Cardiac surgery with cardiopulmonary bypass results in global myocardial ischemia–reperfusion injury, leading to significant postoperative morbidity and mortality. Although cardioplegia is the cornerstone of intraoperative cardioprotection, a number of additional strategies have been identified. The concept of preconditioning and postconditioning, despite its limited direct clinical application, provided an essential contribution to the understanding of myocardial injury and organ protection. Therefore, physicians can use different tools to limit perioperative myocardial injury. These include the choice of anesthetic agents, remote ischemic preconditioning, tight glycemic control, optimization of respiratory parameters during the aortic unclamping phase to limit reperfusion injury, appropriate choice of monitoring to optimize hemodynamic parameters and limit perioperative use of catecholamines, and early reintroduction of cardioprotective agents in the postoperative period. Appropriate management before, during, and after cardiopulmonary bypass will help to decrease myocardial damage. This review aimed to highlight the current advancements in cardioprotection and their potential applications during cardiac surgery.

BACKGROUND:The aim of our study was to test different anesthetic mixtures in order to identify the most suitable one for a surgical cardiac ischemia-reperfusion model in mice. METHODS:1) Sixty four mice were submitted to one of the 6 combinations of ketamine or alfaxalone associated to xylazine, medetomidine or midazolam. Depth and quality of anesthesia were evaluated via 5 reflex scores. 2) Impact of analgesic (buprenorphine or butorphanol), anesthesia reversal (with atipamezole) and surgery (cardiac ischemia-reperfusion surgery) have been tested in the selected protocols. 3) infarction size has been measured with TTC (Triphenyl Tetrazolium Chloride) method in mice anesthetized with best protocols. RESULTS:Protocol involving medetomidine induced the longest surgical anesthesia: (median = 120, {interquartile range = 100-125}) min with ketamine and 53 {25-100} min with alfaxalone. Butorphanol substitution with buprenorphine did not alter time-related anesthesia parameters. Atipamezole reversal considerably reduced both recovery and immobilization time (respectively 22 {18-30} min and 98 {88-99} min vs. 55 {40-70} min and 143 {131-149} min, in groups with no reversal, p = 0.001) with no impact on infarction size measurement. CONCLUSION:In this study, the combination alfaxalone/medetomidine/buprenorphine (80/0,3/0,075 mg.kg-1, s.c.) associated with reversal by atipamezole was a reliable anesthetic protocol for murine surgery, particularly for the study of ischemia-reperfusion.

OBJECTIVES:Cardiac surgery associated-acute kidney injury is a common and serious postoperative complication of cardiac surgery, which is associated with increased postoperative morbidity and mortality. This study aimed to explore the association between cardiopulmonary bypass (CPB) blood flow rate (BFR), and major adverse kidney events (MAKEs) at day 30. DESIGN:Retrospective single-center before-after observational study. Patients were divided in 2 groups according to CPB flow rates: a first group with an institutional protocol targeting a CPB-BFR of >2.2 L/min/m² (low CPB-BFR group), and a second group with a modified institutional protocol targeting a CPB-BFR of >2.4 L/min/m² (high CPB-BFR group). The primary outcome was MAKE at 30 days, defined as the composite of death, renal replacement therapy or persistent renal dysfunction. SETTING:The data were collected from clinical routines in university hospital. PARTICIPANTS:Adult patients who underwent elective and urgent cardiac surgery without severe chronic renal failure, for whom CPB duration was ≥90 minutes. INTERVENTIONS:We included 533 patients (low CPB-BFR group, n = 270; high CPB-BFR group, n = 263). MEASUREMENTS AND MAIN RESULTS:A significant decrease in MAKE at 30 days was observed in the high CPB-BFR group (3% v 8%; odds ratio [OR], 0.779; 95% confidence interval [CI], 0.661-0.919; p < 0.001) mainly mediated by a lower 30-day mortality in the high CPB-BFR group (1% v 5%; OR, 0.697; 95% CI, 0.595-0.817; p = 0.001), as was renal replacement therapy (1% v 4%; OR, 0.739; 95% CI, 0.604-0.904; p = 0.016). CONCLUSIONS:In patients undergoing cardiac surgery, increased CPB-BFR was associated with a decrease in MAKE at 30 days including mortality and renal replacement therapy.

We read with great interest the recent comment about our work.1,2 We thank the authors for their interest in our study that evaluated the relevance of a cardioprotective bundle of care during cardiac surgery with cardiopulmonary bypass. A total of 210 patients were randomized into a control group (standard of care) and a treatment group combining 5 modes of protection: administration of a volatile anesthetic (sevoflurane), remote ischemic preconditioning, tight intraoperative blood glucose control, induction of a moderate respiratory acidosis (pH 7.30) just before the release of the aortic cross-clamp to prevent the "pH paradox" phenomenon, and gentle reperfusion just after aortic unclamping to limit myocardial reperfusion injury.

OBJECTIVE:The ProCCard study tested whether combining several cardioprotective interventions would reduce the myocardial and other biological and clinical damage in patients undergoing cardiac surgery.DESIGN:Prospective, randomized, controlled trial.SETTING:Multicenter tertiary care hospitals.PARTICIPANTS:210 patients scheduled to undergo aortic valve surgery.INTERVENTIONS:A control group (standard of care) was compared to a treated group combining five perioperative cardioprotective techniques: anesthesia with sevoflurane, remote ischemic preconditioning, close intraoperative blood glucose control, moderate respiratory acidosis (pH 7.30) just before aortic unclamping (concept of the "pH paradox"), and gentle reperfusion just after aortic unclamping.MEASUREMENTS AND MAIN RESULTS:The primary outcome was the postoperative 72-h area under the curve (AUC) for high-sensitivity cardiac troponin I (hsTnI). Secondary endpoints were biological markers and clinical events occurring during the 30 postoperative days and the prespecified subgroup analyses. The linear relationship between the 72-h AUC for hsTnI and aortic clamping time, significant in both groups (p < 0.0001), was not modified by the treatment (p = 0.57). The rate of adverse events at 30 days was identical. A non-significant reduction of the 72-h AUC for hsTnI (-24%, p = 0.15) was observed when sevoflurane was administered during cardiopulmonary bypass (46% of patients in the treated group). The incidence of postoperative renal failure was not reduced (p = 0.104).CONCLUSION:This multimodal cardioprotection has not demonstrated any biological or clinical benefit during cardiac surgery. The cardio- and reno-protective effects of sevoflurane and remote ischemic preconditioning therefore remain to be demonstrated in this context.

High-risk pulmonary embolism (PE) requires hemodynamic and respiratory support along with reperfusion strategies. Recently updated European guidelines assign a low class of recommendation to extracorporeal membrane oxygenation (ECMO) for high-risk PE. This systematic review assessed clinical outcomes after ECMO in high-risk PE. We searched electronic databases including PubMed, Embase and Web of Science from January 2000 to April 2020. Efficacy outcomes included in-hospital survival with good neurological outcome and survival at follow-up. Safety outcomes included lower limb ischemia and hemorrhagic and ischemic stroke. Where possible (absence of high heterogeneity), meta-analyses of outcomes were undertaken using a random-effects model. We included 16 uncontrolled case-series (533 participants). In-hospital survival with good neurological outcome ranged between 50% and 95% while overall survival at follow-up ranged from 35% to 95%, both with a major degree of heterogeneity (I 2 > 70%). The prevalence of lower limb ischemia was 8% (95% CI 3% to 15%). The prevalence of stroke (either hemorrhagic or ischemic) was 11% (95% CI 3% to 23%), with notable heterogeneity (I² = 63.35%). Based on currently available literature, it is not possible to draw definite conclusions on the usefulness of ECMO for high-risk PE. Prospective, multicenter, large-scale studies or nationwide registries are needed to best define the role of ECMO for high-risk PE. PROSPERO registration ID: CRD42019136282.

Background Myocardial damage in patients undergoing cardiac surgery increases both morbidity and mortality. Different protective strategies dealing with either preconditioning or postconditioning or assessing a single aspect of cardioprotection have shown conflicting results. We tested the hypothesis that a multimodal approach would improve cardioprotection and limit myocardial damage following cardiac surgery with cardiopulmonary bypass. Methods This study is a pragmatic multicenter (six French institutions), prospective, randomized, single-blinded, controlled trial. The randomization is stratified by centers. In the study, 210 patients scheduled for aortic valve surgery with or without coronary artery bypass grafting will be assigned to a control or a treatment group (105 patients in each group). In the control group, patients receive total intravenous anesthesia with propofol and liberal intraoperative blood glucose management (initiation of insulin infusion when blood glucose, measured every 60 min, is greater than 180 mg/dl), as a standard of care. The treatment group receives a bundle of care combining five techniques of cardioprotection: (1) remote ischemic preconditioning applied before aortic cross-clamping; (2) maintenance of anesthesia with sevoflurane; (3) tight intraoperative blood glucose management (initiation of insulin infusion when blood glucose, measured every 30 min, is greater than 140 mg/dl); (4) moderate respiratory acidosis (pH 7.30) at the end of cardiopulmonary bypass; and (5) a gentle reperfusion protocol following aortic unclamping. The primary outcome is myocardial damage measured by postoperative 72-h area under the curve of high-sensitivity cardiac troponin I. Discussion The ProCCard study will be the first multicenter randomized controlled trial aiming to assess the role of a bundle of care combining several cardioprotective strategies to reduce myocardial damage in patients undergoing cardiac surgery with cardiopulmonary bypass. Trial registration ClinicalTrials.gov, NCT03230136 . Registered on July 26, 2017. Last updated on April 17, 2019.

Calcium homeostasis is essential for cell survival and is precisely controlled by several cellular actors such as the sarco/endoplasmic reticulum and mitochondria. Upon stress induction, Ca2+ released from sarco/endoplasmic reticulum stores and from extracellular Ca2+ pools accumulates in the cytosol and in the mitochondria. This induces Ca2+ overload and ultimately the opening of the mitochondrial permeability transition pore (mPTP), promoting cell death. Currently, it is unclear whether intracellular Ca2+ stores are sufficient to promote the mPTP opening. Ca2+ retention capacity (CRC) corresponds to the maximal Ca2+ uptake by the mitochondria before mPTP opening. In this study, using permeabilized cardiomyocytes isolated from adult mice, we modified the standard CRC assay by specifically inducing reticular Ca2+ release to investigate the respective contributions of reticular Ca2+ and extracellular Ca2+ to mPTP opening in normoxic conditions or after anoxia?reoxygenation. Our experiments revealed that Ca2+ released from the sarco/endoplasmic reticulum is not sufficient to trigger mPTP opening and corresponds to ?50% of the total Ca2+ levels required to open the mPTP. We also studied mPTP opening after anoxia?reoxygenation in the presence or absence of extracellular Ca2+. In both conditions, Ca2+ leakage from internal stores could not trigger mPTP opening by itself but significantly decreased the CRC. Our findings highlight how a modified CRC assay enables the investigation of the role of reticular and extracellular Ca2+ pools in the regulation of the mPTP. We propose that this method may be useful for screening molecules of interest implicated in mPTP regulation.

Background: Volatile anesthetics are known to limit myocardial ischemia–reperfusion injuries. Mitochondria were shown to be major contributors to cardioprotection. Cyclophilin D (CypD) is one of the main regulators of mitochondria-induced cell death. We compared the effect of isoflurane, sevoflurane, and desflurane in the presence or absence of CypD, to clarify its role in the mechanism of cardioprotection induced by these anesthetics. Methods: Oxidative phosphorylation, mitochondrial membrane potential, and H2O2 production were measured in isolated mitochondria from wild-type (WT) or CypD knockout mice in basal conditions and after hypoxia–reoxygenation in the presence or absence of volatile anesthetics. Results: All volatile anesthetics inhibited mitochondrial state 3 of complex I, decreased membrane potential, and increased adenosine diphosphate consumption duration in both WT and CypD knockout mice. However, they differently modified H2O2 production after stimulation by succinate: CypD ablation reduced H2O2 production, isoflurane decreased H2O2 level in WT but not in CypD knockout mice, sevoflurane affected both lines whereas desflurane increased H2O2 production in CypD knockout and had no effect on WT mice. Conclusions: This study showed different effects of isoflurane, sevoflurane, and desflurane on mitochondrial functions and highlighted the implication of CypD in the regulation of adenosine diphosphate consumption and complex I–induced radical oxygen species production.

Background The mitochondrial permeability transition pore (PTP) has been established as an important mediator of ischemia–reperfusion–induced cell death. The matrix protein cyclophilin D (CypD) is the best known regulator of PTP opening. Therefore, the authors hypothesized that isoflurane, by inhibiting the respiratory chain complex I, another regulator of PTP, might reinforce the myocardial protection afforded by CypD inhibition. Methods Adult mouse or isolated cardiomyocytes from wild-type or CypD knockout (CypD-KO) mice were subjected to ischemia or hypoxia followed by reperfusion or reoxygenation. Infarct size was assessed in vivo. Mitochondrial membrane potential and PTP opening were assessed using tetramethylrhodamine methyl ester perchlorate and calcein–cobalt fluorescence, respectively. Fluo-4 AM and rhod-2 AM staining allowed the measurement, by confocal microscopy, of Ca2+ transient and Ca2+ transfer from sarcoplasmic reticulum (SR) to mitochondria after caffeine stimulation. Results Both inhibition of CypD and isoflurane significantly reduced infarct size (−50 and −37%, respectively) and delayed PTP opening (+63% each). Their combination had no additive effect (n = 6/group). CypD-KO mice displayed endogenous protection against ischemia–reperfusion. Isoflurane depolarized the mitochondrial membrane (−28%, n = 5), decreased oxidative phosphorylation (−59%, n = 5), and blunted the caffeine-induced Ca2+ transfer from SR to mitochondria (−22%, n = 7) in the cardiomyocytes of wild-type mice. Importantly, this transfer was spontaneously decreased in the cardiomyocytes of CypD-KO mice (−25%, n = 4 to 5). Conclusions The results suggest that the partial inhibitory effect of isoflurane on respiratory complex I is insufficient to afford a synergy to CypD-induced protection. Isoflurane attenuates the Ca2+ transfer from SR to mitochondria, which is also the prominent role of CypD, and finally prevents PTP opening.

Bei Eingriffen in extrakorporaler Zirkulation (EKZ) kann es nach dem Wiedereröffnen der Aorta zu einem Reperfusionsschaden des Myokards kommen, möglicherweise infolge einer Öffnung von mitochondrialen Permeabilitäts-Transitions-Poren (PTP). Ciclosporin A kann diese PTP-Öffnung hemmen – ob es damit intraoperativ als Schutz vor Reperfusionsschäden eingesetzt werden kann, hat eine Gruppe aus Frankreich untersucht.

Standardized techniques of mitral valve repair (MVR) have recently witnessed the introduction of a 'respect rather than resect' concept, the strategy of which involves the use of artificial chordae. MVR displays several advantages over mitral valve replacement in degenerative mitral regurgitation' (MR), but the risk of reoperation for MVR failure must be taken into account. Different mechanisms could be advocated as the leading cause of MVR failure; procedure-related mechanisms are usually involved in early MVR failure, while valve-related mechanisms are common in late failure. Here, the case is reported of an early failure of MVR using artificial chordae that could be explained by an unusual procedure-related mechanism, namely anterior papillary muscle necrosis. MVR failure is a well-known complication after surgical repair of degenerative MR, but anterior papillary muscle partial necrosis might also be considered a possible mechanism of procedure-related MVR failure, especially when considering the increasing use of artificial chordae. Owing to the encouraging results obtained, mitral valve re-repair might be considered a viable solution, but must be selected after only a meticulous evaluation of the underlying mechanism of MVR failure.

Background: Part of the myocardial damage occurring during cardiac surgery is a consequence of reperfusion injury. Cyclosporine, a potent inhibitor of the opening of the mitochondrial permeability transition pore, attenuates reperfusion injury in patients with acute ST-segment elevation myocardial infarction. This study investigated whether the administration of cyclosporine just before the aortic cross-unclamping would reduce myocardial injury in patients undergoing aortic valve surgery. Methods: This study was a monocentric, prospective, randomized, single-blinded, controlled trial. Sixty-one patients, scheduled for elective aortic valve surgery, were randomly assigned (computer-generated randomization sequence) to receive either an intravenous bolus of cyclosporine (2.5 mg/kg, cyclosporine group, n = 30) or normal saline (control group, n = 31) 10 min before aortic cross-unclamping. The primary endpoint was the 72-h area under the curve for cardiac troponin I. Results: Both groups were similar with respect to baseline characteristics and aortic cross-clamping duration. A significant 35% reduction of area under the curve for cardiac troponin I was observed in the cyclosporine group compared with the control group (242 ± 225 vs. 155 ± 71 arbitrary units, mean ± SD; mean difference, −86.2 ± 42.5; 95% CI, −172.3 to −0.1; P = 0.03). Cyclosporine beneficial effect remained significant after adjustment for aortic cross-clamping duration in each group (mean difference, −88 ± 34, 95% CI, −157 to −19; P = 0.01). None of the treated patients had significant side effects (odds ratio, 0.64; 95% CI, 0.16 to 2.55; P = 0.52). Conclusions: Cyclosporine administration at the time of reperfusion protects against reperfusion injury in patients undergoing aortic valve surgery. The clinical benefit of this protection requires confirmation in a larger clinical trial.

Reperfusion of the heart after an ischemic event leads to the opening of a nonspecific pore in the inner mitochondrial membrane, the mitochondrial permeability transition pore (mPTP). Inhibition of mPTP opening is an effective strategy to prevent cardiomyocyte death. The matrix protein cyclophilin-D (CypD) is the best-known regulator of mPTP opening. In this study we confirmed that preconditioning and postconditioning with CypD inhibitor cyclosporin-A (CsA) reduced cell death after hypoxia–reoxygenation (H/R) in wild-type (WT) cardiomyocytes and HL-1 mouse cardiac cell line as measured by nuclear staining with propidium iodide. The complex I inhibitor rotenone (Rot), alone, had no effect on HL-1 and WT cardiomyocyte death after H/R, but enhanced the native protection of CypD-knocked-out (CypD KO) cardiomyocytes. Reduction of cell death was associated with a delay of mPTP opening challenged by H/R and observed by the calcein loading CoCl2-quenching technique. Simultaneous inhibition of complex I and CypD increased in a synergistic manner the calcium retention capacity in permeabilized cardiomyocytes and cardiac mitochondria. These results demonstrated that protection by complex I inhibition was CypD dependent.

We examined the effects on infarct size and mitochondrial function of ischemic (Isch), cyclosporine A (CsA) and isoflurane (Iso) preconditioning and postconditioning in the in vivo rat model. Anesthetized open-chest rats underwent 30 min of ischemia followed by either 120 min (protocol 1: infarct size assessment) or 15 min of reperfusion (protocol 2: assessment of mitochondrial function). All treatments administered before the 30-min ischemia (Pre-Isch, Pre-CsA, Pre-Iso) significantly reduced infarct as compared to control. In contrast, only Post-Iso significantly reduced infarct size, while Post-Isch and Post-CsA had no significant protective effect. As for the postconditioning-like interventions, the mitochondrial calcium retention capacity significantly increased only in the Post-Iso group (+58 % vs control) after succinate activation. Only Post-Iso increased state 3 (+177 and +62 %, for G/M and succinate, respectively) when compared to control. Also, Post-Iso reduced the hydrogen peroxide (H 2 O 2 ) production (−46 % vs control) after complex I activation. This study suggests that isoflurane, but not cyclosporine A, can prevent lethal reperfusion injury in this in vivo rat model. This might be related to the need for a combined effect on cyclophilin D and complex I during the first minutes of reperfusion.

BACKGROUND:Respiratory variations in arterial pulse pressure (deltaPP(man)) are accurate predictors of fluid responsiveness in mechanically ventilated patients. However, they cannot be continuously monitored. In our study, we assessed the clinical utility of a novel algorithm for automatic estimation of deltaPP (deltaPP(auto)). METHODS:We studied 25 patients referred for coronary artery bypass grafting. DeltaPP(auto) was continuously displayed using a method based on automatic detection algorithms, kernel smoothing, and rank-order filters. All patients were under general anesthesia, mechanical ventilation, and were also monitored with a pulmonary artery catheter. DeltaPP(man) and deltaPP(auto) were recorded simultaneously at eight steps during surgery including before and after intravascular volume expansion (500 mL hetastarch). Responders to volume expansion were defined as patients whose cardiac index increased by more than 15% after volume expansion. RESULTS:Agreement between deltaPP(man) and deltaPP(auto) over the 200 pairs of collected data was 0.7% +/- 3.4% (mean bias +/- SD). Seventeen patients were responders to volume expansion. A threshold deltaPP(man) value of 12% allowed discrimination of responders to volume expansion with a sensitivity of 88% and a specificity of 100%. A threshold deltaPP(auto) value of 10% allowed discrimination of responders to volume expansion with a sensitivity of 82% and a specificity of 88%. CONCLUSION:DeltaPP(auto) is strongly correlated to deltaPP(man) is an accurate predictor of fluid responsiveness, and allows continuous monitoring of deltaPP. This novel algorithm has potential clinical applications.