Secondary outcomes
Regarding secondary outcomes, ASTRALI group showed significantly higher
median of P/F ratios only at T48 (p= 0.003), T72
(p< 0.0001) and T96 (p< 0.0001). ASTRALI
group showed significantly lower median of VP days (1 ± 4) than control
group (4 ± 5) (p= 0.013).
Both groups showed comparable medians of ICU stay (p= 0.649) and
MV days (p= 0.611). These findings are supported by the knowledge
of that ascorbic acid is a cofactor in the hydroxylase enzymes which are
involved in the synthesis of important catecholamines (such as
norepinephrine and vasopressin) and downregulation of hypoxia inducible
factor 1α. (20)
The small sample size used in the
current study may affect the significance of outcomes such as MV days,
because strong evidence that high dose IV ascorbic acid shortens MV days
in critically ill patients was identified in a meta-regression analysis
(2020). (45)
Zhang et al. (2021) showed sustained significant improvement of P/F
ratio of ascorbic acid group (228.5 ± 72.6) than control (150.7 ± 75.3)
(p= 0.01). (35) Saeidreza et al.
(2021) studied the effect of IV ascorbic acid (1.5 gm/ 6hrs for 5 days)
in COVID-19 patients. Results showed improved peripheral capillary
oxygen saturations in ascorbic acid arm over controls.
(46)
In Wang et al. (2019) meta-analysis, results showed that ascorbic acid
was associated with a decreased MV days, but whether this reflected
improved oxygenation was uncertain. (47)
Another meta-analysis in 2015 showed significant reduction of VP
requirements in critically ill patients.
(48) In Zabet et al. (2016) study, IV 25
mg/kg every 6 hrs ascorbic acid in septic shock patients showed lower MV
days (standardized mean difference, SMD = -0.73 [95% CI:
-1.5-0.04]) and reduced vasopressor requirements than control group
(49.64 ± 25.67 Vs. 71.57 ± 1.60
h, p = 0.007). (49)
In contrast, Matthew Li et al. (2021) did not to find any improvement in
VP use or ICU days in ascorbic acid group (1.5 gm/6 hrs) over controls
with COVID-19. (50) In
CITRIS-ALI trial (2019), ascorbic
acid group showed similar oxygenation index and VP use at T96 and T168
of follow up. (43) Also, Flower et al.
(2014) showed nearly similar MV days (SMD=0.15 [95% CI:
-0.70–1.000]) and VP requirements
(SMD= -0.49 [95% CI:
-1.35–0.37]) (51)
In terms of mortality, after Kaplan-Meier analysis, survival curves were
compared. ASTRALI group showed significantly higher 7-days survival than
control group (p= 0.007). Then, Cox regression was used as
multiple comparisons (HR= 0.305 [95% CI: 0.120–0.775],p = 0.008). ASTRALI group
was associated with 75.7% reduction of 7-days mortality (OR=0.243
[95% CI: 0.082 – 0.721], p= 0.011). This reduction in
mortality was partially explained by IL-10 levels after treatment as it
was associated with 6.1% reduction (OR=0.939
[95%
CI: 0.894 – 0.987],p= 0.013). Receiving ascorbic acid “ASTRALI group” was a fair
predictor for 7-days survival (AUROC=0.668, [95% CI: 0.538–0.797],p = 0.019). Also, post treatment IL-10 at a cut-off value of equal
or more than 19.55 pg/mL was a good predictor for 7-days survival
(AUROC=0.708, [95% CI: 0.584–0.831], p = 0.004).
This finding reflects that ascorbic acid may be associated with better
7-days survival via enhancing IL-10 levels in such patients Although our
findings showed short term mortality benefit, results failed to find
this mortality benefit after 28-days follow-up. This may be due to the
small sample size and long-term ICU complications evolved due to
heterogeneity in comorbidities between groups such as diabetes. The
prevalence of diabetes was nearly doubled in ASTRALI group than controls
(45% Vs. 20%) (p= 0.031).
CITRIS-ALI trial (2019) showed that 28-days mortality was lower in the
ascorbic acid group (29.8%) than placebo (46.3%) (p= 0.03).
Although this study failed to show different primary outcomes, the
Kaplan-Meier survival curves for the two groups were significantly
different (p= 0.01) in favor of ascorbic acid group than control.
(43) Wang et al. Meta-analysis (2019)
showed that IV 3-10 gm/day ascorbic acid for critically ill patients was
associated with reduced mortality (OR=0.25 [95% CI: 0.14–0.46)]).
(47) In Zabet et al. (2016) study, IV
ascorbic acid showed significantly reduced 28-days mortality than
control group (14.28% Vs. 64.28%, p = 0.009) (OR=0.09 [95%
CI: 0.01 – 0.59]). (49)
In contrast, Zhang et al. pilot trial (2021) showed no difference in
28-days mortality between ascorbic acid group (26 [95% CI:
9.0-28.0]) and control group (22 [95%CI: 8.50-28.0])
(p= 0.57). (35) But this trial
showed imbalanced sex distribution across groups. Control group was
supported with significantly positive fluid balance than ascorbic acid
group on day 3 (463 Vs. -240, p= 0.02). Also, treatment with high
dose ascorbic acid was started 10 days after symptoms.
Also, Matthew Li et al. (2021) showed increased in-hospital mortality in
ascorbic acid group (88% Vs. 79%, p= 0.049) than control group.
(50) But this study had several
limitations starting from very small size (n=8 for ascorbic acid group
and n=24 for control), retrospective design, and bias liable design.
Very late ascorbic acid treatment was initiated, and heterogeneity of
baseline characteristics was extended even after propensity score
matching to form a control group.
Ferrón-Celma et al. (2009), studied the effect of IV 450 mg/d ascorbic
acid in septic Patients after abdominal surgery. No difference was
detected in 7-days mortality (OR=2.25 [95% CI: 0.38 – 13.47]).
(52) In addition to the small dose of
ascorbic acid used, this study had very small sample size (n=10) and
blinding of outcomes assessment was not clear.