Dietary Restriction in Vascular Surgery

Not Applicable

Completed

• Conditions: Vascular Diseases; Surgery
• Interventions: Dietary Supplement: Protein-Calorie Restriction

• Registration Number: NCT04013412
• Lead Sponsor: Brigham and Women's Hospital

Brief Summary

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. This study is a step in the long-term primary scientific objective to test the hypothesis that brief up regulation of endogenous H2S via pre-operative PCR in elective major surgery improves clinical outcomes in humans. After a successful pilot study of the PCR diet conducted inpatient before carotid endarterectomy, the investigators now aim to expand the study to at home diet among a variety of vascular surgery procedures.

Detailed Description

Hydrogen sulfide (H2S) has emerged as a critical gaseous signaling molecule with a role 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, no clinically useful pharmacologic H2S donors have been developed to date. In a 2015 Cell paper, the study investigators link substantial upregulation of endogenous H2S to short-term manipulation of mammalian dietary intake: simple dietary restriction. The current project serves as the second phase in the accelerated translation of this important discovery toward clinical utility that may substantively impact the vascular patient at several levels: protection from IR injury, intimal hyperplasia, peri-procedural events such as stroke, cardiac dysfunction and myocardial infarction (MI), and promotion of angiogenesis.

Chronic protein and calorie dietary restriction (PCR; reduced food intake without malnutrition) is known for extending longevity in multiple species. PCR is also an established approach to positively impact metabolic fitness and resistance to multiple forms of acute stress. Despite these wide-ranging benefits, potential clinical applications have never been considered feasible in humans due to the practical difficulties associated with voluntary food restriction combined with the assumption that PCR benefits take a long time to accrue. Recent preclinical studies by the applicants reveal a rapid onset of PCR benefits against surgically induced traumatic inflammation, IR injury, and the fibroproliferative vascular response to injury in rodents. Mechanistically, rapid changes in adipose phenotype and associated adipokine profiles appear to underlie these benefits; but the key mediator appears to be endogenous H2S. This field thus stands poised to move to clinical utility, and vascular surgery offers an optimal risk/benefit ratio for translation of the PCR/H2S hypothesis.

For the current project the investigators will complete a randomized, controlled trial to evaluate patient compliance and biologic mechanisms of a short-term pre-operative PCR diet in comparison to a normal ad libitum diet for 4 days before elective major vascular surgery. Both Endpoints relate to the long-term primary scientific objective to test the hypothesis that brief upregulation of endogenous H2S via pre-operative PCR in elective major surgery improves clinical outcomes in humans. After a successful pilot study of the PCR diet conducted inpatient before carotid endarterectomy titled Short-Term Endogenous Hydrogen Sulfide Upregulation (NCT03303534), the investigators now aim to expand the study to at home diet among a variety of vascular surgery procedures.

Eighty subjects undergoing carotid artery endarterectomy, aortic aneurysm repair (open, and endovascular if groin cut down planned), open lower extremity arterial procedures (bypasses, aneurysm repair, arterial and bypass graft reconstructions), major amputation of the lower extremity (below knee and above knee amputations), or open hemodialysis access procedures for either symptomatic or asymptomatic disease will be recruited and enrolled at Brigham and Women's Hospital. Using a randomized (3:2), parallel design, patients will receive either the PCR diet (n=48; ScandiShake \[any of 4 flavors\] mixed with almond milk, calculated individually for a total daily volume to achieve 30% caloric restriction and 70% protein restriction, based on body weight and activity level), or continued routine ad libitum diet (n=32). Daily physical activity will be assessed by questionnaire to determine the activity factor for accurate calorie restriction calculations. Water intake is ad libitum for both cohorts, and both diets can be consumed throughout the day and night (except on the day of surgery). Patients will consume their assigned diets for the four days leading up to surgery until midnight the day of surgery when both cohorts will be fasted for the procedure (per standard clinical guidelines).

Study Timeline

• Study Start: 2018-12-31
• Study First Submitted: 2019-06-24
• Study First Submitted QC: 2019-07-08
• Study First Posted: 2019-07-09
• Primary Completion: 2020-03-31
• Study Completion: 2020-03-31
• Status Verified: 2020-09
• Last Update Submitted: 2020-09-23
• Last Update Posted: 2020-09-25

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 19

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Protein-Calorie Restriction	Protein-Calorie Restriction	Four day dietary intervention immediately before surgery of ScandiShake \[any of 4 flavors\] mixed with almond milk, calculated individually for a total daily volume to achieve 30% caloric restriction and 70% protein restriction, based on body weight and activity level.

Primary Outcome Measures

Name	Time	Method
Outpatient compliance with protein calorie restriction	1 Month	Patient compliance with the PCR diet will be assessed by food record analysis.
Comparison of H2S and related biological markers of stress	1 Month	Biologic 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. H2S and biologic markers will be compared at baseline, immediately before surgery, and the day after surgery.

Trial Locations

Locations (1)

Brigham and Women's Hospital; 🇺🇸 Boston, Massachusetts, United States