A signature of pre-operative biomarkers of cellular senescence to predict risk of cardiac and kidney adverse events after cardiac surgery.

Objective: Understand the potential for pre-operative biomarkers of cellular senescence, a primary aging mechanism, to predict risk of cardiac surgery-associated adverse events. Methods: Biomarkers of senescence were assessed in blood samples collected prior to surgery in 331 patients undergoing CABG +/-valve repair or replacement. Patients were followed throughout the hospital stay and at a 30-day follow-up visit. Logistic regression models for pre-operative risk prediction were built for age-related clinical outcomes with high incidence including KDIGO-defined acute kidney injury (AKI), decline in eGFR ≥25% between pre-op and 30 days, and MACKE30, a composite endpoint of major adverse cardiac and kidney events at 30d. Results: AKI occurred in 19.9% of patients, persistent decline in kidney function at 30d occurred in 11.0%, and MACKE30 occurred in 13.4%. A network of six biomarkers of senescence (p16, p14, LAG3, CD244, CD28 and suPAR) were able to identify patients at risk for AKI (AUC 0.76), kidney decline at 30d (AUC 0.73), and MACKE30 (AUC 0.71). Comparing the top and bottom tertiles of senescence-based risk models, patients in the top tertile had 7.8 (3.3-8.4) higher odds of developing AKI, 4.5 (1.6-12.6) higher odds of developing renal decline at 30d, and 5.7 (2.1-15.6) higher odds of developing MACKE30. All models remained significant when adjusted for clinical variables. Patients with kidney function decline at 30d were largely non-overlapping and clinically distinct from those who experienced AKI, suggesting a different etiology. Typical clinical factors that predispose to AKI (e.g., age, CKD, surgery type) associated with AKI but not the 30d decline endpoint which was instead associated with new-onset atrial fibrillation. Conclusions: A six-member network of biomarkers of senescence, a fundamental mechanism of aging, can identify patients for risk of adverse kidney and cardiac events when measured pre-operatively.

Predictive capabilities of the European registry for patients with mechanical circulatory support right-sided heart failure risk score after left ventricular assist device implantation.

OBJECTIVES: The prediction of right heart failure (RHF) after left ventricular assist device (LVAD) implantation remains a challenge. Recently, risk scores were derived from analysis of the European Registry for Patients with Mechanical Circulatory Support (EUROMACS) data, the EUROMACS-RHF, and the modified postoperative EUROMACS-RHF. The authors assessed the performance characteristics of these 2 risk score formulations in a continuous-flow LVAD cohort at their institution. DESIGN: A retrospective, observational study. SETTING: At a tertiary-care academic medical center. PARTICIPANTS: Adult patients who underwent durable LVAD implantation between 2015 and 2018. INTERVENTIONS: None MEASUREMENTS AND MAIN RESULTS: Early post-LVAD RHF was defined as follows: (1) need for right ventricular assist device, or (2) inotropic or inhaled pulmonary vasodilator support for ≥14 postoperative days. The authors used logistic regression and examined receiver operating characteristic (ROC) curves to evaluate the ability of the 2 risk scores to distinguish between outcome groups. A total of 207 patients met the inclusion criteria. Of the patients, 16% developed RHF (33/207). The EUROMACS-RHF score was not predictive of RHF in the authors' cohort (odds ratio [OR] 1.25; 95% CI [0.99-1.60]; p = 0.06), but the postoperative EUROMACS-RHF CPB score was significantly associated (OR 1.38; 95% CI [1.03-1.89]; p = 0.03). The scores had similar ROC curves, with weak discriminatory performance: 0.601 (95% CI [0.509-0.692]) and 0.599 (95% CI [0.505-0.693]) for EUROMACS-RHF and postoperative EUROMACS-RHF, respectively. CONCLUSIONS: In the authors' single-center retrospective analysis, the EUROMACS-RHF risk score did not predict early RHF. An optimized risk score for the prediction of RHF after LVAD implantation remains an urgent unmet need.

Bedside Allogeneic Erythrocyte Washing with a Cell Saver to Remove Cytokines, Chemokines, and Cell-derived Microvesicles.

BACKGROUND: Removal of cytokines, chemokines, and microvesicles from the supernatant of allogeneic erythrocytes may help mitigate adverse transfusion reactions. Blood bank-based washing procedures present logistical difficulties; therefore, we tested the hypothesis that on-demand bedside washing of allogeneic erythrocyte units is capable of removing soluble factors and is feasible in a clinical setting. METHODS: There were in vitro and prospective, observation cohort components to this a priori planned substudy evaluating bedside allogeneic erythrocyte washing, with a cell saver, during cardiac surgery. Laboratory data were collected from the first 75 washed units given to a subset of patients nested in the intervention arm of a parent clinical trial. Paired pre- and postwash samples from the blood unit bags were centrifuged. The supernatant was aspirated and frozen at -70°C, then batch-tested for cell-derived microvesicles, soluble CD40 ligand, chemokine ligand 5, and neutral lipids (all previously associated with transfusion reactions) and cell-free hemoglobin (possibly increased by washing). From the entire cohort randomized to the intervention arm of the trial, bedside washing was defined as feasible if at least 75% of prescribed units were washed per protocol. RESULTS: Paired data were available for 74 units. Washing reduced soluble CD40 ligand (median [interquartile range]; from 143 [1 to 338] ng/ml to zero), chemokine ligand 5 (from 1,314 [715 to 2,551] to 305 [179 to 488] ng/ml), and microvesicle numbers (from 6.90 [4.10 to 20.0] to 0.83 [0.33 to 2.80] × 106), while cell-free hemoglobin concentration increased from 72.6 (53.6 to 171.6) mg/dl to 210.5 (126.6 to 479.6) mg/dl (P < 0.0001 for each). There was no effect on neutral lipids. Bedside washing was determined as feasible for 80 of 81 patients (99%); overall, 293 of 314 (93%) units were washed per protocol. CONCLUSIONS: Bedside erythrocyte washing was clinically feasible and greatly reduced concentrations of soluble factors thought to be associated with transfusion-related adverse reactions, increasing concentrations of cell-free hemoglobin while maintaining acceptable (less than 0.8%) hemolysis.

Conventional Ultrafiltration During Elective Cardiac Surgery and Postoperative Acute Kidney Injury.

OBJECTIVE: Conventional ultrafiltration (CUF) during cardiopulmonary bypass (CPB) serves to hemoconcentrate blood volume to avoid allogeneic blood transfusions. Previous studies have determined CUF volumes as a continuous variable are associated with postoperative acute kidney injury (AKI) after cardiac surgery, but optimal weight-indexed volumes that predict AKI have not been described. DESIGN: Retrospective cohort. SETTING: Single-center university hospital. PARTICIPANTS: A total of 1,641 consecutive patients who underwent elective cardiac surgery between June 2013 and December 2015. INTERVENTIONS: The CUF volume was removed during CPB in all participants as part of routine practice. The authors investigated the association of dichotomized weight-indexed CUF volume removal with postoperative AKI development to provide pragmatic guidance for clinical practice at the authors' institution. MEASUREMENTS AND MAIN RESULTS: Primary outcomes of postoperative AKI were defined by the Kidney Disease: Improving Global Outcomes staging criteria and dichotomized, weight-indexed CUF volumes (mL/kg) were defined by (1) extreme quartiles (Q3) and (2) Youden's criterion that best predicted AKI development. Multivariate logistic regression models were developed to test the association of these dichotomized indices with AKI status. Postoperative AKI occurred in 827 patients (50.4%). Higher CUF volumes were associated with AKI development by quartiles (CUF >Q3 = 32.6 v CUF < Q1 = 10.4 mL/kg; odds ratio [OR] = 1.68, 95% CI: 1.19-2.3) and Youden's criterion (CUF ≥ 32.9 v CUF <32.9 mL/kg; OR = 1.60, 95% CI: 1.21-2.13). Despite similar intraoperative nadir hematocrits among groups (p = 0.8), higher CUF volumes were associated with more allogeneic blood transfusions (p = 0.002) and longer lengths of stay (p < 0.001). CONCLUSIONS: Removal of weight-indexed CUF volumes > 32 mL/kg increased the risk for postoperative AKI development. Importantly, CUF volume removal of any amount did not mitigate allogeneic blood transfusion during elective cardiac surgery. Prospective studies are needed to validate these findings.

Stellate Ganglion Blockade for the Treatment of Refractory Ventricular Arrhythmias.

OBJECTIVES: This study sought to describe our institutional experience with establishing a neurocardiology service in an attempt to provide autonomic modulation as a treatment for ventricular arrhythmias (VAs). BACKGROUND: Treatment-refractory VAs are commonly driven and exacerbated by heightened sympathetic tone. METHODS: Among patients referred to the neurocardiology service (August 2016 to December 2018), we performed ultrasound-based, bilateral, temporary stellate ganglion blockade (SGB) in 20 consecutive patients. We analyzed outcomes of interest including sustained VA or VA requiring defibrillation in the 24 and 48 h before and 24 and 48 h after SGB. RESULTS: The majority of patients were men (n = 19, 95%), with a mean age of 58 ± 14 years. At the time of SGB, 10 (50%) were on inotropic support and 9 (45%) were on mechanical circulatory support. Besides 1 case of hoarseness, there were no apparent procedural complications. SGB was associated with a reduction in the number of VA episodes from the 24 h before (median 5.5 [interquartile range (IQR): 2.0 to 15.8]) to 24 h after SGB (median 0 [IQR: 0 to 3.8]) (p < 0.001). The number of defibrillation events decreased from 2.5 (IQR: 0 to 10.3) to 0 (IQR: 0 to 2.5) (p = 0.002). Similar findings were observed over the 48-h period before and after the SGB. Overall, 9 of 20 (45%) patients had a complete response with no recurrence of ventricular tachycardia (VT) or ventricular fibrillation (VF) for 48 h after SGB. Four (20%) patients had no recurrent VT or VF following SGB through discharge. Similar response rates were observed in those with ischemic (median 6 [IQR: 1.8 to 18.8] to 0.5 [IQR: 0 to 5.3] events; p = 0.031) and nonischemic (median 3.5 [IQR: 1.8 to 6.8] to 0 [IQR: 0 to 1.3] events; p = 0.012) cardiomyopathy. CONCLUSIONS: Minimally invasive, ultrasound-guided bilateral SGB appears safe and provides substantial reduction in VA burden with approximately 1 in 2 patients exhibiting complete suppression of VT or VF for 48 h.

Association between primary graft dysfunction and acute kidney injury after orthotopic heart transplantation - a retrospective, observational cohort study.

Acute kidney injury (AKI) and primary graft dysfunction (PGD) are serious complications after heart transplantation (HT). The relationship between AKI and PGD is poorly understood. We sought to examine the incidence of AKI and identify risk factors associated with AKI. We hypothesized that PGD is one of the risk factors independently associated with post-HT AKI. We gathered data for all adult patients who underwent HT between 2009 and 2014. AKI was defined by the KDIGO criteria. PGD was categorized using ISHLT criteria. We assessed univariable and multivariable logistic regression to identify risk factors independently associated with post-HT AKI. Out of 316 patients, postoperative AKI occurred in 273 (86%) patients: 188 (68%) stage I, 44 (16%) stage II, and 41 (15%) stage III. Stage II/III AKI was associated with increased risk of mortality at 1 year. There was significant association between severe PGD and stage II/III AKI (P = 0.001, OR 3.63, 95% CI: 1.69-7.94). Other clinical factors significantly associated with stage II/III AKI included longer donor brain death duration and lower recipient baseline creatinine. We found that stage II/III AKI is common and independently associated with severe PGD. Another potentially modifiable risk factor is donor brain death duration.

Annexin A1 Bioactive Peptide Promotes Resolution of Neuroinflammation in a Rat Model of Exsanguinating Cardiac Arrest Treated by Emergency Preservation and Resuscitation.

Neuroinflammation initiated by damage-associated molecular patterns, including high mobility group box 1 protein (HMGB1), has been implicated in adverse neurological outcomes following lethal hemorrhagic shock and polytrauma. Emergency preservation and resuscitation (EPR) is a novel method of resuscitation for victims of exsanguinating cardiac arrest, shown in preclinical studies to improve survival with acceptable neurological recovery. Sirtuin 3 (SIRT3), the primary mitochondrial deacetylase, has emerged as a key regulator of metabolic and energy stress response pathways in the brain and a pharmacological target to induce a neuronal pro-survival phenotype. This study aims to examine whether systemic administration of an Annexin-A1 bioactive peptide (ANXA1sp) could resolve neuroinflammation and induce sirtuin-3 regulated cytoprotective pathways in a novel rat model of exsanguinating cardiac arrest and EPR. Adult male rats underwent hemorrhagic shock and ventricular fibrillation, induction of profound hypothermia, followed by resuscitation and rewarming using cardiopulmonary bypass (EPR). Animals randomly received ANXA1sp (3 mg/kg, in divided doses) or vehicle. Neuroinflammation (HMGB1, TNFα, IL-6, and IL-10 levels), cerebral cell death (TUNEL, caspase-3, pro and antiapoptotic protein levels), and neurologic scores were assessed to evaluate the inflammation resolving effects of ANXA1sp following EPR. Furthermore, western blot analysis and immunohistochemistry were used to interrogate the mechanisms involved. Compared to vehicle controls, ANXA1sp effectively reduced expression of cerebral HMGB1, IL-6, and TNFα and increased IL-10 expression, which were associated with improved neurological scores. ANXA1sp reversed EPR-induced increases in expression of proapoptotic protein Bax and reduction in antiapoptotic protein Bcl-2, with a corresponding decrease in cerebral levels of cleaved caspase-3. Furthermore, ANXA1sp induced autophagic flux (increased LC3II and reduced p62 expression) in the brain. Mechanistically, these findings were accompanied by upregulation of the mitochondrial protein deacetylase Sirtuin-3, and its downstream targets FOXO3a and MnSOD in ANXA1sp-treated animals. Our data provide new evidence that engaging pro-resolving pharmacological strategies such as Annexin-A1 biomimetic peptides can effectively attenuate neuroinflammation and enhance the neuroprotective effects of EPR after exsanguinating cardiac arrest.

Intravenous Lidocaine Does Not Improve Neurologic Outcomes after Cardiac Surgery: A Randomized Controlled Trial.

BACKGROUND: Cognitive decline after cardiac surgery occurs frequently and persists in a significant proportion of patients. Preclinical studies and human trials suggest that intravenous lidocaine may confer protection in the setting of neurologic injury. It was hypothesized that lidocaine administration would reduce cognitive decline after cardiac surgery compared to placebo. METHODS: After institutional review board approval, 478 patients undergoing cardiac surgery were enrolled into this multicenter, prospective, randomized, double-blinded, placebo-controlled, parallel group trial. Subjects were randomized to lidocaine 1 mg/kg bolus after the induction of anesthesia followed by a continuous infusion (48 µg · kg · min for the first hour, 24 µg · kg · min for the second hour, and 10 µg · kg · min for the next 46 h) or saline with identical volume and rate changes to preserve blinding. Cognitive function was assessed preoperatively and at 6 weeks and 1 yr postoperatively using a standard neurocognitive test battery. The primary outcome was change in cognitive function between baseline and 6 weeks postoperatively, adjusting for age, years of education, baseline cognition, race, and procedure type. RESULTS: Among the 420 allocated subjects who returned for 6-week follow-up (lidocaine: N = 211; placebo: N = 209), there was no difference in the continuous cognitive score change (adjusted mean difference [95% CI], 0.02 (-0.05, 0.08); P = 0.626). Cognitive deficit (greater than 1 SD decline in at least one cognitive domain) at 6 weeks occurred in 41% (87 of 211) in the lidocaine group versus 40% (83 of 209) in the placebo group (adjusted odds ratio [95% CI], 0.94 [0.63, 1.41]; P = 0.766). There were no differences in any quality of life outcomes between treatment groups. At the 1-yr follow-up, there continued to be no difference in cognitive score change, cognitive deficit, or quality of life. CONCLUSIONS: Intravenous lidocaine administered during and after cardiac surgery did not reduce postoperative cognitive decline at 6 weeks.

Contribution of Baroreceptor Function to Pain Perception and Perioperative Outcomes.

Baroreceptors are mechanosensitive elements of the peripheral nervous system that maintain homeostasis by coordinating physiologic responses to external and internal stimuli. While it is recognized that carotid and cardiopulmonary baroreceptor reflexes modulate autonomic output to mitigate excessive fluctuations in arterial blood pressure and to maintain intravascular volume, increasing evidence suggests that baroreflex pathways also project to key regions of the central nervous system that regulate somatosensory, somatomotor, and central nervous system arousal. In addition to maintaining autonomic homeostasis, baroreceptor activity modulates the perception of pain, as well as neuroimmune, neuroendocrine, and cognitive responses to physical and psychologic stressors. This review summarizes the role that baroreceptor pathways play in modulating acute and chronic pain perception. The contribution of baroreceptor function to postoperative outcomes is also presented. Finally, methods that enhance baroreceptor function, which hold promise in improving postoperative and pain management outcomes, are presented.

Temporary autonomic modulation with botulinum toxin type A to reduce atrial fibrillation after cardiac surgery.

BACKGROUND: Postoperative atrial fibrillation (POAF) frequently complicates cardiac surgery and is associated with worse outcomes. The cardiac autonomic nervous system is implicated in the pathogenesis of POAF. OBJECTIVE: The purpose of this study was to determine the efficacy and safety of selective cardiac autonomic modulation in preventing POAF. METHODS: In this randomized, double-blind, placebo-controlled trial, adults undergoing cardiac surgery were randomized 1:1 to intraoperative injection of 250 units onabotulinumtoxinA (botulinum toxin type A [BoNTA]) or placebo into epicardial fat pads. The study was powered to detect a 40% reduction in relative risk of POAF. Time to first episode of in-hospital POAF was the primary outcome, evaluated in patients receiving injection. Additionally, incidence of POAF, length of stay (LOS), and adverse events were examined. RESULTS: The trial assigned 145 patients to injection, 15 of whom were dropped before treatment, leaving 130 patients for analysis. Overall, 36.5% (23/63) of BoNTA-treated patients developed POAF compared with 47.8% (32/67) of placebo-treated patients. The time-to-event analysis revealed a hazard ratio of 0.69 (95% confidence interval 0.41-1.19; P = .18) for the BoNTA vs placebo arm. There were no significant differences in postoperative hospital LOS (median [interquartile range] 6.0 [3.4] vs 6.2 [3.7] days; P = .51) or adverse events prolonging LOS (27/63 [42.9%] vs 30/67 [44.8%]; P = .83) in patients receiving BoNTA vs placebo. CONCLUSION: Epicardial injection of onabotulinumtoxinA was without discernible adverse effects, but we failed to detect a significant difference in risk of POAF. Future large-scale studies of epicardial onabotulinumtoxinA injection as a potential POAF prevention strategy should be designed to study smaller, but clinically meaningful, treatment effects.

Genome-Wide Association Study Links Receptor Tyrosine Kinase Inhibitor Sprouty 2 to Thrombocytopenia after Coronary Artery Bypass Surgery.

INTRODUCTION: Thrombocytopenia after cardiac surgery independently predicts stroke, acute kidney injury and death. To understand the underlying risks and mechanisms, we analysed genetic variations associated with thrombocytopenia in patients undergoing coronary artery bypass grafting (CABG) surgery. MATERIALS AND METHODS: Study subjects underwent isolated on-pump CABG surgery at Duke University Medical Center. Post-operative thrombocytopenia was defined as platelet count < 100 × 109/L. Using a logistic regression model adjusted for clinical risk factors, we performed a genome-wide association study in a discovery cohort (n = 860) and validated significant findings in a replication cohort (n = 296). Protein expression was assessed in isolated platelets by immunoblot. RESULTS: A total of 63 single-nucleotide polymorphisms met a priori discovery thresholds for replication, but only 1 (rs9574547) in the intergenic region upstream of sprouty 2 (SPRY2) met nominal significance in the replication cohort. The minor allele of rs9574547 was associated with a lower risk for thrombocytopenia (discovery cohort, odds ratio, 0.45, 95% confidence interval, 0.30-0.67, p = 9.76 × 10-5) with the overall association confirmed by meta-analysis (meta-p = 7.88 × 10-6). Immunoblotting demonstrated expression of SPRY2 and its dynamic regulation during platelet activation. Treatment with a functional SPRY2 peptide blunted platelet extracellular signal-regulated kinase (ERK) phosphorylation after agonist stimulation. CONCLUSION: We identified the association of a genetic polymorphism in the intergenic region of SPRY2 with a decreased incidence of thrombocytopenia after CABG surgery. Because SPRY2-an endogenous receptor tyrosine kinase inhibitor-is present in platelets and modulates essential signalling pathways, these findings support a role for SPRY2 as a novel modulator of platelet responses after cardiac surgery.

Predictive ability of perioperative atrial fibrillation risk indices in cardiac surgery patients: a retrospective cohort study.

PURPOSE: The Multicenter Study of Perioperative Ischemia (McSPI) AFRisk index predicts postoperative atrial fibrillation (POAF) after cardiac surgery, but requires pre-, intra-, and postoperative data. Other more abbreviated risk indices exist, but there is no consensus on which risk index is optimal. We compared the discriminatory capacity of the McSPI AFRisk index with three indices containing only preoperative data (the CHA2DS2Vasc score, POAF score, and Kolek clinical risk prediction model), hypothesizing that the McSPI AFRisk index would have superior predictive capacity. METHODS: We retrospectively evaluated 783 patients undergoing cardiac surgery using cardiopulmonary bypass. The predictive capacity of each index was assessed by comparing receiver-operating characteristic (ROC) curves, scaled Brier scores, net reclassification indices, and the integrated discrimination indices. RESULTS: The incidence of POAF was 32.6%. The area under the curve (AUC) of the ROC curve were 0.77, 0.58, 0.66, and 0.66 for the McSPI AFRisk index, CHA2DS2Vasc score, POAF score, and Kolek clinical risk prediction model, respectively. The McSPI AFRIsk index had the highest AUC (P < 0.0001). The scaled Brier scores for the McSPI AFRisk index, CHA2DS2Vasc score, POAF score, and Kolek clinical risk prediction model were 0.23, 0.02, 0.08, and 0.07, respectively. Both net reclassification indices and integrated discrimination indices showed that the McSPI AFRisk index more appropriately identified patients at high risk of POAF. CONCLUSIONS: The McSPI AFRisk index showed superior ability to predict POAF after cardiac surgery compared with three other indices. When clinicians and investigators wish to measure the risk of POAF after cardiac surgery, they should consider using the McSPI AFRisk index.

Primary graft dysfunction after heart transplantation: Incidence, trends, and associated risk factors.

Changes in heart transplantation (HT) donor and recipient demographics may influence the incidence of primary graft dysfunction (PGD). We conducted a retrospective study to evaluate PGD incidence, trends, and associated risk factors by analyzing consecutive adult patients who underwent HT between January 2009 and December 2014 at our institution. Patients were categorized as having PGD using the International Society for Heart & Lung Transplantation (ISHLT)-defined criteria. Variables, including clinical and demographic characteristics of donors and recipients, were selected to assess their independent association with PGD. A time-trend analysis was performed over the study period. Three-hundred seventeen patients met inclusion criteria. Left ventricular PGD, right ventricular PGD, or both, were observed in 99 patients (31%). Risk factors independently associated with PGD included ischemic time, recipient African American race, and recipient amiodarone treatment. Over the study period, there was no change in the PGD incidence; however, there was an increase in the recipient pretransplantation use of amiodarone. The rate of 30-day mortality was significantly elevated in those with PGD versus those without PGD (6.06% vs 0.92%, P = .01). Despite recent advancements, incidence of PGD remains high. Understanding associated risk factors may allow for implementation of targeted therapeutic interventions.

Pre- and postoperative anemia, acute kidney injury, and mortality after coronary artery bypass grafting surgery: a retrospective observational study.

BACKGROUND: Preoperative and postoperative anemia have been identified individually as potential risk factors for postoperative complications after coronary artery bypass grafting (CABG) surgery. Their interrelationship with acute kidney injury (AKI) and long-term mortality, however, has not been clearly defined and was the purpose of this study. METHODS: We retrospectively evaluated 6,130 adult patients undergoing CABG surgery performed at a single large academic medical center. Preoperative and postoperative hemoglobin concentrations were used as continuous predictors of postoperative AKI and mortality. Additionally, sex-specific preoperative (< 13 g·dL-1 in men and < 12 g·dL-1 in women) and postoperative anemia (the median of the lowest in-hospital values) were used as categorical predictors. AKI was defined according to the Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guidelines, when serum creatinine rose ≥ 50% during the period between day of surgery and postoperative day ten, or when a 0.3 mg·dL-1 (26.5 µmol·L-1) increase was detected in a rolling 48-hr window from the day of surgery to the tenth postoperative day. The association of preoperative and postoperative hemoglobin levels and anemia patterns with postoperative AKI and mortality were assessed via univariable and multivariable Cox proportional hazard analyses with time-varying effects for postoperative serum hemoglobin concentrations. RESULTS: The median preoperative and median minimum postoperative serum hemoglobin concentrations were 13.1 g·dL-1 and 8.8 g·dL-1, respectively. The incidence of AKI was 58%. Overall, 1,880 (30.7%) patients died an average of 6.8 yr after surgery. After adjusting for differences in baseline and clinical characteristics, on any given day, patients with preoperative anemia (multivariable hazard ratio [HR], 1.23; 95% confidence interval [CI], 1.13 to 1.33; P < 0.001) and those with a combination of preoperative and postoperative anemia (multivariable HR, 1.24; 95% CI, 1.09 to 1.40; P < 0.0008) were at an elevated risk for developing postoperative AKI and mortality (preoperative anemia: multivariable HR, 1.29; 95% CI, 1.15 to 1.44; P < 0.001; preoperative and postoperative anemia: multivariable HR, 1.50; 95% CI, 1.25 to 1.79; P < 0.001). CONCLUSIONS: Our findings suggest that preoperative anemia alone and preoperative anemia combined with postoperative anemia are associated with AKI and mortality after CABG surgery.

Neuroprotective Effects of Annexin A1 Tripeptide after Deep Hypothermic Circulatory Arrest in Rats.

Resolution agonists, including lipid mediators and peptides such as annexin A1 (ANXA1), are providing novel approaches to treat inflammatory conditions. Surgical trauma exerts a significant burden on the immune system that can affect and impair multiple organs. Perioperative cerebral injury after cardiac surgery is associated with significant adverse neurological outcomes such as delirium and postoperative cognitive dysfunction. Using a clinically relevant rat model of cardiopulmonary bypass (CPB) with deep hypothermic circulatory arrest (DHCA), we tested the pro-resolving effects of a novel bioactive ANXA1 tripeptide (ANXA1sp) on neuroinflammation and cognition. Male rats underwent 2 h CPB with 1 h DHCA at 18°C, and received vehicle or ANXA1sp followed by timed reperfusion up to postoperative day 7. Immortalized murine microglial cell line BV2 were treated with vehicle or ANXA1sp and subjected to 2 h oxygen-glucose deprivation followed by timed reoxygenation. Microglial activation, cell death, neuroinflammation, and NF-κB activation were assessed in tissue samples and cell cultures. Rats exposed to CPB and DHCA had evident neuroinflammation in various brain areas. However, in ANXA1sp-treated rats, microglial activation and cell death (apoptosis and necrosis) were reduced at 24 h and 7 days after surgery. This was associated with a reduction in key pro-inflammatory cytokines due to inhibition of NF-κB activation in the brain and systemically. Treated rats also had improved neurologic scores and shorter latency in the Morris water maze. In BV2 cells treated with ANXA1sp, similar protective effects were observed including decreased pro-inflammatory cytokines and cell death. Notably, we also found increased expression of ANXA1, which binds to NF-κB p65 and thereby inhibits its transcriptional activity. Our findings provide evidence that treatment with a novel pro-resolving ANXA1 tripeptide is neuroprotective after cardiac surgery in rats by attenuating neuroinflammation and may prevent postoperative neurologic complications.

Platelet Counts and Postoperative Stroke After Coronary Artery Bypass Grafting Surgery.

BACKGROUND: Declining platelet counts may reveal platelet activation and aggregation in a postoperative prothrombotic state. Therefore, we hypothesized that nadir platelet counts after on-pump coronary artery bypass grafting (CABG) surgery are associated with stroke. METHODS: We evaluated 6130 adult CABG surgery patients. Postoperative platelet counts were evaluated as continuous and categorical (mild versus moderate to severe) predictors of stroke. Extended Cox proportional hazard regression analysis with a time-varying covariate for daily minimum postoperative platelet count assessed the association of day-to-day variations in postoperative platelet count with time to stroke. Competing risks proportional hazard regression models examined associations between day-to-day variations in postoperative platelet counts with timing of stroke (early: 0-1 days; delayed: ≥2 days). RESULTS: Median (interquartile range) postoperative nadir platelet counts were 123.0 (98.0-155.0) × 10/L. The incidences of postoperative stroke were 1.09%, 1.50%, and 3.02% for platelet counts >150 × 10/L, 100 to 150 × 10/L, and <100 × 10/L, respectively. The risk for stroke increased by 12% on a given postoperative day for every 30 × 10/L decrease in platelet counts (adjusted hazard ratio [HR], 1.12; 95% confidence interval [CI], 1.01-1.24; P= .0255). On a given day, patients with moderate to severe thrombocytopenia were almost twice as likely to develop stroke (adjusted HR, 1.89; 95% CI, 1.13-3.16; P= .0155) as patients with nadir platelet counts >150 × 10/L. Importantly, such thrombocytopenia, defined as a time-varying covariate, was significantly associated with delayed (≥2 days after surgery; adjusted HR, 2.83; 95% CI, 1.48-5.41; P= .0017) but not early postoperative stroke. CONCLUSIONS: Our findings suggest an independent association between moderate to severe postoperative thrombocytopenia and postoperative stroke, and timing of stroke after CABG surgery.