The effects of propofol cardioplegia on blood and myocardial biomarkers of stress and injury in patients with isolated coronary artery bypass grafting or aortic valve replacement using cardiopulmonary bypass: protocol for a single-center randomized controlled trial

Abstract

Background: Despite improved myocardial protection strategies, cardioplegic arrest and ischemia still result in reperfusion injury. We have previously published a study describing the effects of propofol (an anesthetic agent commonly used in cardiac surgery) on metabolic stress, cardiac function, and injury in a clinically relevant animal model. We concluded that cardioplegia supplementation with propofol at a concentration relevant to the human clinical setting resulted in improved hemodynamic function, reduced oxidative stress, and reduced reperfusion injury when compared to standard cardioplegia.

Objective: The Propofol cardioplegia for Myocardial Protection Trial (ProMPT) aims to translate the successful animal intervention to the human clinical setting. We aim to test the hypothesis that supplementation of the cardioplegic solution with propofol will be cardioprotective for patients undergoing isolated coronary artery bypass graft or aortic valve replacement surgery with cardiopulmonary bypass.

Methods: The trial is a single-center, placebo-controlled, randomized trial with blinding of participants, health care staff, and the research team. Patients aged between 18 and 80 years undergoing nonemergency isolated coronary artery bypass graft or aortic valve replacement surgery with cardiopulmonary bypass at the Bristol Heart Institute are being invited to participate. Participants are randomly assigned in a 1:1 ratio to either cardioplegia supplementation with propofol (intervention) or cardioplegia supplementation with intralipid (placebo) using a secure, concealed, Internet-based randomization system. Randomization is stratified by operation type and minimized by diabetes mellitus status. Biomarkers of cardiac injury and metabolism are being assessed to investigate any cardioprotection conferred. The primary outcome is myocardial injury, studied by measuring myocardial troponin T. The trial is designed to test hypotheses about the superiority of the intervention within each surgical stratum. The sample size of 96 participants has been chosen to achieve 80% power to detect standardized differences of 0.5 at a significance level of 5% (2-tailed) assuming equal numbers in each surgical stratum.

Results: A total of 96 patients have been successfully recruited over a 2-year period. Results are to be published in late 2014.

Conclusions: Designing a practicable method for delivering a potentially protective dose of propofol to the heart during cardiac surgery was challenging. If our approach confirms the potential of propofol to reduce damage during cardiac surgery, we plan to design a larger multicenter trial to detect differences in clinical outcomes.

Trial registration: International Standard Randomized Controlled Trial Number (ISRCTN): 84968882; http://www.controlled-trials.com/ISRCTN84968882/ProMPT (Archived by WebCite at http://www.webcitation.org/6Qi8A51BS).

Keywords: anesthetics; aortic valve; cardiac surgery; cardioplegia; cardiopulmonary bypass; clinical trials, randomized; coronary artery; ischemia; reperfusion; troponin.

Figure 1

CABG warm blood cardioplegia. Propofol is first diluted from 10,000 μg/mL to 2000 μg/mL using 0.9% sodium chloride. The diluted propofol solution is added to the cardioplegia by attaching an additional syringe pump to the line downstream of the blood oxygenator. This method is identical to that used for adding potassium and magnesium to the oxygenated blood. The syringe driver is set to 0.6 mL/min resulting in a 6 μg/mL supplementation of the blood/cardioplegia mix during delivery. For the placebo group, cardioplegia is supplemented with placebo in the same manner as described for propofol. In the event addition of propofol is indicated, this is substituted with an equivalent volume of intralipid.

Figure 2

AVR cold blood cardioplegia. Propofol is first diluted from 10,000 μg/mL to 2000 μg/mL using 0.9% sodium chloride. Diluted propofol is added directly to a 500 mL bag of 4:1 cardioplegia solution by 1:1 (vol:vol) substitution. For the placebo group, cardioplegia is supplemented with placebo in exactly the same manner as described for propofol. In the event addition of propofol is indicated, this is substituted with an equivalent volume of intralipid.

Figure 3

Measurement of myocardial injury and propofol concentration. The primary outcome is myocardial injury, assessed by measuring myocardial troponin T in serum from blood samples collected preoperatively and at 1, 6, 12, 24, and 48 hours after chest closure. The concentration of plasma propofol is measured in blood samples collected from the cardioplegia/bypass circuit immediately before aortic cross-clamping, once during cardioplegia (after blood–cardioplegia mixing), and 10 min post cross-clamp release.