Remifentanil and Glycemic Response in Cardiac Surgery

• Sponsor: Kathirvel Subramaniam (Other)
• Overall Status: Completed
• CT.gov ID: NCT02349152
• Collaborator: Mylan Inc. (Industry)
• Enrollment: 116
• Location: 1
• Arms: 2
• Actual Duration (Months): 23
• Patients Per Site Per Month: 5

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Heart Diseases; Hyperglycemia	Drug: Remifentanil; Drug: Fentanyl	Phase 4

Detailed Description

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 116 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Prevention
• Official Title: 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
• Actual Study Start Date: Jan 1, 2016
• Actual Primary Completion Date: Dec 1, 2016
• Actual Study Completion Date: Dec 1, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Remifentanil group Half of subjects enrolled will be randomized to the remifentanil group	Drug: Remifentanil; 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.; Other Names: Ultiva
Active Comparator: Fentanyl group Half of subjects enrolled will be randomized to the fentanyl group	Drug: Fentanyl; 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.

Outcome Measures

Primary Outcome Measures

1. Blood Glucose Values (More Than One ) > 180 mg% [Intraoperative period]

   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)

Secondary Outcome Measures

1. Insulin Requirement [Intraoperative period; Induction to end of surgery]

   Average dose of insulin (Units/ml) calculated for each group in the intraoperative period

2. Number of Blood Glucose Values > 180 mg% [Intraoperative period, Induction to end of surgery]

   Blood glucose values that exceed 180 mg% will be counted

3. Mean, Peak and Trough Intraoperative Blood Glucose (mg/dl) [Intraoperative period; Induction to end of surgery]

   Blood glucose measured every hour

4. Postoperative Blood Glucose [From ICU Admission (After Surgery) Until 24 hours postoperatively]

   Mean and peak blood glucose levels postoperatively

5. Total Postoperative Regular Insulin [From ICU Admission (After Surgery) Until 24 hours postoperatively]

   Total units of regular insulin required post-operatively

6. Intraoperative Pre-cardiopulmonary Bypass Hemodynamic Stability [induction of anesthesia till systemic heparinization before cardiopulmonary bypass]

   Blood pressure (systolic, diastolic and mean), Heart rate every 5 minutes from induction of anesthesia till systemic heparinization before cardiopulmonary bypass

7. Stress Hormone Levels-Cortisol (µg/dl) [Perioperative period (Intraoperatively and 8 hours postoperatively)]

   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

8. Inflammatory Mediator Levels, Interleukin-1b, Interleukin 6 and Tumor Necrosis Factor (TNF) (pg/ml) [Perioperative period (Intraoperatively and 8 hours postoperatively)]

   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

9. Stress Hormone Levels-ACTH, GH, Glucagon (pg/ml) [Perioperative period (Intraoperatively and 8 hours postoperatively)]

   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

10. Society of Thoracic Surgery Patient Outcomes [30 day 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)

11. Postoperative Pain [Every day 6 hour for 48 hours postoperative period]

    Pain scores; Every day 6 hour for 48 hours postoperative period

12. Emergence From Anesthesia [Immediate postoperative period until 30 days post-operatively]

    Time to extubation after completion of surgery in the operating room and intensive care unit

13. Wound Hyperalgesia [96 hours postoperatively]

    Von frey hair objective testing

14. Development of Chronic Pain [1, 3, 6 and 12 months after discharge from the hospital]

    Telephonic call Numeric pain scale; Scale is 0-10, with 10 being the highest pain.

15. Glycemic Variability [From the start of induction till 24 hours postoperatively]

    Coefficient of variation in blood glucose levels. Denotes how large the fluctuations in blood glucose are. Higher numbers indicate increased variation.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	UPMC Presbyterian Hospital	Pittsburgh	Pennsylvania	United States	15213

Sponsors and Collaborators

• Kathirvel Subramaniam
• Mylan Inc.

Investigators

• Principal Investigator: Kathrivel Subramaniam, MD, University of Pittsburgh Medical Center

Study Documents (Full-Text)

None provided.

More Information

Publications

• Cok OY, Ozkose Z, Pasaoglu H, Yardim S. Glucose response during craniotomy: propofol-remifentanil versus isoflurane-remifentanil. Minerva Anestesiol. 2011 Dec;77(12):1141-8. Epub 2011 May 20.
• Doenst T, Wijeysundera D, Karkouti K, Zechner C, Maganti M, Rao V, Borger MA. Hyperglycemia during cardiopulmonary bypass is an independent risk factor for mortality in patients undergoing cardiac surgery. J Thorac Cardiovasc Surg. 2005 Oct;130(4):1144.
• Ihn CH, Joo JD, Choi JW, Kim DW, Jeon YS, Kim YS, Jung HS, Kwon SY. Comparison of stress hormone response, interleukin-6 and anaesthetic characteristics of two anaesthetic techniques: volatile induction and maintenance of anaesthesia using sevoflurane versus total intravenous anaesthesia using propofol and remifentanil. J Int Med Res. 2009 Nov-Dec;37(6):1760-71.
• Lazar HL, McDonnell M, Chipkin SR, Furnary AP, Engelman RM, Sadhu AR, Bridges CR, Haan CK, Svedjeholm R, Taegtmeyer H, Shemin RJ; Society of Thoracic Surgeons Blood Glucose Guideline Task Force. The Society of Thoracic Surgeons practice guideline series: Blood glucose management during adult cardiac surgery. Ann Thorac Surg. 2009 Feb;87(2):663-9. doi: 10.1016/j.athoracsur.2008.11.011. Review.
• Shinoda T, Murakami W, Takamichi Y, Iizuka H, Tanaka M, Kuwasako Y. Effect of remifentanil infusion rate on stress response in orthopedic surgery using a tourniquet application. BMC Anesthesiol. 2013 Jul 10;13:14. doi: 10.1186/1471-2253-13-14. eCollection 2013.
• Subramaniam B, Lerner A, Novack V, Khabbaz K, Paryente-Wiesmann M, Hess P, Talmor D. Increased glycemic variability in patients with elevated preoperative HbA1C predicts adverse outcomes following coronary artery bypass grafting surgery. Anesth Analg. 2014 Feb;118(2):277-287. doi: 10.1213/ANE.0000000000000100.

• Responsible Party: Kathirvel Subramaniam, Visiting Associate Professor in Anesthesiology, University of Pittsburgh
• ClinicalTrials.gov Identifier: NCT02349152
• Other Study ID Numbers: PRO14110258
• First Posted: Jan 28, 2015
• Last Update Posted: Apr 21, 2020
• Last Verified: Apr 1, 2020

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Kathirvel Subramaniam, Visiting Associate Professor in Anesthesiology, University of Pittsburgh: Cardiopulmonary bypass; Heart surgery
• Additional relevant MeSH terms: Heart Diseases; Hyperglycemia; Fentanyl; Remifentanil

Study Results

Participant Flow

Recruitment Details	The first subject was recruited 01-06-2016. The final subject was recruited 12-28-2016. All enrolled subjects were recruited at Presbyterian Hospital in Pittsburgh, Pennsylvania.
Pre-assignment Detail	No pre-assignment necessary for enrollment

Arm/Group Title	Remifentanil Group	Fentanyl Group
Arm/Group Description	Half of subjects enrolled will be randomized to the remifentanil group Remifentanil: 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.	Half of subjects enrolled will be randomized to the fentanyl group Fentanyl: 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.
Period Title: Overall Study
STARTED	60	56
COMPLETED	54	52
NOT COMPLETED	6	4

Baseline Characteristics

Arm/Group Title	Remifentanil Group	Fentanyl Group	Total
Arm/Group Description	Half of subjects enrolled will be randomized to the remifentanil group Remifentanil: 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.	Half of subjects enrolled will be randomized to the fentanyl group Fentanyl: 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.	Total of all reporting groups
Overall Participants	54	52	106
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	70.0	71.0	70.5
Sex: Female, Male (Count of Participants)
Female	19 35.2%	14 26.9%	33 31.1%
Male	35 64.8%	38 73.1%	73 68.9%
Race and Ethnicity Not Collected (Count of Participants)
Count of Participants [Participants]	0 0%
Region of Enrollment (participants) [Number]
United States	54 100%	52 100%	106 100%

Outcome Measures

1. Primary Outcome

Title	Blood Glucose Values (More Than One ) > 180 mg%
Description	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)
Time Frame	Intraoperative period

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Remifentanil Group	Fentanyl Group
Arm/Group Description	Half of subjects enrolled will be randomized to the remifentanil group Remifentanil: 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.	Half of subjects enrolled will be randomized to the fentanyl group Fentanyl: 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.
Measure Participants	54	52
Count of Participants [Participants]	17 31.5%	33 63.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Remifentanil Group, Fentanyl Group
	Comments	The null hypothesis that there was no difference in the percentage of patients with two or more blood glucose values greater than 180mg/dl between the two groups. Power calculation was performed based on the assumption that continuous remifentanil infusion would reduce the percentage of patients with unacceptable blood glucose values (more than one BG>180 mg/dl) to an absolute value of 20%.
	Type of Statistical Test	Superiority
	Comments	Power calculation was performed based on the assumption that continuous remifentanil infusion would reduce the percentage of patients with unacceptable blood glucose values (more than one BG>180 mg/dl) to an absolute value of 20%. Under these conditions, 52 patients per group would have 90% power to detect a significant difference (alpha= 0.05) between the groups. A total of 116 patients were recruited to allow for dropouts.
Statistical Test of Hypothesis	p-Value	0.001
	Comments
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	1.9
	Confidence Interval	(2-Sided) 95%; 1.3 to 3.0
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Insulin Requirement
Description	Average dose of insulin (Units/ml) calculated for each group in the intraoperative period
Time Frame	Intraoperative period; Induction to end of surgery

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Remifentanil Group	Fentanyl Group
Arm/Group Description	Half of subjects enrolled will be randomized to the remifentanil group Remifentanil: 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.	Half of subjects enrolled will be randomized to the fentanyl group Fentanyl: 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.
Measure Participants	54	52
Median (Full Range) [Units/ml]	2.9	8.1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Remifentanil Group, Fentanyl Group
	Comments
	Type of Statistical Test	Superiority
	Comments	Power calculation was performed based on the assumption that continuous remifentanil infusion would reduce the percentage of patients with unacceptable blood glucose values (more than one BG > 180 mg) to an absolute value of 20%. Under these conditions, 52 patients per group would have 90% power to detect a significant difference (alpha = .05) between the groups. A total of 116 patients were recruited to allow dropouts.
Statistical Test of Hypothesis	p-Value	0.004
	Comments
	Method	t-test, 2 sided
	Comments

3. Secondary Outcome

Title	Number of Blood Glucose Values > 180 mg%
Description	Blood glucose values that exceed 180 mg% will be counted
Time Frame	Intraoperative period, Induction to end of surgery

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Remifentanil Group	Fentanyl Group
Arm/Group Description	Half of subjects enrolled will be randomized to the remifentanil group Remifentanil: 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.	Half of subjects enrolled will be randomized to the fentanyl group Fentanyl: 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.
Measure Participants	54	52
Median (Full Range) [number of glucose values >180mg%]	1.2	2

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Remifentanil Group, Fentanyl Group
	Comments
	Type of Statistical Test	Superiority
	Comments	Power calculation was performed based on the assumption that continuous remifentanil infusion would reduce the percentage of patients with unacceptable blood glucose values (more than one BG>180 mg/dl) to an absolute value of 20%. Under these conditions, 52 patients per group would have 90% power to detect a significant difference (alpha= 0.05) between the groups. A total of 116 patients were recruited to allow for dropouts.
Statistical Test of Hypothesis	p-Value	0.01
	Comments
	Method	Fisher Exact
	Comments

4. Secondary Outcome

Title	Mean, Peak and Trough Intraoperative Blood Glucose (mg/dl)
Description	Blood glucose measured every hour
Time Frame	Intraoperative period; Induction to end of surgery

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Remifentanil Group	Fentanyl Group
Arm/Group Description	Half of subjects enrolled will be randomized to the remifentanil group Remifentanil: 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.	Half of subjects enrolled will be randomized to the fentanyl group Fentanyl: 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.
Measure Participants	54	52
Mean Introperative Blood Glucose	141	156
Peak Intraoperative Blood Glucose	178	205
Lowest Intraoperative Blood Glucose	117	120

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Remifentanil Group, Fentanyl Group
	Comments	Mean Intraoperative Blood Glucose
	Type of Statistical Test	Superiority
	Comments	Power calculation was performed based on the assumption that continuous remifentanil infusion would reduce the percentage of patients with unacceptable blood glucose values (more than one BG > 180 mg) to an absolute value of 20%. Under these conditions, 52 patients per group would have 90% power to detect a significant difference (alpha = .05) between the groups. A total of 116 patients were recruited to allow dropouts.
Statistical Test of Hypothesis	p-Value	0.0001
	Comments
	Method	t-test, 2 sided
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Remifentanil Group, Fentanyl Group
	Comments	Peak Intraoperative Blood Glucose
	Type of Statistical Test	Superiority
	Comments	Power calculation was performed based on the assumption that continuous remifentanil infusion would reduce the percentage of patients with unacceptable blood glucose values (more than one BG > 180 mg) to an absolute value of 20%. Under these conditions, 52 patients per group would have 90% power to detect a significant difference (alpha = .05) between the groups. A total of 116 patients were recruited to allow dropouts.
Statistical Test of Hypothesis	p-Value	0.0003
	Comments
	Method	t-test, 2 sided
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Remifentanil Group, Fentanyl Group
	Comments	Lowest Intraoperative Blood Glucose
	Type of Statistical Test	Superiority
	Comments	Power calculation was performed based on the assumption that continuous remifentanil infusion would reduce the percentage of patients with unacceptable blood glucose values (more than one BG > 180 mg) to an absolute value of 20%. Under these conditions, 52 patients per group would have 90% power to detect a significant difference (alpha = .05) between the groups. A total of 116 patients were recruited to allow dropouts.
Statistical Test of Hypothesis	p-Value	0.98
	Comments
	Method	t-test, 2 sided
	Comments

5. Secondary Outcome

Title	Postoperative Blood Glucose
Description	Mean and peak blood glucose levels postoperatively
Time Frame	From ICU Admission (After Surgery) Until 24 hours postoperatively

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Remifentanil Group	Fentanyl Group
Arm/Group Description	Half of subjects enrolled will be randomized to the remifentanil group Remifentanil: 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.	Half of subjects enrolled will be randomized to the fentanyl group Fentanyl: 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.
Measure Participants	54	52
Mean Postoperative Blood Glucose	139	139
Peak Postoperative Blood Glucose	185	175

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Remifentanil Group, Fentanyl Group
	Comments	Mean post-operative glucose
	Type of Statistical Test	Superiority
	Comments	Power calculation was performed based on the assumption that continuous remifentanil infusion would reduce the percentage of patients with unacceptable blood glucose values (more than one BG > 180 mg) to an absolute value of 20%. Under these conditions, 52 patients per group would have 90% power to detect a significant difference (alpha = .05) between the groups. A total of 116 patients were recruited to allow dropouts.
Statistical Test of Hypothesis	p-Value	0.14
	Comments
	Method	t-test, 2 sided
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Remifentanil Group, Fentanyl Group
	Comments	Peak Postoperative Blood Glucose
	Type of Statistical Test	Superiority
	Comments	Power calculation was performed based on the assumption that continuous remifentanil infusion would reduce the percentage of patients with unacceptable blood glucose values (more than one BG > 180 mg) to an absolute value of 20%. Under these conditions, 52 patients per group would have 90% power to detect a significant difference (alpha = .05) between the groups. A total of 116 patients were recruited to allow dropouts.
Statistical Test of Hypothesis	p-Value	0.25
	Comments
	Method	t-test, 2 sided
	Comments

6. Secondary Outcome

Title	Total Postoperative Regular Insulin
Description	Total units of regular insulin required post-operatively
Time Frame	From ICU Admission (After Surgery) Until 24 hours postoperatively

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Remifentanil Group	Fentanyl Group
Arm/Group Description	Half of subjects enrolled will be randomized to the remifentanil group Remifentanil: 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.	Half of subjects enrolled will be randomized to the fentanyl group Fentanyl: 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.
Measure Participants	54	52
Median (Full Range) [International Units]	28.1	23.5

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Remifentanil Group, Fentanyl Group
	Comments
	Type of Statistical Test	Superiority
	Comments	Power calculation was performed based on the assumption that continuous remifentanil infusion would reduce the percentage of patients with unacceptable blood glucose values (more than one BG > 180 mg) to an absolute value of 20%. Under these conditions, 52 patients per group would have 90% power to detect a significant difference (alpha = .05) between the groups. A total of 116 patients were recruited to allow dropouts.
Statistical Test of Hypothesis	p-Value	0.49
	Comments
	Method	t-test, 2 sided
	Comments

7. Secondary Outcome

Title	Intraoperative Pre-cardiopulmonary Bypass Hemodynamic Stability
Description	Blood pressure (systolic, diastolic and mean), Heart rate every 5 minutes from induction of anesthesia till systemic heparinization before cardiopulmonary bypass
Time Frame	induction of anesthesia till systemic heparinization before cardiopulmonary bypass

Outcome Measure Data

Analysis Population Description

Resources not available to analyze

Arm/Group Title	Remifentanil Group	Fentanyl Group
Arm/Group Description	Half of subjects enrolled will be randomized to the remifentanil group Remifentanil: 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.	Half of subjects enrolled will be randomized to the fentanyl group Fentanyl: 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.
Measure Participants	0	0

8. Secondary Outcome

Title	Stress Hormone Levels-Cortisol (µg/dl)
Description	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
Time Frame	Perioperative period (Intraoperatively and 8 hours postoperatively)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Remifentanil Group	Fentanyl Group
Arm/Group Description	Half of subjects enrolled will be randomized to the remifentanil group Remifentanil: 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.	Half of subjects enrolled will be randomized to the fentanyl group Fentanyl: 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.
Measure Participants	54	52
Serum Cortisol Prebypass	12	12
Serum Cortisol 30 Minute After Start of CPB	6.0	24.5
Serum Cortisol End of CPB	5.0	29.0
Serum Cortisol End of Surgery	8.5	28.0
Serum Cortisol Postoperative (8 Hours)	36.0	45.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Remifentanil Group, Fentanyl Group
	Comments	Prebypass
	Type of Statistical Test	Superiority
	Comments	Power calculation was performed based on the assumption that continuous remifentanil infusion would reduce the percentage of patients with unacceptable blood glucose values (more than one BG > 180 mg) to an absolute value of 20%. Under these conditions, 52 patients per group would have 90% power to detect a significant difference (alpha = .05) between the groups. A total of 116 patients were recruited to allow dropouts.
Statistical Test of Hypothesis	p-Value	0.401
	Comments
	Method	t-test, 2 sided
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Remifentanil Group, Fentanyl Group
	Comments	30 minutes after the start of CPB
	Type of Statistical Test	Non-Inferiority
	Comments	Power calculation was performed based on the assumption that continuous remifentanil infusion would reduce the percentage of patients with unacceptable blood glucose values (more than one BG > 180 mg) to an absolute value of 20%. Under these conditions, 52 patients per group would have 90% power to detect a significant difference (alpha = .05) between the groups. A total of 116 patients were recruited to allow dropouts.
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	t-test, 2 sided
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Remifentanil Group, Fentanyl Group
	Comments	End of CPB
	Type of Statistical Test	Non-Inferiority
	Comments	Power calculation was performed based on the assumption that continuous remifentanil infusion would reduce the percentage of patients with unacceptable blood glucose values (more than one BG > 180 mg) to an absolute value of 20%. Under these conditions, 52 patients per group would have 90% power to detect a significant difference (alpha = .05) between the groups. A total of 116 patients were recruited to allow dropouts.
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	t-test, 2 sided
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Remifentanil Group, Fentanyl Group
	Comments	End of Surgery
	Type of Statistical Test	Non-Inferiority
	Comments	Power calculation was performed based on the assumption that continuous remifentanil infusion would reduce the percentage of patients with unacceptable blood glucose values (more than one BG > 180 mg) to an absolute value of 20%. Under these conditions, 52 patients per group would have 90% power to detect a significant difference (alpha = .05) between the groups. A total of 116 patients were recruited to allow dropouts.
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	t-test, 2 sided
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Remifentanil Group, Fentanyl Group
	Comments	Postoperative (8 hours)
	Type of Statistical Test	Non-Inferiority
	Comments	Power calculation was performed based on the assumption that continuous remifentanil infusion would reduce the percentage of patients with unacceptable blood glucose values (more than one BG > 180 mg) to an absolute value of 20%. Under these conditions, 52 patients per group would have 90% power to detect a significant difference (alpha = .05) between the groups. A total of 116 patients were recruited to allow dropouts.
Statistical Test of Hypothesis	p-Value	0.021
	Comments
	Method	t-test, 2 sided
	Comments

9. Secondary Outcome

Title	Inflammatory Mediator Levels, Interleukin-1b, Interleukin 6 and Tumor Necrosis Factor (TNF) (pg/ml)
Description	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
Time Frame	Perioperative period (Intraoperatively and 8 hours postoperatively)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Remifentanil Group	Fentanyl Group
Arm/Group Description	Half of subjects enrolled will be randomized to the remifentanil group Remifentanil: 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.	Half of subjects enrolled will be randomized to the fentanyl group Fentanyl: 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.
Measure Participants	54	52
IL-1b Pre-bypass	1.2	1.2
IL-1b CPB-30	1.1	1.1
IL-1b CPB-END	1.2	1.2
IL-1b post-bypass	1.1	1.3
IL-1b 8-HR	1.2	1.2
IL-6 Pre-bypass	2.8	2.6
IL-6 CPB-30	7.4	10.3
IL-6 CPB-END	77.2	78.3
IL-6 post-bypass	136	90.9
IL-6 8HR	93.6	92.3
TNFa-Pre-bypass	11.7	10.4
TNFa CPB-30	14.4	12.6
TNFa CPB-END	18.2	14.8
TNFa post-bypass	24.0	17.2
TNFa 8HR	15.4	11.2

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Remifentanil Group, Fentanyl Group
	Comments	Analyzing the IL-1b Pre bypass
	Type of Statistical Test	Superiority
	Comments	Under these conditions, 52 patients per group would have 90% power to detect a significant difference (alpha = .05) between the groups. A total of 116 patients were recruited to allow dropouts.
Statistical Test of Hypothesis	p-Value	0.580
	Comments
	Method	t-test, 2 sided
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Remifentanil Group, Fentanyl Group
	Comments	Analyzing the IL-1b CPB-30
	Type of Statistical Test	Superiority
	Comments	Under these conditions, 52 patients per group would have 90% power to detect a significant difference (alpha = .05) between the groups. A total of 116 patients were recruited to allow dropouts.
Statistical Test of Hypothesis	p-Value	0.815
	Comments
	Method	t-test, 2 sided
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Remifentanil Group, Fentanyl Group
	Comments	Analyzing the CPB-END
	Type of Statistical Test	Superiority
	Comments	Under these conditions, 52 patients per group would have 90% power to detect a significant difference (alpha = .05) between the groups. A total of 116 patients were recruited to allow dropouts.
Statistical Test of Hypothesis	p-Value	0.715
	Comments
	Method	t-test, 2 sided
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Remifentanil Group, Fentanyl Group
	Comments	Analyzing the IL-1b post-bypass
	Type of Statistical Test	Superiority
	Comments	Under these conditions, 52 patients per group would have 90% power to detect a significant difference (alpha = .05) between the groups. A total of 116 patients were recruited to allow dropouts.
Statistical Test of Hypothesis	p-Value	0.330
	Comments
	Method	t-test, 2 sided
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Remifentanil Group, Fentanyl Group
	Comments	Analyzing the IL-1b 8 HR
	Type of Statistical Test	Superiority
	Comments	Under these conditions, 52 patients per group would have 90% power to detect a significant difference (alpha = .05) between the groups. A total of 116 patients were recruited to allow dropouts.
Statistical Test of Hypothesis	p-Value	0.651
	Comments
	Method	t-test, 2 sided
	Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Remifentanil Group, Fentanyl Group
	Comments	Analyzing the IL-6 Pre bypass
	Type of Statistical Test	Superiority
	Comments	Under these conditions, 52 patients per group would have 90% power to detect a significant difference (alpha = .05) between the groups. A total of 116 patients were recruited to allow dropouts.
Statistical Test of Hypothesis	p-Value	0.439
	Comments
	Method	t-test, 2 sided
	Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Remifentanil Group, Fentanyl Group
	Comments	Analyzing the IL-6 CPB-30
	Type of Statistical Test	Superiority
	Comments	Under these conditions, 52 patients per group would have 90% power to detect a significant difference (alpha = .05) between the groups. A total of 116 patients were recruited to allow dropouts.
Statistical Test of Hypothesis	p-Value	0.284
	Comments
	Method	t-test, 2 sided
	Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Remifentanil Group, Fentanyl Group
	Comments	Analyzing the CPB-END
	Type of Statistical Test	Superiority
	Comments	Under these conditions, 52 patients per group would have 90% power to detect a significant difference (alpha = .05) between the groups. A total of 116 patients were recruited to allow dropouts.
Statistical Test of Hypothesis	p-Value	0.779
	Comments
	Method	t-test, 2 sided
	Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Remifentanil Group, Fentanyl Group
	Comments	Analyzing the IL-6 post-bypass
	Type of Statistical Test	Superiority
	Comments	Under these conditions, 52 patients per group would have 90% power to detect a significant difference (alpha = .05) between the groups. A total of 116 patients were recruited to allow dropouts.
Statistical Test of Hypothesis	p-Value	0.274
	Comments
	Method	t-test, 2 sided
	Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Remifentanil Group, Fentanyl Group
	Comments	Analyzing the IL-6 8HR
	Type of Statistical Test	Superiority
	Comments	Under these conditions, 52 patients per group would have 90% power to detect a significant difference (alpha = .05) between the groups. A total of 116 patients were recruited to allow dropouts.
Statistical Test of Hypothesis	p-Value	0.601
	Comments
	Method	t-test, 2 sided
	Comments

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Remifentanil Group, Fentanyl Group
	Comments	Analyzing the TNFa Pre-bypass
	Type of Statistical Test	Superiority
	Comments	Under these conditions, 52 patients per group would have 90% power to detect a significant difference (alpha = .05) between the groups. A total of 116 patients were recruited to allow dropouts.
Statistical Test of Hypothesis	p-Value	0.315
	Comments
	Method	t-test, 2 sided
	Comments

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	Remifentanil Group, Fentanyl Group
	Comments	Analyzing the TNFa CPB-30
	Type of Statistical Test	Superiority
	Comments	Under these conditions, 52 patients per group would have 90% power to detect a significant difference (alpha = .05) between the groups. A total of 116 patients were recruited to allow dropouts.
Statistical Test of Hypothesis	p-Value	0.062
	Comments
	Method	t-test, 2 sided
	Comments

Statistical Analysis 13

Statistical Analysis Overview	Comparison Group Selection	Remifentanil Group, Fentanyl Group
	Comments	Analyzing the TNFa CPB-END
	Type of Statistical Test	Superiority
	Comments	Under these conditions, 52 patients per group would have 90% power to detect a significant difference (alpha = .05) between the groups. A total of 116 patients were recruited to allow dropouts.
Statistical Test of Hypothesis	p-Value	0.090
	Comments
	Method	t-test, 2 sided
	Comments

Statistical Analysis 14

Statistical Analysis Overview	Comparison Group Selection	Remifentanil Group, Fentanyl Group
	Comments	Analyzing the TNFa- post-bypass
	Type of Statistical Test	Superiority
	Comments	Under these conditions, 52 patients per group would have 90% power to detect a significant difference (alpha = .05) between the groups. A total of 116 patients were recruited to allow dropouts.
Statistical Test of Hypothesis	p-Value	0.004
	Comments
	Method	t-test, 2 sided
	Comments

Statistical Analysis 15

Statistical Analysis Overview	Comparison Group Selection	Remifentanil Group, Fentanyl Group
	Comments	Analyzing the TNFa-8HR
	Type of Statistical Test	Superiority
	Comments	Under these conditions, 52 patients per group would have 90% power to detect a significant difference (alpha = .05) between the groups. A total of 116 patients were recruited to allow dropouts.
Statistical Test of Hypothesis	p-Value	0.074
	Comments
	Method	t-test, 2 sided
	Comments

10. Secondary Outcome

Title	Stress Hormone Levels-ACTH, GH, Glucagon (pg/ml)
Description	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
Time Frame	Perioperative period (Intraoperatively and 8 hours postoperatively)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Remifentanil Group	Fentanyl Group
Arm/Group Description	Half of subjects enrolled will be randomized to the remifentanil group Remifentanil: 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.	Half of subjects enrolled will be randomized to the fentanyl group Fentanyl: 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.
Measure Participants	54	52
ACTH pre-bypass	7.4	7.4
ACTH CPB-30	4.4	57.8
ACTH CPB-END	4.4	30.7
ACTH post-bypass	8.0	49.1
ACTH 8-hr	77.0	41.3
GH-Pre-bypass	495	872
GH-CPB-30	826	3202
GH-CPB-END	947	2545
GH-post-bypass	37364	4461
GH-8HR	3658	2696
Glucagon pre-bypass	229	192
Glucagon CPB-30	259	338
Glucagon CPB-End	401	481
Glucagon post-bypass	315	408
Glucagon 8-HR	570	459

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Remifentanil Group, Fentanyl Group
	Comments	Analyzing the ACTH Pre-bypass group
	Type of Statistical Test	Non-Inferiority
	Comments	Under these conditions, 52 patients per group would have 90% power to detect a significant difference (alpha = .05) between the groups. A total of 116 patients were recruited to allow dropouts.
Statistical Test of Hypothesis	p-Value	0.740
	Comments
	Method	t-test, 2 sided
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Remifentanil Group, Fentanyl Group
	Comments	Analyzing the ACTH CPB-30 group.
	Type of Statistical Test	Non-Inferiority
	Comments	Under these conditions, 52 patients per group would have 90% power to detect a significant difference (alpha = .05) between the groups. A total of 116 patients were recruited to allow dropouts.
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	t-test, 2 sided
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Remifentanil Group, Fentanyl Group
	Comments	Analyzing the ACTH CPB-END
	Type of Statistical Test	Non-Inferiority
	Comments	Under these conditions, 52 patients per group would have 90% power to detect a significant difference (alpha = .05) between the groups. A total of 116 patients were recruited to allow dropouts.
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	t-test, 2 sided
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Remifentanil Group, Fentanyl Group
	Comments	Analyzing the ACTH post-bypass
	Type of Statistical Test	Non-Inferiority
	Comments	Under these conditions, 52 patients per group would have 90% power to detect a significant difference (alpha = .05) between the groups. A total of 116 patients were recruited to allow dropouts.
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	t-test, 2 sided
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Remifentanil Group, Fentanyl Group
	Comments	Analyzing the ACTH 8-hr
	Type of Statistical Test	Superiority
	Comments	Under these conditions, 52 patients per group would have 90% power to detect a significant difference (alpha = .05) between the groups. A total of 116 patients were recruited to allow dropouts.
Statistical Test of Hypothesis	p-Value	0.014
	Comments
	Method	t-test, 2 sided
	Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Remifentanil Group, Fentanyl Group
	Comments	Analyzing the GH- Pre-bypass
	Type of Statistical Test	Superiority
	Comments	Under these conditions, 52 patients per group would have 90% power to detect a significant difference (alpha = .05) between the groups. A total of 116 patients were recruited to allow dropouts.
Statistical Test of Hypothesis	p-Value	0.100
	Comments
	Method	t-test, 2 sided
	Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Remifentanil Group, Fentanyl Group
	Comments	GH-CPB-30
	Type of Statistical Test	Superiority
	Comments	Under these conditions, 52 patients per group would have 90% power to detect a significant difference (alpha = .05) between the groups. A total of 116 patients were recruited to allow dropouts.
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	t-test, 2 sided
	Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Remifentanil Group, Fentanyl Group
	Comments	Analyzing the GH-CPB-END
	Type of Statistical Test	Superiority
	Comments	Under these conditions, 52 patients per group would have 90% power to detect a significant difference (alpha = .05) between the groups. A total of 116 patients were recruited to allow dropouts.
Statistical Test of Hypothesis	p-Value	0.009
	Comments
	Method	t-test, 2 sided
	Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Remifentanil Group, Fentanyl Group
	Comments	GH-Post-bypass
	Type of Statistical Test	Superiority
	Comments	Under these conditions, 52 patients per group would have 90% power to detect a significant difference (alpha = .05) between the groups. A total of 116 patients were recruited to allow dropouts.
Statistical Test of Hypothesis	p-Value	0.046
	Comments
	Method	t-test, 2 sided
	Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Remifentanil Group, Fentanyl Group
	Comments	Analyzing the GH-8-hr
	Type of Statistical Test	Superiority
	Comments	Under these conditions, 52 patients per group would have 90% power to detect a significant difference (alpha = .05) between the groups. A total of 116 patients were recruited to allow dropouts.
Statistical Test of Hypothesis	p-Value	0.695
	Comments
	Method	t-test, 2 sided
	Comments

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Remifentanil Group, Fentanyl Group
	Comments	Analyzing the Glucagon Pre Bypass
	Type of Statistical Test	Superiority
	Comments	Under these conditions, 52 patients per group would have 90% power to detect a significant difference (alpha = .05) between the groups. A total of 116 patients were recruited to allow dropouts.
Statistical Test of Hypothesis	p-Value	0.455
	Comments
	Method	t-test, 2 sided
	Comments

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	Remifentanil Group, Fentanyl Group
	Comments	Analyzing the Glucagon CPB-30
	Type of Statistical Test	Superiority
	Comments	Under these conditions, 52 patients per group would have 90% power to detect a significant difference (alpha = .05) between the groups. A total of 116 patients were recruited to allow dropouts.
Statistical Test of Hypothesis	p-Value	0.059
	Comments
	Method	t-test, 2 sided
	Comments

Statistical Analysis 13

Statistical Analysis Overview	Comparison Group Selection	Remifentanil Group, Fentanyl Group
	Comments	Analyzing the Glucagon CPB-END
	Type of Statistical Test	Superiority
	Comments	Under these conditions, 52 patients per group would have 90% power to detect a significant difference (alpha = .05) between the groups. A total of 116 patients were recruited to allow dropouts.
Statistical Test of Hypothesis	p-Value	0.175
	Comments
	Method	t-test, 2 sided
	Comments

Statistical Analysis 14

Statistical Analysis Overview	Comparison Group Selection	Remifentanil Group, Fentanyl Group
	Comments	Analyzing the Glucagon Post-bypass
	Type of Statistical Test	Superiority
	Comments	Under these conditions, 52 patients per group would have 90% power to detect a significant difference (alpha = .05) between the groups. A total of 116 patients were recruited to allow dropouts.
Statistical Test of Hypothesis	p-Value	0.062
	Comments
	Method	t-test, 2 sided
	Comments

Statistical Analysis 15

Statistical Analysis Overview	Comparison Group Selection	Remifentanil Group, Fentanyl Group
	Comments	Analyzing the Glucagon 8-hr
	Type of Statistical Test	Superiority
	Comments	Under these conditions, 52 patients per group would have 90% power to detect a significant difference (alpha = .05) between the groups. A total of 116 patients were recruited to allow dropouts.
Statistical Test of Hypothesis	p-Value	0.261
	Comments
	Method	t-test, 2 sided
	Comments

11. Secondary Outcome

Title	Society of Thoracic Surgery Patient Outcomes
Description	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)
Time Frame	30 day outcomes

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Remifentanil Group	Fentanyl Group
Arm/Group Description	Half of subjects enrolled will be randomized to the remifentanil group Remifentanil: 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.	Half of subjects enrolled will be randomized to the fentanyl group Fentanyl: 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.
Measure Participants	54	52
30 day Mortality	1 1.9%	6 11.5%
30 day Readmission	3 5.6%	10 19.2%
Cerebral Vascular Accident	0 0%	2 3.8%
Prolonged mechanical ventilation	8 14.8%	8 15.4%
renal failure	3 5.6%	3 5.8%
atrial fibrillation	24 44.4%	18 34.6%
cardiac arrest	3 5.6%	3 5.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Remifentanil Group, Fentanyl Group
	Comments	30-day mortality
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.06
	Comments
	Method	Chi-squared
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Remifentanil Group, Fentanyl Group
	Comments	30-day readmission
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.03
	Comments
	Method	Chi-squared
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Remifentanil Group, Fentanyl Group
	Comments	Cerebral Vascular Accident
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.24
	Comments
	Method	Chi-squared
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Remifentanil Group, Fentanyl Group
	Comments	Prolonged Mechanical Ventilation
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.93
	Comments
	Method	Chi-squared
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Remifentanil Group, Fentanyl Group
	Comments	Renal Failure
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	1
	Comments
	Method	Chi-squared
	Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Remifentanil Group, Fentanyl Group
	Comments	Atrial Fibrillation
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.10
	Comments
	Method	Chi-squared
	Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Remifentanil Group, Fentanyl Group
	Comments	cardiac arrest
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	1
	Comments
	Method	Chi-squared
	Comments

12. Secondary Outcome

Title	Postoperative Pain
Description	Pain scores; Every day 6 hour for 48 hours postoperative period
Time Frame	Every day 6 hour for 48 hours postoperative period

Outcome Measure Data

Analysis Population Description

This is a mixed model analysis to account for missing VAS values

Arm/Group Title	Remifentanil Group	Fentanyl Group
Arm/Group Description	Half of subjects enrolled will be randomized to the remifentanil group Remifentanil: 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.	Half of subjects enrolled will be randomized to the fentanyl group Fentanyl: 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.
Measure Participants	54	52
Hours 0-6	6.63 (1.66)	7.18 (2.37)
Hrs 7-12	6.53 (2.23)	6.09 (2.19)
Hrs 13-18	6.59 (2.07)	5.18 (2.76)
Hrs 19-24	5.88 (2.28)	5.73 (2.38)
Hrs 25-30	5.94 (5.94)	5.65 (2.25)
Hrs 31-36	5.89 (2.31)	5.94 (2.44)
Hrs 37-42	5.57 (2.35)	5.18 (2.70)
Hrs 43-48	5.08 (2.74)	5.10 (3.11)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Remifentanil Group, Fentanyl Group
	Comments	Hrs 0-6
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.205
	Comments
	Method	t-test, 2 sided
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Remifentanil Group, Fentanyl Group
	Comments	Hrs 7-12
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.339
	Comments
	Method	t-test, 2 sided
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Remifentanil Group, Fentanyl Group
	Comments	Hrs 13-18
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.006
	Comments
	Method	t-test, 2 sided
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Remifentanil Group, Fentanyl Group
	Comments	Hrs 19-24
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.747
	Comments
	Method	t-test, 2 sided
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Remifentanil Group, Fentanyl Group
	Comments	Hrs 25-30
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.568
	Comments
	Method	t-test, 2 sided
	Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Remifentanil Group, Fentanyl Group
	Comments	Hrs 31-36
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.924
	Comments
	Method	t-test, 2 sided
	Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Remifentanil Group, Fentanyl Group
	Comments	Hrs 37-42
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.501
	Comments
	Method	t-test, 2 sided
	Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Remifentanil Group, Fentanyl Group
	Comments	Hrs 43-48
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.977
	Comments
	Method	t-test, 2 sided
	Comments

13. Secondary Outcome

Title	Emergence From Anesthesia
Description	Time to extubation after completion of surgery in the operating room and intensive care unit
Time Frame	Immediate postoperative period until 30 days post-operatively

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Remifentanil Group	Fentanyl Group
Arm/Group Description	Half of subjects enrolled will be randomized to the remifentanil group Remifentanil: 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.	Half of subjects enrolled will be randomized to the fentanyl group Fentanyl: 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.
Measure Participants	54	52
Median (Full Range) [Hours]	3	2.5

14. Secondary Outcome

Title	Wound Hyperalgesia
Description	Von frey hair objective testing
Time Frame	96 hours postoperatively

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Remifentanil Group	Fentanyl Group
Arm/Group Description	Half of subjects enrolled will be randomized to the remifentanil group Remifentanil: 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.	Half of subjects enrolled will be randomized to the fentanyl group Fentanyl: 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.
Measure Participants	54	52
Preop pain threshold	3.24 (0.94)	3.30 (1.08)
48 Hr pain threshold	3.71 (1.00)	3.83 (1.28)
96 hr pain threshold	3.60 (1.08)	3.72 (1.30)

15. Secondary Outcome

Title	Development of Chronic Pain
Description	Telephonic call Numeric pain scale; Scale is 0-10, with 10 being the highest pain.
Time Frame	1, 3, 6 and 12 months after discharge from the hospital

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Remifentanil Group	Fentanyl Group
Arm/Group Description	Half of subjects enrolled will be randomized to the remifentanil group Remifentanil: 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.	Half of subjects enrolled will be randomized to the fentanyl group Fentanyl: 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.
Measure Participants	54	52
S-LANSS 1 mo	1	3
S-LANSS 3 mo	0	0
S-LANSS 6 mo	0	0
S-LANSS 12 mo	0	0

16. Secondary Outcome

Title	Glycemic Variability
Description	Coefficient of variation in blood glucose levels. Denotes how large the fluctuations in blood glucose are. Higher numbers indicate increased variation.
Time Frame	From the start of induction till 24 hours postoperatively

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Remifentanil Group	Fentanyl Group
Arm/Group Description	Half of subjects enrolled will be randomized to the remifentanil group Remifentanil: 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.	Half of subjects enrolled will be randomized to the fentanyl group Fentanyl: 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.
Measure Participants	54	52
Mean (Full Range) [Percent of Mean Glucose Level]	0.2	0.2

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Remifentanil Group, Fentanyl Group
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.350
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Adverse Events

Arm/Group Title	Remifentanil Group		Fentanyl Group
Arm/Group Description	Half of subjects enrolled will be randomized to the remifentanil group Remifentanil: 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.		Half of subjects enrolled will be randomized to the fentanyl group Fentanyl: 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.
All Cause Mortality
	Remifentanil Group		Fentanyl Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/54 (5.6%)		6/52 (11.5%)
Serious Adverse Events
	Remifentanil Group		Fentanyl Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/54 (1.9%)		5/52 (9.6%)
Cardiac disorders
Pericardial effusion/tamponade	0/54 (0%)		1/52 (1.9%)
Nervous system disorders
Stroke	1/54 (1.9%)		0/52 (0%)
Respiratory, thoracic and mediastinal disorders
Pneumonia	0/54 (0%)		1/52 (1.9%)
Pleural effusion	0/54 (0%)		3/52 (5.8%)
Other (Not Including Serious) Adverse Events
	Remifentanil Group		Fentanyl Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	28/54 (51.9%)		27/52 (51.9%)
Cardiac disorders
Cardiac Arrest	3/54 (5.6%)		3/52 (5.8%)
General disorders
Multisystem Organ Failure	3/54 (5.6%)		2/52 (3.8%)
Readmission within 30 days	2/54 (3.7%)		5/52 (9.6%)
Renal and urinary disorders
Renal Failure	3/54 (5.6%)		3/52 (5.8%)
Dialysis	3/54 (5.6%)		3/52 (5.8%)
Respiratory, thoracic and mediastinal disorders
Prolonged Mechanical Ventilation (>72 hours)	8/54 (14.8%)		8/52 (15.4%)
Reintubation	5/54 (9.3%)		7/52 (13.5%)
Pneumonia	4/54 (7.4%)		3/52 (5.8%)
Surgical and medical procedures
Any postoperative complication	28/54 (51.9%)		27/52 (51.9%)
Sepsis	4/54 (7.4%)		4/52 (7.7%)
Rhythm Requiring Permanent Pacemaker Insertion	2/54 (3.7%)		0/52 (0%)
Rhythm Requiring Permanent Pacemaker/ACID	0/54 (0%)		2/52 (3.8%)
Vascular disorders
Cerebrovascular Accident	0/54 (0%)		2/52 (3.8%)
Transient Ischemic Attacks	1/54 (1.9%)		0/52 (0%)
Pulmonary Thromboembolism	0/54 (0%)		0/52 (0%)
Venous Thromboembolism	1/54 (1.9%)		0/52 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.