Remifentanil and Glycemic Response in Cardiac Surgery

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

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.

Study Overview

• Status: Completed
• Conditions: Hyperglycemia; Heart Diseases
• Intervention / Treatment: Drug: Remifentanil; Drug: Fentanyl

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 Type: Interventional
• Enrollment (Actual): 116
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15213
      • UPMC Presbyterian Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / 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.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Kathirvel Subramaniam
• Collaborators: Mylan Inc.
• Investigators: Principal Investigator: Kathrivel Subramaniam, MD, University of Pittsburgh Medical Center

Publications and helpful links

General Publications

• 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. doi: 10.1016/j.jtcvs.2005.05.049.
• 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. doi: 10.1177/147323000903700612.
• 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.
• 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.
• 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.
• 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. No abstract available.
• Subramaniam K, Sciortino C, Ruppert K, Monroe A, Esper S, Boisen M, Marquez J, Hayanga H, Badhwar V. Remifentanil and perioperative glycaemic response in cardiac surgery: an open-label randomised trial. Br J Anaesth. 2020 Jun;124(6):684-692. doi: 10.1016/j.bja.2020.01.028. Epub 2020 Apr 2.

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2016
• Primary Completion (Actual): December 1, 2016
• Study Completion (Actual): December 1, 2017

Study Registration Dates

• First Submitted: January 13, 2015
• First Submitted That Met QC Criteria: January 27, 2015
• First Posted (Estimate): January 28, 2015

Study Record Updates

• Last Update Posted (Actual): April 21, 2020
• Last Update Submitted That Met QC Criteria: April 12, 2020
• Last Verified: April 1, 2020

More Information

Terms related to this study

• Keywords: Cardiopulmonary bypass; Heart surgery
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Glucose Metabolism Disorders; Metabolic Diseases; Hyperglycemia; Heart Diseases; Physiological Effects of Drugs; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Analgesics, Opioid; Narcotics; Adjuvants, Anesthesia; Remifentanil; Fentanyl
• Other Study ID Numbers: PRO14110258

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No