Effect of Ascorbic Acid, Corticosteroids, and Thiamine on Organ Injury in Septic Shock

Abstract

The combination of ascorbic acid, corticosteroids, and thiamine has been identified as a potential therapy for septic shock.OBJECTIVE To determine whether the combination of ascorbic acid, corticosteroids, and thiamine attenuates organ injury in patients with septic shock. DESIGN, SETTING, AND PARTICIPANTS Randomized, blinded, multicenter clinical trial of ascorbic acid, corticosteroids, and thiamine vs placebo for adult patients with septic shock. Two hundred five patients were enrolled between February 9, 2018, and October 27, 2019, at 14 centers in the United States. Follow-up continued until November 26, 2019.INTERVENTIONS Patients were randomly assigned to receive parenteral ascorbic acid (1500 mg), hydrocortisone (50 mg), and thiamine (100 mg) every 6 hours for 4 days (n = 103) or placebo in matching volumes at the same time points (n = 102). MAIN OUTCOMES AND MEASURESThe primary outcome was change in the Sequential Organ Failure Assessment (SOFA) score (range, 0-24; 0 = best) between enrollment and 72 hours. Key secondary outcomes included kidney failure and 30-day mortality. Patients who received at least 1 dose of study drug were included in analyses. RESULTS Among 205 randomized patients (mean age, 68 [SD,15] years; 90 [44%] women), 200 (98%) received at least 1 dose of study drug, completed the trial, and were included in the analyses (101 with intervention and 99 with placebo group). Overall, there was no statistically significant interaction between time and treatment group with regard to SOFA score over the 72 hours after enrollment (mean SOFA score change from 9.1 to 4.4 [−4.7] points with intervention vs 9.2 to 5.1 [−4.1] points with placebo; adjusted mean difference, −0.8; 95% CI, −1.7 to 0.2; P = .12 for interaction). There was no statistically significant difference in the incidence of kidney failure (31.7% with intervention vs 27.3% with placebo; adjusted risk difference, 0.03; 95% CI, −0.1 to 0.2; P = .58) or in 30-day mortality (34.7% vs 29.3%, respectively; hazard ratio, 1.3; 95% CI, 0.8-2.2; P = .26). The most common serious adverse events were hyperglycemia (12 patients with intervention and 7 patients with placebo), hypernatremia (11 and 7 patients, respectively), and new hospital-acquired infection (13 and 12 patients, respectively). CONCLUSIONS AND RELEVANCEIn patients with septic shock, the combination of ascorbic acid, corticosteroids, and thiamine, compared with placebo, did not result in a statistically significant reduction in SOFA score during the first 72 hours after enrollment. These data do not support routine use of this combination therapy for patients with septic shock.

Reactive Oxygen Species Interact With NLRP3 Inflammasomes and Are Involved in the Inflammation of Sepsis: From Mechanism to Treatment of Progression

“…For example, a clinical trial showed that a 96 h infusion of vitamin C did not result in an improvement of the sequential organ failure assessment score, or alter biomarkers of inflammation and vascular injury in sepsis patients (FowlerIII, Truwit et al, 2019). Similar studies also showed that ascorbic acid did not result in a statistically significant reduction in sequential organ failure assessment score during the first 72 h in patients with septic shock (Moskowitz et al, 2020). At least the previous clinical data did not reveal a negative or harmful effect of vitamin C, which indicates the safety of its use.…”

Mortality in septic patients treated with vitamin C: a systematic meta-analysis

“…Vitamin C represents an inexpensive and easily accessible drug that is considered safe even at extremely high doses (up to 710 mg/kg/day for up to 8 weeks) [ 9 , 52 ]. Interestingly, six studies reported no adverse events related to the intervention [ 9 – 11 , 19 , 20 , 24 ], while three studies documented more frequent adverse events in patients treated with intravenous vitamin C (hypernatremia n = 24, hospital-acquired infections n = 14, hyperglycemia n = 13, gastrointestinal bleeding n = 3, and fluid overload n = 1) [ 14 , 21 , 25 ]. The remaining eight studies did not specifically address this issue [ 12 , 13 , 15 – 18 , 22 , 23 ].…”

“…1 . The same investigators screened the search results according to the title and abstract, reviewed the full-text articles, considered the study for inclusion, and extracted appropriate data from the publications [ 8 – 25 , 33 – 45 ].

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“…As a consequence, potential beneficial or detrimental effects could not be sustainably determined by previously published meta-analyses due to divergent patient subsets, heterogenous interventions, and limited numbers of studies included [ 26 – 28 ]. Notably, only in 2020, eight new large clinical trials were published supporting the high interest and relevance of this topic [ 13 , 14 , 16 , 20 – 22 , 24 , 25 ]. However, consistent data on the effects on mortality of septic patients treated with intravenous vitamin C are still lacking.…”

Forty‐Fourth ASPEN Presidential Address: The 2020 Overture—A New Tune for the Future

“…Questions about its reproducibility and generalizability require further investigation. Since then, a number of follow‐up trials using various study designs have been published and showed conflicting results 60–65 . For example, the VITAMIN Open‐Label Trial failed to demonstrate any survival benefits or reduced need for vasopressors 60 .…”