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

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.

Study Overview

• Status: Completed
• Conditions: Hyperglycemia
• Intervention / Treatment: Drug: 5% dextrose; Drug: Sevoflurane; Drug: Vitamin C; Drug: Simvastatin

Detailed 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.

• Study Type: Interventional
• Enrollment (Actual): 59
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53295-1000
      • Zablocki VA Medical Center, Milwaukee

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 35 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Sevoflurane and Glucose; Endothelial function will be measured via forearm blood flow (FBF). Subjects may get I/R injury (ischemia) without glucose or sevoflurane (placebo); I/R with glucose only (glucose trial); I/R with sevoflurane only (sevo trial); I/R with glucose and sevoflurane (combo trial). Baseline FBF was taken in every trial before any intervention, and FBF was taken during intervention and post I/R. Glucose: 5% dextrose will be infused at 12 ml/hr to a target of 200 mg/dl blood concentration in the experimental forearm for 1 hr to prevent the anesthetic preconditioning (sevoflurane) protection against subsequent I/R injury. Sevoflurane: 1 minimum alveolar concentration (MAC) for 20 min (after 1 hr glucose and before I/R) 26 volunteers were studied 67 times in this arm.	Drug: 5% dextrose; Glucose is infused to prevent the anesthetic preconditioning (sevoflurane) protection against subsequent ischemia/reperfusion injury.; Other Names: Glucose; Drug: Sevoflurane; Sevoflurane will be given to attenuate or prevent the I/R injury during glucose.; Other Names: Sevo
Experimental: Vitamin C and Glucose; To determine if vitamin C can restore the impairment of the endothelium (FBF) caused by the glucose (dextrose infusion). All subjects received glucose and I/R injury (ischemia), either with or without vitamin C. Control baseline FBF was taken in every trial before any intervention, and FBF was taken during intervention and post I/R. Placebo data were the placebo studies from the Sevoflurane and Glucose arm, when appropriate; new subjects (not enrolled in Sevoflurane and Glucose arm) underwent a separate placebo trial. Glucose: 5% dextrose will be infused at 12ml/hr to a target of 200 mg/dl blood concentration in the experimental forearm for 60 min. Vitamin C: 1 gm iv bolus injection 5 min before I/R injury 16 volunteers were studied 25 times in this arm.	Drug: 5% dextrose; Glucose is infused to prevent the anesthetic preconditioning (sevoflurane) protection against subsequent ischemia/reperfusion injury.; Other Names: Glucose; Drug: Vitamin C; Vitamin C is intended to restore the impairment of the endothelium caused by the dextrose infusion.; Other Names: Vit C
Experimental: Statins and Glucose; Volunteers ingested a 40 mg simvastatin (statin) pill for the two evenings prior to study day and the morning of the study to determine the effect of simvastatin on modulating the I/R injury during hyperglycemia (high glucose). Volunteers were studied with statin alone and with statin and glucose. Placebo data were the placebo studies from the Sevoflurane and Glucose arm, when appropriate; new subjects (not enrolled in Sevoflurane and Glucose arm) underwent a separate placebo trial. Glucose: 5% dextrose will be infused at 12ml/hr to a target of 200 mg/dl blood concentration in the experimental forearm for 60 min. Statin: 40 mg of simvastatin 17 volunteers were studied 31 times in this arm.	Drug: 5% dextrose; Glucose is infused to prevent the anesthetic preconditioning (sevoflurane) protection against subsequent ischemia/reperfusion injury.; Other Names: Glucose; Drug: Simvastatin; Simvastatin will be ingested to determine the efficacy of a statin to modulate the forearm response to glucose.; Other Names: Statin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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

Collaborators and Investigators

• Sponsor: US Department of Veterans Affairs
• Investigators: Principal Investigator: Thomas J Ebert, MD PhD, Zablocki VA Medical Center, Milwaukee

Study record dates

Study Major Dates

• Study Start: March 1, 2010
• Primary Completion (Actual): September 1, 2013
• Study Completion (Actual): September 1, 2013

Study Registration Dates

• First Submitted: October 13, 2009
• First Submitted That Met QC Criteria: October 14, 2009
• First Posted (Estimate): October 15, 2009

Study Record Updates

• Last Update Posted (Estimate): March 17, 2015
• Last Update Submitted That Met QC Criteria: March 12, 2015
• Last Verified: March 1, 2015

More Information

Terms related to this study

• Keywords: hyperglycemia; ischemic preconditioning; statin; endothelium; blood vessels; Anesthesia, inhalational; 5% dextrose
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Glucose Metabolism Disorders; Metabolic Diseases; Postoperative Complications; Hyperglycemia; Ischemia; Reperfusion Injury; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Enzyme Inhibitors; Anesthetics, General; Anesthetics; Platelet Aggregation Inhibitors; Antimetabolites; Protective Agents; Micronutrients; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Vitamins; Anesthetics, Inhalation; Antioxidants; Sevoflurane; Simvastatin; Ascorbic Acid
• Other Study ID Numbers: CARA-023-09S