Schulte, Phillip J.

IMPORTANCE Hospitalizations are associated with cognitive decline in older adults. OBJECTIVE To determine the association between hospitalization characteristics and the trajectory of cognitive function in older adults. DESIGN Population‐based longitudinal study of cognitive aging. SETTING Olmsted Medical Center and Mayo Clinic, the only centers in Olmsted County, Minnesota, with hospitalization capacity. PARTICIPANTS Individuals without dementia at baseline, with consecutive cognitive assessments from 2004 through 2017, and at least one visit after the age of 60. MEASUREMENTS The primary outcome was longitudinal changes in global cognitive z ‐score. Secondary outcomes were changes in four cognitive domains: memory, attention/executive function, language, and visuospatial skills. Hospitalization characteristics analyzed included elective versus nonelective, medical versus surgical, critical care versus no critical care admission, and long versus short duration admissions. RESULTS Of 4,587 participants, 1,622 had 1 and more hospital admission. Before hospitalization, the average slope of the global z ‐score was −0.031 units/year. After hospitalization, the rate of annual global z ‐score accelerated by −0.051 (95% CI = −0.057, −0.045) units, P < .001, resulting in an estimated annual slope after the first hospitalization of −0.082. The accelerated decline was found in all four cognitive domains (memory, visuospatial, language, and executive, all P < .001). The acceleration of the decline in global z ‐score following hospitalization was greater for medical compared to surgical hospitalizations (slope change following hospitalization = −0.064 vs −0.034 for medical vs surgical, P < .001), and nonelective compared to elective admissions (slope change following hospitalization = −0.075 vs −0.037 for nonelective vs elective, P < .001). The acceleration of cognitive decline was not different for hospitalization with intensive care unit admission versus not. CONCLUSIONS Hospitalization of older adults is associated with accelerated decline of global and domain‐specific cognitive domains, with the rate of decline dependent upon type of admission. The clinical impact of this accelerated decline will depend on the individual's baseline cognitive reserve and expected longevity.

AbstractBackground and ObjectivesOptimizing perioperative analgesia for patients undergoing major lower‐extremity amputation remains a considerable challenge. The utility of liposomal bupivacaine as a component of peripheral nerve blockade for lower‐extremity amputation is unknown.MethodsWe conducted an observational study comparing three different perioperative analgesic techniques for adults undergoing major lower‐extremity amputation under general anesthesia between 2012 and 2017 at an academic medical center: (1) no regional anesthesia, (2) peripheral nerve blockade with standard bupivacaine, and (3) peripheral nerve blockade with a mixture of standard and liposomal bupivacaine. The primary outcome of cumulative opioid oral morphine milligram equivalent utilization in the first 72 hours postoperatively was compared across groups utilizing multivariable linear regression.ResultsA total of 631 unique anesthetics were included for 578 unique patients, including 416 (66%) without regional anesthesia, 131 (21%) with peripheral nerve blockade with a mixture of standard and liposomal bupivacaine, and 84 (13%) with peripheral nerve blockade with standard bupivacaine alone. Cumulative morphine equivalents were lower in those receiving peripheral nerve blockade with combined standard and liposomal bupivacaine compared with those not receiving regional anesthesia (multiplicative increase 0.67; 95% CI 0.50 to 0.90; P = 0.007). There were no significant differences in opioid utilization between peripheral nerve blockade groups (P = 0.59).ConclusionsPeripheral nerve blockade is associated with reduced opioid requirements after lower‐extremity amputation compared with general anesthesia alone. However, the incorporation of liposomal bupivacaine is not significantly different to blockade employing only standard bupivacaine.

Background and Aims Reliance on exception points to prioritize children for liver transplantation (LT) stems from concerns that the Pediatric End‐Stage Liver Disease (PELD) score underestimates mortality. Renal dysfunction and serum sodium disturbances are negative prognosticators in adult LT candidates and various pediatric populations, but are not accounted for in PELD. We retrospectively evaluated the effect of these parameters in predicting 90‐day wait‐list death/deterioration among pediatric patients (<12 years) listed for isolated LT in the United States between February 2002 and June 2018. Approach and Results Among 4,765 patients, 2,303 (49.3%) were transplanted, and 231 (4.8%) died or deteriorated beyond transplantability within 90 days of listing. Estimated glomerular filtration rate (eGFR) (hazard ratio [HR] 1.09 per 5‐unit decrease, 95% confidence interval [CI] 1.06‐1.10) and dialysis (HR 7.24, 95% CI 3.57‐14.66) were univariate predictors of 90‐day death/deterioration (P < 0.001). The long‐term benefit of LT persisted in patients with renal dysfunction, with LT as a time‐dependent covariate conferring a 2.4‐fold and 17‐fold improvement in late survival among those with mild and moderate‐to‐severe dysfunction, respectively. Adjusting for PELD, sodium was a significant nonlinear predictor of outcome, with 90‐day death/deterioration risk increased at both extremes of sodium (HR 1.20 per 1‐unit decrease below 137 mmol/L, 95% CI 1.16‐1.23; HR per 1‐unit increase above 137 mmol/L 1.13, 95% CI 1.10‐1.17, P < 0.001). A multivariable model incorporating PELD, eGFR, dialysis, and sodium demonstrated improved performance and superior calibration in predicting wait‐list outcomes relative to the PELD score. Conclusions Listing eGFR, dialysis, and serum sodium are potent, independent predictors of 90‐day death/deterioration in pediatric LT candidates, capturing risk not accounted for by PELD. Incorporation of these variables into organ allocation systems may highlight patient subsets with previously underappreciated risk, augment ability of PELD to prioritize patients for transplantation, and ultimately mitigate reliance on nonstandard exceptions.

Objectives: Critically ill surgical patients may receive concomitant aspirin and therapeutic anticoagulation postoperatively, yet the safety of this practice remains unknown. We evaluated the risk of major bleeding with concomitant therapy compared with anticoagulation alone. Design: Observational cohort study. Inverse probability of treatment weighting was used to assess the association between concomitant therapy and a primary outcome of major bleeding. Setting: Postoperative ICUs at an academic medical center. Patients: Adults (≥ 18 yr old) receiving anticoagulation during postoperative ICU admission between 2007 and 2016. Interventions: None. Measurements and Main Results: Nine thousand five hundred eighteen anticoagulated patients were included, including 3,237 (34%) receiving aspirin. A total of 1,874 unique patients (19.7%) experienced a major bleeding event. In inverse probability of treatment weighting analyses, concomitant therapy was associated with increased odds for major bleeding (odds ratio, 1.20; 95% CI, 1.05–1.36; p = 0.006) compared with anticoagulation alone. An interaction test suggested a differential relationship between aspirin use and major bleeding based on aspirin use in the 7 days prior to anticoagulation, such that a strong association between aspirin and major bleeding was observed for recent initiators of aspirin (1.40; 1.13–1.72;p = 0.002) but not for those continuing prior aspirin use. Aspirin use prior to anticoagulation did not modify the relationship between concomitant therapy and new myocardial infarction or stroke (i.e., rates were not increased with aspirin discontinuation prior to anticoagulation). Conclusions: Concomitant aspirin and anticoagulation in critically ill surgical patients was associated with an increased rate of major bleeding. Future investigations are warranted to further define optimal management of antiplatelet therapy during anticoagulation in surgical patients.

TPS594 Background: The standard treatment for upper tract urothelial carcinoma (UTUC) is radical nephroureterectomy (RNU) with bladder cuff resection. Subsequent intravesical recurrence is common and results in patient morbidity and increased healthcare cost. Level 1 evidence has demonstrated reduction of intravesical recurrence with instillation of intravesical Mitomycin C at 10 days following RNU. However, there has been limited adoption of Mitomycin C due to concerns for toxicity and logistics of postoperative drug delivery. Meanwhile, immediate intravesical gemcitabine has been shown to reduce intravesical recurrence following transurethral resection of bladder cancers without increasing toxicity compared to placebo. Moreover, small series have suggested improved efficacy of intraoperative intravesical chemotherapy for RNU. The purpose of the GEMINI trial, therefore, is to prospectively establish the safety and efficacy of intraoperative instillation of intravesical gemcitabine in patients undergoing RNU for UTUC. Methods: GEMINI is a multi-center open-label, single-arm, Phase II study that aims to enroll 90 patients with cTa-T4N0M0 UTUC. Patients receive intraoperative intravesical instillation of gemcitabine at the beginning of RNU, to be held in the bladder for at least 1 hour. The instilled drug will be drained prior to resection of the bladder cuff. Patients will undergo standard of care postoperative surveillance, including cystoscopy at 3, 6, 12, 18, and 24 months. The primary endpoint is 1-year intravesical recurrence-free survival. The historical event rate for no treatment is 30%, and we estimated a 40% relative reduction in event rate with gemcitabine. The study is powered to provide 80% power to detect this difference based on a one-sided exact test of proportions with alpha level 0.05. Secondary endpoints include time to recurrence and stratification of recurrence free survival by tumor grade, tumor stage, neoadjuvant chemotherapy, ureteral tumor location, and history of bladder cancer. Safety and adverse event endpoints will be evaluated. Complete accrual is expected within 3 years.

Background: Physiological alterations during the perianesthetic period may contribute to secondary neurocognitive injury after a concussion. Methods: Patients exposed to concussion and who received an anesthetic within 90 days were matched to unexposed patients without concussion. Intraoperative and postoperative events were compared. Subgroup analyses assessed relationships among patients with a concussion in the prior 30, 31 to 60, and 61 to 90 days and their respective unexposed matches. To facilitate identification of potential targets for further investigation, statistical comparisons are reported before, as well as after, correction for multiple comparisons. Results: Sixty concussion patients were matched to 176 unexposed patients. Before correction, 28.3% postconcussion versus 14.8% unexposed patients reported postanesthesia care unit pain score≥7 (P=0.02); 16.7% concussion versus 6.5% unexposed patients reported headache within 90 days of anesthesia (P=0.02) and 23.5% of patients who received surgery and anesthesia within 30 days of concussion experienced headache within 90 days of anesthesia compared with 7.1% in the unexposed group (P=0.01). Patients who experienced concussion and had anesthesia between 31 and 60 days after injury had a postanesthesia care unit Richmond Agitation and Sedation Scale score of −1.61±1.29 versus a score of −0.2±0.45 in unexposed patients (P=0.002). After adjusting the P-value threshold for multiple comparisons, the P-value for significance was instead 0.0016 for the overall cohort. Our study revealed no significant associations with application of adjusted significance thresholds. Conclusions: There were no differences in intraoperative and postoperative outcomes in patients with recent concussion compared with unexposed patients. Before correction for multiple comparisons, several potential targets for further investigation are identified. Well-powered studies are warranted.