Norepinephrine Infusion During Cardiopulmonary Bypass

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Cardiac Surgery, Cardiopulmonary Bypass

Intervention / Treatment
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* Drug: Placebo
* Drug: Norepinephrine
* Other: Increase infusion rate
* Other: Decrease infusion rate


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: A single center, interventional, parallel, double-blind (patient - and outcome-assessor), prospective, trial in patients scheduled for elective cardiac procedures using CPB. The RCT will be conducted according to Good Clinical Practice (GCP) Guidelines and comply with the principles of the Declaration of Helsinki. The RCT will be registered in a public registry, and the study protocol with its statistical analysis plan will be published before enrolment of the first patient.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>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<br>* 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.<br>Other: Increase infusion rate<br>* 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<br>Other: Decrease infusion rate<br>* 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<br>|
| Active Comparator: Norepinephrine<br>Infusion of norepinephrine (40 µg/ml) will be started following arterial cannulation before initiation of cardiopulmonary bypass and continued until aortic declamping time. | Drug: Norepinephrine<br>* 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.<br>Other: Increase infusion rate<br>* 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<br>Other: Decrease infusion rate<br>* 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<br>|

What is the study measuring?
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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 |