Primary outcomes
Regarding the measured primary outcomes after adjustment to its baseline, ASTRALI group showed significant reductions of median adjusted change % of CRP (-54.2% Vs. -48.2%, p= 0.049) and IL-8 (-71.3% Vs -7.2 %, p< 0.0001) levels than control group. ASTRALI group also showed significant elevations of median adjusted change % of IL-10 (170.2% Vs. 34.4%, p= 0.049) and SOD (58.9% Vs -20.8%, p< 0.0001). Both groups showed comparable median adjusted change % after treatment of IL-1β (p= 0.441) and MDA (p= 0.167). These findings were supported by reports that showed that incubation of high concentration ascorbic acid with peripheral blood lymphocytes increased generation of IL-10 and similar IL-1β. (20) Also, the role of high dose ascorbic acid is well identified in sepsis patients to reduce oxidative stress, inflammatory reactions, endovascular, and immunologic dysfunctions. (42)
Zhang et al. (2021) trial, critically ill COVID-19 patients were assigned to receive placebo or 24 gm daily IV infusion of ascorbic acid for 1 week. Although ascorbic acid group showed significantly reduced pro-inflammatory IL-6 levels (19.4 [95%CI: 10.6-29.2]) than control group (158 [95%CI: 15.3-259.6]), results failed to show differences in CRP levels at days 3 or 7. This failure to show improvement in in CRP levels may be due to advanced COVID-19 that were present before ARDS progression.
In CITRIS-ALI trial (2019), patients with septic ARDS were enrolled to receive 50mg/Kg IV ascorbic acid every 6 hrs or placebo for 96 hr. CRP levels showed no statistical difference (54.1 vs 46.1 μg/mL,p =0.33). (43) Although this trial is considered the one of the most promising trials that supposed to show benefits of high dose ascorbic acid for critically ill patients. The primary outcome of the study was the difference in SOFA score at T96. The results of this trial were criticized due to some statistical problems such as Neyman’s bias and survivorship bias. These problems lead to underestimation of the true benefits of ascorbic acid. Patients’ selection is also questioned because 32% of patients are transferred from another health care facilities. This latency period could alter measuring the outcomes. Finally, plasma VC levels do not fit well with the reported changes of CRP. (44)