Short-Term Endogenous Hydrogen Sulfide Upregulation For Vein Graft Disease

Study Overview
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Brief Summary
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A randomized, controlled trial to evaluate patient compliance and biologic mechanisms of a short-term pre-operative Protein-Calorie Restriction (PCR) diet in comparison to a normal ad libitum diet for 4 days before elective vascular surgery involving a major operation. After a pilot study exploring the safety and feasibility of the PCR diet conducted inpatient before carotid endarterectomy titled Short-Term Endogenous Hydrogen Sulfide Upregulation, and a follow-up study titled Dietary Restriction in Vascular Surgery, the investigators now aim to expand the study to at home diet among a variety of vascular surgery procedures. This study will further elucidate not only the practicality of pre-operative short term dietary restriction, but also provide early data to inform biologic mechanisms and to inform future efficacy trails.

Detailed Description
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Peripheral arterial disease (PAD) remains a major health issue in the United States, especially with the metabolic syndrome and aging population. Surgical bypass using autogenous vein remains the most effective and durable choice for patients with advanced PAD. However, these vascular interventions suffer from high failure rates due to the development of significant occlusive lesions (intimal hyperplasia [IH]). Similar failure mechanisms plague coronary artery bypass grafts and endovascular interventions. Despite decades of vein graft research, our understanding of the biologic mechanisms of vein graft failure remains obscure. Hydrogen sulfide (H2S) has emerged as a critical gaseous signaling molecule in multiple processes including ischemia/reperfusion (IR) injury, angiogenesis, intimal hyperplasia, and anti-inflammatory mechanisms. It even appears to hold anti-atherosclerotic properties. However, the gas is toxic with a half-life of minutes, and it can be rapidly oxidized. Furthermore, clinically useful pharmacologic H2S donors have not been developed to date. In our 2015 Cell paper the investigators link substantial upregulation of endogenous H2S via short-term manipulation of mammalian dietary intake: simple dietary restriction. Our first pilot study had aims to determine the feasibility and safety of a PCR diet in vascular patients, concluding with no significant serious adverse events in any of the patients receiving the diet. The investigators learned that patients do not like having to stay in the hospital research unit pre-operatively. Long term the investigators aim to substantively impact the vascular patient at several levels: protection from IR, intimal hyperplasia, peri-procedural events such as stroke, cardiac dysfunction and myocardial infarction, and promotion of angiogenesis. For the current effort, the investigators will focus on potential biologic mechanisms of PCR and feasibility of eventual larger initiatives to accomplish this long-term aim. A powerful method to upregulate H2S is PCR. Defined as reduced food intake without malnutrition, PCR is best known for extending lifespan in model organisms from yeast to non-human primates. The efficacy of PCR against acute stress, including surgical stress, in preclinical models is also well established. Pilot studies suggest that humans respond to PCR in beneficial ways with respect to metabolic fitness (including improved glucose homeostasis, lipid profiles, and cardiovascular performance). But humans also have great difficulty complying with long-term voluntary food restriction, which is a prime reason that PCR has not been previously exploited in the clinical setting despite promising efficacy. However, recent data in model organisms point to a rapid onset of PCR benefits and challenges the notion that long-term PCR is required for benefits to accrue. In fruit flies, the maximal benefit of PCR on mortality risk occurs within 2-3 days. In rodents, the investigators have shown that surgical stress resistance also occurs within days, and the benefits center on upregulation of endogenous H2S. Nonetheless, except for pre-operative overnight fasting (which serves a different purpose) dietary recommendations are largely absent from peri-op management. Pilot data suggest that adverse post-operative outcomes linked to oxidative stress, inflammation and stress hormones may be modified by brief PCR in humans as well. In subjects who undertook food restriction for 12 hours per day for a month, markers of inflammation decreased significantly. PCR has been shown to reduce oxidative stress in both chronic and acute settings. Similarly, PCR may decrease stress hormone release. PCR also appears to work rapidly even in obese individuals or ill individuals. In gastric bypass surgery, two weeks of PCR reduced the risk of complications and procedure difficulty. With respect to patient compliance, brief (4 days to 2 weeks) pre-operative dietary interventions have been shown to be feasible and safe in selected patients, ranging from obese candidates for laparoscopic surgery to living organ donors. In our own human pilot research, vascular surgery patients have safely completed 3 days of pre-operative PCR diet without serious adverse events or reactions. For the current project the investigators propose a randomized, controlled trial to evaluate patient compliance and biologic effects of a short-term pre-operative PCR diet in comparison to a normal ad libitum diet for 4 days before elective vascular surgery involving an open major operation. This mechanistic clinical study is structured as a prospective, multi-year study of 226 vascular surgery patients undergoing non-emergency lower-extremity arterial vein bypass surgery randomized into two pre-operative dietary groups: observational group (n=90) and PCR (commercially available ScandiShake x 4 days, n=136). This specific dietary intervention to upregulate endogenous H2S is based on our preliminary data balanced with economic and clinical feasibility considerations. The event rate for the control group is assumed to be 33% based on the literature and data largely from our institutions. Our goal is to find a suitable (total) sample size for power 1 - β=0.8 at 5% level of significance. It has been assumed that Relative Risk Reduction (RRR) is 50% or Absolute Risk Reduction (ARR) is 16.5%. Projected total sample size, for treatment group to control group ratio of 1.5 (60% to 40%), is 225.55 which approximate to 226. For the structure of our dietary intervention this means 90 for the control group and 136 for the treatment group. However, it must be emphasized that the primary goal of this project is to decipher mechanisms in humans rather than evaluate clinical efficacy. Employing this randomized (3:2), parallel design, subjects will be assigned to either the supervised PCR diet (Scandi-Shake [any of 4 flavors - vanilla, strawberry, banana cream, and caramel] mixed with almond milk (85 grams Scandi-Shake mix to 240 cc almond milk), calculated individually for a total daily volume to achieve 30% caloric restriction and 70% protein restriction, based on ideal body weight), or continued routine ad libitum diet. The Mifflin St.Jeor equation will be used to calculate the total 24-hour energy needs based on gender, age, height, weight, and activity factor for the PCR diet. Daily physical activity will be assessed by questionnaire to determine the activity factor for accurate calorie restriction calculations. Nutritionists will use this equation to create a unique shake for each individual patient. The entire course of the dietary intervention will occur only during the 4 days prior to surgery. The shakes will be separated into 4 equal portions per day, for a total of 16 portions across the 4 pre-operative days. Patients can consume the 4 daily portions at whichever time of day they choose. The shakes are frozen 24 hours before distribution. Water intake is ad libitum for both cohorts. Subjects will be discretely randomized by the clinical research assistants upon final clearance for their procedure by the anesthesiology service, and their assigned group will be concealed to all subsequent team members (clinicians, research scientists, statistician) until data lock. Subjects in both cohorts will log their diet in the mobile application MealLogger. This app allows the subject to post a photo and short description of their food from a mobile device and directly share the information with the study coordinator. Staff can communicate through the app with subjects to clarify what exactly was eaten.

Official Title
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Short-Term Endogenous Hydrogen Sulfide Upregulation For Vein Graft Disease

Conditions
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Vascular Diseases, Surgery

Intervention / Treatment
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* Dietary Supplement: Scandi-Shake


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 18 years of age or older Patients planned for non-emergency lower extremity vein bypass surgery Projected survival of at least one year Ability to provide informed consent Albumin ≥3.0 and negative pregnancy test (if relevant) No known allergy to Scandi-Shake ingredients Exclusion Criteria: <18 years of age Emergency lower extremity vascular surgery Projected survival of < one year Albumin <3.0 Pregnancy, intention to become pregnant, or lack of standard contraception method Allergy to Scandi-Shake ingredients

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: 3:2 randomization to short-term protein calorie restriction diet versus regular meals prior to elective major vascular surgery
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Protein-calorie restriction<br>Four day dietary intervention immediately before surgery of Scandi-Shake [any of 4 flavors - vanilla, strawberry, banana cream, and caramel] mixed with almond milk (85 grams Scandi-Shake mix to 240 cc almond milk) calculated individually for a total daily volume to achieve 30% caloric restriction and 70% protein restriction, based on gender, age, height, weight, and activity level. | Dietary Supplement: Scandi-Shake<br>* Scandi-Shake [any of 4 flavors - vanilla, strawberry, banana cream, and caramel] mixed with almond milk (85 grams Scandi-Shake mix to 240 cc almond milk), calculated individually for a total daily volume to achieve 30% caloric restriction and 70% protein restriction, based on ideal body weight. The Mifflin St. Jeor equation will be used to calculate the total 24-hour energy needs based on gender, age, height, weight, and activity factor for the PCR diet. Daily physical activity will be assessed by questionnaire to determine the activity factor for accurate calorie restriction calculations. Nutritionists will use this equation to create a unique shake for each individual patient. The shakes will be separated into 4 equal portions per day, for a total of 16 portions across the 4 pre-operative days. Patients can consume the 4 daily portions at whichever time of day they choose. The shakes are frozen 24 hours before distribution.<br>|
| No Intervention: Control<br>Ad libitum diet for four days immediately before surgery | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Compliance with outpatient Protein-Calorie Restriction measured via food diary | Subject compliance with PCR will be measured through direct dietary intake data via food diary in comparison to the ad libitum diet. But one of the indirect goals of the initiative is to better understand how compliance can be assessed in this population. | 1 Month | 
| Compliance with outpatient Protein-Calorie Restriction measured via biologic assays for plasma free amino acids | Subject compliance with PCR will be measured through biologic assays (e.g., plasma free amino acids) in comparison to the ad libitum diet. But one of the indirect goals of the initiative is to better understand how compliance can be assessed in this population. | 1 Month | 
| Compliance with outpatient Protein-Calorie Restriction measured via biologic assays for pre-albumin | Subject compliance with PCR will be measured through biologic assays (e.g., insulin-like growth factor) in comparison to the ad libitum diet. But one of the indirect goals of the initiative is to better understand how compliance can be assessed in this population. | 1 Month | 
| Compliance with outpatient Protein-Calorie Restriction measured via biologic assays insulin-like growth factor | Subject compliance with PCR will be measured through direct dietary intake data via food diary, and we will also have biologic assays for serum markers including plasma free amino acids, pre-albumin, and insulin-like growth factor in comparison to the ad libitum diet. But, one of the indirect goals of the initiative is to better understand how compliance can be assessed in this population. | 1 Month | 
| Change over time from baseline values to values before surgery and day 1 after surgery in the comparison of H2S and standard biological markers of stress in blood | H2S and standard biological markers of stress are collected at baseline, immediately before surgery, and day 1 after surgery. Biological markers include: adipose phenotyping (quantification of adipokines, adipose derived hormones), leukocyte phenotyping and quantification via flow cytometry, and serum assays of IL-1beta, IL-6, IL-8, HGF, leptin, MCP-1, PAI-1, resistin, NGF, TNF, adiponectin, hydrogen sulfide (including production capacity) assays, insulin, lipid panels, FGF 21, pre-albumin, epinephrine, norepinephrine, dopamine, CBC with differential, basic metabolic panel including calcium. These biomarkers will be quantified in the various tissues for individual participants and be mathematically aggregated for groups (i.e., an aggregate unit of measurement will be used) | Baseline, Day 0, Day 1 | 
| Major Adverse Limb Event | Untreated loss of conduit patency and/or severe limb ischemia leading to an intervention or major amputation. Includes acute limb ischemia (including the need for thrombectomy/ thrombolysis), major amputation (above the ankle), need for re-do surgical revascularization for the index limb. | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Comparison of surgical and medical complications | These endpoints will include surgical and medical complications such as cardiac, neurologic, infectious, vascular, wound, and any other clinically significant events that occur within 30 days of surgery | 1 Month | 
| One-year survival | Patient survival after one-year participating in the trial | 1 year | 
| Renal dysfunction, stroke, myocardial infarction, patency of the vein graft (primary, primary assisted, secondary), survival. | Medical record derived complications (using standardized NSQIP definitions and outcomes) +/- PCR. eGFR will be the primary measure of renal function. These data will be integrated mathematically to combine all the features in an additive model to develop the final integrative model. | 1 Month, 1 year | 
| Wound Complication | Superficial Surgical Site Infection (SSI): Infection that involves only skin/ SQ tissue of the incision and at least one of the following: Purulent drainage, Positive wound culture, At least one of the following signs/symptoms of infection: pain or tenderness, localized swelling, redness, or heat AND superficial incision is deliberately opened by the surgeon, unless incision is culture-negative, Diagnosis of superficial SSI by attending Deep SSI: Infection involves deep tissues (fascial/ muscle layers) of the incision and at least one of the following: Purulent drainage from the deep incision, A deep incision spontaneously dehisces or is deliberately opened by a surgeon when the patient has at least one of the following signs or symptoms: fever (> 38C), localized pain, or tenderness, unless site is culture-negative, An abscess or other evidence of infection involving the deep incision, Diagnosis of deep SSI by attending Dehiscence: Skin separation requiring local wound care. | 1 Month |