Norepinephrine Infusion During Cardiopulmonary Bypass (Norcal)

Effects of Norepinephrine Infusion During Cardiopulmonary Bypass on Perioperative Changes in Lactic Acid Level: A Randomized Controlled Study

The primary objective is to test the efficacy and safety of the accuracy of continuous intravenous infusion of norepinephrine during cardiopulmonary bypass (CPB) on the prevention of hyperlactatemia after cardiac surgery.

"Efficacy" would be tested with measurement of the postoperative changes in lactic acid level over time from the baseline value before induction of general anesthesia.

"safety" would be tested with observing the post-cardiotomy need for inotropic and vasopressor support, the incidence of postoperative acute kidney injury (AKI), changes in cardiac troponin level (CnTnI), and signs of ischemic splanchnic injury.

Study Overview

• Status: Completed
• Conditions: Cardiac Surgery; Cardiopulmonary Bypass
• Intervention / Treatment: Drug: Placebo; Other: Increase infusion rate; Other: Decrease infusion rate; Drug: Norepinephrine

Detailed Description

Rationale

1.1. Vasoplegia and cardiac surgery:

Vasoplegia Syndrome (VS), prevailing in about 20% of cardiac surgical procedures (1), is defined as low mean arterial pressure (MAP) with normal or high cardiac indices and which is resistant to treatment with the commonly used vasopressors. (2,3) Vasoplegia might occur either during or after the cardiopulmonary bypass periods or during the postoperative period during the intensive care unit (ICU) stay. (3) Many factors have been found to be related to the increased Vasoplegia during the cardiopulmonary bypass period such as left ventricular ejection fraction more than 40%, male patients, elderly patients, higher body mass index, long cardiopulmonary bypass time, hypotension upon the start of cardiopulmonary bypass, perioperative use of angiotensin-converting enzyme inhibitors (ACE) and presence of infective endocarditis. (4,5)

1.2. Effects of Cardiopulmonary bypass (CPB) on Post cardiotomy Vasoplegia.

Cardiopulmonary bypass itself may intensify the effects of vasoplegia due to hemodilution which decreases the blood viscosity, so, reducing the overall peripheral vascular resistance. Moreover, the interaction of blood with the tubing of the cardiopulmonary bypass machine results in the release of inflammatory mediators which play an important role in reducing the peripheral resistance and aggravating the hypotension. Although compensatory and auto-regulatory mechanisms play an important role in maintaining adequate tissue perfusion, hypotension during the cardiopulmonary bypass period may result in poor outcomes as postoperative stroke (4) especially if the mean arterial pressure is below 65 mmHg. (6)

1.3. Hyperlactatemia after cardiac surgery

Lactate was used as a marker for adequate tissue perfusion since the mid-1800s. Although the literature has illustrated the undesirable effects of high lactate levels, however, the cause, the prevention as well as treatment measures of hyperlactatemia remain obscure. Additionally, lactic acidosis or hyperlactatemia might occur in cases of refractory vasoplegia. A rise in lactate levels is common during cardiac surgery and is well known for its deleterious and its association with poor patients' outcomes. (7)

Owing to its detrimental effects, measures to reduce the effects and treat vasoplegia were used. Firstly, excluding any equipment or mechanical failure such as the arterial line monitor, adjusting the bypass flows for higher cardiac index (CI>2.2), confirming the proper cannula position and ruling out any aortic dissection.

Secondly, adjusting some physiological parameters is of great value as checking hematocrit level for excessive hemodilution, adjusting the anesthetics with severe vasodilatory properties, excluding the possibility of a drug reaction or anaphylaxis and temperature management during hypothermic bypass.

Thirdly, the use of conventional vasopressor agents as phenylephrine, norepinephrine, and vasopressin. Finally, the use of some off-label agents as vitamin C, hydroxocobalamin, angiotensin 2, methylene blue and prostaglandin inhibitors. (8)

1.4. Why this clinical trial?

The use of norepinephrine during CPB has its own potential benefits. It is not clear if the use of continuous norepinephrine infusion during CPB would be effective and safe in lessening the postoperative hyperlactatemia and development of vasoplegia after cardiac surgery.

The here proposed randomized controlled clinical trial will test the use of continuous norepinephrine infusion during CPB with respect to the efficacy and safety to reduce the postoperative rise in blood lactate level.

• Study Type: Interventional
• Enrollment (Actual): 80
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Saudi Arabia
  • Eastern
    • Khobar, Eastern, Saudi Arabia, 31952
      • Dammam University
  • Esatern
    • Dammam, Esatern, Saudi Arabia, 31952
      • Imam Abdulrahamn Bin Faisal University (Former, Dammam University)

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:

• American Society of Anesthesiologists (ASA) physical status between ІІІ and ІV
• Scheduled for any type of elective cardiac surgery using CPB
• General anesthesia provided in an endotracheally intubated patient.

Exclusion Criteria:

• Decline consent to participate.
• Emergency surgery.
• Ejection fraction (EF%) less than 35%.
• Scheduled for re-do surgery.
• Scheduled for emergency surgery.
• Preoperative ventilator or circulatory support.
• Body mass index (BMI) greater than 40 Kg/m2.
• History of alcohol abuse.
• History of drug abuse.
• Pregnancy.
• Consent for another interventional study during anaesthesia
• No written informed consent.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Infusion of normal Saline 0.9%will be started following arterial cannulation before initiation of cardiopulmonary bypass and continued until aortic declamping time.	Drug: Placebo; Patients undergoing different cardiac surgical procedures will receive a continuous intravenous infusion of Normal Saline 0.9% with a starting dose of 0.0025 ml/kg/min.; Other: Increase infusion rate; Infusion rate will be increased as needed in order to maintain a MAP ≥65 mmHg during cardiopulmonary bypass period as per the discretion of the anesthesiologist using 0.00125 ml/kg/min increments; Other: Decrease infusion rate; Infusion rate will be decreased as needed in order to maintain a MAP ≥65 mmHg during cardiopulmonary bypass period as per the discretion of the anesthesiologist using 0.00125 ml/kg/min decrements
Active Comparator: Norepinephrine; Infusion of norepinephrine (40 µg/ml) will be started following arterial cannulation before initiation of cardiopulmonary bypass and continued until aortic declamping time.	Other: Increase infusion rate; Infusion rate will be increased as needed in order to maintain a MAP ≥65 mmHg during cardiopulmonary bypass period as per the discretion of the anesthesiologist using 0.00125 ml/kg/min increments; Other: Decrease infusion rate; Infusion rate will be decreased as needed in order to maintain a MAP ≥65 mmHg during cardiopulmonary bypass period as per the discretion of the anesthesiologist using 0.00125 ml/kg/min decrements; Drug: Norepinephrine; Patients undergoing different cardiac surgical procedures will receive a continuous intravenous infusion of norepinephrine (40 ug/ml) with a starting dose of 0.0025 ml/kg/min.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in lactic acid level	perioperative changes in lactic acid level measured from arterial or venous blood	For 24 hours after surgery from the start of surgery

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean Arterial Pressure (MAP)	invasive arterial blood pressure measurement	For 24 hours after surgery from the start of surgery
Cardiac Index (CI)	measured as l/min/m2	For 24 hours after surgery from the start of surgery
Systemic Vascular Resistance index (SVRI)	measured as dynes.sec.m2/cm5	For 24 hours after surgery from the start of surgery
Stroke volume variation (SVV)	measured as ml/min/m2	For 24 hours after surgery from the start of surgery
Need for rescue doses of phenylephrine	Use of rescue doses of phenylephrine	For the time of surgery
Need for rescue doses of norepinephrine	Use of rescue doses of norepinephrine	For the time of surgery
Need for rescue doses of ephedrine	Use of rescue doses of ephedrine	For the time of surgery
Need for rescue doses of nitroglycerine	Use of rescue doses of nitroglycerine	For the time of surgery
Need for rescue doses of labetalol	Use of rescue doses of labetalol	For the time of surgery
Need for rescue doses of esmolol	Use of rescue doses of esmolol	For the time of surgery
Need for rescue doses of atropine	Use of rescue doses of atropine	For the time of surgery
Need for rescue doses of glycopyrrolate.	Use of rescue doses of glycopyrrolate	For the time of surgery
Intraoperative hypoxemia	Decrease of peripheral oxygen saturation less than 92%	For the time of surgery
Intraoperative hypercapnia	Increase in end tidal carbon dioxide more than 45 mm Hg	For the time of surgery
Intraoperative hypotension	Number of drops in systolic arterial pressure < 90 mmHg for 3 minutes or longer for any reasons	For the time of surgery
Intraoperative bradycardia	Number of drops in heart rate lower than 40 beats.min-1 or 10% of baseline value for more than three minutes for any reasons.	For the time of surgery
Intraoperative myocardial ischemic episodes	Remarkable ischemic changes included those patients with ≥ 1- mv ST-segment depression or ≥ 2-mv ST-segment elevation lasting more than 1 minute	For the time of surgery
Number of patients who required pacemaker insertion	Need for pacemaker insertion following termination of cardiopulmonary bypass.	For the time of surgery
Number of patients who required direct current shocks	Need for direct current shock following termination of cardiopulmonary bypass..	For the time of surgery
Number of patients who need for epinephrine	Need for epinephrine following termination of cardiopulmonary bypass.	For the time of surgery
Number of patients who need for norepinephrine	Need for norepinephrine following termination of cardiopulmonary bypass.	For the time of surgery
Number of patients who need for dobutamine	Need for dobutamine following termination of cardiopulmonary bypass.	For the time of surgery
Number of patients who need for milrinone	Need for milrinone following termination of cardiopulmonary bypass.	For the time of surgery
Number of patients who need for for Intra-Aortic Balloon Pump	Need for intra-aortic balloon counter pulsation pump following termination of cardiopulmonary bypass.	For the time of surgery
Intraoperative need for blood transfusion	The amount of transfused units of blood and blood products	For the time of surgery
Intraoperative fluid intake	The amount of infused crystalloids and colloids	For the time of surgery
ICU Stay	Length of ICU stay	For 30 days after surgery
Hospital Stay	Length of hospital stay	For 30 days after surgery
Mortality at 30 days	Alive or dead on postoperative day 30	For 30 days after surgery
Mortality at 90 days	Alive or dead on postoperative day 90	For 90 days after surgery
Postoperative need for reintubation	Postoperative need for reintubation during the first 30 days following surgery	For 30 days after surgery
Postoperative bleeding	Postoperative bleeding during the first 30 days following surgery	For 30 days after surgery
Postoperative cardiogenic shock	Postoperative cariogenic shock for the first 30 days following surgery	For 30 days after surgery
Postoperative acute kidney injury	Postoperative acute kidney injury for the first 30 days following surgery	For 30 days after surgery
Postoperative splanchnic ischemia	Postoperative mesenteric or splanchnic ischemia for the first 30 days following surgery	For 30 days after surgery
Postoperative myocardial ischemia	Postoperative acute coronary syndrome for the first 30 days following surgery	For 30 days after surgery
Postoperative wound infection	Postoperative wound infection for the first 30 days following surgery	For 30 days after surgery
Postoperative pneumonia	Postoperative pneumonia for the first 30 days following surgery	For 30 days after surgery
Postoperative mediastinitis	Postoperative mediastinitis for the first 30 days following surgery	For 30 days after surgery
Postoperative hypoxemia	Postoperative decrease in peripheral oxygen saturation less than 90 for the first 30 days following surgery	For 30 days after surgery
Postoperative stroke	Postoperative stroke for the first 30 days following surgery	For 30 days after surgery
Postoperative sternotomy	Postoperatively during hospital stay	For 30 days after surgery
Postoperative sternal dehiscence	Postoperatively during hospital stay	For 30 days after surgery

Collaborators and Investigators

• Sponsor: Imam Abdulrahman Bin Faisal University
• Investigators: Study Chair: Mohamed R El Tahan, MD, College of Medicine, Imam Abdulrahman Bin Faisal University

Publications and helpful links

General Publications

• Tsiouris A, Wilson L, Haddadin AS, Yun JJ, Mangi AA. Risk assessment and outcomes of vasoplegia after cardiac surgery. Gen Thorac Cardiovasc Surg. 2017 Oct;65(10):557-565. doi: 10.1007/s11748-017-0789-6. Epub 2017 Jun 13.
• Fischer GW, Levin MA. Vasoplegia during cardiac surgery: current concepts and management. Semin Thorac Cardiovasc Surg. 2010 Summer;22(2):140-4. doi: 10.1053/j.semtcvs.2010.09.007.
• Shaefi S, Mittel A, Klick J, Evans A, Ivascu NS, Gutsche J, Augoustides JGT. Vasoplegia After Cardiovascular Procedures-Pathophysiology and Targeted Therapy. J Cardiothorac Vasc Anesth. 2018 Apr;32(2):1013-1022. doi: 10.1053/j.jvca.2017.10.032. Epub 2017 Oct 27.
• Truby LK, Takeda K, Farr M, Beck J, Yuzefpolskaya M, Colombo PC, Topkara VK, Mancini D, Naka Y, Takayama H. Incidence and Impact of On-Cardiopulmonary Bypass Vasoplegia During Heart Transplantation. ASAIO J. 2018 Jan/Feb;64(1):43-51. doi: 10.1097/MAT.0000000000000623.
• Chan JL, Kobashigawa JA, Aintablian TL, Li Y, Perry PA, Patel JK, Kittleson MM, Czer LS, Zarrini P, Velleca A, Rush J, Arabia FA, Trento A, Esmailian F. Vasoplegia after heart transplantation: outcomes at 1 year. Interact Cardiovasc Thorac Surg. 2017 Aug 1;25(2):212-217. doi: 10.1093/icvts/ivx081.
• Sun LY, Chung AM, Farkouh ME, van Diepen S, Weinberger J, Bourke M, Ruel M. Defining an Intraoperative Hypotension Threshold in Association with Stroke in Cardiac Surgery. Anesthesiology. 2018 Sep;129(3):440-447. doi: 10.1097/ALN.0000000000002298. Erratum In: Anesthesiology. 2019 Feb;130(2):360.
• Cotter EK, Kidd B, Flynn BC. Elevation of Intraoperative Lactate Levels During Cardiac Surgery: Is There Power in This Prognostication? J Cardiothorac Vasc Anesth. 2020 Apr;34(4):885-887. doi: 10.1053/j.jvca.2019.11.049. Epub 2019 Dec 9. No abstract available.
• Ortoleva J, Shapeton A, Vanneman M, Dalia AA. Vasoplegia During Cardiopulmonary Bypass: Current Literature and Rescue Therapy Options. J Cardiothorac Vasc Anesth. 2020 Oct;34(10):2766-2775. doi: 10.1053/j.jvca.2019.12.013. Epub 2019 Dec 14.

Study record dates

Study Major Dates

• Study Start (Actual): May 6, 2020
• Primary Completion (Actual): April 10, 2021
• Study Completion (Actual): September 20, 2021

Study Registration Dates

• First Submitted: March 15, 2020
• First Submitted That Met QC Criteria: March 17, 2020
• First Posted (Actual): March 18, 2020

Study Record Updates

• Last Update Posted (Actual): December 10, 2021
• Last Update Submitted That Met QC Criteria: December 9, 2021
• Last Verified: December 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Adrenergic alpha-Agonists; Adrenergic Agonists; Sympathomimetics; Vasoconstrictor Agents; Norepinephrine
• Other Study ID Numbers: Norcal-03-2020

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: The database will be locked as soon as all data are entered, and all discrepant or missing data are resolved - or if all efforts are employed and the investigators consider that the remaining issues cannot be fixed. At this step, the data will be reviewed before database locking. After that, the study database will be locked and exported for statistical analysis.
• IPD Sharing Time Frame: After completion of the study
• IPD Sharing Access Criteria: Permission for access to the database will be removed for all investigators, and the database will be archived.
• IPD Sharing Supporting Information Type: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); Clinical Study Report (CSR)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No