Inhaled Epoprostenol Compared With Nitric Oxide for Right Ventricular Support After Major Cardiac Surgery.

BACKGROUND: Right ventricular failure (RVF) is a leading driver of morbidity and death after major cardiac surgery for advanced heart failure, including orthotopic heart transplantation and left ventricular assist device implantation. Inhaled pulmonary-selective vasodilators, such as inhaled epoprostenol (iEPO) and nitric oxide (iNO), are essential therapeutics for the prevention and medical management of postoperative RVF. However, there is limited evidence from clinical trials to guide agent selection despite the significant cost considerations of iNO therapy. METHODS: In this double-blind trial, participants were stratified by assigned surgery and key preoperative prognostic features, then randomized to continuously receive either iEPO or iNO beginning at the time of separation from cardiopulmonary bypass with the continuation of treatment into the intensive care unit stay. The primary outcome was the composite RVF rate after both operations, defined after transplantation by the initiation of mechanical circulatory support for isolated RVF, and defined after left ventricular assist device implantation by moderate or severe right heart failure according to criteria from the Interagency Registry for Mechanically Assisted Circulatory Support. An equivalence margin of 15 percentage points was prespecified for between-group RVF risk difference. Secondary postoperative outcomes were assessed for treatment differences and included: mechanical ventilation duration; hospital and intensive care unit length of stay during the index hospitalization; acute kidney injury development including renal replacement therapy initiation; and death at 30 days, 90 days, and 1 year after surgery. RESULTS: Of 231 randomized participants who met eligibility at the time of surgery, 120 received iEPO, and 111 received iNO. Primary outcome occurred in 30 participants (25.0%) in the iEPO group and 25 participants (22.5%) in the iNO group, for a risk difference of 2.5 percentage points (two one-sided test 90% CI, -6.6% to 11.6%) in support of equivalence. There were no significant between-group differences for any of the measured postoperative secondary outcomes. CONCLUSIONS: Among patients undergoing major cardiac surgery for advanced heart failure, inhaled pulmonary-selective vasodilator treatment using iEPO was associated with similar risks for RVF development and development of other postoperative secondary outcomes compared with treatment using iNO. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03081052.

Role of Blood-Brain Barrier Dysfunction in Delirium following Non-cardiac Surgery in Older Adults.

OBJECTIVE: Although animal models suggest a role for blood-brain barrier dysfunction in postoperative delirium-like behavior, its role in postoperative delirium and postoperative recovery in humans is unclear. Thus, we evaluated the role of blood-brain barrier dysfunction in postoperative delirium and hospital length of stay among older surgery patients. METHODS: Cognitive testing, delirium assessment, and cerebrospinal fluid and blood sampling were prospectively performed before and after non-cardiac, non-neurologic surgery. Blood-brain barrier dysfunction was assessed using the cerebrospinal fluid-to-plasma albumin ratio (CPAR). RESULTS: Of 207 patients (median age = 68 years, 45% female) with complete CPAR and delirium data, 26 (12.6%) developed postoperative delirium. Overall, CPAR increased from before to 24 hours after surgery (median change = 0.28, interquartile range [IQR] = -0.48 to 1.24, Wilcoxon p = 0.001). Preoperative to 24 hours postoperative change in CPAR was greater among patients who developed delirium versus those who did not (median [IQR] = 1.31 [0.004 to 2.34] vs 0.19 [-0.55 to 1.08], p = 0.003). In a multivariable model adjusting for age, baseline cognition, and surgery type, preoperative to 24 hours postoperative change in CPAR was independently associated with delirium occurrence (per CPAR increase of 1, odds ratio = 1.30, 95% confidence interval [CI] = 1.03-1.63, p = 0.026) and increased hospital length of stay (incidence rate ratio = 1.15, 95% CI = 1.09-1.22, p < 0.001). INTERPRETATION: Postoperative increases in blood-brain barrier permeability are independently associated with increased delirium rates and postoperative hospital length of stay. Although these findings do not establish causality, studies are warranted to determine whether interventions to reduce postoperative blood-brain barrier dysfunction would reduce postoperative delirium rates and hospital length of stay. ANN NEUROL 2023;94:1024-1035.

Health care resource utilization and clinical outcomes for adult heart transplant recipients with primary graft dysfunction.

INTRODUCTION: The advent of new technologies to reduce primary graft dysfunction (PGD) and improve outcomes after heart transplantation are costly. Adoption of these technologies requires a better understanding of health care utilization, specifically the costs related to PGD. METHODS: Records were examined from all adult patients who underwent orthotopic heart transplantation (OHT) between July 1, 2013 and July 30, 2019 at a single institution. Total costs were categorized into variable, fixed, direct, and indirect costs. Patient costs from time of transplantation to hospital discharge were transformed with the z-score transformation and modeled in a linear regression model, adjusted for potential confounders and in-hospital mortality. The quintile of patient costs was modeled using a proportional odds model, adjusted for confounders and in-hospital mortality. RESULTS: 359 patients were analyzed, including 142 with PGD and 217 without PGD. PGD was associated with a .42 increase in z-score of total patient costs (95% CI: .22-.62; p < .0001). Additionally, any grade of PGD was associated with a 2.95 increase in odds for a higher cost of transplant (95% CI: 1.94-4.46, p < .0001). These differences were substantially greater when PGD was categorized as severe. Similar results were obtained for fixed, variable, direct, and indirect costs. CONCLUSIONS: PGD after OHT impacts morbidity, mortality, and health care utilization. We found that PGD after OHT results in a significant increase in total patient costs. This increase was substantially higher if the PGD was severe. SUMMARY: Primary graft dysfunction after heart transplantation impacts morbidity, mortality, and health care utilization. PGD after OHT is costly and investments should be made to reduce the burden of PGD after OHT to improve patient outcomes.

Perioperative changes in neurocognitive and Alzheimer's disease-related cerebrospinal fluid biomarkers in older patients randomised to isoflurane or propofol for anaesthetic maintenance.

BACKGROUND: Animal studies have shown that isoflurane and propofol have differential effects on Alzheimer's disease (AD) pathology and memory, although it is unclear whether this occurs in humans. METHODS: This was a nested randomised controlled trial within a prospective cohort study; patients age ≥60 yr undergoing noncardiac/non-neurological surgery were randomised to isoflurane or propofol for anaesthetic maintenance. Cerebrospinal fluid (CSF) was collected via lumbar puncture before, 24 h, and 6 weeks after surgery. Cognitive testing was performed before and 6 weeks after surgery. Nonparametric methods and linear regression were used to evaluate CSF biomarkers and cognitive function, respectively. RESULTS: There were 107 subjects (54 randomised to isoflurane and 53 to propofol) who completed the 6-week follow-up and were included in the analysis. There was no significant effect of anaesthetic treatment group, time, or group-by-time interaction for CSF amyloid-beta (Aß), tau, or phospho-tau181p levels, or on the tau/Aß or p-tau181p/Aß ratios (all P>0.05 after Bonferroni correction). In multivariable-adjusted intention-to-treat analyses, there were no significant differences between the isoflurane and propofol groups in 6-week postoperative change in overall cognition (mean difference [95% confidence interval]: 0.01 [-0.12 to 0.13]; P=0.89) or individual cognitive domains (P>0.05 for each). Results remained consistent across as-treated and per-protocol analyses. CONCLUSIONS: Intraoperative anaesthetic maintenance with isoflurane vs propofol had no significant effect on postoperative cognition or CSF Alzheimer's disease-related biomarkers within 6 weeks after noncardiac, non-neurological surgery in older adults. CLINICAL TRIAL REGISTRATION: NCT01993836.

Obstructive Sleep Apnea Among Gravidas With Chronic Hypertension Compared to Matched Controls: A Prospective Cohort Study.

BACKGROUND: Previous studies of obstructive sleep apnea (OSA) risk in gravidas with chronic hypertension (cHTN) did not control for obesity as a risk factor for OSA. We therefore performed this study to evaluate whether OSA is more prevalent among gravidas with cHTN compared to normotensive gravidas matched for body mass index (BMI) and gestational age (primary outcome). We also assessed whether OSA is more severe when comorbid with cHTN in pregnancy (secondary outcome). METHODS: This was a single-center, prospective cohort study. Adult gravidas at 10-20 weeks of gestation, with and without cHTN, were enrolled and BMI matched. All subjects answered OSA screening questionnaires and underwent a home sleep test when they were between 10 and 20 weeks of gestation. Pregnancy outcomes were followed for all subjects. We performed univariable and multivariable logistic regression to model the relationship between cHTN status and OSA. RESULTS: A total of 100 pregnant subjects (50 with cHTN and 50 normotensive) completed a home sleep test of 2 hours or more. There were no differences in demographic variables between the 2 groups, except that gravidas with cHTN were significantly older than normotensive subjects (mean ± standard deviation [SD] 34 ± 4 vs 30 ± 6 years; P < .001). OSA was more prevalent (64% vs 38%; P = .009; odds ratio [95% confidence interval (CI)] 2.90 [1.30-6.65]; P = .01) and more severe in gravidas with cHTN (moderate or severe OSA 59% vs 21%; P = .009). After controlling for age, we found no overall association between cHTN on OSA risk (adjusted odds ratio [95% CI] 2.22 [0.92-5.40]; P = .076). However, among gravidas older than 25 years of age, cHTN was associated with higher odds of OSA (adjusted odds ratio [95% CI], 2.64 [1.06-6.71], P = .038). CONCLUSIONS: cHTN and age are important risk factors for OSA in gravidas. Gravidas with cHTN should be screened for OSA in early pregnancy. Future studies may validate screening tools that include cHTN and age, and investigate the role of OSA therapy in blood pressure control.

Effectiveness of Simulation- Versus Didactic Video-Based Learning to Teach Advanced Lung Isolation Techniques.

OBJECTIVES: Mastery of lung isolation is crucial for optimal cardiothoracic anesthesia education. The authors tested the hypothesis that simulation- is more effective than didactic video-based learning (cognitive, affective, and psychomotor) to teach anesthesiology fellows advanced lung isolation techniques. DESIGN: A prospective randomized study. SETTING: At a single academic heart center, simulation laboratory. PARTICIPANTS: Thirty anesthesiology fellows with equivalent prior experience in basic lung isolation techniques. INTERVENTIONS: Randomized participants received 1 of 2 structured educational interventions of equivalent duration designed to teach advanced lung isolation skills, a simulation workshop, or a video-based didactic session. MEASUREMENTS AND MAIN RESULTS: To assess Bloom's taxonomy domains, performance measurements included pre- and postintervention cognitive tests and affective surveys and a postintervention psychomotor task (time to complete lung isolation). Changes in test and survey scores and time to completion were compared using the Mann-Whitney U test; p values < 0.05 were considered significant. Improvements in lung isolation learning assessments were greater in the simulation group, but significant differences only existed in the affective domain. Specifically, affective survey score increases were greater in the simulation group (simulation- versus video-based didactic: +19.0 v +4.0; p ≤ 0.001), whereas there was no significant difference in cognitive pre- to posttest scores (simulation- versus video-based: +28.6 v +19.1, p = 0.23), and time to achieve lung isolation (simulation- versus video-based: 32 v 36 seconds, p = 0.46). CONCLUSIONS: Although greater affective learning of advanced lung isolation skills occurred with simulation-based compared to didactic video-based education, the authors found no differences between the teaching approaches in cognitive and psychomotor learning among anesthesiology fellows.

Development of New Donor-Specific and Human Leukocyte Antigen Antibodies After Transfusion in Adult Lung Transplantation.

OBJECTIVES: The development of new human leukocyte antigens (HLAs) and donor-specific antibodies (DSAs) in patients are associated with worse outcomes following lung transplantation. The authors aimed to examine the relationship between blood product transfusion in the first 72 hours after lung transplantation and the development of HLA antibodies, including DSAs. DESIGN: A retrospective observational study. SETTING: At a single academic tertiary center. PARTICIPANTS: Adult lung transplant recipients who underwent transplantation between September 2014 and June 2019. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A total of 380 patients were included in this study, and 87 (23%) developed de novo donor-specific antibodies in the first year after transplantation. Eighty-five patients (22%) developed new HLA antibodies that were not donor-specific, and 208 patients (55%) did not develop new HLA antibodies in the first year after transplantation. Factors associated with increased HLA and DSA development included donor pulmonary infection, non-infectious indication for transplant, increased recipient body mass index, and a preoperative calculated panel reactive antibody value above 0. Multivariate analysis identified platelet transfusion associated with an increased risk of de novo HLA antibody development compared to the negative group (odds ratio [OR; 95% CI] 1.18 [1.02-1.36]; p = 0.025). Cryoprecipitate transfusion was associated with de novo DSA development compared to the negative group (OR [95% CI] 2.21 [1.32-3.69] for 1 v 0 units; p = 0.002). CONCLUSIONS: Increased perioperative transfusion of platelets and cryoprecipitate are associated with de novo HLA and DSA development, respectively, in lung transplant recipients during the first year after transplantation.

Pain Trajectories After Valve Surgeries Performed via Midline Sternotomy Versus Mini-Thoracotomy.

OBJECTIVES: Controlling moderate-to-severe pain remains a major challenge after cardiothoracic surgery. Several outcomes have been compared extensively after valve surgery performed via midline sternotomy versus mini-thoracotomy, but postoperative pain (POP) was not adequately examined. Therefore, the authors tested the hypothesis that there is no difference in POP trajectories in patients undergoing valve surgery via midline sternotomy versus mini-thoracotomy. DESIGN: An Institutional Review Board-approved retrospective study. SETTING: At a single, large academic medical center. PARTICIPANTS: Adult patients who underwent mitral or aortic valve surgeries over a 5-year period. INTERVENTIONS: The authors compared the characteristics of pain between valve surgery patients receiving either midline sternotomy or mini-thoracotomy. To identify pain score trajectories, the authors employed latent class linear mixed models and then used multinomial regression models to study the association between incision type and pain trajectory class. MEASUREMENTS AND MAIN RESULTS: The authors' cohort consisted of 1,660 surgical patients-544 (33%) received a midline sternotomy, and 1,116 (66%) received a mini-thoracotomy. The authors identified the following 4 pain trajectory classes: stationary, rapidly improving, slowly improving, and acute worsening pain. Compared to the rapidly improving class, the odds of belonging to the stationary (adjusted odds ratio [aOR] [95% CI] 1.45 [1.01- 2.08]; p = 0.04) or the acute worsening class (aOR [95% CI] 1.71 [1.10-2.67] p = 0.02) were significantly higher for sternotomy patients compared to mini-thoracotomy. CONCLUSIONS: Midline sternotomies are associated with higher odds of having an acute worsening or stationary versus a rapidly improving pain trajectory compared to mini-thoracotomies. Therefore, the choice of incision may play an important role in determining POP trajectory after valve surgery.

Heated Humidified Breathing Circuit Rewarming in Hypothermic Patients Post-Cardiopulmonary Bypass-Pilot Study.

OBJECTIVES: Hypothermia on intensive care unit (ICU) admission after cardiac surgery and cardiopulmonary bypass is common. It contributes to postoperative complications including shivering, coagulopathy, increased blood loss and transfusion requirements, morbid cardiac events, metabolic acidosis, increased wound infections, and prolonged hospital length of stay. The current standard of care for rewarming ICU patients is forced air warming blankets. However, high-quality evidence on additional benefit rendered by other warming methods, such as heated humidified breathing circuits (HHBC), is lacking. Therefore, the authors conducted a pilot study to examine whether the addition of HHBC to standard forced air warming blankets in hypothermic patients (≤35°C) admitted to the ICU after cardiac surgery using cardiopulmonary bypass reduced time to normothermia. DESIGN: Prospective study conducted at a single large academic medical center. PARTICIPANTS: The study group was composed of 14 patients who were enrolled prospectively between April 1 and June 14, 2019. The study group was compared with a 2:1 matched retrospective control group. The matched group consisted of 28 patients from a 12-month period from July 1, 2018 June 30, 2019. INTERVENTIONS: Study patients received warming via forced air warming blankets and HHBC and were compared with patients in a control group who received only warming blankets. Time to normothermia, time to extubation, time to normal pH, blood loss, blood transfusions, and coagulation profile laboratory values were compared between the study and control groups. MEASUREMENTS AND MAIN RESULTS: The present study found no statistical difference in time to normothermia, for which the standard-of-care retrospective group achieved normothermia after a median (Q1-Q3) 4.8 (4.0-6.0) hours compared with 4.4 (3.5-5.5) hours in the prospective group receiving HHBC. All secondary outcomes, including time to extubation, time to normal pH, ICU blood product transfusion, chest tube output, and coagulation profile, were similar. CONCLUSIONS: The present pilot study detected a similar time to normothermia, extubation, and normal pH when HHBC were added to standard forced air warming blankets in hypothermic patients (≤35°C) admitted to the ICU after cardiac surgery using cardiopulmonary bypass. A future larger prospective study designed to detect smaller, but clinically meaningful, reductions in the time to key clinical events for patients treated with HHBC is feasible and warranted.

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.

A pilot study of longitudinal changes in neurocognition, white matter hyperintensities, and cortical thickness in atrial fibrillation patients following catheter ablation vs medical management.

Background: Cerebral microembolization and atrophy complicate atrial fibrillation (AF). Objectives: We aimed to compare changes in neuroimaging findings between AF patients treated with catheter ablation and those treated with medical therapy. Methods: In this pilot study, we evaluated differences in the change in regional white matter hyperintensity burden (WMHb) and cognitive function from baseline to 6 weeks and 1 year in patients treated with AF ablation (n = 12) and patients treated with medical management alone (n = 11). Change in cortical thickness over time in Alzheimer's disease (AD) risk, aging-associated, and shared AD risk/aging regions was also compared between groups. Results: The mean age was 69.7 ± 5.0 years, 78% of patients were male, 39% had persistent AF, and all received oral anticoagulation. There were no significant differences between groups in the change in cognitive function. At 6 weeks, there were no significant differences in periventricular WMHb changes between groups (0.00 vs 0.04, P = .12), but changes in attention/concentration were inversely correlated with periventricular (P = .01) and total (P = .03) WMHb. Medical management patients demonstrated significantly greater cortical thinning in AD risk regions from baseline to 1 year (P = .003). Conclusions: AF patients who underwent ablation demonstrated less cortical thinning in regions associated with AD risk than patients treated with medical therapy. Larger, prospective studies are needed to better understand the relationship between AF therapies and the development of cognitive decline.

Green Light-Based Analgesia - Novel Nonpharmacological Approach to Fibromyalgia Pain: A Pilot Study.

BACKGROUND: There continues to be significant reliance on pharmacological modalities for the management of chronic pain, with a particular focus on opioid analgesics as a singular option for pain management. Fibromyalgia is a prototypical central pain disorder, which is often used as a model to study chronic pain disorders. It has an estimated prevalence of approximately 1.1% to 5.4% in the general population. The widespread use of opioids in patients with fibromyalgia has been well demonstrated in several health claims database studies, with rates of use ranging from 11.3% to 69%. Minimizing opioid exposures reduces misuse risk, but requires adequate opioid-sparing multimodal analgesic strategies, particularly nonopioid analgesic adjuncts, to ensure effective treatment of pain, particularly high-impact pain. We chose fibromyalgia as our study population. Given that it is a disordered sensory processing condition, it may be particularly amenable to the beneficial effects of green-light therapy. OBJECTIVES: Most studies have evaluated exposure to light-emitting diode lights as a mode of green-light delivery; our study used green-light filtering eyeglasses, which would allow the wearer to move about with minimal interference. STUDY DESIGN: We conducted a randomized controlled trial to test the feasibility of green-light filtering eyeglasses in the treatment of chronic pain. SETTING: This study was conducted at Duke University Health System. METHODS: We recruited and randomized adult patients with a known diagnosis of fibromyalgia patients and excluded patients who were unable to wear eyeglasses for at least 4 hours per day or were colorblind according to the Ishihara Colorblindness Test. Patients were assigned to 1 of 3 arms: clear eyeglasses (control), green eyeglasses, or blue eyeglasses. We initially recruited 45 patients and randomly assigned 15 patients per group. RESULTS: To evaluate clinical significance, we determined the rate of >= 10% decline in oral morphine equivalents and found that 33%, 11%, and 8% of the green, blue, and clear eyeglass groups, respectively, achieved this clinically meaningful outcome. LIMITATIONS: This study was powered to detect feasibility of the intervention, rather than conclusive analgesic effects. CONCLUSIONS: Our study demonstrated the feasibility of this treatment approach and study design and supports a future study to determine the efficacy of green light-based analgesia on opioid use, pain, and anxiety. While the reduction of opioid use was not of statistical significance, we believe it to be of clinical significance as there was no increase of patient-reported pain. This warrants further investigation in a large-scale trial of the use of green-light filtration of ambient light to mitigate opioid use and possible mediation of psychological impacts of pain with the use of green-lensed eyeglasses.

EEG pre-burst suppression: characterization and inverse association with preoperative cognitive function in older adults.

The most common complication in older surgical patients is postoperative delirium (POD). POD is associated with preoperative cognitive impairment and longer durations of intraoperative burst suppression (BSup) - electroencephalography (EEG) with repeated periods of suppression (very low-voltage brain activity). However, BSup has modest sensitivity for predicting POD. We hypothesized that a brain state of lowered EEG power immediately precedes BSup, which we have termed "pre-burst suppression" (preBSup). Further, we hypothesized that even patients without BSup experience these preBSup transient reductions in EEG power, and that preBSup (like BSup) would be associated with preoperative cognitive function and delirium risk. Data included 83 32-channel intraoperative EEG recordings of the first hour of surgery from 2 prospective cohort studies of patients ≥age 60 scheduled for ≥2-h non-cardiac, non-neurologic surgery under general anesthesia (maintained with a potent inhaled anesthetic or a propofol infusion). Among patients with BSup, we defined preBSup as the difference in 3-35 Hz power (dB) during the 1-s preceding BSup relative to the average 3-35 Hz power of their intraoperative EEG recording. We then recorded the percentage of time that each patient spent in preBSup, including those without BSup. Next, we characterized the association between percentage of time in preBSup and (1) percentage of time in BSup, (2) preoperative cognitive function, and (3) POD incidence. The percentage of time in preBSup and BSup were correlated (Spearman's ρ [95% CI]: 0.52 [0.34, 0.66], p < 0.001). The percentage of time in BSup, preBSup, or their combination were each inversely associated with preoperative cognitive function (ß [95% CI]: -0.10 [-0.19, -0.01], p = 0.024; -0.04 [-0.06, -0.01], p = 0.009; -0.04 [-0.06, -0.01], p = 0.003, respectively). Consistent with prior literature, BSup was significantly associated with POD (odds ratio [95% CI]: 1.34 [1.01, 1.78], p = 0.043), though this association did not hold for preBSup (odds ratio [95% CI]: 1.04 [0.95, 1.14], p = 0.421). While all patients had ≥1 preBSup instance, only 20.5% of patients had ≥1 BSup instance. These exploratory findings suggest that future studies are warranted to further study the extent to which preBSup, even in the absence of BSup, can identify patients with impaired preoperative cognition and/or POD risk.

A Role for Blood-brain Barrier Dysfunction in Delirium following Non-Cardiac Surgery in Older adults.

Objective: Although animal models suggest a role for blood-brain barrier dysfunction in postoperative delirium-like behavior, its role in postoperative delirium and postoperative recovery in humans is unclear. Thus, we evaluated the role of blood-brain barrier dysfunction in postoperative delirium and hospital length of stay among older surgery patients. Methods: Cognitive testing, delirium assessment, and cerebrospinal fluid and blood sampling were prospectively performed before and after non-cardiac, non-neurologic surgery. Blood-brain barrier dysfunction was assessed using the cerebrospinal fluid-to-plasma albumin ratio (CPAR). Results: Of 207 patients (median age 68, 45% female) with complete CPAR and delirium data, 26 (12.6%) developed postoperative delirium. Overall, CPAR increased from before to 24-hours after surgery (median postoperative change 0.28, [IQR] [-0.48-1.24]; Wilcoxon p=0.001). Preoperative to 24-hour postoperative change in CPAR was greater among patients who developed delirium vs those who did not (median [IQR] 1.31 [0.004, 2.34] vs 0.19 [-0.55, 1.08]; p=0.003). In a multivariable model adjusting for age, baseline cognition, and surgery type, preoperative to 24-hour postoperative change in CPAR was independently associated with delirium incidence (per CPAR increase of 1, OR = 1.30, [95% CI 1.03-1.63]; p=0.026) and increased hospital length of stay (IRR = 1.15 [95% CI 1.09-1.22]; p<0.001). Interpretation: Postoperative increases in blood-brain barrier permeability are independently associated with increased delirium rates and postoperative hospital length of stay. Although these findings do not establish causality, studies are warranted to determine whether interventions to reduce postoperative blood-brain barrier dysfunction would reduce postoperative delirium rates and hospital length of stay.

Conserved YKL-40 changes in mice and humans after postoperative delirium.

Delirium is a common postoperative neurologic complication among older adults. Despite its prevalence (14%-50%) and likely association with inflammation, the exact mechanisms that underpin postoperative delirium are unclear. This project aimed to characterize systemic and central nervous system (CNS) inflammatory changes following surgery in mice and humans. Matched plasma and cerebrospinal fluid (CSF) samples from the "Investigating Neuroinflammation Underlying Postoperative Brain Connectivity Changes, Postoperative Cognitive Dysfunction, Delirium in Older Adults" (INTUIT; NCT03273335) study were compared to murine endpoints. Delirium-like behavior was evaluated in aged mice using the 5-Choice Serial Reaction Time Test (5-CSRTT). Using a well established orthopedic surgical model in the FosTRAP reporter mouse we detected neuronal changes in the prefrontal cortex, an area implicated in attention, but notably not in the hippocampus. In aged mice, plasma interleukin-6 (IL-6), chitinase-3-like protein 1 (YKL-40), and neurofilament light chain (NfL) levels increased after orthopedic surgery, but hippocampal YKL-40 expression was decreased. Given the growing evidence for a YKL-40 role in delirium and other neurodegenerative conditions, we assayed human plasma and CSF samples. Plasma YKL-40 levels were similarly increased after surgery, with a trend toward a greater postoperative plasma YKL-40 increase in patients with delirium. However, YKL-40 levels in CSF decreased following surgery, which paralleled the findings in the mouse brain. Finally, we confirmed changes in the blood-brain barrier (BBB) as early as 9 h after surgery in mice, which warrants more detailed and acute evaluations of BBB integrity following surgery in humans. Together, these results provide a nuanced understanding of neuroimmune interactions underlying postoperative delirium in mice and humans, and highlight translational biomarkers to test potential cellular targets and mechanisms.

Electroencephalogram-Based Complexity Measures as Predictors of Post-operative Neurocognitive Dysfunction.

Physiologic signals such as the electroencephalogram (EEG) demonstrate irregular behaviors due to the interaction of multiple control processes operating over different time scales. The complexity of this behavior can be quantified using multi-scale entropy (MSE). High physiologic complexity denotes health, and a loss of complexity can predict adverse outcomes. Since postoperative delirium is particularly hard to predict, we investigated whether the complexity of preoperative and intraoperative frontal EEG signals could predict postoperative delirium and its endophenotype, inattention. To calculate MSE, the sample entropy of EEG recordings was computed at different time scales, then plotted against scale; complexity is the total area under the curve. MSE of frontal EEG recordings was computed in 50 patients ≥ age 60 before and during surgery. Average MSE was higher intra-operatively than pre-operatively (p = 0.0003). However, intraoperative EEG MSE was lower than preoperative MSE at smaller scales, but higher at larger scales (interaction p < 0.001), creating a crossover point where, by definition, preoperative, and intraoperative MSE curves met. Overall, EEG complexity was not associated with delirium or attention. In 42/50 patients with single crossover points, the scale at which the intraoperative and preoperative entropy curves crossed showed an inverse relationship with delirium-severity score change (Spearman ρ = -0.31, p = 0.054). Thus, average EEG complexity increases intra-operatively in older adults, but is scale dependent. The scale at which preoperative and intraoperative complexity is equal (i.e., the crossover point) may predict delirium. Future studies should assess whether the crossover point represents changes in neural control mechanisms that predispose patients to postoperative delirium.