Protective Effects of L-arginine During Reperfusion by Femoropopliteal Bypass for Lower Limb Ischemic Syndrome in Humans

The symptoms and severity of arterial disease is secondary to perfusion deficit. The specific alteration of the mitochondrial function of ischemic skeletal muscle plays an important role, and therapeutic enhancing mitochondrial function are associated with a clinical improvement with increase in the walking distance of the patient.

In severe ischemia, reperfusion required is accompanied by a deleterious episode through a worsening of endothelial dysfunction (impaired pathway of nitric oxide (NO)), majorant alteration of cellular energy and the hormonal and inflammatory responses. This is reperfusion syndrome, which can lead to grave consequences. Our goal is to limit mitochondrial and endothelial dysfunction (increased by the reperfusion) by stimulating the NO pathway by in situ addition of its precursor, L-arginine. Our working hypothesis is that this cellular improvement will be accompanied by an increase in systolic pressure index and an improvement in the walking distance.

Method: This is a trial with direct individual benefit, comparative, randomized, prospective, single-center, double-blind, versus placebo.

Study Overview

• Status: Completed
• Conditions: Skeletal Muscle Ischemia; Severe Lower Limb Ischemia; Mitochondrial Dysfunction
• Intervention / Treatment: Drug: L-arginine (L-arginine Veyron); Drug: Nacl

Detailed Description

2 groups of 30 patients with severe lower limb ischemia requiring femoropopliteal bypass revascularization participate in the study. The control group (placebo isoosmotic saline) will be compared to the treated group (femoral arterial infusion of 2 g L-Arginine for 30 min).

Heart rate, blood pressure and body temperature will be monitored continuously. The gastrocnemius muscle is biopsied before and 30 minutes after revascularization to analyze mitochondrial respiration and its control. Both femoral and brachial concomitant venous samples will judge the importance of muscle damage (lactate, muscle enzymes) and released mediators (cytokines, NO and endothelin) on the local and general.

Main clinical implications: L-arginine supplementation in atherosclerotic patients requiring femoropopliteal bypass to limit the initial deleterious effects of reperfusion and improve their walking distance and therefore their quality of life. Then extending this treatment to other patients with peripheral arterial disease.

• Study Type: Interventional
• Enrollment (Actual): 60
• Phase: Phase 4

Contacts and Locations

Study Locations

• France
  • Strasbourg, France, 67091
    • SERVICE DE PHYSIOLOGIE ET D'EXPLORATIONS FONCTIONNELLES- Nouvel Hôpital Civil, HUS

Participation Criteria

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:

• atherosclerotic patient with peripheral arterial disease stage 2-4 Leriche and Fontaine classification
• requiring surgical revascularization by femoropopliteal bypass
• above 18 years old

Exclusion Criteria:

• active infectious disease
• severe heart disease
• chronic renal insufficency
• pregnant women
• women of childbearing age and with no effective contraception for at least three months

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: L-Arginine; Femoral arterial infusion of 2 g L-Arginine for 30 min	Drug: L-arginine (L-arginine Veyron)
Placebo Comparator: Nacl; Femoral arterial infusion of Nacl for 30 min	Drug: Nacl

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Protective effect of L-Arginine on skeletal muscle: V0 and Vmax measurements ACR (Acceptor control ratio)=Vmax/V0	Immediate post surgery muscle biopsy analysis

Secondary Outcome Measures

Outcome Measure	Time Frame
Increase walking distance and ankle brachial index	1 month and 3 months after surgery

Collaborators and Investigators

• Sponsor: University Hospital, Strasbourg, France
• Investigators: Principal Investigator: Fabien THAVEAU, MD, Hôpitaux Universitaires de Strasbourg

Study record dates

Study Major Dates

• Study Start: November 1, 2005
• Primary Completion (Actual): March 1, 2012
• Study Completion (Actual): November 1, 2013

Study Registration Dates

• First Submitted: March 25, 2014
• First Submitted That Met QC Criteria: April 15, 2014
• First Posted (Estimate): April 17, 2014

Study Record Updates

• Last Update Posted (Estimate): April 17, 2014
• Last Update Submitted That Met QC Criteria: April 15, 2014
• Last Verified: April 1, 2014

More Information

Terms related to this study

• Keywords: L-arginine
• Additional Relevant MeSH Terms: Pathologic Processes; Ischemia
• Other Study ID Numbers: 3262