Safety and adverse events
Regarding safety and tolerability of the high dose ascorbic acid, median
of VC levels of ASTRALI group were significantly higher than control at
T48 (p< 0.0001), T96 (p< 0.0001) and
T120 (p< 0.0001). At T144, VC levels returned to normal
with was no statistically significant difference between the two groups
(p= 0.739). (Figure 3) The two only reported adverse effects were
hypernatremia and AKI, with similar distributions across groups (p
>0.05).
In a recent pharmacokinetic trial, IV 10 gm/d ascorbic acid bolus or
continuous infusion showed varying decrease in VC levels in all groups
48 hrs after the end of infusion, and no significant difference in VC
level. This varying reduction may be due to differences in all
pharmacokinetic parameters. In patients without a history of
nephrolithiasis, the clinical relevance of hyperoxaluria and stone
formation is negligible. (53)
In phase I safety trial, 24 septic ICU patients were randomized to
receive IV ascorbic acid infusions every 6 hours for 4 days
as 50 mg/kg/d (n = 8), or 200 mg/kg/d (n = 8), or placebo (n = 8).
Patients were monitored for hypernatremia, hypotension, tachycardia, and
GI adverse effects. Mean baseline plasma VC levels for all patients were
17.9 ± 2.4 μM (normal 50-70 μM). Ascorbic acid infusion rapidly and
significantly raised plasma VC levels with no adverse events.
(51) In
Zhang et al. trial, daily infusion
of 24 gm ascorbic acid for 7 days was not associated with significant
incidence of AKI, liver injury, cardiac injury, septic shock, or
coagulation disorders. (35) In two other
trials, no ascorbic acid-related adverse events were identified.
(43, 49)
Reports showed that maintaining plasma VC levels in critically ill
patients requires increased frequency of dosing (4 times or continuous
infusion) due to impaired distribution volume and increased clearance.
There is currently no upper limit of IV dose, although nephrolithiasis
at doses > 100 gm was reported.
(54)
This study had several limitations. Although most of the primary
outcomes were significantly different, the small sample size used may
affect the significance of secondary outcomes, which may be more
clinically important. Some baseline characteristics were not equally
distributed across groups such as diabetes. Because one of our
enrollment sites was a hepatology center, 25% of patients were hepatic.
These deviations may affect the generalizability of our results to
general population of critically ill patients with TRALI. It was not
easy to enroll patients with TRALI. Although all possible means were
used to confirm the diagnosis of TRALI, we cannot guarantee that there
were no other forms of lung injury such as sepsis-induced ALI, ARDS or
TACO. TRALI is a very difficult diagnosis. About 21.3% of patients were
initially admitted with sepsis. Another 13.8% were trauma patients.
Although no patients were enrolled with lung contusions and no
radiological evidence of lung injury at the time of enrollment, both
conditions are risk factors for ARDS. In this study, we focused on
levels of pro-inflammatory and anti-inflammatory markers as primary
outcomes. We did not add more secondary outcomes to avoid the problems
of multiple testing and finding an outcome by chance. Organ failure
assessment was not followed-up, it was not the scope of this trial.