroup (p = 0.02) |
| Wald et al. (2020);5 retrospective, propensity-scored matched analysis | Septic shock requiring vasopressors; n = 557 (47 HAT arm/181 hydrocortisone arm/333 control arm) | HAT therapy arm vs. hydrocortisone arm vs. control arm (standard care); HCT 50 mg/m2/day divided every 6 hours VitC 30 mg/kg/dose q6 h × 4 d up to 1500 mg/dose, thiamine 4 mg/kg/day divided BID | Mortality reduction, HAT therapy vs. matched untreated controls at 30 days (9 vs. 28%, p = 0.03) and 90 days (14 vs. 35%, p = 0.02). HAT therapy vs. matched hydrocortisone only patients (9% vs. 28%, p = 0.03) and 90 days (14 vs. 33%, p = 0.04) |
| Sevransky et al. (2021) VICTAS trial;38 RCT | Septic shock, n = 501 (252/249) | HAT therapy vs. placebo; HCT 50 mg, VitC 1.5 g IV, thiamine 100 mg q6 4 d | No increase in ventilator- and vasopressor-free days within 30 days. However, the trial was terminated early and may have been underpowered to detect a clinically important difference |
HAT hydrocortisone, ascorbic acid, thiamine therapy, HCT hydrocortisone, VitC vitamin C, LR lactated ringers, PCT procalcitonin, RCT, randomized control trial, ICU intensive care unit, [m]SOFA [modified] Sequential Organ Failure Assessment, BSA body surface area, CRP C-reactive protein.