Colleen Shortt

Plasma IL-6 and IL-10 Concentrations Predict AKI and Long-Term Mortality in Adults after Cardiac Surgery

Inflammation has an integral role in the pathophysiology of AKI. We investigated the associations of two biomarkers of inflammation, plasma IL-6 and IL-10, with AKI and mortality in adults undergoing cardiac surgery. Patients were enrolled at six academic centers (n = 960). AKI was defined as a ≥ 50% or ≥ 0.3-mg/dl increase in serum creatinine from baseline. Pre- and postoperative IL-6 and IL-10 concentrations were categorized into tertiles and evaluated for associations with outcomes of in-hospital AKI or postdischarge all-cause mortality at a median of 3 years after surgery. Preoperative concentrations of IL-6 and IL-10 were not significantly associated with AKI or mortality. Elevated first postoperative IL-6 concentration was significantly associated with higher risk of AKI, and the risk increased in a dose-dependent manner (second tertile adjusted odds ratio [OR], 1.61 [95% confidence interval (95% CI), 1.10 to 2.36]; third tertile adjusted OR, 2.13 [95% CI, 1.45 to 3.13]). First postoperative IL-6 concentration was not associated with risk of mortality; however, the second tertile of peak IL-6 concentration was significantly associated with lower risk of mortality (adjusted hazard ratio, 0.75 [95% CI, 0.57 to 0.99]). Elevated first postoperative IL-10 concentration was significantly associated with higher risk of AKI (adjusted OR, 1.57 [95% CI, 1.04 to 2.38]) and lower risk of mortality (adjusted HR, 0.72 [95% CI, 0.56 to 0.93]). There was a significant interaction between the concentration of neutrophil gelatinase-associated lipocalin, an established AKI biomarker, and the association of IL-10 concentration with mortality (P = 0.01). These findings suggest plasma IL-6 and IL-10 may serve as biomarkers for perioperative outcomes.

Ninety-Minute vs 3-h Performance of High-Sensitivity Cardiac Troponin Assays for Predicting Hospitalization for Acute Coronary Syndrome

To the Editor: In patients undergoing transcoronary ablation for septal hypertrophy, concentrations of high-sensitivity cardiac troponin T(hs-cTnT)1 increase within 15 min of the procedure (1). If this situation translates to patients who present with chest discomfort who are suffering an acute myocardial infarction (AMI), hs-cTnT probed at time zero and at least 3 h later should be adequate to diagnose or exclude AMI (2, 3). Moreover, the kinetics shown in those with septal ablation suggest that an even earlier evaluation might be possible for clinical decision-making (1, 2). To assess the usefulness of early troponin measurements, we assessed the performance of hs-cTnT and hs-cTnI at 90 min and 3 h for predicting hospitalization for acute coronary syndrome (ACS) in patients presenting to the emergency department (ED) within 6 h of chest pain onset. This study included patients enrolled in the RING study (Reducing the time Interval for identifying New Guideline defined MI in patients with suspected ACS in the ED; research ethics board approved) (4) who had EDTA plasma frozen (−80 °C) at presentation (baseline), 90 min, and 3 h (n = 130 patients). Inclusion criteria were: ≥18 years old with onset of ACS symptoms in the past 6 h, blood sample collection ordered by the ED physician for cardiac troponin measurement, informed consent obtained, and availability for telephone follow-up. …

Rule-In and Rule-Out of Myocardial Infarction Using Cardiac Troponin and Glycemic Biomarkers in Patients with Symptoms Suggestive of Acute Coronary Syndrome

BACKGROUND Early rule-in/rule-out of myocardial infarction (MI) in patients presenting to the emergency department (ED) is important for patient care and resource allocation. Given that dysglycemia is a strong risk factor for MI, we sought to explore and compare different combinations of cardiac troponin (cTn) cutoffs with glycemic markers for the early rule-in/rule-out of MI. METHODS We included ED patients (n = 1137) with symptoms suggestive of acute coronary syndrome (ACS) who had cTnI, high-sensitivity cTnI (hs-cTnI), hs-cTnT, glucose, and hemoglobin A1c (Hb A1c) measurements. We derived rule-in/rule-out algorithms using different combinations of ROC-derived and literature cutoffs for rule-in and rule-out of MI within 7 days after presentation. These algorithms were then tested for MI/cardiovascular death and ACS/cardiovascular death at 7 days. ROC curves, sensitivity, specificity, likelihood ratios, positive and negative predictive values (PPV and NPV), and CIs were determined for various biomarker combinations. RESULTS MI was diagnosed in 133 patients (11.7%; 95% CI, 9.8-13.8). The algorithms that included cTn and glucose produced the greatest number of patients ruled out/ruled in for MI and yielded sensitivity ≥99%, NPV ≥99.5%, specificity ≥99%, and PPV ≥80%. This diagnostic performance was maintained for MI/cardiovascular death but not for ACS/cardiovascular death. The addition of hemoglobin A1c (Hb A1c) (≥6.5%) to these algorithms did not change these estimates; however, 50 patients with previously unknown diabetes may have been identified if Hb A1c was measured. CONCLUSIONS Algorithms incorporating glucose with cTn may lead to an earlier MI diagnosis and rule-out for MI/cardiovascular death. Addition of Hb A1c into these algorithms allows for identification of diabetes. Future studies extending these findings are needed for ACS/cardiovascular death. ClinicalTrials.gov identifier: NCT01994577.

Cardiac Biomarkers and Acute Kidney Injury After Cardiac Surgery

OBJECTIVES: To examine the relationship of cardiac biomarkers with postoperative acute kidney injury (AKI) among pediatric patients undergoing cardiac surgery. METHODS: Data from TRIBE-AKI, a prospective study of children undergoing cardiac surgery, were used to examine the association of cardiac biomarkers (N-type pro–B-type natriuretic peptide, creatine kinase-MB [CK-MB], heart-type fatty acid binding protein [h-FABP], and troponins I and T) with the development of postoperative AKI. Cardiac biomarkers were collected before and 0 to 6 hours after surgery. AKI was defined as a ≥50% or 0.3 mg/dL increase in serum creatinine, within 7 days of surgery. RESULTS: Of the 106 patients included in this study, 55 (52%) developed AKI after cardiac surgery. Patients who developed AKI had higher median levels of pre- and postoperative cardiac biomarkers compared with patients without AKI (all P < .01). Preoperatively, higher levels of CK-MB and h-FABP were associated with increased odds of developing AKI (CK-MB: adjusted odds ratio 4.58, 95% confidence interval [CI] 1.56–13.41; h-FABP: adjusted odds ratio 2.76, 95% CI 1.27–6.03). When combined with clinical models, both preoperative CK-MB and h-FABP provided good discrimination (area under the curve 0.77, 95% CI 0.68–0.87, and 0.78, 95% CI 0.68–0.87, respectively) and improved reclassification indices. Cardiac biomarkers collected postoperatively did not significantly improve the prediction of AKI beyond clinical models. CONCLUSIONS: Preoperative CK-MB and h-FABP are associated with increased risk of postoperative AKI and provide good discrimination of patients who develop AKI. These biomarkers may be useful for risk stratifying patients undergoing cardiac surgery.

Analytical factors to consider when assessing a high-sensitivity cardiac troponin I assay compared to a contemporary assay in clinical studies☆

Analytical comparisons between high-sensitivity cardiac troponin assays versus their contemporary counterparts are important for education, interpretation and application of clinical study findings. As demonstrated by previous comparisons between high-sensitivity cardiac troponin T (hs-cTnT) and the 4th generation cTnT assay there was an absolute positive bias of approximately 20 ng/l at concentrations below 100 ng/l [1,2]. This is important information that highlights 2 issues: measurement for clinical care should be performed by only one assay to avoid misinterpretation and clinical outcome studies free of incorporation bias are needed for the new high-sensitivity assays as results and cutoffs may not be interchangeable. Both pre-analytical and analytical factors are important when assessing and interpreting study findings derived from various centres. For example, there are published reference intervals and clinical studies for the Architect high-sensitivity cardiac troponin I (hsTnI) assay, but there is limited published data regarding the analytical performance of this assay [3]. We assessed the analytical performance by conducting duplicate testing on clinical samples for the Architect cTnI assay with the hsTnI assay and performed stability testing for the hsTnI assay to further define variation due to storage and testing conditions. Briefly, over a period of 4 months, wemeasured both the cTnI and hsTnI assays in EDTA plasma of every cTnI order from the 3 adult emergency departments (EDs) in Hamilton, Ontario, Canada. For the hsTnI assay different lots of reagents and calibrators in reagent pack sizes of 100 and 500 test volumeswere used over this time frame.We performedDeming regression analysis for cTnI concentrations from the combined group as well as per individual hospital laboratory from 10 ng/l and higher (representing the lower analytical limit for the cTnI assay of 0.01 ug/l or 10 ng/l) and from concentrations 10–100 ng/l. Also, stability at 3 different concentrations made from EDTA plasma patient samples (low pool at 9 ng/l from 48 EDTA plasma samples, mid pool at 47 ng/l from 24 EDTA plasma samples, and high pool at 428 ng/l from 21 EDTA plasma samples) was assessed in duplicate at room temperature, 4 °C and −20 °C over 5 days (i.e., 5 thaws for pool kept at −20 °C). Analyses were performed via Analyse-it software and the study received Research Ethics Board approval. Deming regression analysis for 7381 paired measurable cTnI results from the 3 EDs (cTnI range = 10 to 61,510 ng/l) yielded the following equation: hsTnI = 1.30 (95%CI:1.20 to 1.39) × cTnI−37 (95%CI: −63 to−11); r = 0.95; p b 0.001. Performing the comparison per site indicated that a significant proportional biaswas evident between the hsTnI and cTnI assays amongst all 3 hospitals with only one hospital yielding a significant absolute bias (Site 2) (Fig. 1). Restricting the analysis to only those cTnI concentrations in the lower end range (n = 5509; range = 10 to 100 ng/l) yielded the following equation: hsTnI = 1.12

Perioperative heart-type fatty acid binding protein is associated with acute kidney injury after cardiac surgery

Acute Kidney Injury (AKI) is a common complication after cardiac surgery and is associated with worse outcomes. Since heart fatty acid binding protein (H-FABP) is a myocardial protein that detects cardiac injury, we sought to determine if plasma H-FABP was associated with AKI in the TRIBE-AKI cohort; a multi-center cohort of 1219 patients at high risk for AKI who underwent cardiac surgery. The primary outcomes of interest were any AKI (Acute Kidney Injury Network (AKIN) stage 1 or higher) and severe AKI (AKIN stage 2 or higher). The secondary outcome was long-term mortality after discharge. Patients who developed AKI had higher levels of H-FABP pre- and post-operatively than patients who did not have AKI. In analyses adjusted for known AKI risk factors, first post-operative log(H-FABP) was associated with severe AKI (adjusted OR 5.39 [95% CI, 2.87-10.11] per unit increase), while pre-operative log(H-FABP) was associated with any AKI (2.07 [1.48-2.89]) and mortality (1.67 [1.17-2.37]). These relationships persisted after adjustment for change in serum creatinine (for first postoperative log(H-FABP)) and biomarkers of cardiac and kidney injury, including brain natriuretic peptide, cardiac troponin-I, interleukin-18, liver fatty acid binding protein, kidney injury molecule-1, and neutrophil gelatinase associated lipocalin. Thus, peri-operative plasma H-FABP levels may be used for risk-stratification of AKI and mortality following cardiac surgery.

Economic Considerations of Early Rule-In/Rule-Out Algorithms for The Diagnosis of Myocardial Infarction in The Emergency Department Using Cardiac Troponin and Glycemic Biomarkers

BACKGROUND We have previously demonstrated the utility of a rule-in/rule-out strategy for myocardial infarction (MI) using glycemic biomarkers in combination with cardiac troponin in the emergency department (ED). Given that the cost of assessing patients with possible MI in the ED is increasing, we sought to compare the health services cost of our previously identified early rule-in/rule-out approaches for MI among patients who present to the ED with symptoms suggestive of acute coronary syndrome (ACS). METHODS We compared the cost differences between different rule-in/rule-out strategies for MI using presentation cardiac troponin I (cTnI), high-sensitivity cTnI (hs-cTnI), high-sensitivity cardiac troponin T (hs-cTnT), glucose, and/or hemoglobin A1c (Hb A1c) in 1137 ED patients (7-day MI n = 133) as per our previously defined algorithms and compared them with the European Society of Cardiology (ESC) 0-h algorithm-cutoffs. Costs associated with each decision model were obtained from site-specific sources (length of stay) and provincial sources (Ontario Case Costing Initiative). RESULTS Algorithms incorporating cardiac troponin and glucose for early rule-in/rule-out were the most cost effective and clinically safest methods (i.e., ≤1 MI missed) for early decision making, with hs-cTnI and glucose yielding lower costs compared to cTnI and glucose, despite the higher price for the hs-cTnI test. The addition of Hb A1c to the algorithms increased the cost of these algorithms but did not miss any additional patients with MI. Applying the ESC 0-h algorithm-cutoffs for hs-cTnI and hs-cTnT were the most costly. CONCLUSIONS Rule-in/rule-out algorithms incorporating presentation glucose with high-sensitivity cardiac troponin are the safest and most cost-effective options as compared to the ESC 0-h algorithm-cutoffs.

High-Sensitivity Cardiac Troponin Risk Cutoffs for Acute Cardiac Outcomes at Emergency Department Presentation

The optimal high-sensitivity cardiac troponin (hs-cTn) cutoffs for determining risk in patients who present with acute coronary syndrome symptoms are unknown. In 1137 emergency department patients we calculated adjusted relative risks for a composite outcome (myocardial infarction, unstable angina, heart failure, ventricular arrhythmia, or cardiovascular death) within 7 days for the presentation of hs-cTnT (Roche) and hs-cTnI (Abbott) assay concentrations on the basis of literature cutoffs. Patients with hs-cTn concentrations ≥ 14 ng/L had an adjusted relative risk of 4.9 for the composite outcome, with different hs-cTnT/hs-cTnI concentration ranges yielding higher risks. A common low-risk cutoff of 14 ng/L may be used for hs-cTn with higher cutoffs identifying high-risk patients.

A laboratory score at presentation to rule-out serious cardiac outcomes or death in patients presenting with symptoms suggestive of acute coronary syndrome

BACKGROUND We evaluated whether a low high-sensitivity cardiac troponin (hs-cTn) cutoff combined with glucose, red cell distribution width (RDW), and the estimated glomerular filtration rate (eGFR) can be used to rule-out a serious cardiac outcome or death in patients presenting with symptoms suggestive of acute coronary syndrome (ACS). METHODS This was a prospective observational emergency department (ED) study enrolling consecutive patients presenting with symptoms suggestive of ACS (ClinicalTrials.gov: NCT01994577). The primary outcome was a 7-day composite of myocardial infarction, unstable angina, decompensated congestive heart failure, serious ventricular cardiac arrhythmia, or death. A laboratory score combining glucose, RDW, eGFR with hs-cTnT (Roche) or hs-cTnI (Abbott) was compared to hs-cTn alone using the limit of detection (LoD; hs-cTnT<5ng/l/hs-cTnI<2ng/l) as the cutoff. A benchmark of >99% sensitivity was used to assess the laboratory panel with hs-cTn versus the LoD alone to identify low-risk patients suitable for discharge. RESULTS A total of 1095 patients (n=267 composite-outcomes) had measurements of glucose, RDW, eGFR, hs-cTnT, and hs-cTnI at presentation. Applying the hs-cTn LoD alone as the cutoff missed 5 composite-outcomes (sensitivity=98.1%), however the addition of the laboratory panel to the hs-cTn LoD increased the sensitivity to >99% with approximately 10% of the population identified as low-risk. The percentage of low-risk patients was increased to 15% (1 composite-outcome missed) when employing a low measurable hs-cTnI cutoff with the laboratory panel (laboratory score<2 points). CONCLUSION A laboratory score with hs-cTn may identify low-risk patients suitable for ED discharge at presentation.

Combining presentation high-sensitivity cardiac troponin I and glucose measurements to rule-out an acute myocardial infarction in patients presenting to emergency department with chest pain

BACKGROUND AND AIMS The use of high sensitivity troponin (hs-Tn) may enable early rule out of acute myocardial infarction (AMI) for patients presenting to the emergency department (ED) with chest pain. This study evaluated two approaches to the early rule out of AMI; a combination of a presentation hs-Tn <4ng/L and normal glucose at presentation (dual testing) and a presentation hs-Tn troponin below the limit of detection (LoD). METHODS We utilised prospectively collected data on adult patients presenting with suspected ACS in two EDs in Australia and New Zealand. Blood samples were taken on presentation and tested for glucose and high sensitivity troponin I. The primary endpoint was index AMI and the secondary endpoint was 30-day acute coronary syndrome (ACS). Sensitivity, specificity, positive and negative predictive values were used to assess the diagnostic accuracy of the dual testing and LoD approaches. RESULTS Of the 1412 participants, 182 (12.9%) had index AMI. The LoD and the dual testing approach were 100% sensitive for index AMI. The specificity of the dual testing approach (25.2%) was slightly higher than that of the LoD (20.4%). Sensitivity for ACS was similar for the two approaches (96.5% for dual testing and 98.1% for the LoD). CONCLUSIONS The dual testing and LoD approach identified all patients with index AMI and could be used to reduce the proportion of patients requiring lengthy assessment and inpatient admission. Further investigation is still required to rule out unstable angina pectoris in patients identified as low risk.