Mitochondrial CypD Acetylation Promotes Endothelial Dysfunction and Hypertension.

BACKGROUND: Nearly half of adults have hypertension, a major risk factor for cardiovascular disease. Mitochondrial hyperacetylation is linked to hypertension, but the role of acetylation of specific proteins is not clear. We hypothesized that acetylation of mitochondrial CypD (cyclophilin D) at K166 contributes to endothelial dysfunction and hypertension. METHODS: To test this hypothesis, we studied CypD acetylation in patients with essential hypertension, defined a pathogenic role of CypD acetylation in deacetylation mimetic CypD-K166R mutant mice and endothelial-specific GCN5L1 (general control of amino acid synthesis 5 like 1)-deficient mice using an Ang II (angiotensin II) model of hypertension. RESULTS: Arterioles from hypertensive patients had 280% higher CypD acetylation coupled with reduced Sirt3 (sirtuin 3) and increased GCN5L1 levels. GCN5L1 regulates mitochondrial protein acetylation and promotes CypD acetylation, which is counteracted by mitochondrial deacetylase Sirt3. In human aortic endothelial cells, GCN5L1 depletion prevents superoxide overproduction. Deacetylation mimetic CypD-K166R mice were protected from vascular oxidative stress, endothelial dysfunction, and Ang II-induced hypertension. Ang II-induced hypertension increased mitochondrial GCN5L1 and reduced Sirt3 levels resulting in a 250% increase in GCN5L1/Sirt3 ratio promoting CypD acetylation. Treatment with mitochondria-targeted scavenger of cytotoxic isolevuglandins (mito2HOBA) normalized GCN5L1/Sirt3 ratio, reduced CypD acetylation, and attenuated hypertension. The role of mitochondrial acetyltransferase GCN5L1 in the endothelial function was tested in endothelial-specific GCN5L1 knockout mice. Depletion of endothelial GCN5L1 prevented Ang II-induced mitochondrial oxidative stress, reduced the maladaptive switch of vascular metabolism to glycolysis, prevented inactivation of endothelial nitric oxide, preserved endothelial-dependent relaxation, and attenuated hypertension. CONCLUSIONS: These data support the pathogenic role of CypD acetylation in endothelial dysfunction and hypertension. We suggest that targeting cytotoxic mitochondrial isolevuglandins and GCN5L1 reduces CypD acetylation, which may be beneficial in cardiovascular disease.

Oxidative stress mediates associations between preoperative psychosocial phenotype and pain-related outcomes at 6 months following total knee arthroplasty: a longitudinal cohort study.

OBJECTIVE: Greater preoperative depression, anxiety, and pain catastrophizing are associated with more severe long-term pain following total knee arthroplasty (TKA). In a secondary analysis of previously reported data, we tested the hypothesis that these associations are mediated by oxidative stress (OS). DESIGN: A mixed between/within-subjects longitudinal cohort design. SETTING: A single academic medical center. SUBJECTS: Osteoarthritis patients (n = 91; 62.6% female) undergoing unilateral TKA. METHODS: We assessed depression, anxiety, and catastrophizing, as well as markers of central sensitization (widespread pain, temporal summation of pain) preoperatively. Blood samples were then obtained immediately prior to intraoperative tourniquet placement for quantification of in vivo biomarkers of systemic OS, F2-isoprostanes and isofurans. Post-TKA pain intensity (numeric rating scale worst pain [NRS], McGill Pain Questionnaire-2 [MPQ-2]) and function (PROMIS Pain Interference) were assessed at 6 months following TKA. RESULTS: Greater preoperative depression, catastrophizing, and widespread pain were associated with higher intraoperative combined OS (F2-isoprostanes+isofurans/2), which was in turn associated with higher post-TKA pain intensity and worse function (P < .05). All preoperative phenotype predictors except anxiety were correlated positively with post-TKA pain and/or function (P < .05). Bootstrapped mediation analyses revealed significant (P < .05) indirect (mediated) effects of depression (NRS Worst Pain, MPQ-2, PROMIS Pain Interference), anxiety (MPQ-2, PROMIS Pain Interference), and catastrophizing (PROMIS Pain Interference) on adverse long-term post-TKA outcomes via elevated OS. Central sensitization-related predictors demonstrated only direct effects (P < .05) on post-TKA outcomes that were independent of OS mechanisms. CONCLUSIONS: Results suggest that the adverse impact of depression, anxiety, and pain catastrophizing on post-TKA pain and functional outcomes are mediated in part by elevated OS.

Hyperoxia Increases Kidney Injury During Renal Ischemia and Reperfusion in Mice.

BACKGROUND: Renal ischemia and reperfusion (IR) contribute to perioperative acute kidney injury, and oxygen is a key regulator of this process. We hypothesized that oxygen administration during surgery and renal IR would impact postoperative kidney function and injury in mice. METHODS: Mice were anesthetized, intubated, and mechanically ventilated with a fraction of inspired oxygen (F io2 ) 0.10 (hypoxia), 0.21 (normoxia), 0.60 (moderate hyperoxia), or 1.00 (severe hyperoxia) during 67 minutes of renal IR or sham IR surgery. Additional mice were treated before IR or sham IR surgery with 50 mg/kg tempol, a superoxide scavenger. At 24 hours, mice were sacrificed, and blood and kidney collected. We assessed and compared kidney function and injury across groups by measuring blood urea nitrogen (BUN, primary end point), renal histological injury, renal expression of neutrophil gelatinase-associated lipocalin (NGAL), and renal heme oxygenase 1 ( Ho-1 ), peroxisome proliferator-activated receptor gamma coactivator 1-α ( Pgc1-α ), and glutathione peroxidase 4 ( Gpx-4 ) transcripts, to explore potential mechanisms of any effect of oxygen. RESULTS: Hyperoxia and hypoxia during renal IR surgery decreased renal function and increased kidney injury compared to normoxia. Baseline median (interquartile range) BUN was 22.2 mg/dL (18.4-26.0), and 24 hours after IR surgery, BUN was 17.5 mg/dL (95% confidence interval [CI], 1.3-38.4; P = .034) higher in moderate hyperoxia-treated animals, 51.8 mg/dL (95% CI, 24.9-74.8; P < .001) higher in severe hyperoxia-treated animals, and 64.9 mg/dL (95% CI, 41.2-80.3; P < .001) higher in hypoxia-treated animals compared to animals treated with normoxia ( P < .001, overall effect of hyperoxia). Hyperoxia-induced injury, but not hypoxia-induced injury, was attenuated by pretreatment with tempol. Histological injury scores, renal NGAL staining, and renal transcription of Ho-1 and suppression of Pgc1- α followed the same pattern as BUN, in relation to the effects of oxygen treatment. CONCLUSIONS: In this controlled preclinical study of oxygen treatment during renal IR surgery, hyperoxia and hypoxia impaired renal function, increased renal injury, and impacted expression of genes that affect mitochondrial biogenesis and antioxidant response. These results might have implications for patients during surgery when high concentrations of oxygen are frequently administered, especially in cases involving renal IR.

The Association Between Enhanced Recovery After Cardiac Surgery-Guided Analgesics and Postoperative Delirium.

OBJECTIVES: Delirium is a common postoperative complication associated with death and long-term cognitive impairment. The authors studied the association between opioid-sparing anesthetics, incorporating Enhanced Recovery After Cardiac Surgery (ERACS)-guided analgesics and postoperative delirium. DESIGN: The authors performed a retrospective review of nonemergent coronary, valve, or ascending aorta surgery patients. SETTING: A tertiary academic medical institution. PARTICIPANTS: The study authors analyzed a dataset of elective adult cardiac surgical patients. All patients ≥18 years undergoing elective cardiac surgery from November 2, 2017 until February 2, 2021 were eligible for inclusion. INTERVENTIONS: The ERACS-guided multimodal pain regimen included preoperative oral acetaminophen and gabapentin, and intraoperative intravenous lidocaine, ketamine, and dexmedetomidine. MEASUREMENTS AND MAIN RESULTS: Delirium was measured by bedside nurses using the Confusion Assessment Method for the intensive care unit (ICU). Delirium occurred in 220 of the 1,675 patients (13.7%). The use of any component of the multimodal pain regimen was not associated with delirium (odds ratio [OR]: 0.85 [95% CI: 0.63-1.16]). Individually, acetaminophen was associated with reduced odds of delirium (OR: 0.60 [95% CI: 0.37-0.95]). Gabapentin (OR: 1.36 [95% CI: 0.97-2.21]), lidocaine (OR: 0.86 [95% CI: 0.53-1.37]), ketamine (OR: 1.15 [95% CI: 0.72-1.83]), and dexmedetomidine (OR: 0.79 [95% CI: 0.46-1.31]) were not individually associated with postoperative delirium. Individual ERACS elements were associated with secondary outcomes of hospital length of stay, ICU duration, postoperative opioid administration, and postoperative intubation duration. CONCLUSIONS: The use of an opioid-sparing perioperative ERACS pain regimen was not associated with reduced postoperative delirium, opioid consumption, or additional poor outcomes. Individually, acetaminophen was associated with reduced delirium.

Role of Axl in target organ inflammation and damage due to hypertensive aortic remodeling.

We have shown that excessive endothelial cell stretch causes release of growth arrest-specific 6 (GAS6), which activates the tyrosine kinase receptor Axl on monocytes and promotes immune activation and inflammation. We hypothesized that GAS6/Axl blockade would reduce renal and vascular inflammation and lessen renal dysfunction in the setting of chronic aortic remodeling. We characterized a model of aortic remodeling in mice following a 2-wk infusion of angiotensin II (ANG II). These mice had chronically increased pulse wave velocity, and their aortas demonstrated increased mural collagen. Mechanical testing revealed a marked loss of Windkessel function that persisted for 6 mo following ANG II infusion. Renal function studies showed a reduced ability to excrete a volume load, a progressive increase in albuminuria, and tubular damage as estimated by periodic acid Schiff staining. Treatment with the Axl inhibitor R428 beginning 2 mo after ANG II infusion had a minimal effect on aortic remodeling 2 mo later but reduced the infiltration of T cells, γ/δ T cells, and macrophages into the aorta and kidney and improved renal excretory capacity, reduced albuminuria, and reduced evidence of renal tubular damage. In humans, circulating Axl+/Siglec6+ dendritic cells and phospho-Axl+ cells correlated with pulse wave velocity and aortic compliance measured by transesophageal echo, confirming chronic activation of the GAS6/Axl pathway. We conclude that brief episodes of hypertension induce chronic aortic remodeling, which is associated with persistent low-grade inflammation of the aorta and kidneys and evidence of renal dysfunction. These events are mediated at least in part by GAS6/Axl signaling and are improved with Axl blockade.NEW & NOTEWORTHY In this study, a brief, 2-wk period of hypertension in mice led to progressive aortic remodeling, an increase in pulse wave velocity, and evidence of renal injury, dysfunction, and albuminuria. This end-organ damage was associated with persistent renal and aortic infiltration of CD8+ and γ/δ T cells. We show that this inflammatory response is likely due to GAS6/Axl signaling and can be ameliorated by blocking this pathway. We propose that the altered microvascular mechanical forces caused by increased pulse wave velocity enhance GAS6 release from the endothelium, which in turn activates Axl on myeloid cells, promoting the end-organ damage associated with aortic stiffening.

Mitochondrial Deacetylase Sirt3 Reduces Vascular Dysfunction and Hypertension While Sirt3 Depletion in Essential Hypertension Is Linked to Vascular Inflammation and Oxidative Stress.

RATIONALE: Hypertension represents a major risk factor for stroke, myocardial infarction, and heart failure and affects 30% of the adult population. Mitochondrial dysfunction contributes to hypertension, but specific mechanisms are unclear. The mitochondrial deacetylase Sirt3 (Sirtuin 3) is critical in the regulation of metabolic and antioxidant functions which are associated with hypertension, and cardiovascular disease risk factors diminish Sirt3 level. OBJECTIVE: We hypothesized that reduced Sirt3 expression contributes to vascular dysfunction in hypertension, but increased Sirt3 protects vascular function and decreases hypertension. METHODS AND RESULTS: To test the therapeutic potential of targeting Sirt3 expression, we developed new transgenic mice with global Sirt3OX (Sirt3 overexpression), which protects from endothelial dysfunction, vascular oxidative stress, and hypertrophy and attenuates Ang II (angiotensin II) and deoxycorticosterone acetate-salt induced hypertension. Global Sirt3 depletion in Sirt3-/- mice results in oxidative stress due to hyperacetylation of mitochondrial superoxide dismutase (SOD2), increases HIF1α (hypoxia-inducible factor-1), reduces endothelial cadherin, stimulates vascular hypertrophy, increases vascular permeability and vascular inflammation (p65, caspase 1, VCAM [vascular cell adhesion molecule-1], ICAM [intercellular adhesion molecule-1], and MCP1 [monocyte chemoattractant protein 1]), increases inflammatory cell infiltration in the kidney, reduces telomerase expression, and accelerates vascular senescence and age-dependent hypertension; conversely, increased Sirt3 expression in Sirt3OX mice prevents these deleterious effects. The clinical relevance of Sirt3 depletion was confirmed in arterioles from human mediastinal fat in patients with essential hypertension showing a 40% decrease in vascular Sirt3, coupled with Sirt3-dependent 3-fold increases in SOD2 acetylation, NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) activity, VCAM, ICAM, and MCP1 levels in hypertensive subjects compared with normotensive subjects. CONCLUSIONS: We suggest that Sirt3 depletion in hypertension promotes endothelial dysfunction, vascular hypertrophy, vascular inflammation, and end-organ damage. Our data support a therapeutic potential of targeting Sirt3 expression in vascular dysfunction and hypertension.

Impact of Intraoperative Data on Risk Prediction for Mortality After Intra-Abdominal Surgery.

BACKGROUND: Risk prediction models for postoperative mortality after intra-abdominal surgery have typically been developed using preoperative variables. It is unclear if intraoperative data add significant value to these risk prediction models. METHODS: With IRB approval, an institutional retrospective cohort of intra-abdominal surgery patients in the 2005 to 2015 American College of Surgeons National Surgical Quality Improvement Program was identified. Intraoperative data were obtained from the electronic health record. The primary outcome was 30-day mortality. We evaluated the performance of machine learning algorithms to predict 30-day mortality using: 1) baseline variables and 2) baseline + intraoperative variables. Algorithms evaluated were: 1) logistic regression with elastic net selection, 2) random forest (RF), 3) gradient boosting machine (GBM), 4) support vector machine (SVM), and 5) convolutional neural networks (CNNs). Model performance was evaluated using the area under the receiver operator characteristic curve (AUROC). The sample was randomly divided into a training/testing split with 80%/20% probabilities. Repeated 10-fold cross-validation identified the optimal model hyperparameters in the training dataset for each model, which were then applied to the entire training dataset to train the model. Trained models were applied to the test cohort to evaluate model performance. Statistical significance was evaluated using P < .05. RESULTS: The training and testing cohorts contained 4322 and 1079 patients, respectively, with 62 (1.4%) and 15 (1.4%) experiencing 30-day mortality, respectively. When using only baseline variables to predict mortality, all algorithms except SVM (area under the receiver operator characteristic curve [AUROC], 0.83 [95% confidence interval {CI}, 0.69-0.97]) had AUROC >0.9: GBM (AUROC, 0.96 [0.94-1.0]), RF (AUROC, 0.96 [0.92-1.0]), CNN (AUROC, 0.96 [0.92-0.99]), and logistic regression (AUROC, 0.95 [0.91-0.99]). AUROC significantly increased with intraoperative variables with CNN (AUROC, 0.97 [0.96-0.99]; P = .047 versus baseline), but there was no improvement with GBM (AUROC, 0.97 [0.95-0.99]; P = .3 versus baseline), RF (AUROC, 0.96 [0.93-1.0]; P = .5 versus baseline), and logistic regression (AUROC, 0.94 [0.90-0.99]; P = .6 versus baseline). CONCLUSIONS: Postoperative mortality is predicted with excellent discrimination in intra-abdominal surgery patients using only preoperative variables in various machine learning algorithms. The addition of intraoperative data to preoperative data also resulted in models with excellent discrimination, but model performance did not improve.

Society of Cardiovascular Anesthesiologists Clinical Practice Update for Management of Acute Kidney Injury Associated With Cardiac Surgery.

Cardiac surgery-associated acute kidney injury (CS-AKI) is common and is associated with increased risk for postoperative morbidity and mortality. Our recent survey of the Society of Cardiovascular Anesthesiologists (SCA) membership showed 6 potentially renoprotective strategies for which clinicians would most value an evidence-based review (ie, intraoperative target blood pressure, choice of specific vasopressor agent, erythrocyte transfusion threshold, use of alpha-2 agonists, goal-directed oxygen delivery on cardiopulmonary bypass [CPB], and the "Kidney Disease Improving Global Outcomes [KDIGO] bundle of care"). Thus, the SCA's Continuing Practice Improvement Acute Kidney Injury Working Group aimed to provide a practice update for each of these strategies in cardiac surgical patients based on the evidence from randomized controlled trials (RCTs). PubMed, EMBASE, and Cochrane library databases were comprehensively searched for eligible studies from inception through February 2021, with search results updated in August 2021. A total of 15 RCTs investigating the effects of the above-mentioned strategies on CS-AKI were included for meta-analysis. For each strategy, the level of evidence was assessed using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) methodology. Across the 6 potentially renoprotective strategies evaluated, current evidence for their use was rated as "moderate," "low," or "very low." Based on eligible RCTs, our analysis suggested using goal-directed oxygen delivery on CPB and the "KDIGO bundle of care" in high-risk patients to prevent CS-AKI (moderate level of GRADE evidence). Our results suggested considering the use of vasopressin in vasoplegic shock patients to reduce CS-AKI (low level of GRADE evidence). The decision to use a restrictive versus liberal strategy for perioperative red cell transfusion should not be based on concerns for renal protection (a moderate level of GRADE evidence). In addition, targeting a higher mean arterial pressure during CPB, perioperative use of dopamine, and use of dexmedetomidine did not reduce CS-AKI (a low or very low level of GRADE evidence). This review will help clinicians provide evidence-based care, targeting improved renal outcomes in adult patients undergoing cardiac surgery.

Perioperative high density lipoproteins, oxidative stress, and kidney injury after cardiac surgery.

Oxidative stress promotes acute kidney injury (AKI). Higher HDL cholesterol concentrations are associated with less AKI. To test the hypothesis that HDL antioxidant activity is associated with AKI after cardiac surgery, we quantified HDL particle (HDL-P) size and number, paraoxonase-1 (PON-1) activity, and isofuran concentrations in 75 patients who developed AKI and 75 matched control patients. Higher preoperative HDL-P was associated with less AKI (OR: 0.80; 95% CI, 0.71-0.91; P = 0.001), higher PON-1 activity ( P < 0.001), and lower plasma concentrations of isofurans immediately after surgery (P = 0.02). Similarly, higher preoperative small HDL-P was associated with less AKI, higher PON-1 activity, and lower isofuran concentrations. Higher intraoperative particle losses were associated with less AKI (OR: 0.79; 95% CI 0.67-0.93; P = 0.005), and with decreased postoperative isofuran concentrations (P = 0.04) . Additionally, higher preoperative small HDL-P and increased intraoperative small particle loss were associated with improved long-term renal function (P = 0.003, 0.01, respectively). In conclusion, a higher preoperative concentration of HDL-P, particularly small particles, is associated with lower oxidative damage and less AKI. Perioperative changes in HDL-P concentrations are also associated with AKI. Small HDL-P may represent a novel modifiable risk factor for AKI.

Intraoperative venous congestion and acute kidney injury in cardiac surgery: an observational cohort study.

BACKGROUND: Increased intravascular volume has been associated with protection from acute kidney injury (AKI), but in patients with congestive heart failure, venous congestion is associated with increased AKI. We tested the hypothesis that intraoperative venous congestion is associated with AKI after cardiac surgery. METHODS: In patients enrolled in the Statin AKI Cardiac Surgery trial, venous congestion was quantified as the area under the curve (AUC) of central venous pressure (CVP) >12, 16, or 20 mm Hg during surgery (mm Hg min). AKI was defined using Kidney Disease Improving Global Outcomes (KDIGO) criteria and urine concentrations of tissue inhibitor of metalloproteinase-2 and insulin-like growth factor binding protein 7 ([TIMP-2]⋅[IGFBP7]), a marker of renal stress. We measured associations between venous congestion, AKI and [TIMP-2]⋅[IGFBP7], adjusted for potential confounders. Values are reported as median (25th-75th percentile). RESULTS: Based on KDIGO criteria, 104 of 425 (24.5%) patients developed AKI. The venous congestion AUCs were 273 mm Hg min (81-567) for CVP >12 mm Hg, 66 mm Hg min (12-221) for CVP >16 mm Hg, and 11 mm Hg min (1-54) for CVP >20 mm Hg. A 60 mm Hg min increase above the median venous congestion AUC above each threshold was independently associated with increased AKI (odds ratio=1.06; 95% confidence interval [CI], 1.02-1.10; P=0.008; odds ratio=1.12; 95% CI, 1.02-1.23; P=0.013; and odds ratio=1.30; 95% CI, 1.06-1.59; P=0.012 for CVP>12, >16, and >20 mm Hg, respectively). Venous congestion before cardiopulmonary bypass was also associated with increased [TIMP-2]⋅[IGFBP7] measured during cardiopulmonary bypass and after surgery, but neither venous congestion after cardiopulmonary bypass nor venous congestion throughout surgery was associated with postoperative [TIMP-2]⋅[IGFBP7]. CONCLUSION: Intraoperative venous congestion was independently associated with increased AKI after cardiac surgery.

The incidence, risk, presentation, pathophysiology, treatment, and effects of perioperative acute kidney injury.

PURPOSE: Present clinical updates, current research findings, and consensus statements relevant to the care of the acute kidney injury (AKI) patient. PRINCIPAL FINDINGS: Acute kidney injury is one of the most frequent and debilitating complications of surgery and critical illness. Consensus criteria use serum creatinine and urine output measurements to diagnose AKI and allow for objective diagnosis and more accurate comparisons across populations. New serum and urine biomarkers may provide earlier evidence of AKI, but their clinical utility, while increasing, remains limited. Avoidance of nephrotoxins, intravascular fluid management, and maintenance of renal perfusion are the mainstays of preventive management and treatment of AKI. Optimal timing for the initiation of renal replacement therapy is controversial and remains under investigation. CONCLUSIONS: Acute kidney injury continues to affect large numbers of patients receiving surgery or in the intensive care unit, but specific advances in resuscitation techniques, endpoint refinements, epidemiology, biomarkers, and pathology are providing the necessary framework to reduce AKI and associated morbidity.

RéSUMé: OBJECTIF: Présenter les mises à jour cliniques, les résultats de recherche actuels et les énoncés de consensus pertinents concernant les soins des patients atteints d'insuffisance rénale aiguë (IRA). CONSTATATIONS PRINCIPALES: L'insuffisance rénale aiguë est l'une des complications les plus fréquentes et débilitantes de la chirurgie et des maladies critiques. Les critères consensuels se fondent sur des mesures de la créatininémie et de la diurèse pour diagnostiquer l'IRA et favorisent un diagnostic objectif et des comparaisons plus précises entre les populations. Les nouveaux biomarqueurs sériques et urinaires pourraient permettre une identification précoce de l'IRA mais leur utilité clinique, certes croissante, demeure limitée. Les piliers d'une prise en charge et d'un traitement préventif de l'IRA demeurent la minimisation de l'exposition aux néphrotoxines, la gestion liquidienne intravasculaire et le maintien de la perfusion rénale. Le moment optimal pour l'amorce d'un traitement substitutif de l'insuffisance rénale demeure controversé et reste à déterminer. CONCLUSION: L'insuffisance rénale aiguë continue d'affecter un grand nombre de patients recevant une chirurgie ou à l'unité de soins intensifs, mais des progrès spécifiques dans les techniques de réanimation, les indicateurs de résultat, dans l'épidémiologie, les biomarqueurs et la pathologie fournissent le cadre nécessaire pour réduire l'IRA et la morbidité associée.

Potential Renoprotective Strategies in Adult Cardiac Surgery: A Survey of Society of Cardiovascular Anesthesiologists Members to Explore the Rationale and Beliefs Driving Current Clinical Decision-Making.

OBJECTIVES: The authors sought to (1) characterize the rationale underpinning anesthesiologists' use of various perioperative strategies hypothesized to affect renal function in adult patients undergoing cardiac surgery, (2) characterize existing belief about the quality of evidence addressing the renal impact of these strategies, and (3) identify potentially renoprotective strategies for which anesthesiologists would most value a detailed, evidence-based review. DESIGN: Survey of perioperative practice in adult patients undergoing cardiac surgery. SETTING: Online survey. PARTICIPANTS: Members of the Society of Cardiovascular Anesthesiologists (SCA). INTERVENTIONS: None. MEASUREMENTS & MAIN RESULTS: The survey was distributed to more than 2,000 SCA members and completed in whole or in part by 202 respondents. Selection of target intraoperative blood pressure (and relative hypotension avoidance) was the strategy most frequently reported to reflect belief about its potential renal effect (79%; 95% CI: 72-85). Most respondents believed the evidence supporting an effect on renal injury of intraoperative target blood pressure during cardiac surgery was of high or moderate quality. Other factors, including a specific nonrenal rationale, surgeon preference, department- or institution-level decisions, tradition, or habit, also frequently were reported to affect decision making across queried strategies. Potential renoprotective strategies most frequently requested for inclusion in a subsequent detailed, evidence-based review were intraoperative target blood pressure and choice of vasopressor agent to achieve target pressure. CONCLUSIONS: A large number of perioperative strategies are believed to variably affect renal injury in adult patients undergoing cardiac surgery, with wide variation in perceived quality of evidence for a renal effect of these strategies.

Intraoperative Oxidative Damage and Delirium after Cardiac Surgery.

BACKGROUND: Mechanisms of postoperative delirium remain poorly understood, limiting development of effective treatments. We tested the hypothesis that intraoperative oxidative damage is associated with delirium and neuronal injury and that disruption of the blood-brain barrier modifies these associations. METHODS: In a prespecified cohort study of 400 cardiac surgery patients enrolled in a clinical trial of atorvastatin to reduce kidney injury and delirium, we measured plasma concentrations of F2-isoprostanes and isofurans using gas chromatography-mass spectrometry to quantify oxidative damage, ubiquitin carboxyl-terminal hydrolase isozyme L1 to quantify neuronal injury, and S100 calcium-binding protein B using enzyme-linked immunosorbent assays to quantify blood-brain barrier disruption before, during, and after surgery. We performed the Confusion Assessment Method for the Intensive Care Unit twice daily to diagnose delirium. We measured the independent associations between intraoperative F2-isoprostanes and isofurans and delirium (primary outcome) and postoperative ubiquitin carboxyl-terminal hydrolase isozyme L1 (secondary outcome), and we assessed if S100 calcium-binding protein B modified these associations. RESULTS: Delirium occurred in 109 of 400 (27.3%) patients for a median (10th, 90th percentile) of 1.0 (0.5, 3.0) days. In the total cohort, plasma ubiquitin carboxyl-terminal hydrolase isozyme L1 concentration was 6.3 ng/ml (2.7, 14.9) at baseline and 12.4 ng/ml (7.9, 31.2) on postoperative day 1. F2-isoprostanes and isofurans increased throughout surgery, and the log-transformed sum of intraoperative F2-isoprostanes and isofurans was independently associated with increased odds of postoperative delirium (odds ratio, 3.70 [95% CI, 1.41 to 9.70]; P = 0.008) and with increased postoperative ubiquitin carboxyl-terminal hydrolase isozyme L1 (ratio of geometric means, 1.42 [1.11 to 1.81]; P = 0.005). The association between increased intraoperative F2-isoprostanes and isofurans and increased postoperative ubiquitin carboxyl-terminal hydrolase isozyme L1 was amplified in patients with elevated S100 calcium-binding protein B (P = 0.049). CONCLUSIONS: Intraoperative oxidative damage was associated with increased postoperative delirium and neuronal injury, and the association between oxidative damage and neuronal injury was stronger among patients with increased blood-brain barrier disruption.

Mean platelet volume and cardiac-surgery-associated acute kidney injury: a retrospective study.

PURPOSE: Increased mean platelet volume (MPV) may indicate platelet activation, platelet aggregation, and a resulting prothrombotic state. Such changes in the postoperative period have been associated with organ injury and adverse outcomes. We hypothesized that changes in MPV after cardiac surgery are associated with both a higher risk of acute kidney injury (AKI) and mortality. METHODS: In this retrospective study, we evaluated consecutive patients undergoing adult cardiac surgery patients between 12 December 2011 and 5 June 2018. The change in MPV was derived by calculating the difference between the baseline MPV before surgery and the average postoperative MPV just prior to the occurrence of AKI. We defined postoperative AKI according to Kidney Disease: Improving Global Outcomes Clinical Practice Guideline for Acute Kidney Injury as either a ≥ 50% increase in serum creatinine in the first ten postoperative days, or an increase of ≥ 0.3 mg·dL-1 during any 48-hr window across the ten-day postoperative period. Multivariable logistic regression analysis was used to examine the association between MPV change and postoperative AKI and mortality. RESULTS: Of the 4,204 patients studied, 1,373 (32.7%) developed postoperative AKI, including 83 (2.0%) and 38 (0.9%) who developed stages II and III AKI, respectively. Compared with patients who had an increase in median postoperative MPV of 0.2 femtolitre (fL), those with an increase of 0.8 fL had an 80% increase in the odds of developing AKI (adjusted odds ratio [aOR], 1.80; 95% confidence interval [CI],1.36 to 2.38; P < 0.001) and were almost twice as likely to progress to a higher severity AKI (aOR, 1.66; 95% CI, 1.28 to 2.16; P < 0.001). Change in MPV was not associated with mortality (aOR,1.32; 95% CI, 0.92 to 1.89; P = 0.14). CONCLUSION: Increased MPV change in the postoperative period was associated with both increased risk and severity of AKI, but not mortality.

RéSUMé: OBJECTIF: Un volume plaquettaire moyen (VPM) augmenté peut être indicatif d'une activation plaquettaire, d'une agrégation plaquettaire, et de l'état prothrombotique qui en résulte. De tels changements en période postopératoire ont été associés à des lésions aux organes et à des devenirs défavorables. Nous avons émis l'hypothèse que des changements du VPM après une chirurgie cardiaque seraient associés à un risque plus élevé d'insuffisance rénale aiguë et de mortalité. MéTHODE: Dans cette étude rétrospective, nous avons évalué des patients adultes consécutifs subissant une chirurgie cardiaque entre le 12 décembre 2011 et le 5 juin 2018. Le changement de VPM a été dérivé en calculant la différence entre le VPM de base avant la chirurgie et le VPM postopératoire moyen juste avant la survenue de l'IRA. Nous avons défini une IRA postopératoire sur la base des Directives Kidney Disease: Improving Global Outcomes Clinical Practice Guideline for Acute Kidney Injury (Les maladies rénales: Guide d'exercice clinique pour améliorer les devenirs globaux pour l'insuffisance rénale aiguë) en tant qu'une augmentation ≥ 50 % de la créatine sérique au cours des dix premiers jours postopératoires, ou une augmentation de ≥ 0,3 mg·dL−1 pendant toute fenêtre de 48 h au cours des dix premiers jours postopératoires. Une analyse multivariée de régression logistique a été utilisée pour examiner l'association entre le changement de VPM et l'IRA postopératoire et la mortalité. RéSULTATS: Parmi les 4204 patients à l'étude, 1373 (32,7 %) ont souffert d'IRA postopératoire, y compris 83 (2,0 %) et 38 (0,9 %) qui ont développé des IRA de stade II et III, respectivement. Par rapport aux patients ayant manifesté une augmentation du VPM postopératoire médian de 0,2 femtolitre (fL), ceux affichant une augmentation de 0,8 fL ont démontré une augmentation de 80 % de la probabilité d'IRA (rapport de cotes ajusté [RCA], 1,80; intervalle de confiance [IC] 95 %, 1,36 à 2,38; P < 0,001) et couraient un risque pratiquement deux fois plus élevé de voir leur IRA progresser à un stade plus grave (RCA, 1,66; IC 95 %, 1,28 à 2,16; P < 0,001). Les changements de VPM n'étaient pas associés à la mortalité (RCA, 1,32; IC 95 %, 0,92 à 1,89; P = 0,14). CONCLUSION: Une augmentation accrue du VPM en période postopératoire a été associée à un risque et une gravité accrus d'IRA, mais pas à la mortalité.

Mitochondrial DNA Haplogroups and Delirium During Sepsis.

OBJECTIVES: Studies suggest that mitochondrial dysfunction underlies some forms of sepsis-induced organ failure. We sought to test the hypothesis that variations in mitochondrial DNA haplogroup affect susceptibility to sepsis-associated delirium, a common manifestation of acute brain dysfunction during sepsis. DESIGN: Retrospective cohort study. SETTING: Medical and surgical ICUs at a large tertiary care center. PATIENTS: Caucasian and African American adults with sepsis. MEASUREMENTS AND MAIN RESULTS: We determined each patient's mitochondrial DNA haplogroup using single-nucleotide polymorphisms genotyping data in a DNA databank and extracted outcomes from linked electronic medical records. We then used zero-inflated negative binomial regression to analyze age-adjusted associations between mitochondrial DNA haplogroups and duration of delirium, identified using the Confusion Assessment Method for the ICU. Eight-hundred ten patients accounted for 958 sepsis admissions, with 802 (84%) by Caucasians and 156 (16%) by African Americans. In total, 795 patient admissions (83%) involved one or more days of delirium. The 7% of Caucasians belonging to mitochondrial DNA haplogroup clade IWX experienced more delirium than the 49% in haplogroup H, the most common Caucasian haplogroup (age-adjusted rate ratio for delirium 1.36; 95% CI, 1.13-1.64; p = 0.001). Alternatively, among African Americans the 24% in haplogroup L2 experienced less delirium than those in haplogroup L3, the most common African haplogroup (adjusted rate ratio for delirium 0.60; 95% CI, 0.38-0.94; p = 0.03). CONCLUSIONS: Variations in mitochondrial DNA are associated with development of and protection from delirium in Caucasians and African Americans during sepsis. Future studies are now required to determine whether mitochondrial DNA and mitochondrial dysfunction contribute to the pathogenesis of delirium during sepsis so that targeted treatments can be developed.

Latent variable modeling improves AKI risk factor identification and AKI prediction compared to traditional methods.

BACKGROUND: Acute kidney injury (AKI) is diagnosed based on postoperative serum creatinine change, but AKI models have not consistently performed well, in part due to the omission of clinically important but practically unmeasurable variables that affect creatinine. We hypothesized that a latent variable mixture model of postoperative serum creatinine change would partially account for these unmeasured factors and therefore increase power to identify risk factors of AKI and improve predictive accuracy. METHODS: We constructed a two-component latent variable mixture model and a linear model using data from a prospective, 653-subject randomized clinical trial of AKI following cardiac surgery (NCT00791648) and included established AKI risk factors and covariates known to affect serum creatinine. We compared model fit, discrimination, power to detect AKI risk factors, and ability to predict AKI between the latent variable mixture model and the linear model. RESULTS: The latent variable mixture model demonstrated superior fit (likelihood ratio of 6.68 × 1071) and enhanced discrimination (permutation test of Spearman's correlation coefficients, p < 0.001) compared to the linear model. The latent variable mixture model was 94% (-13 to 1132%) more powerful (median [range]) at identifying risk factors than the linear model, and demonstrated increased ability to predict change in serum creatinine (relative mean square error reduction of 6.8%). CONCLUSIONS: A latent variable mixture model better fit a clinical cohort of cardiac surgery patients than a linear model, thus providing better assessment of the associations between risk factors of AKI and serum creatinine change and more accurate prediction of AKI. Incorporation of latent variable mixture modeling into AKI research will allow clinicians and investigators to account for clinically meaningful patient heterogeneity resulting from unmeasured variables, and therefore provide improved ability to examine risk factors, measure mechanisms and mediators of kidney injury, and more accurately predict AKI in clinical cohorts.

Risk factors for delirium after cardiac surgery: a historical cohort study outlining the influence of cardiopulmonary bypass.

PURPOSE: Cardiopulmonary bypass (CPB) induces a significant inflammatory response that may increase the risk for delirium. We hypothesized that exposure to CPB during coronary artery bypass grafting (CABG) surgery would correlate with an increased risk of delirium. METHODS: We reviewed clinical data from two databases at our medical centre - the Cardiac Surgery Perioperative Outcomes Database and the Society of Thoracic Surgeons Database. Patients undergoing elective CABG surgery (on-pump and off-pump) from November 1, 2009 to September 30, 2015 were included in the study. Delirium was defined as any postoperative positive Confusion Assessment Method for the Intensive Care Unit exam during the intensive care unit stay. We performed logistic regression to isolate the association between CPB exposure and delirium adjusted for predetermined risk factors and potential confounders. RESULTS: During the study period, 2,280 patients underwent elective CABG surgery, with 384 patients (16.9%) exposed to CPB. Delirium was diagnosed in 451 patients (19.8%). Exposure to CPB showed a significant independent association with delirium. Patients exposed to CPB for 142 min (90th percentile of CPB duration) vs those exposed for 54 min (10th percentile) had an adjusted relative risk (RR) of delirium of 2.18 (95% confidence interval [CI], 1.39 to 3.07; P = 0.002) vs a RR of 1.51 (95% CI, 0.92 to 2.29; P = 0.10), respectively. CONCLUSIONS: The use and duration of cardiopulmonary bypass were associated with an increased risk of delirium in patients undergoing CABG surgery. TRIAL REGISTRATION: www.clinicaltrials.gov , NCT02548975. Registered 4 September 2015.

Acute kidney injury following cardiac surgery: current understanding and future directions.

Acute kidney injury (AKI) complicates recovery from cardiac surgery in up to 30 % of patients, injures and impairs the function of the brain, lungs, and gut, and places patients at a 5-fold increased risk of death during hospitalization. Renal ischemia, reperfusion, inflammation, hemolysis, oxidative stress, cholesterol emboli, and toxins contribute to the development and progression of AKI. Preventive strategies are limited, but current evidence supports maintenance of renal perfusion and intravascular volume while avoiding venous congestion, administration of balanced salt as opposed to high-chloride intravenous fluids, and the avoidance or limitation of cardiopulmonary bypass exposure. AKI that requires renal replacement therapy occurs in 2-5 % of patients following cardiac surgery and is associated with 50 % mortality. For those who recover from renal replacement therapy or even mild AKI, progression to chronic kidney disease in the ensuing months and years is more likely than for those who do not develop AKI. Cardiac surgery continues to be a popular clinical model to evaluate novel therapeutics, off-label use of existing medications, and nonpharmacologic treatments for AKI, since cardiac surgery is fairly common, typically elective, provides a relatively standardized insult, and patients remain hospitalized and monitored following surgery. More efficient and time-sensitive methods to diagnose AKI are imperative to reduce this negative outcome. The discovery and validation of renal damage biomarkers should in time supplant creatinine-based criteria for the clinical diagnosis of AKI.