Remote Ischemic Preconditioning, Myocardial Protection
Conditions
Brief summary
The purpose of this study is to compare a treatment called remote ischemic preconditioning (rIP) to no treatment. rIP is a simple treatment that is believed to help patients recover better after heart surgery. This treatment involves applying a large blood pressure cuff to one leg. The blood pressure cuffs will be inflated for 5 minutes and then deflated for 5 minutes. This will be done 4 times in a row.
Detailed description
Purpose: 1. Determine, in a pilot study, if surrogate markers of rIP can be detected in patients presenting for cardiac surgery. Specifically measure the effect of rIP on the expression profile of HSP-70, iNOS, PKC-E, p38 MAPK, PI3K, and sarcolemmal KATP 2. Determine if rIP influences the expression of genes known to influence substrate preference and thereby myocardial metabolism in patients undergoing heart surgery. Specifically the expression of HIF-1a, PPAR-a and AMPK Hypothesis: We hypothesize that rIP provides myocardial protection in patients presenting for heart surgery and that this protection is defined by a distinct gene expression profile with regards to genes involved in rIP and myocardial metabolism. Study Design: This proposal is for a randomized blinded pilot study on the use of rIP in patients requiring heart surgery. Study Population: The study will include 100 male and female patients undergoing elective heart surgery with cardiopulmonary bypass (CPB). Randomization: Patients will be randomized 1:1 to receive either rIP or no treatment. Blinding Procedures: The patient will be blinded as well as those performing the experimental analysis. Interventions: Remote Ischemic Preconditioning rIP will be induced immediately following induction of anesthesia. Four 5 minute cycles of lower unilateral limb ischemia and reperfusion induced tourniquet inflation to 300 mmHg will constitute the preconditioning stimulus. Blood sample collection/analysis 1. Two cardiac biopsies (50 - 200 mg) will be collected pre-bypass and post- bypass and will be analyzed for gene and protein expression. 2. Blood samples (4 mL) will be drawn immediately before induction of anesthesia, and at the same times as cardiac tissue samples are harvested and analyzed for gene/protein expression as well as at 1, 24, 48 and 72 hours post surgery. Troponin I and NT-ProBNP will be measured at baseline, 1, 24, 48 and 72 hours after surgery and 3 mL of blood will be collected for these tests. A total of 43 mL of blood will be collected per patient. 3. rIP induced changes in leukocyte gene expression will be measured at the aforementioned time points. Other ECG assessment on post-operative day 1, 2, and 3. National Institute of Health stroke scale assessment will be conducted at screening and post operatively prior to hospital discharge. Each patient will receive a telephone follow-up call at 30 days post operatively to collect adverse events and mortality data. Experimental Methods: 1. qRT-PCR will be used to measure gene expression. 2. Immunoblotting will be used to measure protein expression
Interventions
DEVICEBlood Pressure Cuff
The blood pressure cuff will be inflated for 5 minutes and then deflated for 5 minutes. This will be done 4 times in a row.
Sponsors
University of Alberta
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
DOUBLE (Subject, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Written informed consent * Age 18 through 80 years, inclusive * Scheduled for heart surgery with CPB
Exclusion criteria
* Females of childbearing potential * Emergency surgery * Previous sternotomy * Myocardial infarction within 48 hours prior to surgery * Diabetes and/or BMI \>35 * Need for Alpha2-agonists perioperatively * Peripheral Vascular Disease
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Myocardial Protection Against Ischemic Injury | 72 hours post operatively | High-sensitivity cardiac troponin T release as measured by peak hscTnT values and area-under-the-curve. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| All-cause Death and Cardiovascular Long-term Outcome | 6-month cardiovascular outcome | Death and re-hospitalization due to any cause including heart and renal failure and new atrial fibrillation |
Countries
Canada
Participant flow
Pre-assignment details
2 patients were withdrawn for logistical reasons
Participants by arm
| Arm | Count |
|---|---|
| Ischemic Preconditioned Group (rIP) A 15-cm sterile blood pressure cuff was placed around the right thigh and connected to the inflating device, and the patient was draped obscuring the visibility of the cuff. Subsequently, the patient was randomly allocated (by opening of an envelope) to RIPC consisting of four 5-min cycles of lower limb ischemia-reperfusion induced by a tourniquet inflated to 300 mmHg
Blood Pressure Cuff: The blood pressure cuff will be inflated for 5 minutes and then deflated for 5 minutes. This will be done 4 times in a row. | 27 |
| Placebo No rIP as described for rIP group | 28 |
| Total | 55 |
Baseline characteristics
| Characteristic | Placebo | Total | Ischemic Preconditioned Group (rIP) |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 13 Participants | 27 Participants | 14 Participants |
| Age, Categorical Between 18 and 65 years | 15 Participants | 28 Participants | 13 Participants |
| Age, Continuous | 62 Years STANDARD_DEVIATION 10 | 61 Years STANDARD_DEVIATION 8 | 59 Years STANDARD_DEVIATION 7 |
| Race and Ethnicity Not Collected | — | 0 Participants | — |
| Region of Enrollment Canada | 28 participants | 55 participants | 27 participants |
| Sex: Female, Male Female | 4 Participants | 5 Participants | 1 Participants |
| Sex: Female, Male Male | 24 Participants | 50 Participants | 26 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 27 | 1 / 28 |
| other Total, other adverse events | 0 / 27 | 0 / 28 |
| serious Total, serious adverse events | 3 / 27 | 3 / 28 |
Outcome results
Primary
Myocardial Protection Against Ischemic Injury
High-sensitivity cardiac troponin T release as measured by peak hscTnT values and area-under-the-curve.
Time frame: 72 hours post operatively
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ischemic Preconditioned Group (rIP) | Myocardial Protection Against Ischemic Injury | 298 pg/ml | Standard Deviation 266 |
| Placebo | Myocardial Protection Against Ischemic Injury | 231 pg/ml | Standard Deviation 133 |
Secondary
All-cause Death and Cardiovascular Long-term Outcome
Death and re-hospitalization due to any cause including heart and renal failure and new atrial fibrillation
Time frame: 6-month cardiovascular outcome
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ischemic Preconditioned Group (rIP) | All-cause Death and Cardiovascular Long-term Outcome | 0 Participants |
| Placebo | All-cause Death and Cardiovascular Long-term Outcome | 1 Participants |