Temporary cessation of blood supply to the flap tissues from clamping of donor vascular
pedicle (ischemia) followed by restoration of flap tissue perfusion (reperfusion) after
micro-anastomosis are inevitable in any free flap surgery. In combination, the ischemia and
reperfusion process during free flap tissue transfers induce a state of increased oxidative
stress, which may lead to complications such as flap failure and non-healing wounds at either
donor or recipient sites. The negative impacts of which include additional wounds from flap
loss, higher costs and increased duration of hospital stay.
Previous studies had demonstrated the beneficial effects of ascorbic acid in end-organ
protection against ischemia and reperfusion injury. In addition, parenteral ascorbic acid has
been shown to be remarkably safe even at high dose in both clinical and nonclinical models.
Nonetheless, the data on efficacy of ascorbic acid in free flap survival in human is very
limited.
The aims of this prospective, multicentre, double-blind, randomized, placebo-controlled pilot
study are to measure the extent of oxidative stress in participants undergoing free flap
reconstructive surgery before and after administration of parenteral ascorbic acid; and to
evaluate its efficacy on modulation of inflammation, flap viability and wound healing.
Eligible participants will be randomized to receive 1 gram of parenteral ascorbic acid and
0.9% normal saline (as placebo) 8 hourly for 7 days (from pre-operative day 2 until
post-operative day 5). Blood sampling will be performed on day 0 (pre-operative), day 3
(post-operative day 1) and day 5 (post-operative day 3) of intravenous ascorbic acid or
placebo infusion for measurement of i) oxidative stress biomarkers, including isoprostane
level, gene expression of glutamate-cystein ligase (GCL) and total glutathione level) ii)
inflammatory markers, including leucocytes count and gene expression of TNF-α and IL-1.
Post-operative outcomes of free flap surgery, up to post-operative 14 days, including flap
viability, wound healing at both donor and recipient sites and duration of ICU and hospital
stay will be evaluated.
The investigators estimate that a total sample of 28 participants (14 on each arm) will be
necessary for 80% power to detect a 33% oxidative stress reduction with medium effect size
(0.5) at 5% level of significance (α) between treatment (intravenous ascorbic acid) and
placebo group (0.9% normal saline). A total of 34 participants are required to account for
20% of dropouts.
Primary analysis of this study utilizes an intention-to-treat approach and includes all
randomized participants undergoing elective free flap reconstructive surgery. The mean
difference between the baseline (pre-operative) and post-operative oxidative stress and
inflammatory levels will be analyzed and compared between the intravenous ascorbic acid and
placebo group using analysis of variance (ANOVA) for all normally distributed dataset whilst
the non-parametric Kruskal-Wallis test is used, if otherwise. The effect size of such
difference will be determined and compared. Subsequently, correlation between reduction of
oxidative stress and post-operative flap outcomes in the intravenous ascorbic acid group will
be evaluated. The secondary outcomes such as flap viability (percentage of flap necrosis),
wound healing at both recipient and donor sites (percentage of wound dehiscence and
percentage of skin graft failure to take/loss), duration of hospital and ICU stay and wound
infection rate will be presented as mean with standard deviation (SD) or median with
interquartile range (IQR) based on their normality distribution and are compared with
Student's t-test or Mann-Whitney U test.