Effectiveness of IV Vitamin C in Reducing Oxidative Stress Associated With Free Flap Surgery

NCT05327348 | Unknown Phase 3

• 4 other identifiers: MECID No,UMMC: 202086-8956PV042-2021NMRR-21-1378-60482 (IIR)USM/JEPeM/21070522
• Study Type: interventional
• Target: 34
• Locations: 1 country
• Sites: 3

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.

Conditions

Oxidative Stress; Ischemia-reperfusion Injury

Keywords

Free Flap Reconstructive Surgery; Perioperative Parenteral Ascorbic Acid

Outcome Measures

Primary Outcomes (3)

• Oxidative stress biomarker: Plasma isoprostane level

  Plasma isoprostane level will be analyzed using a competitive ELISA assay and expressed in unit of pg/ml.

  Change from preoperative baseline level at day 5 of infusion (post-operative)

• Oxidative stress biomarker: Gene expression of glutamate-cystein ligase (GCL)

  The expression of glutamate cysteine ligase (GCL) will be quantitated using real time quantitative polymerase chain reaction (qRT-CR). The differences in gene expression, expressed as fold-change, will be calculated using the 2 -DΔCt algorithm where GAPDH will be used as the housekeeping gene.

  Change from preoperative baseline level at day 5 of infusion (post-operative)

• Oxidative stress biomarker: Total glutathione level

  Total glutathione level (GSSG + GSH) will be determined using a Glutathione Assay Kit, which will be expressed in unit of µM.

  Change from preoperative baseline level at day 5 of infusion (post-operative)

Secondary Outcomes (7)

• Inflammatory biomarkers levels: Leucocytes counts

  Change from preoperative baseline level at day 5 of infusion (post-operative)

• Inflammatory biomarkers levels: Gene expression of TNF-α

  Change from preoperative baseline level at day 5 of infusion (post-operative)

• Inflammatory biomarkers levels: Gene expression of IL-1

  Change from preoperative baseline level at day 5 of infusion (post-operative)

• Post-operative outcomes: Flap viability

  From post-operative day 1 until day 14 (2 weeks)

• Post-operative outcomes: Wound dehiscence

  From post-operative day 1 until day 14 (2 weeks)

Study Arms (2)

Parenteral Ascorbic Acid

EXPERIMENTAL

Intravenous ascorbic acid 1 gram 8 hourly (3 grams per day) for 7 days

Drug: Intravenous Ascorbate

0.9% Normal Saline

PLACEBO COMPARATOR

Intravenous 0.9% normal saline 10 mL 8 hourly for 7 days

Drug: Normal Saline 10 mL Injection

Interventions

Intravenous Ascorbate DRUG

Intravenous ascorbic acid 1 gram 8 hourly (3 grams per day) over 15 minutes for 7 days since pre-operative day 1 until post-operative day 5.

Also known as: Ascorbic Acid Injection

Parenteral Ascorbic Acid

Normal Saline 10 mL Injection DRUG

Intravenous 0.9% normal saline 8 hourly bolus infusion over 15 minutes for 7 days since pre-operative day 1 until post-operative day 5.

Also known as: 0.9% Normal Saline

0.9% Normal Saline

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

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

You may not qualify if:

• 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

Sponsors & Collaborators

• University of Malaya: lead

Study Sites (3)

Hospital Universiti Sains Malaysia

Kubang Kerian, Kelantan, 16150, Malaysia

NOT YET RECRUITING

Hospital Kuala Lumpur

Kuala Lumpur, 50586, Malaysia

RECRUITING

University of Malaya Medical Centre

Kuala Lumpur, 59100, Malaysia

RECRUITING

Related Publications (13)

• 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.

  PMID: 30589864 BACKGROUND

• 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.

  PMID: 18617006 BACKGROUND

• 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.

  PMID: 15378577 BACKGROUND

• 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.

  BACKGROUND

• 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.

  PMID: 21953354 BACKGROUND

• 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.

  PMID: 26351497 BACKGROUND

• 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.

  PMID: 17559880 BACKGROUND

• 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.

  PMID: 24365194 BACKGROUND

• 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.

  PMID: 7880053 BACKGROUND

• 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.

  PMID: 24484547 BACKGROUND

• 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.

  PMID: 20628650 BACKGROUND

• 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.

  PMID: 23670640 BACKGROUND

• 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.

  PMID: 25848948 BACKGROUND

MeSH Terms

Conditions

Reperfusion Injury

Interventions

Ascorbic Acid; Saline Solution; Injections

Condition Hierarchy (Ancestors)

Vascular Diseases; Cardiovascular Diseases; Postoperative Complications; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Sugar Acids; Acids, Acyclic; Carboxylic Acids; Organic Chemicals; Hydroxy Acids; Carbohydrates; Crystalloid Solutions; Isotonic Solutions; Solutions; Pharmaceutical Preparations; Drug Administration Routes; Drug Therapy; Therapeutics

Study Officials

• Raymond Yii Shi Liang, MBBS

  University of Malaya Medical Centre

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Raymond Yii Shi Liang, MBBS

CONTACT

+60379494422; raymond.yii@ummc.edu.my

Alizan B Abdul Khalil, MBBS

CONTACT

+60379494422; alizankhalil@gmail.com

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 28, 2022
• First Posted: April 14, 2022
• Study Start: September 25, 2022
• Primary Completion: July 31, 2023
• Study Completion: July 31, 2023
• Last Updated: November 25, 2022

Record last verified: 2022-11

Data Sharing

• IPD Sharing: Will not share

Locations

MY (3)