Remifentanil and Glycemic Response in Cardiac Surgery

Study Overview
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Brief Summary
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This study evaluates the effect of using remifentanil during cardiopulmonary bypass surgery to supress the hyperglycemic response in perioperative period. Half of the participants will receive continuous intravenous remifentanil during surgery, while the other half will receive intermittent intravenous fentanyl during surgery. Intermittent intravenous fentanyl administration is this institution's standard of care.

Detailed Description
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Stress-induced hyperglycemia is a well-known phenomena that occurs during cardiopulmonary bypass surgery. Hyperglycemia increases the incidence of major adverse events and mortality in patients undergoing cardiac surgery. Remifentanil, an ultra-short acting opioid analgesic, has been shown to reduce the stress response to cardiopulmonary bypass when compared to intermittent fentanyl and inhalation anesthesia. This in turn, will reduce the occurence of perioperative hyperglycemia, glycemic variability and insulin requirements in patients undergoing cardiac surgery. NOTE; Primary Outcome changed on 06/15/2015-Change Approved by University of Pittsburgh IRB on 06/22/2015- First patient enrolled January 2016. Primary outcome measure; Percentage of patients with two or more than two intraoperative blood glucose levels more than 180 mg% in both groups will be estimated and the difference in this parameter between the two groups will form the primary outcome measure of this study.

Official Title
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The Effect of Intraoperative Continuous Remifentanil Infusion on Glycemic Response and Variability in Patients Undergoing Cardiac Surgery With Cardiopulmonary Bypass: A Prospective, Randomized, Open Label Clinical Trial

Conditions
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Heart Diseases, Hyperglycemia

Intervention / Treatment
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* Drug: Remifentanil
* Drug: Fentanyl


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Open cardiac surgery through sternotomy approach (coronary artery bypass, valve surgery, and any other open heart surgeries) Surgery with use of cardiopulmonary bypass Patients over 18 years of age Both female and male genders All races Exclusion Criteria: Minimally invasive heart surgery through thoracotomy approach Patients receiving regional analgesia such as intrathecal morphine Patients undergoing procedures under deep hypothermic circulatory arrest Patients with active infections such as acute infective endocarditis Emergency surgery Patients undergoing transplantations and ventricular assist device insertion Patients on any mechanical circulatory support preoperatively Patient's refusal Allergy to remifentanil Positive pregnancy test Morbid obesity End stage liver and kidney disease

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Remifentanil group<br>Half of subjects enrolled will be randomized to the remifentanil group | Drug: Remifentanil<br>* Subjects in the experimental group will receive remifentanil infusion 0.1-0.4ug/kg/minute before induction of anesthesia and continued until skin closure. During cardiopulmonary bypass, remifentanil infusion will be increased to 0.5-1 ug/kg/min as hemodynamically tolerated.<br>* Other names: Ultiva;|
| Active Comparator: Fentanyl group<br>Half of subjects enrolled will be randomized to the fentanyl group | Drug: Fentanyl<br>* Subjects in the control group will initially receive intermittent boluses of Fentanyl in the range of 50-250 ug. Additional fentanyl can be given titrated to hemodynamic parameters throughout surgery.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Blood Glucose Values (More Than One ) > 180 mg% | Percentage of patients with two or more intraoperative blood glucose levels greater than 180 mg/dl. Percentage in both groups will be estimated, then the difference in this statistic will form the primary outcome measure of this study. (Primary Outcome changed on 06/15/2015-Change Approved by University of Pittsburgh IRB on 06/22/2015- First patient enrolled January 2016) | Intraoperative period | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Insulin Requirement | Average dose of insulin (Units/ml) calculated for each group in the intraoperative period | Intraoperative period; Induction to end of surgery | 
| Number of Blood Glucose Values > 180 mg% | Blood glucose values that exceed 180 mg% will be counted | Intraoperative period, Induction to end of surgery | 
| Mean, Peak and Trough Intraoperative Blood Glucose (mg/dl) | Blood glucose measured every hour | Intraoperative period; Induction to end of surgery | 
| Postoperative Blood Glucose | Mean and peak blood glucose levels postoperatively | From ICU Admission (After Surgery) Until 24 hours postoperatively | 
| Total Postoperative Regular Insulin | Total units of regular insulin required post-operatively | From ICU Admission (After Surgery) Until 24 hours postoperatively | 
| Intraoperative Pre-cardiopulmonary Bypass Hemodynamic Stability | Blood pressure (systolic, diastolic and mean), Heart rate every 5 minutes from induction of anesthesia till systemic heparinization before cardiopulmonary bypass | induction of anesthesia till systemic heparinization before cardiopulmonary bypass | 
| Stress Hormone Levels-Cortisol (µg/dl) | Serum cortisol levels (measured as µg/dl) taken at: Prebypass, cardiopulmonary bypass (2 samples: at start of bypass and end of bypass), postbypass, ICU 8 hours postoperative period | Perioperative period (Intraoperatively and 8 hours postoperatively) | 
| Inflammatory Mediator Levels, Interleukin-1b, Interleukin 6 and Tumor Necrosis Factor (TNF) (pg/ml) | Inflammatory mediator levels, Interleukin-1b (IL-1b), Interleukin 6 (IL-6) and Tumor Necrosis Factor Alpha (TNFa) (all measured in pg/ml) taken at: Prebypass, cardiopulmonary bypass (2 samples:30 min start of bypass (CPB-30) and end of bypass (CPB-END), postbypass, ICU 8 hours postoperative period | Perioperative period (Intraoperatively and 8 hours postoperatively) | 
| Stress Hormone Levels-ACTH, GH, Glucagon (pg/ml) | Adreno-corticotrophic hormone (ACTH), Growth Hormone (GH) and Glucagon (measured as pg/ml) taken at: Prebypass, cardiopulmonary bypass (2 samples: 30 mins after start of bypass (CPB 30) and end of bypass (CPB END), post-bypass and ICU 8 hours postoperative period | Perioperative period (Intraoperatively and 8 hours postoperatively) | 
| Society of Thoracic Surgery Patient Outcomes | Postoperative outcomes collected from the Society of Thoracic Surgery (STS) database. 30 day Mortality (outcome 1) and 30 day Readmission (outcome 2) cerebral vascular accident(outcome 3), prolonged mechanical ventilation (outcome 4), renal failure (outcome 5), atrial fibrillation (outcome 6), cardiac arrest (outcome 7) | 30 day outcomes | 
| Postoperative Pain | Pain scores; Every day 6 hour for 48 hours postoperative period | Every day 6 hour for 48 hours postoperative period | 
| Emergence From Anesthesia | Time to extubation after completion of surgery in the operating room and intensive care unit | Immediate postoperative period until 30 days post-operatively | 
| Wound Hyperalgesia | Von frey hair objective testing | 96 hours postoperatively | 
| Development of Chronic Pain | Telephonic call Numeric pain scale; Scale is 0-10, with 10 being the highest pain. | 1, 3, 6 and 12 months after discharge from the hospital | 
| Glycemic Variability | Coefficient of variation in blood glucose levels. Denotes how large the fluctuations in blood glucose are. Higher numbers indicate increased variation. | From the start of induction till 24 hours postoperatively | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cardiopulmonary bypass, Heart surgery