Ascorbic Acid to Prevent Postreperfusion Syndrome in Liver Transplantation (VITACTOH)

Intravenous Vitamin C for the Prevention of Postreperfusion Syndrome in Orthotopic Liver Transplantation From Deceased Donors

The goal of this clinical trial is to test the efficacy of intravenous ascorbic acid in preventing the postreperfusion syndrome in liver transplantation. The main questions it aims to answer are:

• Can intravenous ascorbic acid prevent postreperfusion syndrome in liver transplantation ?
• Can ascorbic acid decrease the incidence of liver graft dysfunction after liver transplantation?
• Can ascorbic acid decreased the incidence of postoperative complications after liver transplantation ?

Participants will receive 1.5 g of intravenous ascorbic acid diluted in 100 ml of saline or 100 ml of saline alone, during the anhepatic phase of liver transplantation before reperfusion of the new graft.

Researchers will compared the incidence of postreperfusion syndrome in both groups.

Study Overview

• Status: Recruiting
• Conditions: Liver Transplantation; Ascorbic Acid; Postreperfusion Syndrome
• Intervention / Treatment: Drug: Ascorbic acid; Drug: 0.9% Saline solution

Detailed Description

Researches will compared:

• Incidence of postreperfusion syndrome in liver transplantation
• Changes in interleukin values and other inflammatory markers before and after transplantation
• Incidence of liver graft dysfunction between groups
• Incidence of acute renal failure and other complications between groups

• Study Type: Interventional
• Enrollment (Anticipated): 70
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Luis Gajate, MD PhD; Phone Number: +34913368269; Email: gajate.luis@gmail.com
• Study Contact Backup: Name: Ines de la Hoz, MD; Phone Number: +34913368269; Email: delahozpoloines@gmail.com

Study Locations

• Spain
  • Madrid, Spain, 28034
    • Recruiting
    • Hospital Universitario Ramon y Cajal
    • Contact: Ines de la Hoz, MD; Phone Number: +34913368269; Email: delahozpoloines@gmail.com
    • Contact: Luis Gajate, MD PhD; Phone Number: +34913368269; Email: gajate.luis@gamil.com
    • Principal Investigator: Ines de la Hoz, MD
    • Principal Investigator: Luis Gajate, MD PhD
    • Sub-Investigator: Diego Parise, MD
    • Sub-Investigator: Maria del Carmen Martin Gonzalez, MD
    • Sub-Investigator: Angélica de Pablo, MD
    • Sub-Investigator: Cristina Cerro, MD
    • Sub-Investigator: Javier Nuño, MD PhD
    • Sub-Investigator: Oscar Pastor, MD PhD
    • Sub-Investigator: Miguel Rodriguez García, MD PhD
    • Sub-Investigator: Mercedes Espiño, MD PhD
    • Sub-Investigator: Ascensión Martín Grande, MD
    • Sub-Investigator: Cristina Fernandez, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 67 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patients undergoing liver transplantation

Exclusion Criteria:

• Pregnancy
• Allergy to ascorbic acid
• Nephrolithiasis
• Glucose-6-phosphate dehydrogenase (G6PD) deficiency
• Hyperoxaluria
• Hyperuricemia
• Haemochromatosis
• Sickle cell anemia
• Serum Creatinine > 1.2 mg/dl in women and 1.3 mg/dl in men
• Split liver graft
• Acute liver failure
• Living donor liver transplantation
• Controlled donor asystolia
• Treatment with: indinavir, Vitamin B12, Cyclosporine, iron, deferoxamine, disulfiram

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Ascorbic acid; 1.5 gr of ascorbic acid diluted in 100 ml of 0.9% saline solution will be administered intravenously during the anhepatic phase of liver transplantation	Drug: Ascorbic acid; 1.5 gr of ascorbic acid; Other Names: Vitamin C
Placebo Comparator: Saline solution; 100 ml of 0.9% saline solution will be administered during the anhepatic phase of liver transplantation	Drug: 0.9% Saline solution; 100 ml of 0.9% saline solution; Other Names: Saline

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Postreperfusion syndrome	When mean arterial pressure decreases by more than 30% relative to the value at the end of the anhepatic phase and lasts for at least 1 min	Within the first 5 minutes after reperfusion of the grafted liver

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Ascorbic acid serum levels	Quantification of ascorbic acid levels before and after liver transplantation	Immediately before induction of anesthesia and 12 hours after repercussion of the graft
Interleukin1beta (IL-1β) levels	Quantification of IL-1β before and after liver transplantation	Immediately before induction of anesthesia and 12 hours after repercussion of the graft
Tumor Necrosis Factor-alpha (TNFα) levels	Quantification of TNFα before and after liver transplantation	Immediately before induction of anesthesia and 12 hours after repercussion of the graft
Interleukin-6 levels (IL-6)	Quantification of IL-6 before and after liver transplantation	Immediately before induction of anesthesia and 12 hours after repercussion of the graft
Interleukin-8 (IL-8) levels	Quantification of IL-8 before and after liver transplantation	Immediately before induction of anesthesia and 12 hours after repercussion of the graft
Interferon gamma (IFNγ) levels	Quantification of IFNγ before and after liver transplantation	Immediately before induction of anesthesia and 12 hours after repercussion of the graft
Primary graft dysfunction	Incidence of primary graft nonfunction and early graft dysfunction. Graft nonfunction: lack of liver function leading to death if not retransplanted Early graft dysfunction: Olthoff's criteria	First postoperative week
Acute renal failure	Postoperative renal failure after liver transplantation as Kidney Disease Improving Global Outcomes (KDIGO) definition	First postoperative week
Mechanical ventilation	Duration of mechanical ventilation (hours) until extubation of the patient	Postoperative until day 30
Mortality	Mortality of any cause	Up to day 30
Length of hospitalization	Length of stay in hospital (days)	Through study completion (30 days)
Length of Intensive Care Unit (ICU) stay	Length of ICU stay	Through study completion (30 days)
Duration of vasopressor support after transplantation	Duration of vasopressor or inotropic support after transplantation	Postoperative until study completion (30 days)
Maximum dose of vasopressor support after transplantation	Maximum dose of vasopressor or inotropic support after transplantation	Postoperative until study completion (30 days)

Collaborators and Investigators

• Sponsor: Hospital Universitario Ramon y Cajal
• Investigators: Principal Investigator: Luis Gajate, MD PhD, Hospital Universitario Ramon y Cajal

Publications and helpful links

General Publications

• Zabet MH, Mohammadi M, Ramezani M, Khalili H. Effect of high-dose Ascorbic acid on vasopressor's requirement in septic shock. J Res Pharm Pract. 2016 Apr-Jun;5(2):94-100. doi: 10.4103/2279-042X.179569.
• Tanaka H, Matsuda T, Miyagantani Y, Yukioka T, Matsuda H, Shimazaki S. Reduction of resuscitation fluid volumes in severely burned patients using ascorbic acid administration: a randomized, prospective study. Arch Surg. 2000 Mar;135(3):326-31. doi: 10.1001/archsurg.135.3.326.
• Wilson JX. Mechanism of action of vitamin C in sepsis: ascorbate modulates redox signaling in endothelium. Biofactors. 2009 Jan-Feb;35(1):5-13. doi: 10.1002/biof.7.
• Aggarwal S, Kang Y, Freeman JA, Fortunato FL, Pinsky MR. Postreperfusion syndrome: cardiovascular collapse following hepatic reperfusion during liver transplantation. Transplant Proc. 1987 Aug;19(4 Suppl 3):54-5. No abstract available.
• Siniscalchi A, Dante A, Spedicato S, Riganello L, Zanoni A, Cimatti M, Pierucci E, Bernardi E, Miklosova Z, Moretti C, Faenza S. Hyperdynamic circulation in acute liver failure: reperfusion syndrome and outcome following liver transplantation. Transplant Proc. 2010 May;42(4):1197-9. doi: 10.1016/j.transproceed.2010.03.097.
• Paugam-Burtz C, Kavafyan J, Merckx P, Dahmani S, Sommacale D, Ramsay M, Belghiti J, Mantz J. Postreperfusion syndrome during liver transplantation for cirrhosis: outcome and predictors. Liver Transpl. 2009 May;15(5):522-9. doi: 10.1002/lt.21730.
• Blanot S, Gillon MC, Lopez I, Ecoffey C. Circulating endotoxins and postreperfusion syndrome during orthotopic liver transplantation. Transplantation. 1995 Jul 15;60(1):103-6. doi: 10.1097/00007890-199507150-00019. No abstract available.
• Bezinover D, Kadry Z, McCullough P, McQuillan PM, Uemura T, Welker K, Mastro AM, Janicki PK. Release of cytokines and hemodynamic instability during the reperfusion of a liver graft. Liver Transpl. 2011 Mar;17(3):324-30. doi: 10.1002/lt.22227.
• Blanot S, Gillon MC, Ecoffey C, Lopez I. Circulating endotoxins during orthotopic liver transplantation and post-reperfusion syndrome. Lancet. 1993 Oct 2;342(8875):859-60. doi: 10.1016/0140-6736(93)92715-6. No abstract available.
• Ishine N, Yagi T, Ishikawa T, Sasaki H, Nakagawa K, Tanaka N. Hemodynamic analysis of post-reperfusion syndrome and the effect of preventing this syndrome using thromboxane A2 synthetase inhibitor (OKY-046) in swine liver transplantation. Transplant Proc. 1997 Feb-Mar;29(1-2):378-81. doi: 10.1016/s0041-1345(96)00127-3. No abstract available.
• Girn HR, Ahilathirunayagam S, Mavor AI, Homer-Vanniasinkam S. Reperfusion syndrome: cellular mechanisms of microvascular dysfunction and potential therapeutic strategies. Vasc Endovascular Surg. 2007 Aug-Sep;41(4):277-93. doi: 10.1177/1538574407304510.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): November 17, 2020
• Primary Completion (Anticipated): June 30, 2023
• Study Completion (Anticipated): July 30, 2023

Study Registration Dates

• First Submitted: February 15, 2023
• First Submitted That Met QC Criteria: March 2, 2023
• First Posted (Estimate): March 3, 2023

Study Record Updates

• Last Update Posted (Estimate): March 3, 2023
• Last Update Submitted That Met QC Criteria: March 2, 2023
• Last Verified: March 1, 2023

More Information

Terms related to this study

• Keywords: Postreperfusion syndrome
• Additional Relevant MeSH Terms: Pathologic Processes; Disease; Syndrome; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Protective Agents; Micronutrients; Vitamins; Antioxidants; Ascorbic Acid
• Other Study ID Numbers: EC 20/606

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: All individual participant data (IPD) that underlie results in a publication
• IPD Sharing Time Frame: 6 months after publication
• IPD Sharing Access Criteria: Access by mail to principal investigator: gajate.luis@gmail.com
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No