Rab7a activation promotes degradation of select tight junction proteins at the blood-brain barrier after ischemic stroke.

The stability of tight junctions (TJs) between endothelial cells (ECs) is essential to maintain blood-brain barrier (BBB) function in the healthy brain. Following ischemic stroke, TJ strand dismantlement due to protein degradation leads to BBB dysfunction, yet the mechanisms driving this process are poorly understood. Here, we show that endothelial-specific ablation of Rab7a, a small GTPase that regulates endolysosomal protein degradation, reduces stroke-induced TJ strand disassembly resulting in decreased paracellular BBB permeability and improved neuronal outcomes. Two pro-inflammatory cytokines, TNFα and IL1ß, but not glucose and oxygen deprivation, induce Rab7a activation via Ccz1 in brain ECs in vitro, leading to increased TJ protein degradation and impaired paracellular barrier function. Silencing Rab7a in brain ECs in vitro reduces cytokine-driven endothelial barrier dysfunction by suppressing degradation of a key BBB TJ protein, Claudin-5. Thus, Rab7a activation by inflammatory cytokines promotes degradation of select TJ proteins leading to BBB dysfunction after ischemic stroke.

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.

Intraoperative prediction of cardiac surgery-associated acute kidney injury using urinary biomarkers of cell cycle arrest.

OBJECTIVE: Tissue inhibitor of metalloproteinases 2 (TIMP-2) and insulin-like growth factor-binding protein 7 (IGFBP7) are postoperative urinary biomarkers of renal stress and acute kidney injury (AKI). We conducted this study to test the hypothesis that intraoperative concentrations of urinary [TIMP-2]·[IGFBP7] are associated with postoperative AKI. METHODS: We measured urinary [TIMP-2]·[IGFBP7] at 8 perioperative timepoints in 400 patients who participated in a randomized controlled trial of atorvastatin for AKI in cardiac surgery. We compared [TIMP-2]·[IGFBP7] between subjects who did and did not develop KDIGO stage 2 or 3 AKI within 48 hours of surgery, adjusted for AKI risk factors. RESULTS: Fourteen patients (3.5%) met the primary endpoint of stage 2 or 3 AKI within 48 hours of surgery, and an additional 77 patients (19.3%) developed stage 1 AKI. Patients who developed stage 2 or 3 AKI displayed bimodal elevations of [TIMP-2]·[IGFBP7], with a first elevation (median, 0.45 [ng/mL]2/1000) intraoperatively and a second elevation (1.45 [ng/mL]2/1000) 6 hours postoperatively. Patients who did not develop AKI did not have any elevations in [TIMP-2]·[IGFBP7]. Each 10-fold increase in intraoperative [TIMP-2]·[IGFBP7] was independently associated with a 290% increase in the odds of stage 2 or 3 AKI (P = .01), and each 10-fold increase in the 6 hours postoperative [TIMP-2]·[IGFBP7] was independently associated with a 650% increase in the odds of stage 2 or 3 AKI (P < .001). The maximum [TIMP-2]·[IGFBP7] between these 2 timepoints provided an area under the receiver operating characteristic curve of 0.82 (95% confidence interval [CI], 0.73-0.90), 100% sensitivity, and 100% negative predictive value using the >0.3 cutoff to predict stage 2 or 3 AKI. CONCLUSIONS: Intraoperative elevations of [TIMP-2]·[IGFBP7] can predict moderate or severe AKI and could provide an opportunity to alter postoperative management to prevent kidney injury.

Effect of Preoperative Beta-Blocker Use on Outcomes Following Cardiac Surgery.

Recent studies suggest that the use of preoperative ß blockers in cardiac surgery may not provide improved mortality rates and may even contribute to negative clinical outcomes. We therefore assessed the role of ß blockers on several outcomes after cardiac surgery (delirium, acute kidney injury [AKI], stroke, atrial fibrillation (AF), mortality, and hospital length of stay) in 4,076 patients who underwent elective coronary artery bypass grafting, coronary artery bypass grafting + valve, or valve cardiac surgery from November 1, 2009, to September 30, 2015, at Vanderbilt Medical Center. Clinical data from 2 prospectively collected datasets at our institution were reviewed: the Cardiac Surgery Perioperative Outcomes Database and the Society of Thoracic Surgeons Database. Preoperative ß-blocker use was defined by Society of Thoracic Surgeons guidelines as patients receiving a ß blocker within 24 hours preceding surgery. Of the included patients, 2,648 (65.0%) were administered a ß blocker within 24 hours before surgery. Adjusting for possible confounders, preoperative ß-blocker use was associated with increased odds of AKI stage 2 (odds ratio 1.96, 95% confidence interval 1.19 to 3.24, p <0.01). There was no evidence that ß-blocker use had an independent association with postoperative delirium, AKI stages 1 and 3, stroke, AF, mortality, or prolonged length of stay. A secondary propensity score analysis did not show a marginal association between ß-blocker use and any outcome. In conclusion, we did not find significant evidence that preoperative ß-blocker use was associated with postoperative delirium, AF, AKI, stroke, or mortality.

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.

Intravenous vs Oral Acetaminophen as an Adjunct to Multimodal Analgesia After Total Knee Arthroplasty: A Prospective, Randomized, Double-Blind Clinical Trial.

BACKGROUND: The efficacy of intravenous (IV) acetaminophen compared with its oral formulation for postoperative analgesia is unknown. We hypothesized that the addition of acetaminophen to a multimodal analgesia regimen would provide improved pain management in patients after total knee arthroplasty (TKA) and that the effect of acetaminophen would be variable based on the route of delivery. METHODS: The study was a single-center, randomized, double-blinded, placebo-controlled clinical trial on the efficacy of IV vs oral acetaminophen in patients undergoing unilateral TKA. One hundred seventy-four subjects were randomized to one of the 3 groups: IV acetaminophen group (IV group, n = 57) received 1 g IV acetaminophen and oral placebo before postanesthesia care unit (PACU) admission; oral acetaminophen group (PO group, n = 58) received 1 g oral acetaminophen and volume-matched IV normal saline; placebo group (Placebo group, n = 59) received oral placebo and volume-matched IV normal saline. Pain scores were obtained every 15 minutes during PACU stay. Average pain scores, maximum pain score, and pain scores before physical therapy were compared among the 3 groups. Secondary outcomes included total opiate consumption, time to PACU discharge, time to rescue analgesia, and time to breakthrough pain. RESULTS: The average PACU pain score was similar in the IV group (0.56 ± 0.99 [mean ± standard deviation]) compared with the PO group (0.67 ± 1.20; P = .84) and Placebo group (0.58 ± 0.99; P = .71). Total opiate consumption at 6 hours (0.47 mg hydromorphone equivalents ± 0.56 vs 0.54 ± 0.53 vs 0.54 ± 0.61; P = .69) and at 24 hours (1.25 ± 1.30 vs 1.49 ± 1.34 vs 1.36 ± 1.31; P = .46) were also similar between the IV, PO, and Placebo groups. No significant differences were found between all groups for any other outcome. CONCLUSION: Neither IV nor oral acetaminophen provides additional analgesia in the immediate postoperative period when administered as an adjunct to multimodal analgesia in patients undergoing TKA in the setting of a spinal anesthetic.

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.

Seasonal Incidence of Emergent Coronary Artery Bypass Grafting Surgery.

BACKGROUND: Emergent coronary artery bypass grafting (CABG) surgery is often required in the case of severe coronary artery disease, which is refractory to traditional management. The objective of our study was to test the hypothesis that there is seasonal variation in the incidence of emergent CABG. METHODS: A sinusoidal logistic regression model was used to analyze operative data at our cardiovascular institute of 270 cases spanning 5939 calendar days. RESULTS: A cyclic peak risk for emergent CABG was observed for late winter (calendar day 66; P = .036). The odds ratios for the 1-, 2- and 3-month window surrounding this peak were 1.8 (95% CI = 0.94-3.5, P = .072), 1.6 (95% CI = 1.06-2.5, P = .024) and 1.4 (95% CI = 0.9-1.8, P = .066), respectively. CONCLUSION: Our results suggest that a seasonal variation may exist in the incidence of patients presenting with severe coronary artery disease requiring emergent CABG. This information is useful in the scheduling of hospital resources and staff. It also provides important etiology clues underlying coronary artery disease that may lead to future interventions or targeted therapies.

Predicting, preventing, and identifying delirium after cardiac surgery.

Delirium after cardiac surgery is a major problem. The exact mechanisms behind delirium are not understood. Potential pathways of delirium include neurotransmitter interference, global cognitive disorder, and neuroinflammation. Several predisposing and precipitating risk factors have been identified for postoperative delirium. The development of delirium following cardiac surgery is associated with worse outcomes in the perioperative period. Multiple interventions are being explored for the prevention and treatment of delirium. Studies investigating the potential roles of biomarkers in delirium as well as pharmacological interventions to reduce the incidence and duration of delirium are necessary to mitigate this negative outcome.

Comparison of Risk of Atrial Fibrillation in Black Versus White Patients After Coronary Artery Bypass Grafting.

Obesity has been identified as a risk factor for postoperative atrial fibrillation (POAF) after coronary artery bypass grafting (CABG). However, no studies have addressed the influence of race on this association. A total of 13,594 patients undergoing first-time, isolated CABG without preoperative AF between 1992 and 2011 were included in our study. The association between body mass index and POAF was compared by race. Relative risk and 95% CIs were computed using maximum likelihood log-binomial regression. Increasing levels of body mass index were associated with higher POAF risk after CABG in black but not white patients (pinteraction = 0.0009).

Goal-directed therapy in the operating room: is there any benefit?

PURPOSE OF REVIEW: This article reviews the current evidence behind goal-directed therapy (GDT) in multiple medical settings. RECENT FINDINGS: Although some studies advocate for the use of GDT, others do not and more studies are necessary to evaluate the efficacy of GDT in medicine. Previously accepted guidelines for treating patients in septic shock which include GDT in their algorithms are not supported by the findings in recent randomized, controlled trials. No generally accepted guidelines for GDT are available for perioperative use, but there is evidence supporting GDT in high-risk surgery such as major abdominal surgery and cardiac surgery. Clinicians should be aware of the potential benefits of GDT in these settings and use these evidence-based findings to help guide clinical decisions in these patient populations. SUMMARY: The use of GDT may be beneficial depending on the clinical setting, but more evidence supporting its use is necessary before it can be considered standard of care.

Conditional long-term survival following minimally invasive robotic mitral valve repair: a health services perspective.

BACKGROUND: Conditional survival is defined as the probability of surviving an additional number of years beyond that already survived. The aim of this study was to compute conditional survival in patients who received a robotically assisted, minimally invasive mitral valve repair procedure (RMVP). METHODS: Patients who received RMVP with annuloplasty band from May 2000 through April 2011 were included. A 5- and 10-year conditional survival model was computed using a multivariable product-limit method. RESULTS: Non-smoking men (≤65 years) who presented in sinus rhythm had a 96% probability of surviving at least 10 years if they survived their first year following surgery. In contrast, recent female smokers (>65 years) with preoperative atrial fibrillation only had an 11% probability of surviving beyond 10 years if alive after one year post-surgery. CONCLUSIONS: In the context of an increasingly managed healthcare environment, conditional survival provides useful information for patients needing to make important treatment decisions, physicians seeking to select patients most likely to benefit long-term following RMVP, and hospital administrators needing to comparatively assess the life-course economic value of high-tech surgical procedures.

Goal-directed therapy: what we know and what we need to know.

Goal-directed therapy (GDT) utilizes monitoring techniques to help guide clinicians with administering fluids, vasopressors, inotropes, or other treatments to patients in various clinical settings. Multiple studies have investigated the potential benefits of GDT, but no consensus on the use of GDT exists. Future trials which address fluid and inotrope choice as well as expanding the results to evaluate patient-centered outcomes in addition to survival are warranted.

Increased coronary artery disease severity in black women undergoing coronary bypass surgery.

Race and sex disparities are believed to play an important role in heart disease. The purpose of this study was to examine the association between race, sex, and number of diseased vessels at the time of coronary artery bypass grafting (CABG), and subsequent postoperative outcomes. The 13,774 patients undergoing first-time, isolated CABG between 1992 and 2011 were included. Trend in the number of diseased vessels between black and white patients, stratified by sex, were analyzed using a Cochran-Armitage trend test. Models were adjusted for age, procedural status (elective vs. nonelective), and payor type (private vs. nonprivate insurance). Black female CABG patients presented with an increasingly greater number of diseased vessels than white female CABG patients (adjusted P(trend) = 0.0021). A similar trend was not observed between black and white male CABG patients (adjusted P(trend) = 0.18). Black female CABG patients were also more likely to have longer intensive care unit and hospital lengths of stay than other race-sex groups.Our findings suggest that black female CABG patients have more advanced coronary artery disease than white female CABG patients. Further research is needed to determine the benefit of targeted preventive care and preoperative workup for this high-risk group.

Discharge ß-Blocker Use and Race after Coronary Artery Bypass Grafting.

INTRODUCTION: The use of discharge ß-blockers after cardiac surgery is associated with a long-term mortality benefit. ß-Blockers have been suggested to be less effective in black cardiovascular patients compared with whites. To date, racial differences in the long-term survival of coronary artery bypass grafting (CABG) patients who receive ß-blockers at discharge have not been examined. METHODS: A retrospective cohort study was conducted on patients undergoing CABG between 2002 and 2011. Long-term survival was compared in patients who were and who were not discharged with ß-blockers. Hazard ratios (HR) and 95% confidence intervals (CI) were computed using a Cox regression model. P-for-interaction between race and discharge ß-blocker use was computed using a likelihood ratio test. RESULTS: A total of 853 (88%) black (n = 970) and 3,038 (88%) white (n = 3,460) patients had a history of ß-blocker use at discharge (N = 4,430). Black patients who received ß-blockers survived longer than those not receiving ß-blockers and the survival advantage was comparable with white patients (black, adjusted HR = 0.33, 95% CI = 0.23-0.46; white, adjusted HR = 0.48, 95% CI = 0.39-0.58; p-for-interaction = 0.74). Among patients discharged on ß-blockers, we did not observe a long-term survival advantage for white compared with black patients (HR = 1.2, 95% CI = 0.95-1.5). CONCLUSION: ß-Blocker use at discharge was associated with a survival advantage among black patients after CABG and a similar association was observed in white patients.

Risk-adjusted survival after coronary artery bypass grafting: implications for quality improvement.

Mortality represents an important outcome measure following coronary artery bypass grafting. Shorter survival times may reflect poor surgical quality and an increased number of costly postoperative complications. Quality control efforts aimed at increasing survival times may be misleading if not properly adjusted for case-mix severity. This paper demonstrates how to construct and cross-validate efficiency-outcome plots for a specified time (e.g., 6-month and 1-year survival) after coronary artery bypass grafting, accounting for baseline cardiovascular risk factors. The application of this approach to regional centers allows for the localization of risk stratification rather than applying overly broad and non-specific models to their patient populations.

Conditional survival of heart failure patients after coronary artery bypass grafting.

AIMS: Conditional survival is defined as the probability of surviving an additional number of years beyond that already survived. The aim of this study was to estimate conditional survival in heart failure patients after coronary artery bypass grafting (CABG). METHODS: Heart failure patients with multivessel coronary artery disease undergoing first-time, isolated CABG between 1992 and 2011 were included in this study. Conditional survival estimates were computed for 1, 5, and 10 years after already surviving 0.5, 1, 2, 3, 4, and 5 years. RESULTS: Compared with traditional survival estimates, conditional survival was consistently higher at all time periods. The overall 2-year adjusted survival estimate was 84% compared with the 1-year conditional survival rate of 95% for 1-year survivors. Similarly, the overall 10-year adjusted survival rate was 36% from the time of surgery compared with the 5-year conditional survival of 54% for patients who had survived 5 years. CONCLUSION: Conditional survival provides a more accurate estimate of long-term survival in heart failure patients who have already survived for a certain amount of time after CABG. This information is useful for patients and physicians who manage their long-term care.

Seasonal incidence of hospital admissions for Stanford type A aortic dissection.

The objective of this study was to test the hypothesis that there is seasonal variation in the incidence of Stanford type A aortic dissection (SA-AoD) among patients admitted to our cardiovascular surgical service. A sinusoidal logistic regression model was used to analyze event data for 6081 calendar days. A cyclic peak risk for SA-AoD was observed for calendar day 304 (p=0.019). The odds ratios for the 3- and 6-month window surrounding this peak were 1.6 (p=0.054) and 1.7 (p=0.0040), respectively. Our results suggest than a seasonal variation exists in the incidence of SA-AoD.

Operative status and survival after coronary artery bypass grafting.

BACKGROUND: The effect of race on long-term survival of patients undergoing elective and nonelective coronary artery bypass grafting (CABG) is currently unknown. The purpose of this study was to compare long-term survival between black and white CABG patients by operative status. METHODS: Long-term survival of black versus white patients undergoing elective and nonelective CABG procedures between 1992 and 2011 was compared. Survival probabilities were computed using the Kaplan-Meier product-limit method and stratified by race. Hazard ratios (HR) and 95% confidence intervals (CI) were computed using a Cox regression model. RESULTS: A total of 13,774 patients were included in this study. The median follow-up time for study participants was 8.2 years. Black patients undergoing elective CABG died sooner than whites (adjusted HR = 1.4, 95% CI = 1.2-1.5). Survival was similar between blacks and whites in the nonelective population (adjusted HR = 1.0, 95% CI = 0.96-1.1). CONCLUSIONS: Black race was a statistically significant predictor of long-term survival after elective but not nonelective CABG.

The impact of race and postoperative atrial fibrillation on operative mortality after elective coronary artery bypass grafting.

OBJECTIVE: Black patients are less likely to develop postoperative atrial fibrillation (POAF) following coronary artery bypass grafting (CABG) than whites. However, the influence of race and POAF on operative mortality has not been examined. The objective of this study was to determine the influence of race and POAF on operative mortality after CABG. METHODS: Patients undergoing elective CABG between 1992 and 2011 were included. Operative mortality was compared between patients with and those without new-onset POAF by race. Relative risk (RR) and 95% confidence intervals (CI) were computed using Poisson (robust variance estimates) and log-binomial regression models. RESULTS: A total of 1215 (23%) patients developed POAF (white n=1060; black n=155) following CABG (N=5387). Operative mortality differed by POAF status within race category (white POAF: adjusted RR=1.4, 95% CI=0.86-2.2; black POAF: adjusted RR=5.0, 95% CI=1.9-13; Pinteraction=0.0016). Black POAF patients had a 2-fold increased risk of operative death compared with white POAF patients (Padjusted=0.052). CONCLUSION: POAF was observed to be a stronger predictor of operative mortality in black compared with white patients undergoing elective CABG.