Hyperglycemia
Conditions
Keywords
hyperglycemia, statin, blood vessels, ischemic preconditioning, Anesthesia, inhalational, endothelium, 5% dextrose
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.
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.
Interventions
DRUG5% dextrose
Glucose is infused to prevent the anesthetic preconditioning (sevoflurane) protection against subsequent ischemia/reperfusion injury.
DRUGVitamin C
Vitamin C is intended to restore the impairment of the endothelium caused by the dextrose infusion.
DRUGSimvastatin
Simvastatin will be ingested to determine the efficacy of a statin to modulate the forearm response to glucose.
DRUGSevoflurane
Sevoflurane will be given to attenuate or prevent the I/R injury during glucose.
Sponsors
US Department of Veterans Affairs
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 35 Years
Healthy volunteers
Yes
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Forearm Blood Flow | Baseline, Glucose Control, 15-min post ischemia | 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). |
Countries
United States
Participant flow
Recruitment details
Volunteers were sought from our research subject database.
Pre-assignment details
None. This was not a clinical intervention study but basic science research in young healthy humans. Primary exclusion criteria included anyone on beta-blockers or other med that would affect vascular responses; pregnant or lactating women; substance abusers; smokers; and cardiovascular, renal or systemic disease including hypertension & diabetes.
Participants by arm
| Arm | Count |
|---|---|
| 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 trial); I/R with glucose only (glucose trial); I/R with sevoflurane only (sevoflurane trial); I/R with glucose and sevoflurane (combined trial). Control 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 12ml/hr to a target of 200 mg/dl blood concentration in the experimental forearm for 60 min to prevent the anesthetic preconditioning (sevoflurane) protection against subsequent I/R injury.
Sevoflurane: 1 minimum alveolar concentration (MAC) for 20 min (after hour of glucose and before I/R) 26 volunteers were studied 67 times in this arm. | 26 |
| 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. | 16 |
| Statin 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. | 17 |
| Total | 59 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Failed arterial cannulation | 1 | 0 | 3 |
Baseline characteristics
| Characteristic | Sevoflurane and Glucose | Vitamin C and Glucose | Statin and Glucose | Total |
|---|---|---|---|---|
| Age, Customized 18-35 years old | 26 participants | 16 participants | 17 participants | 59 participants |
| Region of Enrollment United States | 26 participants | 16 participants | 17 participants | 59 participants |
| Sex: Female, Male Female | 14 Participants | 10 Participants | 9 Participants | 33 Participants |
| Sex: Female, Male Male | 12 Participants | 6 Participants | 8 Participants | 26 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 0 / 26 | 0 / 16 | 0 / 17 |
| serious Total, serious adverse events | 0 / 26 | 0 / 16 | 0 / 17 |
Outcome results
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).
Time frame: Baseline, Glucose Control, 15-min post ischemia
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sevoflurane and Glucose | Forearm Blood Flow | Baseline | 6.48 ml/100 ml tissue/min | Standard Error 0.86 |
| Sevoflurane and Glucose | Forearm Blood Flow | Control, Glucose | 8.26 ml/100 ml tissue/min | Standard Error 1 |
| Sevoflurane and Glucose | Forearm Blood Flow | Post Ischemia, Glucose | 7.10 ml/100 ml tissue/min | Standard Error 0.65 |
| Sevoflurane and Glucose | Forearm Blood Flow | Intervention Baseline | 8.47 ml/100 ml tissue/min | Standard Error 0.82 |
| Sevoflurane and Glucose | Forearm Blood Flow | Control, after intervention | 7.90 ml/100 ml tissue/min | Standard Error 0.84 |
| Sevoflurane and Glucose | Forearm Blood Flow | Post Ischemia, intervention | 8.45 ml/100 ml tissue/min | Standard Error 1.18 |
| Vitamin C and Glucose | Forearm Blood Flow | Post Ischemia, intervention | 9.91 ml/100 ml tissue/min | Standard Error 1.63 |
| Vitamin C and Glucose | Forearm Blood Flow | Baseline | 9.2 ml/100 ml tissue/min | Standard Error 2.92 |
| Vitamin C and Glucose | Forearm Blood Flow | Intervention Baseline | 8.84 ml/100 ml tissue/min | Standard Error 1.39 |
| Vitamin C and Glucose | Forearm Blood Flow | Control, after intervention | 9.3 ml/100 ml tissue/min | Standard Error 1.73 |
| Vitamin C and Glucose | Forearm Blood Flow | Control, Glucose | 9.2 ml/100 ml tissue/min | Standard Error 2.92 |
| Vitamin C and Glucose | Forearm Blood Flow | Post Ischemia, Glucose | 7.6 ml/100 ml tissue/min | Standard Error 2.42 |
| Statin and Glucose | Forearm Blood Flow | Control, Glucose | 9.91 ml/100 ml tissue/min | Standard Error 1.43 |
| Statin and Glucose | Forearm Blood Flow | Post Ischemia, Glucose | 7.00 ml/100 ml tissue/min | Standard Error 1.01 |
| Statin and Glucose | Forearm Blood Flow | Post Ischemia, intervention | 6.26 ml/100 ml tissue/min | Standard Error 0.82 |
| Statin and Glucose | Forearm Blood Flow | Intervention Baseline | 8.17 ml/100 ml tissue/min | Standard Error 1.06 |
| Statin and Glucose | Forearm Blood Flow | Baseline | 7.32 ml/100 ml tissue/min | Standard Error 1.06 |
| Statin and Glucose | Forearm Blood Flow | Control, after intervention | 9.28 ml/100 ml tissue/min | Standard Error 1.34 |