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

November 22, 2022 updated by: University of Malaya

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

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.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Anticipated)

34

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • Malaysia
      • Kuala Lumpur, Malaysia, 50586
        • Recruiting
        • Hospital Kuala Lumpur
        • Contact:
        • Contact:
        • Principal Investigator:
          • Chai Siew Cheng, MD
      • Kuala Lumpur, Malaysia, 59100
        • Recruiting
        • University of Malaya Medical Centre
        • Contact:
        • Contact:
        • Principal Investigator:
          • Alizan B Abdul Khalil, MBBS
    • Kelantan
      • Kubang Kerian, Kelantan, Malaysia, 16150
        • Not yet recruiting
        • Hospital Universiti Sains Malaysia
        • Contact:
        • Contact:
          • Wan Azman Wan Sulaiman, MD
          • Phone Number: +6097676894
          • Email: wazman@usm.my
        • Principal Investigator:
          • Wan Azman Wan Sulaiman, MD

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: TREATMENT
  • Allocation: RANDOMIZED
  • Interventional Model: PARALLEL
  • Masking: DOUBLE

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
EXPERIMENTAL: Parenteral Ascorbic Acid
Intravenous ascorbic acid 1 gram 8 hourly (3 grams per day) for 7 days
Drug: Intravenous Ascorbate
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.
Other Names:
  • Ascorbic Acid Injection
PLACEBO_COMPARATOR: 0.9% Normal Saline
Intravenous 0.9% normal saline 10 mL 8 hourly for 7 days
Drug: Normal Saline 10 mL Injection
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.
Other Names:
  • 0.9% Normal Saline

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Oxidative stress biomarker: Plasma isoprostane level
Time Frame: Change from preoperative baseline level at day 5 of infusion (post-operative)
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)
Time Frame: Change from preoperative baseline level at day 5 of infusion (post-operative)
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
Time Frame: Change from preoperative baseline level at day 5 of infusion (post-operative)
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 Outcome Measures

Outcome Measure
Measure Description
Time Frame
Inflammatory biomarkers levels: Leucocytes counts
Time Frame: Change from preoperative baseline level at day 5 of infusion (post-operative)
Leucocytes count will be measured through flow cytometry White blood cells Differential Fluorescence (WDF) scattergram using Sysmex XN-10 (Sysmex Corporation TM , Kobe, Japan) and expressed in unit of X10^9/L.
Change from preoperative baseline level at day 5 of infusion (post-operative)
Inflammatory biomarkers levels: Gene expression of TNF-α
Time Frame: Change from preoperative baseline level at day 5 of infusion (post-operative)
The expression of TNF-α 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)
Inflammatory biomarkers levels: Gene expression of IL-1
Time Frame: Change from preoperative baseline level at day 5 of infusion (post-operative)
The expression of IL-1 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)
Post-operative outcomes: Flap viability
Time Frame: From post-operative day 1 until day 14 (2 weeks)

Flap viability is the survival of flap without tissue loss. For flap viability assessment, total flap loss is defined as complete necrosis (death) of flap (100% flap loss), whilst partial flap loss refers to incomplete necrosis of flap. By using simple tracing technique, the percentage of flap necrosis is calculated as:

[Necrotic flap surface area (cm^2)/Total flap surface area (cm^2)] × 100%
From post-operative day 1 until day 14 (2 weeks)
Post-operative outcomes: Wound dehiscence
Time Frame: From post-operative day 1 until day 14 (2 weeks)
Surgical wound dehiscence is defined as separation of the margins of a closed surgical incision that has been made in skin, with or without exposure or protrusion of underlying tissue, organs or implants. Wound dehiscence is assessed upon suture removal. It is categorized as either partial (1-99%) or complete (100%), depending on the depth/thickness of skin layers involvement. Partial wound dehiscence is defined as separation of wound edge up to level of epidermis and dermis layer of sutured wounds, whereas complete wound dehiscence refers to complete separation of wound edge involving the full thickness of skin. The percentage of wound dehiscence in relative to the total wound size is calculated.
From post-operative day 1 until day 14 (2 weeks)
Post-operative outcomes: Graft loss
Time Frame: From post-operative day 1 until day 14 (2 weeks)

Skin graft recipient area is inspected at post-operative day 5 for assessment of graft take. Graft loss is categorized as partial (1-99%) or complete (100%). The percentage of skin graft failure to take/loss is calculated as:

[Graft failure to take or loss surface area (cm^2)/Total skin graft area surface area (cm^2)] X 100%
From post-operative day 1 until day 14 (2 weeks)
Post-operative outcomes: Wound infection
Time Frame: From post-operative day 1 until day 14 (2 weeks)

Wound infection is defined by presence of clinical sign and symptoms of infection associated with wound, including:

i) Local signs: Erythema - localized or spreading (cellulitis); Pus/purulent or haemopurulent exudate; Abscess; Swelling/induration; Local warmth; Malodour; Crepitus; Dehiscence; Unexpected pain or tenderness.

ii) Systemic signs: Malaise; Loss of appetite; Pyrexia or hypothermia; Tachycardia; Tachypnoea; Elevated C-reactive protein (CRP); Elevated or suppressed white blood cell count; Sepsis or Septic Shock.
From post-operative day 1 until day 14 (2 weeks)

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Malaya

Investigators

  • Principal Investigator: Raymond Yii Shi Liang, MBBS, University of Malaya Medical Centre

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (ACTUAL)

September 25, 2022

Primary Completion (ANTICIPATED)

July 31, 2023

Study Completion (ANTICIPATED)

July 31, 2023

Study Registration Dates

First Submitted

March 28, 2022

First Submitted That Met QC Criteria

April 6, 2022

First Posted (ACTUAL)

April 14, 2022

Study Record Updates

Last Update Posted (ACTUAL)

November 25, 2022

Last Update Submitted That Met QC Criteria

November 22, 2022

Last Verified

November 1, 2022

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • MECID No,UMMC: 202086-8956
  • PV042-2021 (OTHER_GRANT: UMSC C.A.R.E)
  • NMRR-21-1378-60482 (IIR) (OTHER: MOH Malaysia)
  • USM/JEPeM/21070522 (OTHER: USM Malaysia)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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