Regulatory variants in TCF7L2 are associated with thoracic aortic aneurysm.

Thoracic aortic aneurysm (TAA) is characterized by dilation of the aortic root or ascending/descending aorta. TAA is a heritable disease that can be potentially life threatening. While 10%-20% of TAA cases are caused by rare, pathogenic variants in single genes, the origin of the majority of TAA cases remains unknown. A previous study implicated common variants in FBN1 with TAA disease risk. Here, we report a genome-wide scan of 1,351 TAA-affected individuals and 18,295 control individuals from the Cardiovascular Health Improvement Project and Michigan Genomics Initiative at the University of Michigan. We identified a genome-wide significant association with TAA for variants within the third intron of TCF7L2 following replication with meta-analysis of four additional independent cohorts. Common variants in this locus are the strongest known genetic risk factor for type 2 diabetes. Although evidence indicates the presence of different causal variants for TAA and type 2 diabetes at this locus, we observed an opposite direction of effect. The genetic association for TAA colocalizes with an aortic eQTL of TCF7L2, suggesting a functional relationship. These analyses predict an association of higher expression of TCF7L2 with TAA disease risk. In vitro, we show that upregulation of TCF7L2 is associated with BCL2 repression promoting vascular smooth muscle cell apoptosis, a key driver of TAA disease.

Perioperative Mortality of the COVID-19 Recovered Patient Compared to a Matched Control: A Multicenter Retrospective Cohort Study.

BACKGROUND: Surgical procedures performed on patients with recent exposure to COVID-19 infection have been associated with increased mortality risk in previous studies. Accordingly, elective surgery is often delayed after infection. The study aimed to compare 30-day hospital mortality and postoperative complications (acute kidney injury, pulmonary complications) of surgical patients with a previous COVID-19 infection to a matched cohort of patients without known previous COVID-19. The authors hypothesized that COVID-19 exposure would be associated with an increased mortality risk. METHODS: In this retrospective observational cohort study, patients presenting for elective inpatient surgery across a multicenter cohort of academic and community hospitals from April 2020 to April 2021 who had previously tested positive for COVID-19 were compared to controls who had received at least one previous COVID-19 test but without a known previous COVID-19-positive test. The cases were matched based on anthropometric data, institution, and comorbidities. Further, the outcomes were analyzed stratified by timing of a positive test result in relation to surgery. RESULTS: Thirty-day mortality occurred in 229 of 4,951 (4.6%) COVID-19-exposed patients and 122 of 4,951 (2.5%) controls. Acute kidney injury was observed in 172 of 1,814 (9.5%) exposed patients and 156 of 1,814 (8.6%) controls. Pulmonary complications were observed in 237 of 1,637 (14%) exposed patients and 164 of 1,637 (10%) controls. COVID-19 exposure was associated with an increased 30-day mortality risk (adjusted odds ratio, 1.63; 95% CI, 1.38 to 1.91) and an increased risk of pulmonary complications (1.60; 1.36 to 1.88), but was not associated with an increased risk of acute kidney injury (1.03; 0.87 to 1.22). Surgery within 2 weeks of infection was associated with a significantly increased risk of mortality and pulmonary complications, but that effect was nonsignificant after 2 weeks. CONCLUSIONS: Patients with a positive test for COVID-19 before elective surgery early in the pandemic have an elevated risk of perioperative mortality and pulmonary complications but not acute kidney injury as compared to matched controls. The span of time from positive test to time of surgery affected the mortality and pulmonary risk, which subsided after 2 weeks.

Hypoxemia in School-age Children Undergoing One-lung Ventilation: A Retrospective Cohort Study from the Multicenter Perioperative Outcomes Group.

BACKGROUND: Risk factors for hypoxemia in school-age children undergoing one-lung ventilation remain poorly understood. The hypothesis was that certain modifiable and nonmodifiable factors may be associated with increased risk of hypoxemia in school-age children undergoing one-lung ventilation and thoracic surgery. METHODS: The Multicenter Perioperative Outcomes Group database was queried for children 4 to 17 yr of age undergoing one-lung ventilation. Patients undergoing vascular or cardiac procedures were excluded. The original cohort was divided into two cohorts: 4 to 9 and 10 to 17 yr of age inclusive. All records were reviewed electronically for the primary outcome of hypoxemia during one-lung ventilation, which was defined as an oxygen saturation measured by pulse oximetry (Spo2) less than 90% for 3 min or longer continuously, while severe hypoxemia was defined as Spo2 less than 90% for 5 min or longer. Potential modifiable and nonmodifiable risk factors associated with these outcomes were evaluated using separate multivariable least absolute shrinkage and selection operator regression analyses for each cohort. The covariates evaluated included age, extremes of weight, American Society of Anesthesiologists Physical Status of III or higher, duration of one-lung ventilation, preoperative Spo2 less than 98%, approach to one-lung ventilation, right operative side, video-assisted thoracoscopic surgery, lower tidal volume ventilation (defined as tidal volume of 6 ml/kg or less and positive end-expiratory pressure of 4 cm H2O or greater for more than 80% of the duration of one-lung ventilation), and procedure type. RESULTS: The prevalence of hypoxemia in the 4- to 9-yr-old cohort and the 10- to 17-yr-old cohort was 24 of 228 (10.5% [95% CI, 6.5 to 14.5%]) and 76 of 1,012 (7.5% [95% CI, 5.9 to 9.1%]), respectively. The prevalence of severe hypoxemia in both cohorts was 14 of 228 (6.1% [95% CI, 3.0 to 9.3%]) and 47 of 1,012 (4.6% [95% CI, 3.3 to 5.8%]). Initial Spo2 less than 98% was associated with hypoxemia in the 4- to 9-yr-old cohort (odds ratio, 4.20 [95% CI, 1.61 to 6.29]). Initial Spo2 less than 98% (odds ratio, 2.76 [95% CI, 1.69 to 4.48]), extremes of weight (odds ratio, 2.18 [95% CI, 1.29 to 3.61]), and right-sided cases (odds ratio, 2.33 [95% CI, 1.41 to 3.92]) were associated with an increased risk of hypoxemia in the older cohort. Increasing age (1-yr increment; odds ratio, 0.88 [95% CI, 0.80 to 0.97]) was associated with a decreased risk of hypoxemia. CONCLUSIONS: An initial room air oxygen saturation of less than 98% was associated with an increased risk of hypoxemia in all children 4 to 17 yr of age. Extremes of weight, right-sided cases, and decreasing age were associated with an increased risk of hypoxemia in children 10 to 17 yr of age.

Polygenic Score for the Prediction of Postoperative Nausea and Vomiting: A Retrospective Derivation and Validation Cohort Study.

BACKGROUND: Postoperative nausea and vomiting (PONV) is a key driver of unplanned admission and patient satisfaction following surgery. Because traditional risk factors do not completely explain variability in risk, we hypothesize that genetics may contribute to the overall risk for this complication. The objective of this research is to perform a genome-wide association study of PONV, derive a polygenic risk score for PONV, assess associations between the risk score and PONV in a validation cohort, and compare any genetic contributions to known clinical risks for PONV. METHODS: Surgeries with integrated genetic and perioperative data performed under general anesthesia at Michigan Medicine and Vanderbilt University Medical Center were studied. PONV was defined as nausea or emesis occurring and documented in the PACU. In the Discovery Phase, genome-wide association studies were performed on each genetic cohort and the results were meta-analyzed. Next, in the Polygenic Phase, we assessed whether a polygenic score, derived from genome-wide association study in a derivation cohort from Vanderbilt University Medical Center, improved prediction within a validation cohort from Michigan Medicine, as quantified by discrimination (C-statistic) and net reclassification index. RESULTS: Of 64,523 total patients, 5,703 developed PONV (8.8%). We identified 46 genetic variants exceeding P<1x10-5 threshold, occurring with minor allele frequency > 1%, and demonstrating concordant effects in both cohorts. Standardized polygenic score was associated with PONV in a basic model, controlling for age and sex, (aOR 1.027 per standard deviation increase in overall genetic risk, 95% CI 1.001-1.053, P=0.044), a model based on known clinical risks (aOR 1.029, 95% CI 1.003-1.055, P=0.030), and a full clinical regression, controlling for 21 demographic, surgical, and anesthetic factors, (aOR 1.029, 95% CI 1.002-1.056, P=0.033). The addition of polygenic score improved overall discrimination in models based on known clinical risk factors (c-statistic: 0.616 compared to 0.613, P=0.028) and improved net reclassification of 4.6% of cases. CONCLUSION: Standardized polygenic risk was associated with PONV in all three of our models, but the genetic influence was smaller than exerted by clinical risk factors. Specifically, a patient with a polygenic risk score > 1 standard deviation above the mean, has 2-3% greater odds of developing PONV when compared to the baseline population, which is at least an order of magnitude smaller than the increase associated with having prior PONV/motion sickness (55%), having a history of migraines (17%), or being female (83%), and is not clinically significant. Furthermore, the use of a polygenic risk score does not meaningfully improve discrimination compared to clinical risk factors and is not clinically useful.

Association between inspired oxygen fraction and development of postoperative pulmonary complications in thoracic surgery: a multicentre retrospective cohort study.

BACKGROUND: Limited data exist to guide oxygen administration during one-lung ventilation for thoracic surgery. We hypothesised that high intraoperative inspired oxygen fraction during lung resection surgery requiring one-lung ventilation is independently associated with postoperative pulmonary complications (PPCs). METHODS: We performed this retrospective multicentre study using two integrated perioperative databases (Multicenter Perioperative Outcomes Group and Society of Thoracic Surgeons General Thoracic Surgery Database) to study adult thoracic surgical procedures using one-lung ventilation. The primary outcome was a composite of PPCs (atelectasis, acute respiratory distress syndrome, pneumonia, respiratory failure, reintubation, and prolonged ventilation >48 h). The exposure of interest was high inspired oxygen fraction (FiO2), defined by area under the curve of a FiO2 threshold > 80%. Univariate analysis and logistic regression modelling assessed the association between intraoperative FiO2 and PPCs. RESULTS: Across four US medical centres, 141/2733 (5.2%) procedures conducted in 2716 patients (55% female; mean age 66 yr) resulted in PPCs. FiO2 was univariately associated with PPCs (adjusted OR [aOR]: 1.17, 95% confidence interval [CI]: 1.04-1.33, P=0.012). Logistic regression modelling showed that duration of one-lung ventilation (aOR: 1.20, 95% CI: 1.03-1.41, P=0.022), but not the time-weighted average FiO2 (aOR: 1.01, 95% CI: 1.00-1.02, P=0.165), was associated with PPCs. CONCLUSIONS: Our results do not support limiting the inspired oxygen fraction for the purpose of reducing postoperative pulmonary complications in thoracic surgery involving one-lung ventilation.

Bronchial Blocker Versus Endobronchial Intubation in Young Children Undergoing One-Lung Ventilation: A Multicenter Retrospective Cohort Study.

BACKGROUND: Thoracic surgery and one-lung ventilation in young children carry significant risks. Approaches to one-lung ventilation in young children include endobronchial intubation (mainstem intubation) and use of a bronchial blocker. We hypothesized that endobronchial intubation is associated with a greater prevalence of airway complications compared to use of a bronchial blocker. METHODS: The Multicenter Perioperative Outcomes Group database was queried from 2004 to 2022 for one-lung ventilation cases in children, 2 months to 3 years of age, inclusive. Airway notes and free-text comments were manually reviewed for airway complications. Documented airway complications were considered the primary outcome and were divided into "Moderate" and "Critical." Moderate airway complications were bronchial blocker or endotracheal tube movement leading to loss of isolation, hypoxemia requiring ventilatory intervention, bronchial blocker migration into the trachea, significant impairment of ventilation, and other. Critical complications included reintubation or airway replacement intraoperatively, complete endotracheal tube occlusion, cardiac arrest or airway-related bradycardia, and procedure aborted due to an airway issue. An adjusted propensity score-matched analysis was then used to assess the impact of a bronchial blocker on the outcomes of moderate and critical complications. RESULTS: After exclusions, 704 patients were included in the primary analysis. In unadjusted analyses, no statistically significant difference was observed in moderate airway complications between endobronchial intubation and bronchial blocker cohorts: 37 of 444 (8.3%; 95% confidence interval [CI], 5.9%-11.3%) vs 28 of 260 (10.8%; 95% CI, 7.3%-15.2%) with P = .281. In the unadjusted analysis, the prevalence of critical airway complications was significantly higher in the endobronchial intubation cohort compared to the bronchial blocker cohort: 28 of 444 (6.3%; 95% CI, 4.2%-9.0%) vs 5 of 260 (1.9%; 95% CI, 0.6%-4.4%) with P = .008. In the propensity-matched cohort analysis, endobronchial intubation was associated with a slightly increased risk of critical complications compared to use of a bronchial blocker: 14 of 243 (5.8%; 95% CI, 2.8%-8.7%) vs 5 of 243 (2.1%; 95% CI, 0.3%-3.8%) with P = .035. CONCLUSIONS: Endobronchial intubation might be associated with a slightly increased risk of critical airway complications compared to use of a bronchial blocker in young children undergoing thoracic surgery and one-lung ventilation. Further, prospective studies are needed before a definitive change in practice is recommended.

Opioid Dose Variation in Cardiac Surgery: A Multicenter Study of Practice.

BACKGROUND: Although high-opioid anesthesia was long the standard for cardiac surgery, some anesthesiologists now favor multimodal analgesia and low-opioid anesthetic techniques. The typical cardiac surgery opioid dose is unclear, and the degree to which patients, anesthesiologists, and institutions influence this opioid dose is unknown. METHODS: We reviewed data from nonemergency adult cardiac surgeries requiring cardiopulmonary bypass performed at 30 academic and community hospitals within the Multicenter Perioperative Outcomes Group registry from 2014 through 2021. Intraoperative opioid administration was measured in fentanyl equivalents. We used hierarchical linear modeling to attribute opioid dose variation to the institution where each surgery took place, the primary attending anesthesiologist, and the specifics of the surgical patient and case. RESULTS: Across 30 hospitals, 794 anesthesiologists, and 59,463 cardiac cases, patients received a mean of 1139 (95% confidence interval [CI], 1132-1146) fentanyl mcg equivalents of opioid, and doses varied widely (standard deviation [SD], 872 µg). The most frequently used opioids were fentanyl (86% of cases), sufentanil (16% of cases), hydromorphone (12% of cases), and morphine (3% of cases). 0.6% of cases were opioid-free. 60% of dose variation was explainable by institution and anesthesiologist. The median difference in opioid dose between 2 randomly selected anesthesiologists across all institutions was 600 µg of fentanyl (interquartile range [IQR], 283-1023 µg). An anesthesiologist's intraoperative opioid dose was strongly correlated with their frequency of using a sufentanil infusion (r = 0.81), but largely uncorrelated with their use of nonopioid analgesic techniques (|r| < 0.3). CONCLUSIONS: High-dose opioids predominate in cardiac surgery, with substantial dose variation from case to case. Much of this variation is attributable to practice variability rather than patient or surgical differences. This suggests an opportunity to optimize opioid use in cardiac surgery.

Identifying Variation in Intraoperative Management of Brain-Dead Organ Donors and Opportunities for Improvement: A Multicenter Perioperative Outcomes Group Analysis.

BACKGROUND: Intraoperative events and clinical management of deceased organ donors after brain death are poorly characterized and may consequently vary between hospitals and organ procurement organization (OPO) regions. In a multicenter cohort, we sought to estimate the incidence of hypotension and anesthetic and nonanesthetic medication use during organ recovery procedures. METHODS: We used data from electronic anesthetic records generated during organ recovery procedures from brain-dead adults across a Multicenter Perioperative Outcomes Group (MPOG) cohort of 14 US hospitals and 4 OPO regions (2014-2020). Hypotension, defined as mean arterial pressure or MAP <60 mm Hg for at least 10 cumulative minutes was the primary outcome of interest. The associations between hypotension and age, sex, race, anesthesia time, OPOs, and OPO case volume were examined using multivariable mixed-effects Poisson regression analyses with robust standard error estimates. We calculated intraclass correlation coefficients (ICCs) to describe the variation between-MPOG centers and the OPO regions in the use of medications, time of the operation, and duration of the operation. RESULTS: We examined 1338 brain-dead adult donors, with a mean age of 42± (standard deviation [SD] 15) years; 60% (n = 801) were males and 67% (n = 891) non-Hispanic White. During the entire intraoperative monitoring period, 321 donors (24%, 95% confidence interval [CI], 22%-26%) had hypotension for a median of 13.8% [quartile1-quartile 3: 9.4%-21%] of the monitoring period and a minimum of 10 minutes to a maximum of 96 minutes [(median: 17, quartile1-quartile 3: 12-24]). The probability having hypotension in donors 35 to 64 years and 65 years and older were approximately 30% less than in donors 18 to 34 years of age (adjusted relative risk ratios, aRR, 0.68, 95% CI, 0.55-0.82, aRR, 0.63, 95% CI, 0.42-0.94, respectively). Donors received intravenous heparin (96.4%, n = 1291), neuromuscular blockers (89.5%, n = 1198), vasoactive medications (82.7%, n = 1108), crystalloids (76.2%, n = 1020), halogenated anesthetic gases (63.5%, n = 850), diuretics (43.8%, n = 587), steroids (16.7%, n = 224), and opioids (23.2%, n = 310). The largest practice heterogeneity observed between the MPOG center and OPO regions was steroids (between-center ICCs = 0.65, 95% CI, 0.62-0.75, between-region ICCs = 0.39, 95% CI, 0.27-0.63) and diuretics (between-center ICCs = 0.44, 95% CI, 0.36-0.6, between-region ICCs = 0.30, 95% CI, 0.22-0.49). CONCLUSIONS: Despite guidelines recommending maintenance of MAP >60 mm Hg in adult brain-dead organ donors, hypotension during recovery procedures was common. Future research is needed to clarify the relationship between intraoperative events with donation and transplantation outcomes and to identify best practices for the anesthetic management of brain-dead donors in the operating room.

Comparing the effects and potencies of perchlorate and nitrate on amphibian metamorphosis using a modified amphibian metamorphosis assay (AMA).

A modified amphibian metamorphosis assay was performed in which Nieuwkoop and Faber (NF) stage 47 Xenopus laevis larvae were exposed to different concentrations of either perchlorate (ClO4 -) or nitrate (NO3 -) for 32 days. Larvae were exposed to 0.0 (control), 5, 25, 125, 625, and 3125 µg/L ClO4 -, or 0 (control), 23, 71, 217, 660, and 2000 mg/L NO3 -. The primary endpoints were survival, hind limb length (HLL), forelimb emergence and development, developmental stage (including time to NF stage 62 [MT62]), thyroid histopathology, wet weight, and snout-vent length (SVL). Developmental delay as evidenced by altered stage distribution and increased MT62, a higher degree of thyroid follicular cell hypertrophy, and an increase in the prevalence of follicular cell hyperplasia was observed at concentrations ≥125 µg/L ClO4 -. The no observed effect concentration (NOEC) for developmental endpoints was 25.0 µg/L ClO4 - and the NOEC for growth endpoints was 3125 µg/L ClO4 -. Exposure to nitrate did not adversely affect MT62, but a decreasing trend in stage distribution and median developmental stage at ≥217 mg/L NO3 - was observed. No histopathologic effects associated with nitrate exposure were observed. An increasing trend in SVL-normalized HLL was observed at 2000 mg/L NO3 -. Nitrate did not alter larval growth. The NOEC for developmental endpoints was 71 mg/L NO3 -, and 2000 mg/L NO3 - for growth endpoints. The present study provided additional evidence that the effects and potency of nitrate and perchlorate on metamorphosis and growth in X. laevis are considerably different.

Practical Considerations for Obtaining Perioperative Transesophageal Echocardiography Accreditation: Collective Experiences at Early-Adopting Centers.

The Intersocietal Accreditation Commission (IAC) is a nonprofit accrediting organization committed to ensuring the quality of diagnostic imaging and related procedures. It comprises a collaboration of stakeholders spanning numerous medical professionals and specialties. In a recent initiative, IAC Echocardiography introduced a new accreditation specifically for Perioperative Transesophageal Echocardiography (PTE). This accreditation process is anchored in rigorous clinical peer review to ensure diagnostic quality and report accuracy, thus maintaining high standards of medical care. The authors present the inaugural 4 sites to achieve IAC accreditation for PTE, which have collaborated to share their experiences in achieving this accreditation. This review endeavors to offer actionable insights and proven solutions to navigate the accreditation journey for others. Mirroring the IAC Standards and Guidelines for PTE accreditation, this review is divided into three pivotal sections as follows: (1) organization of a perioperative echocardiography service, including stakeholder engagement to facilitate the application for accreditation; (2) performance of examinations and reporting; and (3) instituting quality improvement strategies and establishing a robust program. The pursuit of accreditation in PTE is to transcend a mere compliance exercise. It signifies a dedication to excellence, continual growth, and, above all, to the well-being of patients.

The Association of Oxygen Delivery and Transfusion on Cardiopulmonary Bypass with Acute Kidney Injury.

OBJECTIVES: To estimate whether the association of transfusion and acute kidney injury (AKI) has a threshold of oxygen delivery below which transfusion is beneficial but above which it is harmful. DESIGN: Retrospective study SETTING: Cardiovascular operating room and intensive care unit PARTICIPANTS: Patients undergoing cardiac surgery with continuous oxygen delivery monitoring during cardiopulmonary bypass INTERVENTIONS: None MEASUREMENTS AND MAIN RESULTS: Logistic regression was used to estimate the associations between oxygen delivery (mean, cumulative deficit, and bands of oxygen delivery), transfusion, and their interaction and AKI. A subgroup analysis of transfused and nontransfused patients with exact matching on cumulative oxygen deficit and time on bypass with adjustment for propensity to receive a transfusion using logistic regression. Nine hundred ninety-one of 4,203 patients developed AKI within 7 days. After adjustment for confounders, lower mean oxygen delivery (odds ratio [OR], 0.968; 95% confidence interval [CI], 0.949-0.988; p = 0.002) and transfusions (OR, 1.442; 95% CI, 1.077, 1.932; p = 0.014) were associated with increased odds of AKI by 7 days. As oxygen delivery decreased, the risk of AKI increased, with the slope of the OR steeper at <160 mL/m2/min. In the subgroup analysis, matched transfused patients were more likely than matched nontransfused patients to develop AKI (45% [n = 145] v 31% [n = 101]; p < 0.001). However, after propensity score adjustment, the difference was nonsignificant (OR, 1.181; 95% CI, 0.796-1.752; p = 0.406). CONCLUSIONS: We found a nonlinear relationship between oxygen delivery and AKI. We found no level of oxygen delivery at which transfusion was associated with a decreased risk of AKI.

Overview and Clinical Applications of Artificial Intelligence and Machine Learning in Cardiac Anesthesiology.

Artificial intelligence- (AI) and machine learning (ML)-based applications are becoming increasingly pervasive in the healthcare setting. This has in turn challenged clinicians, hospital administrators, and health policymakers to understand such technologies and develop frameworks for safe and sustained clinical implementation. Within cardiac anesthesiology, challenges and opportunities for AI/ML to support patient care are presented by the vast amounts of electronic health data, which are collected rapidly, interpreted, and acted upon within the periprocedural area. To address such challenges and opportunities, in this article, the authors review 3 recent applications relevant to cardiac anesthesiology, including depth of anesthesia monitoring, operating room resource optimization, and transthoracic/transesophageal echocardiography, as conceptual examples to explore strengths and limitations of AI/ML within healthcare, and characterize this evolving landscape. Through reviewing such applications, the authors introduce basic AI/ML concepts and methodologies, as well as practical considerations and ethical concerns for initiating and maintaining safe clinical implementation of AI/ML-based algorithms for cardiac anesthesia patient care.

Intraoperative Use of Albumin in Major Noncardiac Surgery: Incidence, Variability, and Association With Outcomes.

BACKGROUND: The impact of albumin use during major surgery is unknown, and a dearth of evidence governing its use in major noncardiac surgery has long precluded its standardization in clinical guidelines. OBJECTIVE: In this study, we investigate institutional variation in albumin use among medical centers in the United States during major noncardiac surgery and explore the association of intraoperative albumin administration with important postoperative outcomes. METHODS: The study is an observational retrospective cohort analysis performed among 54 U.S. hospitals in the Multicenter Perioperative Outcomes Group and includes adult patients who underwent major noncardiac surgery under general anesthesia between January 2014 and June 2020. The primary endpoint was the incidence of albumin administration. Secondary endpoints are acute kidney injury (AKI), net-positive fluid balance, pulmonary complications, and 30-day mortality. Albumin-exposed and albumin-unexposed cases were compared within a propensity score-matched cohort to evaluate associations of albumin use with outcomes. RESULTS: Among 614,215 major surgeries, predominantly iso-oncotic albumin was administered in 15.3% of cases and featured significant inter-institutional variability in use patterns. Cases receiving intraoperative albumin involved patients of higher American Society of Anesthesiologists physical status and featured larger infused crystalloid volumes, greater blood loss, and vasopressor use. Overall, albumin was most often administered at high-volume surgery centers with academic affiliation, and within a propensity score-matched cohort (n=153,218), the use of albumin was associated with AKI (aOR 1.24, 95% CI 1.20-1.28, P <0.001), severe AKI (aOR 1.45, 95% CI 1.34-1.56, P <0.001), net-positive fluid balance (aOR 1.18, 95% CI 1.16-1.20, P <0.001), pulmonary complications (aOR 1.56, 95% CI 1.30-1.86, P <0.001), and 30-day all-cause mortality (aOR 1.37, 95% CI 1.26-1.49, P <0.001). CONCLUSIONS: Intravenous albumin is commonly administered among noncardiac surgeries with significant inter-institutional variability in use in the United States. Albumin administration was associated with an increased risk of postoperative complications.

Postoperative Acute Kidney Injury by Age and Sex: A Retrospective Cohort Association Study.

BACKGROUND: Acute kidney injury (AKI) after noncardiac surgery is common and has substantial health impact. Preclinical and clinical studies examining the influence of sex on AKI have yielded conflicting results, although they typically do not account for age-related changes. The objective of the study was to determine the association of age and sex groups on postoperative AKI. The authors hypothesized that younger females would display lower risk of postoperative AKI than males of similar age, and the protection would be lost in older females. METHODS: This was a multicenter retrospective cohort study across 46 institutions between 2013 and 2019. Participants included adult inpatients without pre-existing end-stage kidney disease undergoing index major noncardiac, nonkidney/urologic surgeries. The authors' primary exposure was age and sex groups defined as females 50 yr or younger, females older than 50 yr, males 50 yr or younger, and males older than 50 yr. The authors' primary outcome was development of AKI by Kidney Disease-Improving Global Outcomes serum creatinine criteria. Exploratory analyses included associations of ascending age groups and hormone replacement therapy home medications with postoperative AKI. RESULTS: Among 390,382 patients, 25,809 (6.6%) developed postoperative AKI (females 50 yr or younger: 2,190 of 58,585 [3.7%]; females older than 50 yr: 9,320 of 14,4047 [6.5%]; males 50 yr or younger: 3,289 of 55,503 [5.9%]; males older than 50 yr: 11,010 of 132,447 [8.3%]). When adjusted for AKI risk factors, compared to females younger than 50 yr (odds ratio, 1), the odds of AKI were higher in females older than 50 yr (odds ratio, 1.51; 95% CI, 1.43 to 1.59), males younger than 50 yr (odds ratio, 1.90; 95% CI, 1.79 to 2.01), and males older than 50 yr (odds ratio, 2.06; 95% CI, 1.96 to 2.17). CONCLUSIONS: Younger females display a lower odds of postoperative AKI that gradually increases with age. These results suggest that age-related changes in women should be further studied as modifiers of postoperative AKI risk after noncardiac surgery.

Patient-, Clinician-, and Institution-level Variation in Inotrope Use for Cardiac Surgery: A Multicenter Observational Analysis.

BACKGROUND: Conflicting evidence exists regarding the risks and benefits of inotropic therapies during cardiac surgery, and the extent of variation in clinical practice remains understudied. Therefore, the authors sought to quantify patient-, anesthesiologist-, and hospital-related contributions to variation in inotrope use. METHODS: In this observational study, nonemergent adult cardiac surgeries using cardiopulmonary bypass were reviewed across a multicenter cohort of academic and community hospitals from 2014 to 2019. Patients who were moribund, receiving mechanical circulatory support, or receiving preoperative or home inotropes were excluded. The primary outcome was an inotrope infusion (epinephrine, dobutamine, milrinone, dopamine) administered for greater than 60 consecutive min intraoperatively or ongoing upon transport from the operating room. Institution-, clinician-, and patient-level variance components were studied. RESULTS: Among 51,085 cases across 611 attending anesthesiologists and 29 hospitals, 27,033 (52.9%) cases received at least one intraoperative inotrope, including 21,796 (42.7%) epinephrine, 6,360 (12.4%) milrinone, 2,000 (3.9%) dobutamine, and 602 (1.2%) dopamine (non-mutually exclusive). Variation in inotrope use was 22.6% attributable to the institution, 6.8% attributable to the primary attending anesthesiologist, and 70.6% attributable to the patient. The adjusted median odds ratio for the same patient receiving inotropes was 1.73 between 2 randomly selected clinicians and 3.55 between 2 randomly selected institutions. Factors most strongly associated with increased likelihood of inotrope use were institutional medical school affiliation (adjusted odds ratio, 6.2; 95% CI, 1.39 to 27.8), heart failure (adjusted odds ratio, 2.60; 95% CI, 2.46 to 2.76), pulmonary circulation disorder (adjusted odds ratio, 1.72; 95% CI, 1.58 to 1.87), loop diuretic home medication (adjusted odds ratio, 1.55; 95% CI, 1.42 to 1.69), Black race (adjusted odds ratio, 1.49; 95% CI, 1.32 to 1.68), and digoxin home medication (adjusted odds ratio, 1.48; 95% CI, 1.18 to 1.86). CONCLUSIONS: Variation in inotrope use during cardiac surgery is attributable to the institution and to the clinician, in addition to the patient. Variation across institutions and clinicians suggests a need for future quantitative and qualitative research to understand variation in inotrope use affecting outcomes and develop evidence-based, patient-centered inotrope therapies.

Cardiometabolic disease and obesity patterns differentially predict acute kidney injury after total joint replacement: a retrospective analysis.

BACKGROUND: Acute kidney injury (AKI) is a frequent yet understudied postoperative total joint arthroplasty complication. This study aimed to describe cardiometabolic disease co-occurrence using latent class analysis, and associated postoperative AKI risk. METHODS: This retrospective analysis examined patients ≥18 years old undergoing primary total knee or hip arthroplasties within the US Multicenter Perioperative Outcomes Group of hospitals from 2008 to 2019. AKI was defined using modified Kidney Disease: Improving Global Outcomes (KDIGO) criteria. Latent classes were constructed from eight cardiometabolic diseases including hypertension, diabetes, and coronary artery disease, excluding obesity. A mixed-effects logistic regression model was constructed for the outcome of any AKI and the exposure of interaction between latent class and obesity status adjusting for preoperative and intraoperative covariates. RESULTS: Of 81 639 cases, 4007 (4.9%) developed AKI. Patients with AKI were more commonly older and non-Hispanic Black, with more significant comorbidity. A latent class model selected three groups of cardiometabolic patterning, labelled 'hypertension only' (n=37 223), 'metabolic syndrome (MetS)' (n=36 503), and 'MetS+cardiovascular disease (CVD)' (n=7913). After adjustment, latent class/obesity interaction groups had differential risk of AKI compared with those in 'hypertension only'/non-obese. Those 'hypertension only'/obese had 1.7-fold increased odds of AKI (95% confidence interval [CI]: 1.5-2.0). Compared with 'hypertension only'/non-obese, those 'MetS+CVD'/obese had the highest odds of AKI (odds ratio 3.1, 95% CI: 2.6-3.7), whereas 'MetS+CVD'/non-obese had 2.2 times the odds of AKI (95% CI: 1.8-2.7; model area under the curve 0.76). CONCLUSIONS: The risk of postoperative AKI varies widely between patients. The current study suggests that the co-occurrence of metabolic conditions (diabetes mellitus, hypertension), with or without obesity, is a more important risk factor for acute kidney injury than individual comorbid diseases.

Optimizing the Design and Analysis of Future AKI Trials.

AKI is a complex clinical syndrome associated with an increased risk of morbidity and mortality, particularly in critically ill and perioperative patient populations. Most AKI clinical trials have been inconclusive, failing to detect clinically important treatment effects at predetermined statistical thresholds. Heterogeneity in the pathobiology, etiology, presentation, and clinical course of AKI remains a key challenge in successfully testing new approaches for AKI prevention and treatment. This article, derived from the "AKI" session of the "Kidney Disease Clinical Trialists" virtual workshop held in October 2021, reviews barriers to and strategies for improving the design and implementation of clinical trials in patients with, or at risk of, developing AKI. The novel approaches to trial design included in this review span adaptive trial designs that increase the knowledge gained from each trial participant; pragmatic trial designs that allow for the efficient enrollment of sufficiently large numbers of patients to detect small, but clinically significant, treatment effects; and platform trial designs that use one trial infrastructure to answer multiple clinical questions simultaneously. This review also covers novel approaches to clinical trial analysis, such as Bayesian analysis and assessing heterogeneity in the response to therapies among trial participants. We also propose a road map and actionable recommendations to facilitate the adoption of the reviewed approaches. We hope that the resulting road map will help guide future clinical trial planning, maximize learning from AKI trials, and reduce the risk of missing important signals of benefit (or harm) from trial interventions.

Prediction of Postoperative Deterioration in Cardiac Surgery Patients Using Electronic Health Record and Physiologic Waveform Data.

BACKGROUND: Postoperative hemodynamic deterioration among cardiac surgical patients can indicate or lead to adverse outcomes. Whereas prediction models for such events using electronic health records or physiologic waveform data are previously described, their combined value remains incompletely defined. The authors hypothesized that models incorporating electronic health record and processed waveform signal data (electrocardiogram lead II, pulse plethysmography, arterial catheter tracing) would yield improved performance versus either modality alone. METHODS: Intensive care unit data were reviewed after elective adult cardiac surgical procedures at an academic center between 2013 and 2020. Model features included electronic health record features and physiologic waveforms. Tensor decomposition was used for waveform feature reduction. Machine learning-based prediction models included a 2013 to 2017 training set and a 2017 to 2020 temporal holdout test set. The primary outcome was a postoperative deterioration event, defined as a composite of low cardiac index of less than 2.0 ml min-1 m-2, mean arterial pressure of less than 55 mmHg sustained for 120 min or longer, new or escalated inotrope/vasopressor infusion, epinephrine bolus of 1 mg or more, or intensive care unit mortality. Prediction models analyzed data 8 h before events. RESULTS: Among 1,555 cases, 185 (12%) experienced 276 deterioration events, most commonly including low cardiac index (7.0% of patients), new inotrope (1.9%), and sustained hypotension (1.4%). The best performing model on the 2013 to 2017 training set yielded a C-statistic of 0.803 (95% CI, 0.799 to 0.807), although performance was substantially lower in the 2017 to 2020 test set (0.709, 0.705 to 0.712). Test set performance of the combined model was greater than corresponding models limited to solely electronic health record features (0.641; 95% CI, 0.637 to 0.646) or waveform features (0.697; 95% CI, 0.693 to 0.701). CONCLUSIONS: Clinical deterioration prediction models combining electronic health record data and waveform data were superior to either modality alone, and performance of combined models was primarily driven by waveform data. Decreased performance of prediction models during temporal validation may be explained by data set shift, a core challenge of healthcare prediction modeling.

Multicentre analysis of practice patterns regarding benzodiazepine use in cardiac surgery.

BACKGROUND: There is controversy regarding optimal use of benzodiazepines during cardiac surgery, and it is unknown whether and to what extent there is variation in practice. We sought to describe benzodiazepine use and sources of variation during cardiac surgeries across patients, clinicians, and institutions. METHODS: We conducted an analysis of adult cardiac surgeries across a multicentre consortium of USA academic and private hospitals from 2014 to 2019. The primary outcome was administration of a benzodiazepine from 2 h before anaesthesia start until anaesthesia end. Institutional-, clinician-, and patient-level variables were analysed via multilevel mixed-effects models. RESULTS: Of 65 508 patients cared for by 825 anaesthesiology attending clinicians (consultants) at 33 institutions, 58 004 patients (88.5%) received benzodiazepines with a median midazolam-equivalent dose of 4.0 mg (inter-quartile range [IQR], 2.0-6.0 mg). Variation in benzodiazepine dosage administration was 54.7% attributable to institution, 14.7% to primary attending anaesthesiology clinician, and 30.5% to patient factors. The adjusted median odds ratio for two similar patients receiving a benzodiazepine was 2.68 between two randomly selected clinicians and 4.19 between two randomly selected institutions. Factors strongly associated (adjusted odds ratio, <0.75, or >1.25) with significantly decreased likelihoods of benzodiazepine administration included older age (>80 vs ≤50 yr; adjusted odds ratio=0.04; 95% CI, 0.04-0.05), university affiliation (0.08, 0.02-0.35), recent year of surgery (0.42, 0.37-0.49), and low clinician case volume (0.44, 0.25-0.75). Factors strongly associated with significantly increased likelihoods of benzodiazepine administration included cardiopulmonary bypass (2.26, 1.99-2.55), and drug use history (1.29, 1.02-1.65). CONCLUSIONS: Two-thirds of the variation in benzodiazepine administration during cardiac surgery are associated with institutions and attending anaesthesiology clinicians (consultants). These data, showing wide variations in administration, suggest that rigorous research is needed to guide evidence-based and patient-centred benzodiazepine administration.

Fluids, vasopressors, and acute kidney injury after major abdominal surgery between 2015 and 2019: a multicentre retrospective analysis.

BACKGROUND: Practice patterns related to intraoperative fluid administration and vasopressor use have potentially evolved over recent years. However, the extent of such changes and their association with perioperative outcomes, such as the development of acute kidney injury (AKI), have not been studied. METHODS: We performed a retrospective analysis of major abdominal surgeries in adults across 26 US hospitals between 2015 and 2019. The primary outcome was AKI as defined by the Kidney Disease Improving Global Outcomes definition (KDIGO) using only serum creatinine criteria. Univariable linear predictive additive models were used to describe the dose-dependent risk of AKI given fluid administration or vasopressor use. RESULTS: Over the study period, we observed a decrease in the volume of crystalloid administered, a decrease in the proportion of patients receiving more than 10 ml kg-1 h-1 of crystalloid, an increase in the amount of norepinephrine equivalents administered, and a decreased duration of hypotension. The incidence of AKI increased between 2016 and 2019. An increase of crystalloid administration from 1 to 10 ml kg-1 h-1 was associated with a 58% decreased risk of AKI. CONCLUSIONS: Despite decreased duration of hypotension during the study period, decreased fluid administration and increased vasopressor use were associated with increased incidence of AKI. Crystalloid administration below 10 ml kg-1 h-1 was associated with an increased risk of AKI. Although no causality can be concluded, these data suggest that prevention and treatment of hypotension during abdominal surgery with liberal use of vasopressors at the expense of fluid administration is associated with an increased risk of postoperative AKI.