Year in Review 2023: Noteworthy Literature in Cardiac Anesthesiology.

Notable clinical research published in 2023 related to cardiac anesthesia included studies focused on resuscitation and pharmacology, regional anesthesia, technological advances, and novel gene therapies. We reviewed 241 articles to identify 25 noteworthy studies that represent the most significant research related to cardiac anesthesia from the past year. Overall, improvements in clinical practice have enabled decreased morbidity and mortality with a renewed focus on mechanical circulatory support and transplantation.

Year in Review 2022: Noteworthy Literature in Cardiac Anesthesiology.

Last year researchers made substantial progress in work relevant to the practice of cardiac anesthesiology. We reviewed 389 articles published in 2022 focused on topics related to clinical practice to identify 16 that will impact the current and future practice of cardiac anesthesiology. We identified 4 broad themes including risk prediction, postoperative outcomes, clinical practice, and technological advances. These articles are representative of the best work in our field in 2022.

Hyperoxemia During Cardiac Surgery Is Associated With Postoperative Pulmonary Complications.

The use of hyperoxemia during cardiac surgery remains controversial. We hypothesized that intraoperative hyperoxemia during cardiac surgery is associated with an increased risk of postoperative pulmonary complications. DESIGN: Retrospective cohort study. SETTING: We analyzed intraoperative data from five hospitals within the Multicenter Perioperative Outcomes Group between January 1, 2014, and December 31, 2019. We assessed intraoperative oxygenation of adult patients undergoing cardiac surgery with cardiopulmonary bypass (CPB). Hyperoxemia pre and post CPB was quantified as the area under the curve (AUC) of Fio2 above 0.21 in minutes when the corresponding peripheral oxygen saturation was greater than 92% measured by pulse oximetry. We quantified hyperoxemia during CPB as the AUC of Pao2 greater than 200 mm Hg measured by arterial blood gas. We analyzed the association of hyperoxemia during all phases of cardiac surgery with the frequency of postoperative pulmonary complications within 30 days, including acute respiratory insufficiency or failure, acute respiratory distress syndrome, need for reintubation, and pneumonia. PATIENTS: Twenty-one thousand six hundred thirty-two cardiac surgical patients. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: During 21,632 distinct cardiac surgery cases, 96.4% of patients spent at least 1 minute in hyperoxemia (99.1% pre-CPB, 98.5% intra-CPB, and 96.4% post-CPB). Increasing exposure to hyperoxemia was associated with an increased risk of postoperative pulmonary complications throughout three distinct surgical periods. During CPB, increasing exposure to hyperoxemia was associated with an increased odds of developing postoperative pulmonary complications (p < 0.001) in a linear manner. Hyperoxemia before CPB (p < 0.001) and after CPB (p = 0.02) were associated with increased odds of developing postoperative pulmonary complications in a U-shaped relationship. CONCLUSIONS: Hyperoxemia occurs almost universally during cardiac surgery. Exposure to hyperoxemia assessed continuously as an AUC during the intraoperative period, but particularly during CPB, was associated with an increased incidence of postoperative pulmonary complications.

Year in Review 2021: Noteworthy Literature in Cardiothoracic Anesthesia.

In 2021, progress in clinical science related to Cardiac Anesthesiology continued, but at a slower rate due to the ongoing pandemic and disruptions to clinical research. Most progress was incremental and addressed persistent questions related to our field. To identify articles for this review, we completed a structured review using our previously reported methods (1). Specifically, we used the search terms: "cardiac anesthesiology and outcomes" (n = 177), "cardiothoracic anesthesiology" (n = 34), "cardiac anesthesia," and "clinical outcomes" (n = 42) filtered on clinical trials and the year 2021 in PubMed. We also reviewed clinical trials from the most prominent clinical journals to identify additional studies for a narrative review. We then selected the most noteworthy publications for inclusion in this review and identified key themes.

Year in Review 2020: Noteworthy Literature in Cardiothoracic Anesthesiology.

The year 2020 was marred by the emergence of a deadly pandemic that disrupted every aspect of life. Despite the disruption, notable research accomplishments in the practice of cardiothoracic anesthesiology occurred in 2020 with an emphasis on optimizing care, improving outcomes, and expanding what is possible for patients undergoing cardiac surgery. This year's edition of Noteworthy Literature Review will focus on specific themes in cardiac anesthesiology that include preoperative anemia, predictors of acute kidney injury following cardiac surgery, pain management modalities, anticoagulation strategies after transcatheter aortic valve replacement, mechanical circulatory support, and future directions in research.

Intense light as anticoagulant therapy in humans.

Blood coagulation is central to myocardial ischemia and reperfusion (IR) injury. Studies on the light elicited circadian rhythm protein Period 2 (PER2) using whole body Per2-/- mice found deficient platelet function and reduced clotting which would be expected to protect from myocardial IR-injury. In contrast, intense light induction of PER2 protected from myocardial IR-injury while Per2 deficiency was detrimental. Based on these conflicting data, we sought to evaluate the role of platelet specific PER2 in coagulation and myocardial ischemia and reperfusion injury. We demonstrated that platelets from mice with tissue-specific deletion of Per2 in the megakaryocyte lineage (Per2loxP/loxP-PF4-CRE) significantly clot faster than platelets from control mice. We further found increases in infarct sizes or plasma troponin levels in Per2loxP/loxP-PF4-CRE mice when compared to controls. As intense light increases PER2 protein in human tissues, we also performed translational studies and tested the effects of intense light therapy on coagulation in healthy human subjects. Our human studies revealed that intense light therapy repressed procoagulant pathways in human plasma samples and significantly reduced the clot rate. Based on these results we conclude that intense light elicited PER2 has an inhibitory function on platelet aggregation in mice. Further, we suggest intense light as a novel therapy to prevent or treat clotting in a clinical setting.

Pathologic Shear and Elongation Rates Do Not Cause Cleavage of Von Willebrand Factor by ADAMTS13 in a Purified System.

INTRODUCTION: Pathological flows in patients with severe aortic stenosis are associated with acquired von Willebrand syndrome. This syndrome is characterized by excessive cleavage of von Willebrand factor by its main protease, A Disintegrin and Metalloproteinase with a Thrombospondin Type 1 Motif, Member 13 (ADAMTS13) leading to decreased VWF function and mucocutaneous bleeding. Aortic valve replacement and correction of the flow behavior to physiological levels reverses the syndrome, supporting the association between pathological flow and acquired von Willebrand syndrome. We investigated the effects of shear and elongational rates on von Willebrand factor cleavage in the presence of ADAMTS13. METHODS: We identified acquired von Willebrand syndrome in five patients with severe aortic stenosis. Doppler echography values from these patients were used to develop three computational fluid dynamic (CFD) aortic valve models (normal, mild and severe stenosis). Shear, elongational rates and exposure times identified in the CFD simulations were used as parameters for the design of microfluidic devices to test the effects of pathologic shear and elongational rates on the structure and function of von Willebrand factor. RESULTS: The shear rates (0-10,000s-1), elongational rates (0-1000 s-1) and exposure times (1-180 ms) tested in our microfluidic designs mimicked the flow features identified in patients with aortic stenosis. The shear and elongational rates tested in vitro did not lead to excessive cleavage or decreased function of von Willebrand factor in the presence of the protease. CONCLUSIONS: High shear and elongational rates in the presence of ADAMTS13 are not sufficient for excessive cleavage of von Willebrand Factor.

Noteworthy Literature in Cardiac Anesthesia for 2019.

This article represents a selective review of literature published in 2019. Initial results from PubMed searching for a combination of terms, including cardiac anesthesiology and anesthesiology outcomes, yielded more than 1400 publications. From there, we manually screened the results and identified 5 major themes for the year of 2019, including transcatheter techniques, delirium and anesthesiology, coagulation management following cardiopulmonary bypass, perfusion management with del Nido cardioplegia, and applied clinical research. The following research accomplishments have expanded what is possible and set ambitious goals for the future.

Intense Light-Mediated Circadian Cardioprotection via Transcriptional Reprogramming of the Endothelium.

Consistent daylight oscillations and abundant oxygen availability are fundamental to human health. Here, we investigate the intersection between light-sensing (Period 2 [PER2]) and oxygen-sensing (hypoxia-inducible factor [HIF1A]) pathways in cellular adaptation to myocardial ischemia. We demonstrate that intense light is cardioprotective via circadian PER2 amplitude enhancement, mimicking hypoxia-elicited adenosine- and HIF1A-metabolic adaptation to myocardial ischemia under normoxic conditions. Whole-genome array from intense light-exposed wild-type or Per2-/- mice and myocardial ischemia in endothelial-specific PER2-deficient mice uncover a critical role for intense light in maintaining endothelial barrier function via light-enhanced HIF1A transcription. A proteomics screen in human endothelia reveals a dominant role for PER2 in metabolic reprogramming to hypoxia via mitochondrial translocation, tricarboxylic acid (TCA) cycle enzyme activity regulation, and HIF1A transcriptional adaption to hypoxia. Translational investigation of intense light in human subjects identifies similar PER2 mechanisms, implicating the use of intense light for the treatment of cardiovascular disease.

TNF-α-driven inflammation and mitochondrial dysfunction define the platelet hyperreactivity of aging.

Aging and chronic inflammation are independent risk factors for the development of atherothrombosis and cardiovascular disease. We hypothesized that aging-associated inflammation promotes the development of platelet hyperreactivity and increases thrombotic risk during aging. Functional platelet studies in aged-frail adults and old mice demonstrated that their platelets are hyperreactive and form larger thrombi. We identified tumor necrosis factor α (TNF-α) as the key aging-associated proinflammatory cytokine responsible for platelet hyperreactivity. We further showed that platelet hyperreactivity is neutralized by abrogating signaling through TNF-α receptors in vivo in a mouse model of aging. Analysis of the bone marrow compartments showed significant platelet-biased hematopoiesis in old mice reflected by increased megakaryocyte-committed progenitor cells, megakaryocyte ploidy status, and thrombocytosis. Single-cell RNA-sequencing analysis of native mouse megakaryocytes showed significant reprogramming of inflammatory, metabolic, and mitochondrial gene pathways in old mice that appeared to play a significant role in determining platelet hyperreactivity. Platelets from old mice (where TNF-α was endogenously increased) and from young mice exposed to exogenous TNF-α exhibited significant mitochondrial changes characterized by elevated mitochondrial mass and increased oxygen consumption during activation. These mitochondrial changes were mitigated upon TNF-α blockade. Similar increases in platelet mitochondrial mass were seen in platelets from patients with myeloproliferative neoplasms, where TNF-α levels are also increased. Furthermore, metabolomics studies of platelets from young and old mice demonstrated age-dependent metabolic profiles that may differentially poise platelets for activation. Altogether, we present previously unrecognized evidence that TNF-α critically regulates megakaryocytes resident in the bone marrow niche and aging-associated platelet hyperreactivity and thrombosis.

Mass spectrometry-based molecular mapping of native FXIIIa cross-links in insoluble fibrin clots.

The roles of factor XIIIa-specific cross-links in thrombus formation, regression, or probability for embolization are largely unknown. A molecular understanding of fibrin architecture at the level of these cross-links could inform the development of therapeutic strategies to prevent the sequelae of thromboembolism. Here, we present an MS-based method to map native factor XIIIa cross-links in the insoluble matrix component of whole-blood or plasma-fibrin clots and in in vivo thrombi. Using a chaotrope-insoluble digestion method and quantitative cross-linking MS, we identified the previously mapped fibrinogen peptides that are responsible for covalent D-dimer association, as well as dozens of novel cross-links in the αC region of fibrinogen α. Our findings expand the known native cross-linked species from one to over 100 and suggest distinct antiparallel registries for interprotofibril association and covalent attachment of serpins that regulate clot dissolution.

Metabolomics assessment reveals oxidative stress and altered energy production in the heart after ischemic acute kidney injury in mice.

Acute kidney injury (AKI) is a systemic disease associated with widespread effects on distant organs, including the heart. Normal cardiac function is dependent on constant ATP generation, and the preferred method of energy production is via oxidative phosphorylation. Following direct ischemic cardiac injury, the cardiac metabolome is characterized by inadequate oxidative phosphorylation, increased oxidative stress, and increased alternate energy utilization. We assessed the impact of ischemic AKI on the metabolomics profile in the heart. Ischemic AKI was induced by 22 minutes of renal pedicle clamping, and 124 metabolites were measured in the heart at 4 hours, 24 hours, and 7 days post-procedure. Forty-one percent of measured metabolites were affected, with the most prominent changes observed 24 hours post-AKI. The post-AKI cardiac metabolome was characterized by amino acid depletion, increased oxidative stress, and evidence of alternative energy production, including a shift to anaerobic forms of energy production. These metabolomic effects were associated with significant cardiac ATP depletion and with echocardiographic evidence of diastolic dysfunction. In the kidney, metabolomics analysis revealed shifts suggestive of energy depletion and oxidative stress, which were reflected systemically in the plasma. This is the first study to examine the cardiac metabolome after AKI, and demonstrates that effects of ischemic AKI on the heart are akin to the effects of direct ischemic cardiac injury.

Selective organ ischaemia/reperfusion identifies liver as the key driver of the post-injury plasma metabolome derangements.

BACKGROUND: Understanding the molecular mechanisms in perturbation of the metabolome following ischaemia and reperfusion is critical in developing novel therapeutic strategies to prevent the sequelae of post-injury shock. While the metabolic substrates fueling these alterations have been defined, the relative contribution of specific organs to the systemic metabolic reprogramming secondary to ischaemic or haemorrhagic hypoxia remains unclear. MATERIALS AND METHODS: A porcine model of selected organ ischaemia was employed to investigate the relative contribution of liver, kidney, spleen and small bowel ischaemia/reperfusion to the plasma metabolic phenotype, as gleaned through ultra-high performance liquid chromatography-mass spectrometry-based metabolomics. RESULTS: Liver ischaemia/reperfusion promotes glycaemia, with increases in circulating carboxylic acid anions and purine oxidation metabolites, suggesting that this organ is the dominant contributor to the accumulation of these metabolites in response to ischaemic hypoxia. Succinate, in particular, accumulates selectively in response to the hepatic ischemia, with levels 6.5 times spleen, 8.2 times small bowel, and 6 times renal levels. Similar trends, but lower fold-change increase in comparison to baseline values, were observed upon ischaemia/reperfusion of kidney, spleen and small bowel. DISCUSSION: These observations suggest that the liver may play a critical role in mediating the accumulation of the same metabolites in response to haemorrhagic hypoxia, especially with respect to succinate, a metabolite that has been increasingly implicated in the coagulopathy and pro-inflammatory sequelae of ischaemic and haemorrhagic shock.

High Throughput Metabolomics in Clinical Studies: Review and New Applications to Remote Ischemic Preconditioning.

Metabolomic analysis has made substantial contributions to the understanding of diverse pathological processes and has the potential to improve diagnosis and identify novel therapeutic targets. As early success in perinatal medicine, nutrition, chronic diseases, cancer and trauma demonstrates, metabolomics is approaching feasibility in terms of guiding improvement in population-level diagnosis and treatment. A key barrier to implementing metabolomics as a routine diagnostic tool is rapid sample extraction and data analysis along with the establishment of normal values for novel metabolic markers. This review covers key advancements in clinical metabolomics and applies a high throughput metabolomics method as a proof of principle to identify novel metabolites associated with remote ischemic preconditioning.

Hemorrhagic shock and tissue injury drive distinct plasma metabolome derangements in swine.

BACKGROUND: Tissue injury and hemorrhagic shock induce significant systemic metabolic reprogramming in animal models and critically injured patients. Recent expansions of the classic concepts of metabolomic aberrations in tissue injury and hemorrhage opened the way for novel resuscitative interventions based on the observed abnormal metabolic demands. We hypothesize that metabolic demands and resulting metabolic signatures in pig plasma will vary in response to isolated or combined tissue injury and hemorrhagic shock. METHODS: A total of 20 pigs underwent either isolated tissue injury, hemorrhagic shock, or combined tissue injury and hemorrhagic shock referenced to a sham protocol (n = 5/group). Plasma samples were analyzed by UHPLC-MS. RESULTS: Hemorrhagic shock promoted a hypermetabolic state. Tissue injury alone dampened metabolic responses in comparison to sham and hemorrhagic shock, and attenuated the hypermetabolic state triggered by shock with respect to energy metabolism (glycolysis, glutaminolysis, and Krebs cycle). Tissue injury and hemorrhagic shock had a more pronounced effect on nitrogen metabolism (arginine, polyamines, and purine metabolism) than hemorrhagic shock alone. CONCLUSION: Isolated or combined tissue injury and hemorrhagic shock result in distinct plasma metabolic signatures. These findings indicate that optimized resuscitative interventions in critically ill patients are possible based on identifying the severity of tissue injury and hemorrhage.

Correlation of pre-operative plasma protein concentrations in cardiac surgery patients with bleeding outcomes using a targeted quantitative proteomics approach.

PURPOSE: Despite recent advancements in the use of thrombelastography (TEG) in the surgical setting, adequate technology to accurately predict bleeding phenotypes for patients undergoing cardiopulmonary bypass on the basis of non-mechanical parameters is lacking. While basic science and translational studies have provided key mechanistic insights about the protein components of coagulation cascades and regulatory mediators of hemostasis and fibrinolysis, targeted protein assays are still missing and the association of protein profiles to bleeding phenotypes and TEG readouts have yet to be discovered. OBJECTIVE: To identify protein biomarkers of bleeding phenotypes of cardiopulmonary bypass patients in pre-operative plasma. EXPERIMENTAL DESIGN: We applied a targeted proteomics approach to quantify 123 plasma proteins from 23 patients undergoing cardiopulmonary bypass (CPB) and sternotomy. We then correlated these measurements to bleeding outcomes and TEG parameters, associated with speed of clot formation and strength. RESULTS: In this pilot study, we demonstrate the feasibility of protein quantitation as a viable strategy to predict low versus high bleeding phenotypes (loss of < or > than 20% of estimated blood volume, calculated as 70 mL/kg for BMI<29.9, 60 mL/kg for BMI = 30-39.9, and 50 mL/kg for BMI>40. Statistical elaborations highlighted a core set of proteins showing significant correlations to either total blood loss or TEG R/MA parameters. CONCLUSION AND CLINICAL RELEVANCE: Though prospective verification and validation in larger cohorts will be necessary, this report suggests a potential for targeted quantitative proteomics of pre-operative plasma protein concentrations in the prediction of estimated blood loss following CPB.