Derivation and Validation of Thresholds Using Synthetic Data Methods for Single-Test Screening of Emergency Department Patients with Possible Acute Myocardial Infarction Using a Point-of-Care Troponin Assay.

BACKGROUND: Single-sample (screening) rule-out of acute myocardial infarction (AMI) with troponin requires derivation of a single-test screening threshold. In data sets with small event numbers, the lowest one or two concentrations of myocardial infarction (MI) patients dictate the threshold. This is not optimal. We aimed to demonstrate a process incorporating both real and synthetic data for deriving such thresholds using a novel pre-production high-precision point-of-care assay. METHODS: cTnI concentrations were measured from thawed plasma using the Troponin I Next (TnI-Nx) assay (i-STAT; Abbott) in adults on arrival to the emergency department with symptoms suggestive of AMI. The primary outcome was an AMI or cardiac death within 30 days. We used internal-external validation with synthetic data production based on clinical and demographic data, plus the measured TnI-Nx concentration, to derive and validate decision thresholds for TnI-Nx. The target low-risk threshold was a sensitivity of 99% and a high-risk threshold specificity of >95%. RESULTS: In total, 1356 patients were included, of whom 191 (14.1%) had the primary outcome. A total of 500 synthetic data sets were constructed. The mean low-risk threshold was determined to be 5 ng/L. This categorized 38% (95% CI, 6%-68%) to low-risk with a sensitivity of 99.0% (95% CI, 98.6%-99.5%) and a negative predictive value of 99.4% (95% CI, 97.6%-99.8%). A similarly derived high-risk threshold of 25 ng/L had a specificity of 95.0% (95% CI, 94.8%-95.1%) and a positive predictive value of 74.8% (95% CI, 71.5%-78.0%). CONCLUSIONS: With the TnI-Nx assay, we successfully demonstrated an approach using synthetic data generation to derive low-risk thresholds for safe and effective screening.

Comparison of three creatinine-based equations to predict adverse outcome in a cardiovascular high-risk cohort: an investigation using the SPRINT research materials.

Background: Novel creatinine-based equations have recently been proposed but their predictive performance for cardiovascular outcomes in participants at high cardiovascular risk in comparison to the established CKD-EPI 2009 equation is unknown. Method: In 9361 participants from the United States included in the randomized controlled SPRINT trial, we calculated baseline estimated glomerular filtration rate (eGFR) using the CKD-EPI 2009, CKD-EPI 2021, and EKFC equations and compared their predictive value of cardiovascular events. The statistical metric used is the net reclassification improvement (NRI) presented separately for those with and those without events. Results: During a mean follow-up of 3.1 ± 0.9 years, the primary endpoint occurred in 559 participants (6.0%). When using the CKD-EPI 2009, the CKD-EPI 2021, and the EKFC equations, the prevalence of CKD (eGFR <60 ml/min/1.73 m2 or >60 ml/min/1.73 m2 with an ACR ≥30 mg/g) was 37% vs. 35.3% (P = 0.02) vs. 46.4% (P < 0.001), respectively. The corresponding mean eGFR was 72.5 ± 20.1 ml/min/1.73 m2 vs. 73.2 ± 19.4 ml/min/1.73 m2 (P < 0.001) vs. 64.6 ± 17.4 ml/min/1.73 m2 (P < 0.001). Neither reclassification according to the CKD-EPI 2021 equation [CKD-EPI 2021 vs. CKD-EPI 2009: NRIevents: -9.5% (95% confidence interval (CI) -13.0% to -5.9%); NRInonevents: 4.8% (95% CI 3.9% to 5.7%)], nor reclassification according to the EKFC equation allowed better prediction of cardiovascular events compared to the CKD-EPI 2009 equation (EKFC vs. CKD-EPI 2009: NRIevents: 31.2% (95% CI 27.5% to 35.0%); NRInonevents: -31.1% (95% CI -32.1% to -30.1%)). Conclusion: Substituting the CKD-EPI 2009 with the CKD-EPI 2021 or the EKFC equation for calculation of eGFR in participants with high cardiovascular risk without diabetes changed the prevalence of CKD but was not associated with improved risk prediction of cardiovascular events for both those with and without the event.

The Drug Burden Index and Level of Frailty as Determinants of Healthcare Costs in a Cohort of Older Frail Adults in New Zealand.

OBJECTIVES: Frailty is common in older people and is associated with increased use of healthcare services and ongoing use of multiple medications. This study provides insights into the healthcare cost structure of a frail group of older adults in Aotearoa, New Zealand. Furthermore, we investigated the relationship between participants' anticholinergic and sedative medication burden and their total healthcare costs to explore the viability of deprescribing interventions within this cohort. METHODS: Healthcare cost analysis was conducted using data collected during a randomized controlled trial within a frail, older cohort. The collected information included participant demographics, medications used, frailty, cost of service use of aged residential care and outpatient hospital services, hospital admissions, and dispensed medications. RESULTS: Data from 338 study participants recruited between 25 September 2018 and 30 October 2020 with a mean age of 80 years were analyzed. The total cost of healthcare per participant ranged from New Zealand $15 (US dollar $10) to New Zealand $270 681 (US dollar $175 943) over 6 months postrecruitment into the study. Four individuals accounted for 26% of this cohort's total healthcare cost. We found frailty to be associated with increased healthcare costs, whereas the drug burden was only associated with increased pharmaceutical costs, not overall healthcare costs. CONCLUSIONS: With no relationship found between a patient's anticholinergic and sedative medication burden and their total healthcare costs, more research is required to understand how and where to unlock healthcare cost savings within frail, older populations.

Post Hoc Analyses of a Randomized Controlled Trial for the Effect of Pharmacist Deprescribing Intervention on the Anticholinergic Burden in Frail Community-Dwelling Older Adults.

OBJECTIVES: Anticholinergic burden is detrimental to cognitive health. Multiple studies found that a high anticholinergic burden is associated with an increased risk for dementia, changes to the brain structure, function, and cognitive decline. We performed a post hoc analysis of a randomized controlled deprescribing trial. We compared the effect of the intervention on baseline anticholinergic burden across the treatment and control groups and the time of recruitment before and after a lockdown due to the COVID pandemic with subgroup analyses by baseline frailty index. DESIGN: Randomized controlled trial. SETTINGS AND PARTICIPANTS: We analyzed data from a de-prescribing trial of older adults (>65 years) previously conducted in New Zealand that was focused on reducing the Drug Burden Index (DBI). METHODS: We used the anticholinergic cognitive burden (ACB) to quantify the impact of the intervention on reducing the anticholinergic burden. Participants not taking anticholinergics at the start of the trial were excluded. The primary outcome for this subgroup analysis was a change in ACB, measured with the gHedges statistic describing the difference in standard deviation units of this change between intervention and control. For this analysis, the trial participants were stratified into low, medium, and high frailty and timing into prior- and post-lockdown (public health measures for COVID-19). RESULTS: Among the 295 participants in this analysis, the median (IQR) age was 79 (74, 85), and 67% were women. For the primary outcome gHedges = -0.04 (95% CI -0.26 to 0.19) with a -0.23 mean reduction in ACB in the intervention arm and -0.19 in the control arm. Before lockdown gHedges = -0.38 (95% CI -0.84 to 0.04) and post-lockdown gHedges = 0.07 (95% CI -0.19 to 0.33). The mean change in ACB for each of the frailty strata was as follows: low frailty (-0.02; 95% CI -0.65 to 0.18); medium frailty (0.05; 95% CI -0.28 to 0.38); high frailty (0.08; 95% CI -0.40 to 0.56). CONCLUSIONS AND IMPLICATIONS: The study did not provide evidence for the effect of pharmacist deprescribing intervention on reducing the anticholinergic burden. However, this post hoc analysis examined the impact of COVID on the effectiveness of the intervention, and further research in this area may be warranted.

Chronic health conditions and mortality among older adults with complex care needs in Aotearoa New Zealand.

BACKGROUND: Older people have more comorbidities than younger groups and multimorbidity will increase. Often chronic conditions affect quality of life, functional ability and social participation. Our study aim was to quantify the prevalence of chronic conditions over a three-year period and their association with mortality after accounting for demographics. METHODS: We conducted a retrospective cohort study using routinely collected health data including community-dwelling older adults in New Zealand who had an interRAI Home Care assessment between 1 January 2017 and 31 December 2017. Descriptive statistics and differences between variables of interest among ethnic groups were reported. Cumulative density plots of mortality were developed. Logistic regression models adjusted for age and sex to estimate mortality were created independently for each combination of ethnicity and disease diagnosis. RESULTS: The study cohort consisted of 31,704 people with a mean (SD) age of 82.3 years (8.0), and of whom 18,997 (59.9%) were female. Participants were followed for a median 1.1 (range 0 to 3) years. By the end of the follow-up period 15,678 (49.5%) people had died. Nearly 62% of Maori and Pacific older adults and 57% of other ethnicities had cognitive impairment. Diabetes the next most prevalent amongst Maori and Pacific peoples, and coronary heart disease amongst Non-Maori/Non-Pacific individuals. Of the 5,184 (16.3%) who had congestive heart failure (CHF), 3,450 (66.6%) died. This was the highest mortality rate of any of the diseases. There was a decrease in mortality rate with age for both sexes and all ethnicities for those with cancer. CONCLUSIONS: Cognitive impairment was the most common condition in community dwelling older adults who had an interRAI assessment. Cardiovascular disease (CVD) has the highest mortality risk for all ethnic groups, and in non-Maori/non-Pacific group of advanced age, risk of mortality with cognitive impairment is as high as CVD risk. We observed an inverse for cancer mortality risk with age. Important differences between ethnic groups are reported.

Deprescribing Anticholinergic and Sedative Drugs to Reduce Polypharmacy in Frail Older Adults Living in the Community: A Randomized Controlled Trial.

BACKGROUND: Polypharmacy is associated with poor outcomes in older adults. Targeted deprescribing of anticholinergic and sedative medications may improve health outcomes for frail older adults. Our pharmacist-led deprescribing intervention was a pragmatic 2-arm randomized controlled trial stratified by frailty. We compared usual care (control) with the intervention of pharmacists providing deprescribing recommendations to general practitioners. METHODS: Community-based older adults (≥65 years) from 2 New Zealand district health boards were recruited following a standardized interRAI needs assessment. The Drug Burden Index (DBI) was used to quantify the use of sedative and anticholinergic medications for each participant. The trial was stratified into low, medium, and high-frailty. We hypothesized that the intervention would increase the proportion of participants with a reduction in DBI ≥ 0.5 within 6 months. RESULTS: Of 363 participants, 21 (12.7%) in the control group and 21 (12.2%) in the intervention group had a reduction in DBI ≥ 0.5. The difference in the proportion of -0.4% (95% confidence interval [CI]: -7.9% to 7.0%) provided no evidence of efficacy for the intervention. Similarly, there was no evidence to suggest the effectiveness of this intervention for participants of any frailty level. CONCLUSION: Our pharmacist-led medication review of frail older participants did not reduce the anticholinergic/sedative load within 6 months. Coronavirus disease 2019 (COVID-19) lockdown measures required modification of the intervention. Subgroup analyses pre- and post-lockdown showed no impact on outcomes. Reviewing this and other deprescribing trials through the lens of implementation science may aid an understanding of the contextual determinants preventing or enabling successful deprescribing implementation strategies.

Machine learning with D-dimer in the risk stratification for pulmonary embolism: a derivation and internal validation study.

AIM: To develop a machine learning model to predict the diagnosis of pulmonary embolism (PE). METHODS AND RESULTS: We undertook a derivation and internal validation study to develop a risk prediction model for use in patients being investigated for possible PE. The machine learning technique, generalized logistic regression using elastic net, was chosen following an assessment of seven machine learning techniques and on the basis that it optimized the area under the receiver operator characteristic curve (AUC) and Brier score. Models were developed both with and without the addition of D-dimer. A total of 3347 patients were included in the study of whom, 219 (6.5%) had PE. Four clinical variables (O2 saturation, previous deep venous thrombosis or PE, immobilization or surgery, and alternative diagnosis equal or more likely than PE) plus D-dimer contributed to the machine learning models. The addition of D-dimer improved the AUC by 0.16 (95% confidence interval 0.13-0.19), from 0.73 to 0.89 (0.87-0.91) and decreased the Brier score by 14% (10-18%). More could be ruled out with a higher positive likelihood ratio than by the Wells score combined with D-dimer, revised Geneva score combined with D-dimer, or the Pulmonary Embolism Rule-out Criteria score. Machine learning with D-dimer maintained a low-false-negative rate at a true-negative rate of nearly 53%, which was better performance than any of the other alternatives. CONCLUSION: A machine learning model outperformed traditional risk scores for the risk stratification of PE in the emergency department. However, external validation is needed.

Deprescribing to reduce polypharmacy: study protocol for a randomised controlled trial assessing deprescribing of anticholinergic and sedative drugs in a cohort of frail older people living in the community.

BACKGROUND: Targeted deprescribing of anticholinergic and sedative medications in older people may improve their health outcomes. This trial will determine if pharmacist-led reviews lead to general practitioners deprescribing anticholinergic and sedative medications in older people living in the community. METHODS AND ANALYSIS: The standard protocol items: Recommendations for Interventional Trials (SPIRIT) checklist was used to develop and report the protocol. The trial will involve older adults stratified by frailty (low, medium, and high). This will be a pragmatic two-arm randomized controlled trial to test general practitioner uptake of pharmacist recommendations to deprescribe anticholinergic and sedative medications that are causing adverse side effects in patients. STUDY POPULATION: Community-dwelling frail adults, 65 years or older, living in the Canterbury region of New Zealand, seeking publicly funded home support services or admission to aged residential care and taking at least one anticholinergic or sedative medication regularly. INTERVENTION: New Zealand registered pharmacists using peer-reviewed deprescribing guidelines will visit participants at home in the community, review their medications, and recommend anticholinergic and sedative medications that could be deprescribed to the participant's general practitioner. The total use of anticholinergic and sedative medications will be quantified using the Drug Burden Index (DBI). OUTCOMES: The primary outcome will be the change in total DBI between baseline and 6-month follow-up. Secondary outcomes will include entry into aged residential care, prolonged hospitalization, and death. DATA COLLECTION POINTS: Data will be collected at the time of interRAI assessments (T0), at the time of the baseline review (T1), at 6 months following the baseline review (T2), and at the end of the study period, or end of study participation for participants admitted into aged residential care, or who died (T3). ETHICS AND DISSEMINATION: Ethical approval has been obtained from the Human, Disability and Ethics Committee: ethical number (17CEN265). TRIAL REGISTRATION: ClinicalTrials.gov ACTRN12618000729224 . Registered on May 2, 2018, with the Australian New Zealand Clinical Trials Registry.

Long-term outcomes in patients with pulmonary embolism: results from a longitudinal cohort study.

BACKGROUND: Patients with pulmonary embolism (PE) have increased mortality in short-term; however, long-term prognosis is not well defined. AIM: In this long-term cohort study, we aimed to determine if PE was associated with increased risk of mortality or serious clinical events (SCE). Secondary aims were to ascertain predictors of mortality and SCE. METHODS: Patients admitted with clinical suspicion of PE were prospectively recruited from July 2002 to May 2003 and followed up until March 2015. Clinical outcomes in patients with PE were compared to those without PE. SCE was defined as composite of mortality, malignancy, cardiovascular events, recurrent venous thromboembolism and chronic thromboembolic pulmonary hypertension. RESULTS: A total of 501 patients with median follow up of 11.9 years (interquartile range 3.91-12.28) was included. PE was diagnosed in 104 (20.7%) patients. Overall, 45.9% died and 57.1% developed SCE during follow up, with no significant difference in PE and no-PE groups (both P > 0.5). Major determinants of mortality were age (hazard ratio (HR) 1.06 per year, 95% confidence interval (CI) 1.05-1.08), malignancy (HR 2.19, 95% CI 1.64-2.91) and congestive heart failure (HR 1.72, 95% CI 1.23-2.42). Factors associated with increased risk of SCE were age (HR 1.05 per year, 95% CI 1.04-1.06), malignancy (HR 1.93, 95% CI 1.48-2.52) and congestive heart failure (HR 1.77, 95% CI 1.29-2.43). In patients without PE, elevated D-dimer concentration was not found to be associated with diagnosis of malignancy during follow up (HR 1.31, 95% CI 0.55-3.12). CONCLUSIONS: In this prospective study, we did not find association between PE and risk of all-cause mortality or SCE. Major determinants of poor clinical outcomes were advancing age and underlying comorbidities.

Effect of Capacity to Undertake Instrumental Activities of Daily Living on Entry to Aged Residential Care in Older People With Heart Failure.

Background: Heart failure is a common condition in older people with complex medical needs. A key factor in resilience after heart failure is the capacity to perform the instrumental activities of daily living (IADLs). Knowing the association between capacity to perform IADLs and entry into aged residential care will help health professionals plan interventions that will allow older people to remain independent longer. Methods: We analyzed the association between the capacity to perform eight IADLs and entry into ARC. Participants included New Zealanders aged ≥65 years with a diagnosis of heart failure, and who had an InterRAI 9.1 Home Care assessment between July 2012 and June 2018. A multivariable competing risks regression model for entry to ARC with death as the competing risks was used to establish sub-hazard ratios (SHR) for IADL capacity. Co-variates included demographic variables, co-morbidities, living arrangements, cognitive performance, depression, timed walk, alcohol use, smoking, activities of daily living, recent hospitalization and history of falls. Results: There were 13,220 participants with heart failure who were followed for a median 1.69 (0.70-3.17) years. There were 3,177 (24.0%) participants who entered aged residential care and 5,714 (43.2%) who died without having first entered residential care. Overall capacity to perform specific IADLs was "very poor" for housework (85.5%), shopping (68.0%), stairs (61.7%), meal preparation (53.0%), and transportation (52.2%). In the multivariable model, compared to adequate capacity (the reference) poorer capacity for managing finance, managing medications, meal preparation and transport were all associated with increased risk of entering aged residential care, with SHR from 1.05 to 1.18. Overall, the IADL capacity explained ~10% of the risk of entering aged residential care. Conclusion: Capacity to perform IADL is a key factor in maintaining resilience in older people with heart failure. Capacity to manage finances, transport and medications, prepare meals, and transport oneself with minimal supervision could reduce the risk of entry into aged residential care. Developing early interventions and support for people with poor capacity to perform their IADL may help reduce admission into aged residential care.

Neutrophil Gelatinase-Associated Lipocalin Measured on Clinical Laboratory Platforms for the Prediction of Acute Kidney Injury and the Associated Need for Dialysis Therapy: A Systematic Review and Meta-analysis.

RATIONALE & OBJECTIVE: The usefulness of measures of neutrophil gelatinase-associated lipocalin (NGAL) in urine or plasma obtained on clinical laboratory platforms for predicting acute kidney injury (AKI) and AKI requiring dialysis (AKI-D) has not been fully evaluated. We sought to quantitatively summarize published data to evaluate the value of urinary and plasma NGAL for kidney risk prediction. STUDY DESIGN: Literature-based meta-analysis and individual-study-data meta-analysis of diagnostic studies following PRISMA-IPD guidelines. SETTING & STUDY POPULATIONS: Studies of adults investigating AKI, severe AKI, and AKI-D in the setting of cardiac surgery, intensive care, or emergency department care using either urinary or plasma NGAL measured on clinical laboratory platforms. SELECTION CRITERIA FOR STUDIES: PubMed, Web of Science, Cochrane Library, Scopus, and congress abstracts ever published through February 2020 reporting diagnostic test studies of NGAL measured on clinical laboratory platforms to predict AKI. DATA EXTRACTION: Individual-study-data meta-analysis was accomplished by giving authors data specifications tailored to their studies and requesting standardized patient-level data analysis. ANALYTICAL APPROACH: Individual-study-data meta-analysis used a bivariate time-to-event model for interval-censored data from which discriminative ability (AUC) was characterized. NGAL cutoff concentrations at 95% sensitivity, 95% specificity, and optimal sensitivity and specificity were also estimated. Models incorporated as confounders the clinical setting and use versus nonuse of urine output as a criterion for AKI. A literature-based meta-analysis was also performed for all published studies including those for which the authors were unable to provide individual-study data analyses. RESULTS: We included 52 observational studies involving 13,040 patients. We analyzed 30 data sets for the individual-study-data meta-analysis. For AKI, severe AKI, and AKI-D, numbers of events were 837, 304, and 103 for analyses of urinary NGAL, respectively; these values were 705, 271, and 178 for analyses of plasma NGAL. Discriminative performance was similar in both meta-analyses. Individual-study-data meta-analysis AUCs for urinary NGAL were 0.75 (95% CI, 0.73-0.76) and 0.80 (95% CI, 0.79-0.81) for severe AKI and AKI-D, respectively; for plasma NGAL, the corresponding AUCs were 0.80 (95% CI, 0.79-0.81) and 0.86 (95% CI, 0.84-0.86). Cutoff concentrations at 95% specificity for urinary NGAL were>580ng/mL with 27% sensitivity for severe AKI and>589ng/mL with 24% sensitivity for AKI-D. Corresponding cutoffs for plasma NGAL were>364ng/mL with 44% sensitivity and>546ng/mL with 26% sensitivity, respectively. LIMITATIONS: Practice variability in initiation of dialysis. Imperfect harmonization of data across studies. CONCLUSIONS: Urinary and plasma NGAL concentrations may identify patients at high risk for AKI in clinical research and practice. The cutoff concentrations reported in this study require prospective evaluation.

Gait Speed at Discharge and Risk for Readmission or Death: A Prospective Study of an Emergency Ward Population.

BACKGROUND: There has been a growing interest in measuring gait speed for assessing long-term mortality and risk for hospital readmission in different populations. OBJECTIVE: We studied the association between a 10-meter gait speed test at hospital discharge and the risk for 30- and 90-day hospital readmission or death in a mixed population of patients hospitalized for emergency care. PATIENTS AND METHODS: Patients were prospectively included from 5 wards at the Karolinska University Hospital. The 10-meter gait speed test was measured on the day of discharge. Statistical analysis was performed using logistic regression. RESULTS: A total of 344 patients were included. Forty-one patients (n=41) were readmitted to hospital or died within 30 days, and 81 were readmitted or died within 90 days after discharge. Readmitted patients were older and had more comorbidities. A 0.1 m/s reduction in gait speed was associated with a 13% greater odds of readmission or death within 30 days (OR 1.13 [95% CI 1.00-1.26]). The area under the receiver operating characteristic curve (AUC) was 0.59 (95% CI 0.51-0.68). The results were similar for 90-day readmission or death where a 0.1 m/s decrement in gait speed was associated with an OR of 1.13 (95% CI 1.04-1.24). When age, eGFR, hemoglobin concentration, and active cancer, which all were univariate predictors of 30-day readmissions, were added to the model it yielded an AUC of 0.68 (95% CI 0.60 to 0.77). CONCLUSION: In a mixed population of patients hospitalized for emergency care, low gait speed at discharge was associated with an increased risk of 30- and 90-day readmission or death. However, the test did not discriminate well between those who were readmitted or died and those who did not; therefore we do not recommend its use as a stand-alone test in this population.

Early acetaminophen-protein adducts predict hepatotoxicity following overdose (ATOM-5).

BACKGROUND & AIMS: Acetaminophen-protein adducts are specific biomarkers of toxic acetaminophen (paracetamol) metabolite exposure. In patients with hepatotoxicity (alanine aminotransferase [ALT] >1,000 U/L), an adduct concentration ≥1.0 nmol/ml is sensitive and specific for identifying cases secondary to acetaminophen. Our aim was to characterise acetaminophen-protein adduct concentrations in patients following acetaminophen overdose and determine if they predict toxicity. METHODS: We performed a multicentre prospective observational study, recruiting patients 14 years of age or older with acetaminophen overdose regardless of intent or formulation. Three serum samples were obtained within the first 24 h of presentation and analysed for acetaminophen-protein adducts. Acetaminophen-protein adduct concentrations were compared to ALT and other indicators of toxicity. RESULTS: Of the 240 patients who participated, 204 (85%) presented following acute ingestions, with a median ingested dose of 20 g (IQR 10-40), and 228 (95%) were treated with intravenous acetylcysteine at a median time of 6 h (IQR 3.5-10.5) post-ingestion. Thirty-six (15%) patients developed hepatotoxicity, of whom 22 had an ALT ≤1,000 U/L at the time of initial acetaminophen-protein adduct measurement. Those who developed hepatotoxicity had a higher initial acetaminophen-protein adduct concentration compared to those who did not, 1.63 nmol/ml (IQR 0.76-2.02, n = 22) vs. 0.26 nmol/ml (IQR 0.15-0.41; n = 204; p <0.0001), respectively. The AUROC for hepatotoxicity was 0.98 (95% CI 0.96-1.00; n = 226; p <0.0001) with acetaminophen-protein adduct concentration and 0.89 (95% CI 0.82-0.96; n = 219; p <0.0001) with ALT. An acetaminophen-protein adduct concentration of 0.58 nmol/ml was 100% sensitive and 91% specific for identifying patients with an initial ALT ≤1,000 U/L who would develop hepatotoxicity. Adding acetaminophen-protein adduct concentrations to risk prediction models improved prediction of hepatotoxicity to a level similar to that obtained by more complex models. CONCLUSION: Acetaminophen-protein adduct concentration on presentation predicted which patients with acetaminophen overdose subsequently developed hepatotoxicity, regardless of time of ingestion. An adduct threshold of 0.58 nmol/L was required for optimal prediction. LAY SUMMARY: Acetaminophen poisoning is one of the most common causes of liver injury. This study examined a new biomarker of acetaminophen toxicity, which measures the amount of toxic metabolite exposure called acetaminophen-protein adduct. We found that those who developed liver injury had a higher initial level of acetaminophen-protein adducts than those who did not. CLINICAL TRIAL REGISTRATION: Australian Toxicology Monitoring (ATOM) Study-Australian Paracetamol Project: ACTRN12612001240831 (ANZCTR) Date of registration: 23/11/2012.

Heart failure and the risk of acute kidney injury in relation to ejection fraction in patients undergoing coronary artery bypass grafting.

BACKGROUND: We studied the association between heart failure with reduced or preserved ejection fraction (EF) and the risk of acute kidney injury (AKI) in patients undergoing coronary artery bypass surgery (CABG). METHODS: We included all patients who underwent isolated CABG in Sweden 2003 to 2013. AKI was defined according to the Kidney Disease Improving Global Outcomes definition, as an increase in postoperative serum creatinine concentration by ≥26 µmol/L or ≥50%, compared to preoperative values. Adjusted odds ratios (OR) for AKI were calculated using logistic regression for patients with and without heart failure, and among patients with heart failure, by EF categories (<30% severely reduced; 30-40% moderately reduced; ≥50% preserved). RESULTS: Included were 36,403 patients of whom 3914 (11%) had heart failure. In patients with heart failure, 26% developed AKI compared with 14% in patients without heart failure. After adjustment for background characteristics, including preoperative kidney function and EF, the OR for AKI was 1.12 (95% CI 1.02-1.23) in patients with heart failure compared with no heart failure. Among patients with heart failure, the adjusted OR for AKI among patients with EF <30% vs. ≥50% was 1.32 (95% CI 1.06-1.65) and for 30-49% vs. ≥50% 1.06 (95% CI 0.87-1.28), respectively. CONCLUSION: Patients with heart failure who underwent CABG had an increased risk for AKI postoperatively even after adjustment for comorbidity such as EF. Among patients with heart failure, having a severely reduced EF was associated with AKI compared to patents with preserved EF.

Combining Novel Renal Injury Markers with Delta Serum Creatinine Early after Cardiac Surgery and Risk-Stratification for Serious Adverse Outcomes: An Exploratory Analysis.

OBJECTIVE: To evaluate the prognostic utility of multiple novel urinary biomarkers of renal injury when used alone, in pair-wise combination with an early delta serum creatinine (ΔSCr) term, and combined as a broad biomarker panel for the prediction of serious adverse outcomes that may reflect AKI in patients undergoing cardiac surgery. DESIGN: Post-hoc analysis of prospective observational study. SETTING: Academic medical center. PARTICIPANTS: 603 adults undergoing cardiac surgery. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Urinary cystatin-c, kidney injury molecule-1, chemokine (C-C motif) ligand 2 and interleukin-18 were measured at baseline and <1 hour, 3 hours and 18-24 hours after separation from cardiopulmonary bypass (CPB). ΔSCr-initial was defined as the difference in SCr from baseline to first postoperative measure. The primary outcome of hospital mortality or renal replacement therapy occurred in 25 patients. Concordant elevation of any urinary biomarker measured 3 hours after CPB together with ΔSCr-initial ≥0 mg.dL-1 provided excellent early risk stratification for the primary outcome (OR ≥15.1, 95% CI 4.1-55.4). Combining four urinary biomarkers together with ΔSCr-initial and neutrophil gelatinase-associated lipocalin, previously reported from the same cohort, to provide a 6-point AKI risk score enabled early identification of patients reaching the primary outcome (ROCAUC 0.86, 95% CI 0.79-0.92) with potentially useful sensitivity and specificity at varied cut-points. CONCLUSIONS: Combining novel urinary biomarkers of renal injury with a creatinine-based metric soon after cardiac surgery provided excellent prognostic utility for serious adverse outcomes. Future studies are required to confirm these findings and determine optimal biomarker combinations for cost-effective risk stratification.

Nephrotoxicity-induced proteinuria increases biomarker diagnostic thresholds in acute kidney injury.

BACKGROUND: Paraquat ingestion is frequently fatal. While biomarkers of kidney damage increase during paraquat-induced acute kidney injury (AKI), significant concurrent proteinuria may alter diagnostic thresholds for diagnosis and prognosis to an unknown extent. This study evaluated the effect of albuminuria on biomarker cutoffs for diagnosis and outcome prediction. METHODS: This was a multi-centre prospective clinical study of patients following acute paraquat self-poisoning in 5 Sri Lankan hospitals. Biomarker concentrations were quantified using ELISA and microbead assays and correlated with urinary albumin. Functional-AKI was defined by the Acute Kidney Injury Network serum creatinine definition and alternatively by a ≥50% increase in serum cystatin C. Albuminuria was defined as albumin-creatinine ratio >30 mg/g. The study outcomes were compared with a retrospective analysis of a pre-clinical study of paraquat-induced nephrotoxicity with appropriate controls. RESULTS: Albuminuria was detected in 34 of 50 patients, and increased with functional-AKI severity. The concentrations of uNGAL, uCysC, uClusterin, uß2M, and uKIM-1 were higher in albuminuric compared to non-albuminuric patients (p < 0.001). Albuminuria correlated with biomarker concentration (r > 0.6, p < 0.01) and was associated with death (p = 0.006). Optimal biomarker cutoffs for prediction of death were higher in the albuminuric group. Similar outcomes with more detailed analysis were obtained in experimental paraquat nephrotoxicity. CONCLUSION: Albuminuria was associated with paraquat-induced nephrotoxicity and increased excretion of low-molecular weight protein biomarkers. AKI biomarker cutoffs for diagnosis, outcome prediction and AKI stratification increased in the presence of albuminuria. This may lead to over-diagnosis of AKI in conditions independently associated with proteinuria.

Dexamethasone Modifies Cystatin C-Based Diagnosis of Acute Kidney Injury During Cisplatin-Based Chemotherapy.

BACKGROUND/AIMS: Plasma cystatin C (pCysC) may be superior to serum creatinine (sCr) as a surrogate of GFR. However, the performance of pCysC for diagnosing acute kidney injury (AKI) after cisplatin-based chemotherapy is potentially affected by accompanying corticosteroid anti-emetic therapy and hydration. METHODS: In a prospective observational study pCysC, sCr, urinary kidney injury molecule-1 (KIM-1), and urinary clusterin were measured over 2 weeks in 27 patients given first-cycle chemotherapy. The same variables were measured over 2 weeks in Sprague-Dawley rats given a single intraperitoneal injection of dexamethasone, cisplatin, or both, and in controls. RESULTS: In patients, pCysC increases were greater than sCr 41% vs. 16%, mean paired difference 25% (95% CI: 16-34%)], relative increases were ≥ 50% in 9 patients (35%) for pCysC compared with 2 (8%) for sCr (p = 0.04) and increases in sCr were accompanied by increased KIM-1 and clusterin excretion, but increases in pCysC alone were not. In rats, dexamethasone administration produced dose-dependent increases in pCysC (and augmented cisplatin-induced increases in pCysC), but did not augment histological injury, increases in sCr, or KIM-1 and clusterin excretion. CONCLUSIONS: In the presence of dexamethasone, elevation of pCysC does not reliably diagnose AKI after cisplatin-based chemotherapy.

Neutrophil gelatinase-associated lipocalin (NGAL) fails as an early predictor of contrast induced nephropathy in chronic kidney disease (ANTI-CI-AKI study).

The aim of the study was to evaluate the diagnostic accuracy of urinary neutrophil gelatinase- associated lipocalin (uNGAL) in patients with chronic kidney disease (CKD) as an early biomarker for contrast induced acute kidney injury (CI-AKI) and to investigate whether patients with an uNGAL increase might benefit from an additional intravenous volume expansion with regard to CI-AKI-incidence. We performed a prospective randomized controlled trial in 617 CKD-patients undergoing intra-arterial angiography. Urinary NGAL was measured the day before and 4-6hrs after angiography. In the event of a significant rise of uNGAL patients were randomized either into Group A, who received intravenous saline post procedure or Group B, who did not receive post-procedural i.v. fluids. Ten patients (1.62%) exhibited a significant rise of uNGAL after angiography and were randomized of whom one developed a CI-AKI. In the entire cohort the incidence of CI-AKI was 9.4% (58 patients) resulting in a specificity of 98.4% (95% CI: 97.0-99.3%) and a sensitivity of 1.72% (95% CI: 0.044-9.2%) of uNGAL for the diagnosis of CI-AKI. In this study uNGAL failed to predict CI-AKI and was an inadequate triage tool to guide an early intervention strategy to prevent CI-AKI. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01292317.

Low Versus Standard Urine Output Targets in Patients Undergoing Major Abdominal Surgery: A Randomized Noninferiority Trial.

OBJECTIVE: To determine whether a low perioperative minimum urine output target is safe and fluid sparing when compared with the standard target. BACKGROUND: A minimum hourly urine output of 0.5 mL/kg is a key target guiding perioperative fluid therapy. Few data support this standard practice, which may contribute to perioperative fluid overloading. METHODS: We randomized patients without significant risk factors for acute kidney injury undergoing elective colectomy to a minimum urine output target of 0.2 mL/kg/h (low group) or 0.5 mL/kg/h (standard group) from induction of anesthesia until 8 AM 2 days after surgery. Maintenance fluids were standardized and additional fluids administered to achieve the targets. Primary outcome was noninferiority for urine neutrophil gelatinase-associated lipocalin on the day after surgery. RESULTS: Between November 21, 2011 and July 11, 2013, 40 participants completed the study. The low group received 3170 mL (95% confidence interval 2380-3960) intravenous fluids versus 5490 mL (95% confidence interval 4570-6410) in the standard group (P = 0.0004), and was noninferior for neutrophil gelatinase-associated lipocalin [14.7 µg/L (interquartile range 7.60-28.9) vs 18.4 µg/L (interquartile range 8.30-21.2); Pnoninferiority = 0.0011], serum cystatin C (Pnoninferiority < 0.0001), serum creatinine (Pnoninferiority = 0.0004), and measured glomerular filtration (Pnoninferiority = 0.0003). Effective renal plasma flow increased in both groups after surgery, and more in the standard group (Pnoninferiority = 0.125). CONCLUSIONS: A perioperative urine output target of 0.2 mL/kg/h is noninferior to the standard target of 0.5 mL/kg/h and results in a large intravenous fluid sparing. This target should be adopted in surgical patients without significant kidney injury risk factors.