Clinical trial NCT04312971: Norepinephrine Infusion During Cardiopulmonary Bypass
Official title: Effects of Norepinephrine Infusion During Cardiopulmonary Bypass on Perioperative Changes in Lactic Acid Level: A Randomized Controlled Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Cardiac Surgery
Cardiopulmonary Bypass
Lead sponsor: Imam Abdulrahman Bin Faisal University
Sponsor class: OTHER
First posted: 2020-03-18
Enrollment: 80
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention 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.
Primary purpose: PREVENTION

Brief summary: 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: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Changes in lactic acid level
timeFrame: For 24 hours after surgery from the start of surgery
Secondary outcomes:
measure: Mean Arterial Pressure (MAP)
timeFrame: For 24 hours after surgery from the start of surgery
measure: Cardiac Index (CI)
timeFrame: For 24 hours after surgery from the start of surgery
measure: Systemic Vascular Resistance index (SVRI)
timeFrame: For 24 hours after surgery from the start of surgery
measure: Stroke volume variation (SVV)
timeFrame: For 24 hours after surgery from the start of surgery
measure: Need for rescue doses of phenylephrine
timeFrame: For the time of surgery
measure: Need for rescue doses of norepinephrine
timeFrame: For the time of surgery
measure: Need for rescue doses of ephedrine
timeFrame: For the time of surgery
measure: Need for rescue doses of nitroglycerine
timeFrame: For the time of surgery
measure: Need for rescue doses of labetalol
timeFrame: For the time of surgery
measure: Need for rescue doses of esmolol
timeFrame: For the time of surgery
measure: Need for rescue doses of atropine
timeFrame: For the time of surgery
measure: Need for rescue doses of glycopyrrolate.
timeFrame: For the time of surgery
measure: Intraoperative hypoxemia
timeFrame: For the time of surgery
measure: Intraoperative hypercapnia
timeFrame: For the time of surgery
measure: Intraoperative hypotension
timeFrame: For the time of surgery
measure: Intraoperative bradycardia
timeFrame: For the time of surgery
measure: Intraoperative myocardial ischemic episodes
timeFrame: For the time of surgery
measure: Number of patients who required pacemaker insertion
timeFrame: For the time of surgery
measure: Number of patients who required direct current shocks
timeFrame: For the time of surgery
measure: Number of patients who need for epinephrine
timeFrame: For the time of surgery
measure: Number of patients who need for norepinephrine
timeFrame: For the time of surgery
measure: Number of patients who need for dobutamine
timeFrame: For the time of surgery
measure: Number of patients who need for milrinone
timeFrame: For the time of surgery
measure: Number of patients who need for for Intra-Aortic Balloon Pump
timeFrame: For the time of surgery
measure: Intraoperative need for blood transfusion
timeFrame: For the time of surgery
measure: Intraoperative fluid intake
timeFrame: For the time of surgery
measure: ICU Stay
timeFrame: For 30 days after surgery
measure: Hospital Stay
timeFrame: For 30 days after surgery
measure: Mortality at 30 days
timeFrame: For 30 days after surgery
measure: Mortality at 90 days
timeFrame: For 90 days after surgery
measure: Postoperative need for reintubation
timeFrame: For 30 days after surgery
measure: Postoperative bleeding
timeFrame: For 30 days after surgery
measure: Postoperative cardiogenic shock
timeFrame: For 30 days after surgery
measure: Postoperative acute kidney injury
timeFrame: For 30 days after surgery
measure: Postoperative splanchnic ischemia
timeFrame: For 30 days after surgery
measure: Postoperative myocardial ischemia
timeFrame: For 30 days after surgery
measure: Postoperative wound infection
timeFrame: For 30 days after surgery
measure: Postoperative pneumonia
timeFrame: For 30 days after surgery
measure: Postoperative mediastinitis
timeFrame: For 30 days after surgery
measure: Postoperative hypoxemia
timeFrame: For 30 days after surgery
measure: Postoperative stroke
timeFrame: For 30 days after surgery
measure: Postoperative sternotomy
timeFrame: For 30 days after surgery
measure: Postoperative sternal dehiscence
timeFrame: For 30 days after surgery
Other outcomes:
Locations:
city: Khobar
country: Saudi Arabia
facility: Dammam University
state: Eastern
city: Dammam
country: Saudi Arabia
facility: Imam Abdulrahamn Bin Faisal University (Former, Dammam University)
state: Esatern
Study officials:
affiliation: College of Medicine, Imam Abdulrahman Bin Faisal University
name: Mohamed R El Tahan, MD
role: STUDY_CHAIR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.