BABEL (Better tArgeting, Better outcomes for frail ELderly patients) advance care planning: a comprehensive approach to advance care planning in nursing homes: a cluster randomised trial.

BACKGROUND: Nursing home (NH) residents should have the opportunity to consider, discuss and document their healthcare wishes. However, such advance care planning (ACP) is frequently suboptimal. OBJECTIVE: Assess a comprehensive, person-centred ACP approach. DESIGN: Unblinded, cluster randomised trial. SETTING: Fourteen control and 15 intervention NHs in three Canadian provinces, 2018-2020. SUBJECTS: 713 residents (442 control, 271 intervention) aged ≥65 years, with elevated mortality risk. METHODS: The intervention was a structured, $\sim$60-min discussion between a resident, substitute decision-maker (SDM) and nursing home staff to: (i) confirm SDMs' identities and role; (ii) prepare SDMs for medical emergencies; (iii) explain residents' clinical condition and prognosis; (iv) ascertain residents' preferred philosophy to guide decision-making and (v) identify residents' preferred options for specific medical emergencies. Control NHs continued their usual ACP processes. Co-primary outcomes were: (a) comprehensiveness of advance care planning, assessed using the Audit of Advance Care Planning, and (b) Comfort Assessment in Dying. Ten secondary outcomes were assessed. P-values were adjusted for all 12 outcomes using the false discovery rate method. RESULTS: The intervention resulted in 5.21-fold higher odds of respondents rating ACP comprehensiveness as being better (95% confidence interval [CI] 3.53, 7.61). Comfort in dying did not differ (difference = -0.61; 95% CI -2.2, 1.0). Among the secondary outcomes, antimicrobial use was significantly lower in intervention homes (rate ratio = 0.79, 95% CI 0.66, 0.94). CONCLUSIONS: Superior comprehensiveness of the BABEL approach to ACP underscores the importance of allowing adequate time to address all important aspects of ACP and may reduce unwanted interventions towards the end of life.

Applying the Knowledge-to-Action Framework to Engage Stakeholders and Solve Shared Challenges with Person-Centered Advance Care Planning in Long-Term Care Homes.

As they near the end of life, long term care (LTC) residents often experience unmet needs and unnecessary hospital transfers, a reflection of suboptimal advance care planning (ACP). We applied the knowledge-to-action framework to identify shared barriers and solutions to ultimately improve the process of ACP and improve end-of-life care for LTC residents. We held a 1-day workshop for LTC residents, families, directors/administrators, ethicists, and clinicians from Manitoba, Alberta, and Ontario. The workshop aimed to identify: (1) shared understandings of ACP, (2) barriers to respecting resident wishes, and (3) solutions to better respect resident wishes. Plenary and group sessions were recorded and thematic analysis was performed. We identified four themes: (1) differing provincial frameworks, (2) shared challenges, (3) knowledge products, and 4) ongoing ACP. Theme 2 had four subthemes: (i) lacking clarity on substitute decision maker (SDM) identity, (ii) lacking clarity on the SDM role, (iii) failing to share sufficient information when residents formulate care wishes, and (iv) failing to communicate during a health crisis. These results have informed the development of a standardized ACP intervention currently being evaluated in a randomized trial in three Canadian provinces.

Early intraoperative iron-binding proteins are associated with acute kidney injury after cardiac surgery.

OBJECTIVES: Iron regulation is an important modifier of renal ischemia-reperfusion injury, but the role of iron-binding proteins during cardiopulmonary bypass remains unclear. The goal was to characterize iron-binding proteins throughout ischemia-reperfusion injury to determine their association with acute kidney injury development. METHODS: A prospective observational cohort of adult patients who underwent cardiac surgery (n = 301) was obtained, and acute kidney injury was defined by Kidney Disease Improving Global Outcomes. Serum ferritin, transferrin saturation, and urine hepcidin-25 were measured. RESULTS: Intraoperative serum ferritin was lower at the start of cardiopulmonary bypass (P = .005) and 1-hour cardiopulmonary bypass (P = .001) in patients with acute kidney injury versus patients without acute kidney injury. Lower serum ferritin and higher transferrin saturation at 1-hour cardiopulmonary bypass were independent predictors of acute kidney injury (serum ferritin odds ratio, 0.66; 95% confidence interval [CI], 0.48-0.91; transferrin saturation odds ratio, 1.26; 95% CI, 1.02-1.55) and improved model discrimination (area under the curve [AUC], 0.76; 95% CI, 0.67-0.85) compared with clinical prediction alone (AUC, 0.72; 95% CI, 0.62-0.81; ΔAUC and net reclassification index, P = .01). Lower ferritin, higher transferrin saturation at 1-hour cardiopulmonary bypass, and lower urine hepcidin-25 at postoperative day 1 were also independent predictors for acute kidney injury development, and this model demonstrated an AUC of 0.80 (0.72-0.87), which was superior to clinical prediction (ΔAUC P = .002, integrated discrimination improvement and net reclassification index P = .003). CONCLUSIONS: Our findings suggest that lower levels of intraoperative iron-binding proteins may reflect an impaired capacity to rapidly handle catalytic iron released during cardiopulmonary bypass, leading to kidney injury. These data highlight the importance of iron homeostasis in human ischemia-reperfusion injury and suggest it is a potentially modifiable risk during cardiac surgery. Intraoperative detection of incipient acute kidney injury may be feasible and could be used as an enrichment strategy for clinical trials.

Activity-Based Protein Profiling of Intraoperative Serine Hydrolase Activities during Cardiac Surgery.

The processes involved in the initiation of acute kidney injury (AKI) following cardiopulmonary bypass (CPB) are thought to occur during the intraoperative period. Such a rapid development might indicate that some of the inductive events are not dependent on de novo protein synthesis, raising the possibility that changes in activities of pre-existing enzymes could contribute to the development of AKI. Activity-based protein profiling (ABPP) was used to compare the serine hydrolase enzyme activities present in the urines of CPB patients who subsequently developed AKI versus those who did not (non-AKI) during the intra- and immediate postoperative periods. Sequential urines collected from a nested case-control cohort of AKI and non-AKI patients were reacted with a serine hydrolase activity probe, fluorophosphonate-TAMRA, and separated by SDS-PAGE. The patterns and levels of probe-labeled proteins in the two groups were initially comparable. However, within 1 h of CPB there were significant pattern changes in the AKI group. Affinity purification and mass spectrometry-based analysis of probe-labeled enzymes in AKI urines at 1 h CPB and arrival to the intensive care unit (ICU) identified 28 enzymes. Quantitative analysis of the activity of one of the identified enzymes, kallikrein-1, revealed some trends suggesting differences in the levels and temporal patterns of enzyme activity between a subset of patients who developed AKI and those who did not. A comparative analysis of affinity-purified probe reacted urinary proteins from these patient groups during the intraoperative period suggested the presence of both shared and unique enzyme patterns. These results indicate that there are intraoperative changes in the levels and types of serine hydrolase activities in patients who subsequently develop AKI. However, the role of these activity differences in the development of AKI remains to be determined.

Urinary Hepcidin-25 Is Elevated in Patients That Avoid Acute Kidney Injury Following Cardiac Surgery.

BACKGROUND: Acute kidney injury (AKI) following cardiac surgery leads to increased morbidity and mortality. Characterization and validation of early biomarkers of AKI may ultimately facilitate early therapeutic intervention. We have previously identified that elevated urinary hepcidin-25 is inversely and independently associated with the development of AKI in adult cardiac surgery patients. Hepcidin-25 is an antimicrobial peptide that sequesters iron intracellularly, and its elevation following human ischemia reperfusion injury may represent a renoprotective response to minimize renal injury. OBJECTIVE: Our goal was to validate urinary hepcidin-25 as a non-invasive biomarker in an independent cardiac surgery cohort, within the context of clinical AKI predictors. DESIGN: Prospective observational cohort study. SETTING: Adult cardiac surgery program at St. Boniface Hospital, Winnipeg, Manitoba, Canada. PATIENTS: Adult cardiac surgery patients undergoing cardiopulmonary bypass (CPB), n = 306. MEASUREMENTS: Urine hepcidin-25, measured on post-operative day (POD) 1. METHODS: A prospective, observational cohort of adult CPB patients (n = 306) was collected with serial perioperative urine samples. Urine hepcidin-25 at POD 1 was measured by competitive ELISA. Its diagnostic performance was evaluated in conjunction with clinical parameters and the Thakar clinical prediction score, using multivariate logistic regression. RESULTS: Urinary hepcidin-25 is elevated following cardiac surgery in AKI and non-AKI patients. Elevated urinary hepcidin-25 concentration was inversely associated with AKI on both univariate (odds ratio [OR]: 0.61, 95% confidence interval [CI]: 0.45-0.83, P = .002) and multivariate analysis (OR: 0.67, 95% CI: 0.50-0.95, P = .02). A combined model with clinical risk factors demonstrated that baseline estimated glomerular filtration rate (eGFR), diabetes mellitus, and urinary hepcidin-25 concentration had an overall area under the curve (AUC) of 0.82 (0.75-0.88) for predicting subsequent AKI development, which was superior to clinical prediction alone as determined by the Thakar score. LIMITATIONS: (1) A single-center observational study. (2) Polyclonal antibody-based competitive ELISA. CONCLUSION: Hepcidin-25 is inversely associated with AKI in a multivariate model when combined with eGFR and diabetes mellitus, with an overall AUC of 0.82. Notably, urinary hepcidin-25 improves on clinical AKI prediction compared to the Thakar score alone.

CONTEXTE: L'insuffisance rénale aiguë (IRA) qui survient à la suite d'une chirurgie cardiaque est associée à une augmentation du taux de morbidité et de mortalité. La caractérisation et la validation de biomarqueurs précoces d'une IRA permettraient éventuellement une intervention thérapeutique plus opportune. Nous avions antérieurement déterminé qu'un taux élevé d'hepcidine-25 est inversement et indépendamment associé au développement d'une IRA à la suite d'une chirurgie cardiaque chez les patients adultes. L'hepcidine-25 est un peptide antimicrobien qui capte le fer intracellulaire. L'élévation de sa concentration à la suite d'une lésion d'ischémie-reperfusion pourrait être une réponse rénoprotectrice permettant de limiter les lésions inflammatoires. OBJECTIFS DE L'ÉTUDE: Nous avions pour objectif de valider la qualité de biomarqueur non invasif de l'hépcidine-25 urinaire dans une cohorte indépendante de patients subissant une chirurgie cardiaque, dans le contexte des prédicteurs cliniques de l'IRA. TYPE D'ÉTUDE: Il s'agit d'une étude de cohorte observationnelle prospective. CADRE: L'étude a été réalisée au Canada, dans le cadre du programme de chirurgie cardiaque du St. Boniface Hospital de Winnipeg, au Manitoba. PATIENTS: La cohorte était constituée de 306 patients adultes subissant un pontage cardiopulmonaire. MESURES: Le taux d'hepcidine-25 urinaire a été mesuré le jour suivant l'intervention. MÉTHODOLOGIE: Une série d'échantillons d'urine périopératoires a été collectée chez une cohorte prospective et observationnelle constituée de 306 patients adultes subissant un pontage cardiopulmonaire. Le taux d'hepcidine-25 a été mesuré à l'aide d'un test ELISA compétitif, et sa performance diagnostique évaluée conjointement avec les paramètres cliniques et le score prédictif de Thakar en utilisant une régression logistique multivariée. RÉSULTATS: Le taux d'hepcidine-25 urinaire était élevé en post-opératoire chez tous les patients de la cohorte, qu'ils soient ou non atteints d'insuffisance rénale. Une concentration élevée d'hepcidine-25 urinaire a été inversement associée à la survenue d'une IRA tant selon l'analyse univariée (RC=0,61; IC à 95 % 0,45-0,83; p=0,002) que selon l'analyse multivariée (RC=0,67; IC à 95 % 0,50-0,95; p=0,002). Un modèle combinant certains facteurs de risque cliniques a démontré que le DFG initial, le diabète sucré et la concentration d'hepcidine-25 urinaire présentaient une surface sous la courbe (SSC) de 0,82 (0,75-0,88) pour la prédiction du développement d'une IRA à la suite d'une chirurgie cardiaque. Ce niveau d'exactitude s'est avéré supérieur à la prédiction clinique déterminée par le score de Thakar. LIMITES DE L'ÉTUDE: Deux principaux facteurs limitent la portée de l'étude : d'abord, le fait qu'il s'agit d'une étude observationnelle menée dans un seul centre, puis, la variabilité inhérente au test ELISA compétitif pour les anticorps polyclonaux. CONCLUSION: Dans une analyse multivariée, lorsque combinée au DFG et au diabète sucré, l'hepcidine-25 urinaire est inversement associée à la survenue d'une IRA (SSC globale de 0,82). Ainsi, comparativement au score de Thakar utilisé seul, la mesure du taux d'hepcidine-25 urinaire prédit plus exactement le risque d'IRA.

Improving the Prediction of Cardiac Surgery-Associated Acute Kidney Injury.

INTRODUCTION: Acute kidney injury (AKI) is a potentially fatal complication of cardiac surgery. The inability to predict cardiac surgery-associated AKI is a major barrier to prevention and early treatment. Current clinical risk models for the prediction of cardiac surgery-associated AKI are insufficient, particularly in patients with preexisting kidney dysfunction. METHODS: To identify intraoperative variables that might improve the performance of a validated clinical risk score (Cleveland Clinic Score, CCS) for the prediction of cardiac surgery-associated AKI, we conducted a prospective cohort study in 289 consecutive elective cardiac surgery patients at a tertiary care center. We compared the area under the receiver operator characteristic curve (AUC) of a base model including only the CCS with models containing additional selected intraoperative variables including mean arterial pressure, hematocrit, duration of procedure, blood transfusions, and fluid balance. AKI was defined by the Kidney Disease Improving Global Outcomes 2012 criteria. RESULTS: The CCS alone gave an AUC of 0.72 (95% confidence interval, 0.62-0.82) for postoperative AKI. Nadir intraoperative hematocrit was the only variable that improved AUC for postoperative AKI when added to the CCS (AUC = 0.78; 95% confidence interval, 0.70-0.87; P = 0.002). In the subcohort of patients without preexisting chronic kidney disease (n = 214), where the CCS underperformed (AUC, 0.60 [0.43-0.76]), the improvement with the addition of nadir hematocrit was more marked (AUC, 0.74 [0.62-0.86]). Other variables did not improve discrimination. DISCUSSION: Nadir intraoperative hematocrit is useful in improving discrimination of clinical risk scores for AKI, and may provide a target for intervention.

A proteomic evaluation of urinary changes associated with cardiopulmonary bypass.

BACKGROUND: The urinary proteome of patients undergoing cardiopulmonary bypass (CPB) may provide important insights into systemic and renal changes associated with the procedure. Such information may ultimately provide a basis to differentiate changes or properties associated with the development of acute kidney injury. While mass spectrometry (MS) analysis offers the potential for in-depth compositional analysis it is often limited in coverage and relative quantitation capacity. The aim of this study was to develop a process flow for the preparation and comparison of the intraoperative urinary proteome. METHODS: Urines were collected from patients at the start of CPB and 1-h into CPB. Pooled samples (n = 5) from each time point were processed using a modified Filter Assisted Sample Preparation protocol. The resulting peptides were analyzed by 2D-LC-MS/MS and by 1D-LC-MS/MS SWATH (Sequential Window acquisition of All Theoretical fragment ion spectra). RESULTS: The 2D-LC-MS/MS analysis identified 1324 proteins in the two pools, of which 744 were quantifiable. The SWATH approach provided quantitation for 730 proteins, 552 of which overlapped with the common population from the 2D-IDA results. Intensity correlation filtering between the two methods gave 475 proteins for biological interpretation. Proteins displaying greater than threefold changes (>log2 1.59) at 1-hour CPB relative to the initiation of CPB (26 down-regulated and 22 up-regulated) were selected for further analysis. Up-regulated proteins were enriched in GO terms related to humoral immune response, predominantly innate immunity (C4b, lactotransferrin, protein S100-A8, cathelicidin, myeloperoxidase) and extracellular matrix reorganization (e.g. MMP-9). CONCLUSIONS: This study describes a scheme for processing urine from patients undergoing CPB for mass spectrometry-based analysis. The introduction of SWATH into the workflow offers a sample and instrument sparing approach to obtaining consistent in-depth sample analysis. The design of the methodology is such that it can be readily applied to large numbers of clinical samples with the potential for automation. The results also suggest that activation of the innate immune responses occur during cardiac bypass surgery.