Clinical trial NCT05327348: Effectiveness of IV Vitamin C in Reducing Oxidative Stress Associated With Free Flap Surgery
Official title: The Efficacy of Perioperative Parenteral Ascorbic Acid in Reducing Oxidative Stress Among Patients Undergoing Free Flap Reconstructive Surgery: A Prospective Multicenter Randomized Controlled Pilot Trial
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: Oxidative Stress
Ischemia-reperfusion Injury
Keywords: Free Flap Reconstructive Surgery
Perioperative Parenteral Ascorbic Acid
Lead sponsor: University of Malaya
Sponsor class: OTHER
First posted: 2022-04-14
Enrollment: 34
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Ischemia and reperfusion injury during free flap reconstructive surgery creates a state of increased oxidative stress that can adversely affect the flap outcomes. Ascorbic acid (AA) had been proven to have beneficial effect on end-organ protection and flap survival from ischemia-reperfusion injury via its antioxidant properties.

The investigators hypothesise that perioperative parenteral ascorbic acid treatment may reduce oxidative stress among participants undergoing free flap reconstructive surgery along with reduction in inflammatory markers, improved rate of flap viability and wound healing at both donor and recipient sites.

Detailed description: 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.

Eligibility criteria: Inclusion Criteria:

- Adults (age 18 years and older, male or female) who are planned for elective free flap reconstructive surgery.

Exclusion Criteria:

* Hypersensitivity to vitamin C
* Oliguria (urine output \<400mL/day) or anuria (urine output \<100mL/day)
* Renal failure (serum creatinine level ≥175.0 %mol/L)
* Hemodialysis
* Renal calculi
* Thalassemia
* Glucose-6-phosphate dehydrogenase (G6PD) deﬁciency
* Unfit for surgery
* Pregnancy or lactating
* Hemochromatosis
* Hyperoxaluria

Primary outcomes:
measure: Oxidative stress biomarker: Plasma isoprostane level
timeFrame: Change from preoperative baseline level at day 5 of infusion (post-operative)
measure: Oxidative stress biomarker: Gene expression of glutamate-cystein ligase (GCL)
timeFrame: Change from preoperative baseline level at day 5 of infusion (post-operative)
measure: Oxidative stress biomarker: Total glutathione level
timeFrame: Change from preoperative baseline level at day 5 of infusion (post-operative)
Secondary outcomes:
measure: Inflammatory biomarkers levels: Leucocytes counts
timeFrame: Change from preoperative baseline level at day 5 of infusion (post-operative)
measure: Inflammatory biomarkers levels: Gene expression of TNF-α
timeFrame: Change from preoperative baseline level at day 5 of infusion (post-operative)
measure: Inflammatory biomarkers levels: Gene expression of IL-1
timeFrame: Change from preoperative baseline level at day 5 of infusion (post-operative)
measure: Post-operative outcomes: Flap viability
timeFrame: From post-operative day 1 until day 14 (2 weeks)
measure: Post-operative outcomes: Wound dehiscence
timeFrame: From post-operative day 1 until day 14 (2 weeks)
measure: Post-operative outcomes: Graft loss
timeFrame: From post-operative day 1 until day 14 (2 weeks)
measure: Post-operative outcomes: Wound infection
timeFrame: From post-operative day 1 until day 14 (2 weeks)
Other outcomes:
Locations:
city: Kubang Kerian
country: Malaysia
facility: Hospital Universiti Sains Malaysia
state: Kelantan
city: Kuala Lumpur
country: Malaysia
facility: Hospital Kuala Lumpur
city: Kuala Lumpur
country: Malaysia
facility: University of Malaya Medical Centre
Study officials:
affiliation: University of Malaya Medical Centre
name: Raymond Yii Shi Liang, MBBS
role: PRINCIPAL_INVESTIGATOR
References:
citation: Ballestin A, Casado JG, Abellan E, Vela FJ, Alvarez V, Uson A, Lopez E, Marinaro F, Blazquez R, Sanchez-Margallo FM. Ischemia-reperfusion injury in a rat microvascular skin free flap model: A histological, genetic, and blood flow study. PLoS One. 2018 Dec 27;13(12):e0209624. doi: 10.1371/journal.pone.0209624. eCollection 2018.
citation: Schafer M, Werner S. Oxidative stress in normal and impaired wound repair. Pharmacol Res. 2008 Aug;58(2):165-71. doi: 10.1016/j.phrs.2008.06.004. Epub 2008 Jun 19.
citation: Siemionow M, Arslan E. Ischemia/reperfusion injury: a review in relation to free tissue transfers. Microsurgery. 2004;24(6):468-75. doi: 10.1002/micr.20060.
citation: Stepanovs J, Ozoliņa A, Rovīte V, Mamaja B, Vanags I. Factors Affecting the Risk of Free Flap Failure in Microvascular Surgery. Proc Latv Acad Sci Sect B Nat Exact, Appl Sci. 2016;70(6):356-364. doi:10.1515/prolas-2016-0039.
citation: Tsai MS, Huang CH, Tsai CY, Chen HW, Lee HC, Cheng HJ, Hsu CY, Wang TD, Chang WT, Chen WJ. Ascorbic acid mitigates the myocardial injury after cardiac arrest and electrical shock. Intensive Care Med. 2011 Dec;37(12):2033-40. doi: 10.1007/s00134-011-2362-6. Epub 2011 Sep 28.
citation: Azari O, Kheirandish R, Azizi S, Farajli Abbasi M, Ghahramani Gareh Chaman S, Bidi M. Protective Effects of Hydrocortisone, Vitamin C and E Alone or in Combination against Renal Ischemia-Reperfusion Injury in Rat. Iran J Pathol. 2015 Fall;10(4):272-80.
citation: Lee WY, Lee JS, Lee SM. Protective effects of combined ischemic preconditioning and ascorbic acid on mitochondrial injury in hepatic ischemia/reperfusion. J Surg Res. 2007 Sep;142(1):45-52. doi: 10.1016/j.jss.2006.08.043. Epub 2007 Jun 7.
citation: Wang ZJ, Hu WK, Liu YY, Shi DM, Cheng WJ, Guo YH, Yang Q, Zhao YX, Zhou YJ. The effect of intravenous vitamin C infusion on periprocedural myocardial injury for patients undergoing elective percutaneous coronary intervention. Can J Cardiol. 2014 Jan;30(1):96-101. doi: 10.1016/j.cjca.2013.08.018.
citation: Zaccaria A, Weinzweig N, Yoshitake M, Matsuda T, Cohen M. Vitamin C reduces ischemia-reperfusion injury in a rat epigastric island skin flap model. Ann Plast Surg. 1994 Dec;33(6):620-3. doi: 10.1097/00000637-199412000-00010.
citation: Fowler AA 3rd, Syed AA, Knowlson S, Sculthorpe R, Farthing D, DeWilde C, Farthing CA, Larus TL, Martin E, Brophy DF, Gupta S; Medical Respiratory Intensive Care Unit Nursing; Fisher BJ, Natarajan R. Phase I safety trial of intravenous ascorbic acid in patients with severe sepsis. J Transl Med. 2014 Jan 31;12:32. doi: 10.1186/1479-5876-12-32.
citation: Padayatty SJ, Sun AY, Chen Q, Espey MG, Drisko J, Levine M. Vitamin C: intravenous use by complementary and alternative medicine practitioners and adverse effects. PLoS One. 2010 Jul 7;5(7):e11414. doi: 10.1371/journal.pone.0011414.
citation: Stephenson CM, Levin RD, Spector T, Lis CG. Phase I clinical trial to evaluate the safety, tolerability, and pharmacokinetics of high-dose intravenous ascorbic acid in patients with advanced cancer. Cancer Chemother Pharmacol. 2013 Jul;72(1):139-46. doi: 10.1007/s00280-013-2179-9. Epub 2013 May 14.
citation: Hoffer LJ, Robitaille L, Zakarian R, Melnychuk D, Kavan P, Agulnik J, Cohen V, Small D, Miller WH Jr. High-dose intravenous vitamin C combined with cytotoxic chemotherapy in patients with advanced cancer: a phase I-II clinical trial. PLoS One. 2015 Apr 7;10(4):e0120228. doi: 10.1371/journal.pone.0120228. eCollection 2015.