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

NCT00995670 | Completed Results

• 1 other identifier: CARA-023-09S
• Study Type: interventional
• Target: 59
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Hyperglycemia

Keywords

hyperglycemia; statin; blood vessels; ischemic preconditioning; Anesthesia, inhalational; endothelium; 5% dextrose

Outcome Measures

Primary Outcomes (1)

• 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

Study Arms (3)

Sevoflurane and Glucose

EXPERIMENTAL

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; Drug: Sevoflurane

Vitamin C and Glucose

EXPERIMENTAL

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; Drug: Vitamin C

Statins and Glucose

EXPERIMENTAL

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; Drug: Simvastatin

Interventions

5% dextrose DRUG

Glucose is infused to prevent the anesthetic preconditioning (sevoflurane) protection against subsequent ischemia/reperfusion injury.

Also known as: Glucose

Sevoflurane and Glucose; Statins and Glucose; Vitamin C and Glucose

Vitamin C DRUG

Vitamin C is intended to restore the impairment of the endothelium caused by the dextrose infusion.

Also known as: Vit C

Vitamin C and Glucose

Simvastatin DRUG

Simvastatin will be ingested to determine the efficacy of a statin to modulate the forearm response to glucose.

Also known as: Statin

Statins and Glucose

Sevoflurane DRUG

Sevoflurane will be given to attenuate or prevent the I/R injury during glucose.

Also known as: Sevo

Sevoflurane and Glucose

Eligibility Criteria

• Age: 18 Years - 35 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Young, healthy volunteers, 18-35 yr of age;
• Females will be studied at the same phase of their estrous cycle in each protocol.

You may not qualify if:

• 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.

Sponsors & Collaborators

• US Department of Veterans Affairs: lead

Study Sites (1)

Zablocki VA Medical Center, Milwaukee

Milwaukee, Wisconsin, 53295-1000, United States

Location

MeSH Terms

Conditions

Hyperglycemia

Interventions

Glucose; Ascorbic Acid; Simvastatin; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Sevoflurane

Condition Hierarchy (Ancestors)

Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases

Intervention Hierarchy (Ancestors)

Hexoses; Monosaccharides; Sugars; Carbohydrates; Sugar Acids; Acids, Acyclic; Carboxylic Acids; Organic Chemicals; Hydroxy Acids; Lovastatin; Naphthalenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Polycyclic Compounds; Anticholesteremic Agents; Hypolipidemic Agents; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Pharmacologic Actions; Chemical Actions and Uses; Enzyme Inhibitors; Lipid Regulating Agents; Therapeutic Uses; Methyl Ethers; Ethers; Hydrocarbons, Fluorinated; Hydrocarbons, Halogenated

Limitations and Caveats

Some substudies were not completed because we had difficulty creating ischemia/reperfusion (I/R) injury or a consistent FBF response, which was critical to the purpose of the study to investigate the role of glucose and statins in I/R injury.

Results Point of Contact

• Title: Thomas J. Ebert, MD, PhD
• Organization: Zablocki VA Medical Center

thomas.ebert@va.gov

414-384-2000

Study Officials

• Thomas J Ebert, MD PhD

  Zablocki VA Medical Center, Milwaukee

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: SINGLE GROUP
• Sponsor Type: FED
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 13, 2009
• First Posted: October 15, 2009
• Study Start: March 1, 2010
• Primary Completion: September 1, 2013
• Study Completion: September 1, 2013
• Last Updated: March 17, 2015
• Results First Posted: March 17, 2015

Record last verified: 2015-03

Locations

US (1)