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)