Ischemia/Reperfusion Injury of Human Endothelium: Role of Glucose and Statins

Hyperglycemia Clinical Trial

Official title:

Ischemia/Reperfusion Injury of Human Endothelium: Role of Glucose and Statins

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00995670
• Other study ID #: CARA-023-09S
• Status: Completed
• Phase: N/A
• First received: October 13, 2009
• Last updated: March 12, 2015
• Start date: March 2010
• Est. completion date: September 2013

Study information

• Verified date: March 2015
• Source: VA Office of Research and Development
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Federal Government
• Study type: Interventional

Clinical Trial Summary

Anesthetic preconditioning (APC, a brief exposure to an anesthetic gas) has become an area of intense research interest because of its ability to protect tissue and organs from injury resulting from a cessation of blood flow and then a re-establishment of flow. The blood vessel lining plays a key role in this injury. This research will examine, in human volunteers, several important modifiers of APC in human blood vessels: high blood sugar, vitamin C, and statin drugs. Thus, the proposed studies will advance the investigators' understanding of mechanisms of this injury in humans and explore important modifiers of APC protection from injury.

Description:

Injury to vital organs and tissue can occur when blood flow is stopped and then re-established. This happens in a variety of clinical situations and contributes to poor outcomes. A newer concept of protection from this injury by an anesthetic drug might occur because of the effect of the volatile anesthetics on the tissue that lines blood vessels. Thus, a brief exposure to a volatile anesthetic before a cessation of blood flow, called anesthetic preconditioning (APC), can substantially reduce the resulting injury to the lining of the blood vessels. In animal models, high levels of blood sugar block this protection, while cholesterol lowering drugs (statins) restore the protection and may independently protect blood vessel lining from injury. The interactions of high blood sugar and statin drugs on the blood vessel reaction to APC and a subsequent 20-min cessation of blood flow to the forearm will be studied in humans. In addition, the involvement of reactive oxygen species (ROS) in the harmful effects of high blood sugar and the beneficial effects of statins will be explored. The following four hypotheses will be studied: 1) high blood sugar blocks the anesthetic protection of blood vessels from injury in a dose and time dependent manner; 2) reactive oxygen species are involved in the inhibition of APC by high blood sugar; 3) statins modulate injury in a dose related manner; and 4) statins reduce high blood sugar inhibition of APC.

A standard model to evaluate forearm blood vessel function will be used. Thin rubber-band-like strain gauges will be strapped around each forearm and the change in their stretch during a variety of interventions on the experimental arm (the other arm will not receive any interventions and will be the control arm) will be measured. These interventions will allow the investigator to determine whether the hypotheses listed above are true. During all studies, there will be a 20-min arrest of the forearm circulation. Additional effects of injury, APC, high blood sugar, and statins will be determined by evaluating blood vessel inflammatory responses from "markers" in blood samples taken before and after I/R injury. Several studies will involve varying the forearm blood glucose concentration for brief (30 min) to longer (2 hours) periods prior to APC and injury. The ROS scavenger vitamin C will be used to evaluate the role of ROS in adverse effects of high blood sugar. There are several other studies that will continue to seek the mechanism of action of this effect via the use of other drug interactions.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 59
• Est. completion date: September 2013
• Est. primary completion date: September 2013
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Both
• Age group: 18 Years to 35 Years

Eligibility

Inclusion Criteria:

• Young, healthy volunteers, 18-35 yr of age;

• Females will be studied at the same phase of their estrous cycle in each protocol.

Exclusion Criteria:

• Beta-blocker therapy or any medication that might interfere with vascular responses;

• Pregnant or lactating women;

• Substance abusers;

• Smokers;

• Anyone with cardiovascular, renal, or other systemic disease including hypertension and/or diabetes;

• Also excluded are volunteers with family history of malignant hyperthermia, or significant gastro-esophageal reflux.

Study Design

Allocation: Non-Randomized, Endpoint Classification: Pharmacodynamics Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Basic Science

Related Conditions & MeSH terms

• Hyperglycemia
• Reperfusion Injury

Intervention

Drug:
• 5% dextrose
Glucose is infused to prevent the anesthetic preconditioning (sevoflurane) protection against subsequent ischemia/reperfusion injury.
• Vitamin C
Vitamin C is intended to restore the impairment of the endothelium caused by the dextrose infusion.
• Simvastatin
Simvastatin will be ingested to determine the efficacy of a statin to modulate the forearm response to glucose.
• Sevoflurane
Sevoflurane will be given to attenuate or prevent the I/R injury during glucose.

Locations

Country	Name	City	State
United States	Zablocki VA Medical Center, Milwaukee	Milwaukee	Wisconsin

Sponsors (1)

Lead Sponsor	Collaborator
VA Office of Research and Development

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Forearm Blood Flow	endothelial (forearm blood flow) responses to acetylcholine stimulation at baseline, and under conditions of high glucose before and after ischemia/reperfusion injury, and same with the addition of an intervention: sevoflurane (Arm 1), vitamin C (Arm 2), and high statin (Arm 3).	Baseline, Glucose Control, 15-min post ischemia	No