Perioperative Vitamin C Lung Transplant

Study Overview
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Brief Summary
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This study is being done to determine if parenterally administered ascorbic acid (Vitamin C) given at the time of lung transplant is safe. Vitamin C may be an effective intervention towards primary graft dysfunction (PGD). The study will enroll 69 participants who consent to the intervention. Participants who do not consent to the intervention will be treated according to standard-of-care, but may choose to be consented to have their data retrospectively reviewed. Based on our consent rate, this group may include 40-70 participants. Participants will be on study for up to 12 months.

Detailed Description
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PGD is a frequent and severe outcome that impacts both short- and long-term outcomes after lung transplantation. Major pathophysiologic contributors include ischemia and reperfusion injury, mitochondrial dysfunction and endothelial failure. No directed therapy exists. Vitamin C is a first-line antioxidant that also acts at the endothelium and mitochondria to decrease permeability and leak, inhibit mitochondrial dysfunction and improve ischemia and reperfusion. When combined with steroids, part of standard care for lung transplant recipients, these effects may be enhanced and synergistically inhibit instigators of patient injury. A pilot trial will ensure safety of this potential intervention and guide future research into this important outcome measure. It will be readily received in the literature. For the present study, vitamin C will be administered parenterally at a dose of 1,500 mg every 6 hours, a dose that is widely accepted and used in other clinical contexts where the drug is studied, such as sepsis. This will predictably reconstitute levels and achieve supratherapeutic benefit towards oxidant scavenging, while avoiding the potential pro-oxidant effects seen at exceedingly high doses. To this end, the investigators will exclude patients where the standard dosing of vitamin C will exceed 100 mg/kg/day (excluding patients <60 kg). Dosing will continue through post-operative day (POD) 3 to effectively assess for the impact of vitamin C on PGD. Primary Objectives To assess whether parenterally administered ascorbic acid (vitamin C) is safe in the lung transplant population To estimate adherence to ascorbic acid administration protocol in this study population and to identify obstacles to feasibility of future trials using this protocol Secondary Objectives To assess whether parenterally administered ascorbic acid (vitamin C) may decrease the rate and severity of PGD after lung transplant To establish the incidence of vitamin C and vitamin B1 (thiamine) deficiencies in the lung transplant population, and the responsiveness of vitamin C levels to our selected parenteral therapy To identify interventions that will optimize the post-operative wellbeing of patients receiving lung transplants by decreasing primary graft dysfunction (short and intermediate-to-long term Stop Criteria Anuria x 3-hours Moderate, Grade 2 AKI (doubling of baseline creatinine) An acute, unexplained hemoglobin drop of >2 mg/dL

Official Title
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Vitamin C: Assessing Safety After Lung Transplant

Conditions
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Primary Graft Dysfunction, Lung Transplant; Complications

Intervention / Treatment
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* Drug: Vitamin C


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participant is scheduled for lung transplantation Exclusion Criteria: Non-English speaking Subject is known or believed to be pregnant Subject is a prisoner. Subject has impaired decision-making capacity. Subject has known allergy to vitamin C. Subject has history of nephrolithiasis, oxalosis or hyperoxaluria. (Cystic Fibrosis patients are at risk of occult oxalosis / hyperoxaluria, therefore they will also be excluded from the study.) Glucose-6-phosphate dehydrogenase (G6PD) deficiency Sickle cell anemia Heredity hemochromatosis Baseline creatinine >2 mg/dL or any current kidney injury Weight <60 kg Vitamin C supplement use or administration (including HAT therapy) within the last month prior to transplantation Current enrolment in another research study Not suitable for study participation due to other reasons at the discretion of the investigators.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: This is a pilot single-arm unblinded trial to assess whether parenterally administered ascorbic acid (vitamin C) is safe in the lung transplant population.The investigators will not randomize or control; a retrospective cohort of participants not treated with vitamin C will be reviewed from 2015-2020. Those participants who decline the intervention will have the choice to consent to having their data be considered as part of the (non-retrospective) controls and be considered in our statistical analysis for outcomes, including analysis between this group and the historical controls. All participants who consent will be administered the therapy and participants will be evaluated via an intention-to-treat analysis.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Vitamin C Arm<br>Ascorbic Acid will be administered at a dose of 1500 mg in 100 mL of saline over 30 minutes intravenously once every 6 hours for a total of 72 hours | Drug: Vitamin C<br>* Vitamin C is a first-line antioxidant that directly scavenges free radicals, inhibits reactive oxygen species (ROS) producing enzymes and recovers other cellular antioxidants<br>* Other names: ascorbic acid;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence and Severity of Kidney Injury Post Operative Day (POD) 1 | The primary endpoint is the safety of the vitamin C intervention. This will be measured by the incidence and severity of kidney injuries on POD 1, POD 2, POD 3, POD 4, and POD 7. Acute kidney injury (AKI) is defined as any creatinine (Cr) that is 1.5-times the participant's baseline / immediate preoperative creatinine. Severity escalates with increasing ratios: Mild, stage 1 AKI (Cr 1.5-1.99x baseline); Moderate, stage 2 AKI (Cr 2-2.9x baseline); and Severe, stage 3 AKI (Cr >3x baseline or any initiation of dialysis). | Post Operative Day 1 | 
| Incidence and Severity of Kidney Injury POD 2 | The primary endpoint is the safety of the vitamin C intervention. This will be measured by the incidence and severity of kidney injuries on POD 1, POD 2, POD 3, POD 4, and POD 7. Acute kidney injury (AKI) is defined as any creatinine (Cr) that is 1.5-times the participant's baseline / immediate preoperative creatinine. Severity escalates with increasing ratios: Mild, stage 1 AKI (Cr 1.5-1.99x baseline); Moderate, stage 2 AKI (Cr 2-2.9x baseline); and Severe, stage 3 AKI (Cr >3x baseline or any initiation of dialysis). | Post Operative Day 2 | 
| Incidence and Severity of Kidney Injury POD 3 | The primary endpoint is the safety of the vitamin C intervention. This will be measured by the incidence and severity of kidney injuries on POD 1, POD 2, POD 3, POD 4, and POD 7. Acute kidney injury (AKI) is defined as any creatinine (Cr) that is 1.5-times the participant's baseline / immediate preoperative creatinine. Severity escalates with increasing ratios: Mild, stage 1 AKI (Cr 1.5-1.99x baseline); Moderate, stage 2 AKI (Cr 2-2.9x baseline); and Severe, stage 3 AKI (Cr >3x baseline or any initiation of dialysis). | Post Operative Day 3 | 
| Incidence and Severity of Kidney Injury POD 4 | The primary endpoint is the safety of the vitamin C intervention. This will be measured by the incidence and severity of kidney injuries on POD 1, POD 2, POD 3, POD 4, and POD 7. Acute kidney injury (AKI) is defined as any creatinine (Cr) that is 1.5-times the participant's baseline / immediate preoperative creatinine. Severity escalates with increasing ratios: Mild, stage 1 AKI (Cr 1.5-1.99x baseline); Moderate, stage 2 AKI (Cr 2-2.9x baseline); and Severe, stage 3 AKI (Cr >3x baseline or any initiation of dialysis). | Post Operative Day 4 | 
| Incidence and Severity of Kidney Injury POD 7 | The primary endpoint is the safety of the vitamin C intervention. This will be measured by the incidence and severity of kidney injuries on POD 1, POD 2, POD 3, POD 4, and POD 7. Acute kidney injury (AKI) is defined as any creatinine (Cr) that is 1.5-times the participant's baseline / immediate preoperative creatinine. Severity escalates with increasing ratios: Mild, stage 1 AKI (Cr 1.5-1.99x baseline); Moderate, stage 2 AKI (Cr 2-2.9x baseline); and Severe, stage 3 AKI (Cr >3x baseline or any initiation of dialysis). | Post Operative Day 7 | 
| Incidence of New Dialysis Initiation |  | up to Post Operative Day 7 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Participant Vitamin C Levels |  | Baseline, Post Operative Day 1, Post Operative Day 2, Post Operative Day 3 | 
| Participant Thiamine Levels |  | Baseline, Post Operative Day 1, Post Operative Day 2, Post Operative Day 3 | 
| Incidence of Primary Graft Dysfunction (PGD) | Primary Graft Dysfunction is defined as chest x-ray (CXR)-infiltrates with or without depressed oxygenation function, assessed by the PF-Ratio, which is the PaO2 / FiO2. | up to Post Operative Day 7 | 
| Incidence and Severity of PGD on POD 3 | Primary Graft Dysfunction is defined as chest x-ray (CXR)-infiltrates with or without depressed oxygenation function, assessed by the PF-Ratio, which is the PaO2 / FiO2. Severity is defined as: PGD Grade 1 = CXR findings and any PF Ratio > 300; PGD Grade 2 = CXR findings and PF Ratio 200-300; and PGD Grade 3 = CXR findings and PF Ratio <200. | Post Operative Day 3 | 
| Tacrolimus Levels |  | Post Operative Days 2, 3, 4, and 7 | 
| Tacrolimus Doses |  | Post Operative Days 4 and 7 | 
| Post-Operative Well Being: Mortality |  | at Post Operative Day 30 and Post Operative Day 90 via chart review | 
| Post-Operative Well Being: Atrial Fibrillation |  | up to Post Operative Day 7 | 
| Post-Operative Well Being: ICU Length of Stay |  | up to Post Operative Day 30 (chart review) | 
| Post-Operative Well Being: Hospital Length of Stay |  | up to Post Operative Day 90 (chart review) | 
| Post-Operative Well Being: Nadir Cardiac Index |  | up to 72 hours post op | 
| Post-Operative Well Being: Peak Pulmonary Artery Systolic Pressure |  | up to 72 hours post op | 
| Post-Operative Well Being: Peak Pulmonary Artery Diastolic Pressure |  | up to 72 hours post op | 
| Post-Operative Well Being: Duration of Inotrope Need |  | up to 72 hours post op | 
| Post-Operative Well Being: Duration of Vasopressor |  | up to 72 hours post op | 
| Post-Operative Well Being: Total Dose of Vasopressor |  | up to 72 hours post op | 
| Post-Operative Well Being: Daily Crystalloid Volume | for 0-24h, 24-48h and 48-72h; total volume balance at 72-hours | up to 72 hours post op | 
| Post-Operative Well Being: Daily Blood Product Transfusion Volume | for 0-24h, 24-48h and 48-72h; total volume balance at 72-hours | up to 72 hours post op | 
| Post-Operative Well Being: Daily Chest Tube Output Volume | for 0-24h, 24-48h and 48-72h; total volume balance at 72-hours | up to 72 hours post op | 
| Post-Operative Well Being: Duration of Post-Operative Mechanical Ventilation |  | up to Post Operative Day 7 | 
| Post-Operative Well Being: PaO2 / FIO2 ratios | The PF Ratio assesses the lungs' ability to oxygenate the blood. It is defined as the ratio of the partial pressure of oxygen in the arteries (PaO2 in mmHg) to the fractional inspired oxygen content from the ventilator (FiO2 in %). | Post Operative Day 1, Post Operative Day 2, Post Operative Day 3 | 
| Post-Operative Well Being: Time to Clearance of Lactate | Clearance is defined as a lactate <1 mmol/L. | up to Post Operative Day 3 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Vitamin C