Propofol cardioprotection for on-pump aortocoronary bypass surgery in patients with type 2 diabetes mellitus (PRO-TECT II): a phase 2 randomized-controlled trial

Abstract

Purpose The efficacy of myocardial conditioning strategies is compromised in patients with advanced age, diabetes, or low ejection fraction. We conducted a singlecentre parallel-arm blinded randomized-controlled trial to determine whether propofol provides perioperative myocardial protection. Methods Patients enrolled in this study were scheduled for primary aortocoronary bypass surgery utilizing normothermic cardiopulmonary bypass (CPB) with blood cardioplegia. The participants were stratified by diabetic status and left ventricular ejection fraction and randomly assigned to receive either an elevated dose of propofolpreviously associated with experimental cardioprotectionor an isoflurane preconditioning regime. The primary endpoint was the coronary sinus (CS) concentration of 15-F 2t -isoprostane (isoP). Secondary endpoints included inhospital low cardiac output syndrome (LCOS) and major adverse cardiac events, 12-and 24-hr CS cardiac troponin I (cTnI) release, and myocardial B-cell lymphoma 2 (Bcl-2) protein expression. Results Data were analyzed from 125 of 137 randomized participants. Participants receiving propofol experienced a greater mean (SD) increase from baseline in CS 15-F 2t -isoP levels compared with those receiving isoflurane [26.9 (10.9) pgÁmL -1 vs 12.1 (10.4) pgÁmL -1 , respectively; mean difference, 14.8; 95% confidence interval (CI), 11.0 to 18.6; P \ 0.001] but a decreased incidence of LCOS (20.9% vs 57.1%, respectively; relative risk [RR],0.37; 95% CI, 0.22 to 0.62; P \ 0.001). The incidence of LCOS was similar between groups in participants without type 2 diabetes mellitus (DM2) (P = 0.382) but significantly decreased in the propofol DM2 subgroup compared with the isoflurane DM2 subgroup (17.9% vs 70.3%, respectively; RR, 0.26; 95% CI, 0.13 to 0.52; P \ 0.001). Propofol was associated with an increase in myocardial Bcl-2 protein expression (P = 0.005), a lower incidence of a CS cTnI threshold for myocardial infarction (P = 0.014), and fewer heart failure events (P \ 0.001). Conclusion Propofol may be a preemptive intraoperative cardioprotectant for patients with DM2 under conditions of normothermic CPB and blood cardioplegic arrest. The study is registered at www.clinicaltrials.gov (NCT00734383) and www.controlled-trials.com (ISRCTN70879185). RésuméObjectif L'efficacité des stratégies de conditionnement myocardique est compromise chez les patients âgés ainsi que chez ceux atteints de diabète ou présentant une fraction d'éjection faible. Nous avons réalisé une étude randomisée contrô lée unicentrique à bras parallèles et en aveugle afin de déterminer si le propofol procurait une protection myocardique en période périopératoire. Méthode Les patients enrô lés dans cette étude devaient subir une chirurgie de pontage aorto-coronarien primaire avec circulation extracorporelle (CEC) normothermique et cardioplégie sanguine. Les participants ont été stratifiés par statut diabétique et fraction d'éjection ventriculaire gauche, puis aléatoirement répartis en deux groupes, dont l'un recevrait...

Propofol Through Upregulating Caveolin-3 Attenuates Post-Hypoxic Mitochondrial Damage and Cell Death in H9C2 Cardiomyocytes During Hyperglycemia

“…The intravenous anesthetic propofol has recently been shown to attenuate post-ischemic myocardial injury in diabetic patients undergoing cardiac surgery [5], but the underlying mechanism has not been explored. In order to exclude the interference of fat emulsion solvent of propofol on experimental results, pure propofol powder was used.…”

“…However, accumulating evidences showed that the cardioprotective effects of ischemic preconditioning, ischemic postconditioning, or anesthetic conditioning were attenuated or abolished in hearts from diabetes. Interestingly, a most recent clinical trial study showed that infusion of clinically achievable high-dose propofol, a widely used intravenous anesthetic, during cardiopulmonary bypass in diabetic patients receiving coronary artery bypass grafting conferred cardioprotection manifested as reduced cardiac troponin I release and decreased major adverse cardiac events [5]. We previously showed that propofol when applied before and during ischemia, and early reperfusion, dose-dependently reduced lipid peroxidation and conferred cardioprotection in isolated rat heats [6].…”

Répercussions de l’hyperoxie sur les résultats après une chirurgie cardiaque : revue systématique et synthèse narrative

“…Mean (standard deviation [SD]) CPB times were reported in ten trials and ranged from 63 (26) to 156 (10) min. 1,9,22,23,[26][27][28][29][30][31] Mean (SD) aortic cross clamp times were reported in ten trials and ranged from 43 (12) to 112 (43) min. 1,8,9,[22][23][24]26,28,29,31 There was marked heterogeneity in the timing of the study intervention in these trials.…”

“…These mechanisms are hyperoxia-related cardiovascular dysregulation, direct tissue injury from increased production of reactive oxygen species (ROS), and enhancement of ischemiareperfusion injury. [9][10][11][12] High partial pressures of oxygen have multiple direct effects on the heart and peripheral vasculature. Oxygen has a direct vasoconstrictive effect that leads to an increase in systemic vascular resistance as well as an increased coronary vascular resistance.…”

L’étude de la cardioprotection induite par le propofol: du mécanisme au phénomène clinique, et vice-versa

“…[3][4][5] In the current issue of the Journal, Ansley et al have pursued a different approach: They report the results of their clinical Phase 2 trial (PRO-TECT II) that assessed the impact of administering a targeted dose of systemic propofol during the ischemia-reperfusion interval in patients undergoing heart surgery. 6 They hypothesized that the antioxidant properties of propofol impart anesthetic preconditioning and protect ischemic myocardium from oxidative injury during cardiac surgery. Their study intervention (i.e., high-dose propofol) was derived from prior experimental studies [7][8][9] that determined an optimal mean (standard deviation) propofol concentration in the systemic circulation [5.74 (2.50) lgÁmL -1 ] and blood microplegia [2.04 (1.14) lgÁmL -1 ] when the propofol was delivered during the ischemia-reperfusion interval.…”