Soluble ST2 predicts outcome and hemorrhagic transformation after acute stroke.

OBJECTIVE: ST2 is a member of the toll-like receptor superfamily that can alter inflammatory signaling of helper T-cells. We investigated whether soluble ST2 (sST2) could independently predict outcome and hemorrhagic transformation (HT) in the setting of stroke. METHODS: We measured sST2 in patients enrolled in the Specialized Program of Translational Research in Acute Stroke (SPOTRIAS) network biomarker study. 646 patients had plasma samples collected at the time of hospital admission and 210 patients had a second sample collected 48 h after stroke onset. Functional outcome was assessed using the modified Rankin Scale (mRS), with good and poor outcomes defined as mRS 0-2 and 3-6, respectively. HT was classified using ECASS criteria. The relationships between sST2, outcome, and HT were evaluated using multivariable logistic regression, Kaplan-Meier survival analysis and receiver operating characteristic curves. RESULTS: 646 patients were included in the analysis (mean age 69 years; 44% women), with a median NIHSS of 5 [IQR: 2-12]. The median sST2 level on hospital admission was 35.0 ng/mL [IQR: 25.7-49.8 ng/mL] and at 48 h it was 37.4 ng/mL [IQR 27.9-55.6 ng/mL]. sST2 was independently associated with poor outcome (OR: 2.77, 95% CI: 1.54-5.06; P = 0.003) and mortality (OR: 3.56, 95% CI: 1.58-8.38, P = 0.001) after multivariable adjustment. Plasma sST2 was also associated with hemorrhagic transformation after adjustment for traditional risk factors (OR: 5.58, 95% CI: 1.40-37.44, P = 0.039). INTERPRETATION: Soluble ST2 may serve as a prognostic biomarker for outcome and hemorrhagic transformation in patients with acute stroke. ST2 may link neuroinflammation and secondary injury after stroke.

Markers of diuretic resistance in emergency department patients with acute heart failure.

BACKGROUND: Loop diuretics are common therapy for emergency department (ED) patients with acute heart failure (AHF). Diuretic resistance (DR) is a term used to describe blunted natriuretic response to loop diuretics. It would be important to detect DR prior to it becoming clinically apparent, so early interventions can be initiated. However, several definitions have been proposed, and it is not clear if they identify similar patients. We compared these definitions and described the clinical characteristics of patients who fulfilled them. METHODS: To qualify for this secondary analysis of 1033 ED patients with AHF, all patients needed to receive intravenous diuretics in the ED and have urine available within 24 h of their ED evaluation. A poor diuretic response, suggesting DR, was characterized by (1) a fractional sodium excretion (FeNa) of less than 0.2%; (2) spot urinary sodium of less than 50 meq/L; and (3) a urinary Na/K ratio <1.0. McNemar's test was used to compare the different cohorts identified by the three definitions. Secondary analyses evaluated associations between each DR definition and hospital length of stay (LOS), ED revisits and rehospitalizations for AHF, and mortality using the Wilcoxon rank-sum tests and linear regression or Pearson chi-square test and logistic regression, as appropriate. RESULTS: The median age of the 187 patients was 64, and 50% were African-American. There were 5.9% of patients with a FeNa less than 0.2%, 17.1% had urinary sodium less than 50 meq/L, and 10.7% had a urinary Na/K ratio <1.0. The three definitions identified significantly different patients with very little overlap (p < 0.02 for all comparisons). There were 37 (19.8%) patients who were readmitted to the ED or hospital or died within 30 days of ED evaluation. Patients with spot urinary sodium less than 50 meq/L were more likely to be readmitted (p = 0.03). CONCLUSIONS: The patient proportion with poor natriuresis and DR varies depending on the definition used. Early ED therapy would be impacted at different rates if clinical decisions are made based on these definitions. These findings need to be further explored in a prospective ED-based study. TRIAL REGISTRATION: ClinicalTrials.gov, NCT00508638.

Apolipoprotein A-I and Paraoxonase-1 Are Potential Blood Biomarkers for Ischemic Stroke Diagnosis.

BACKGROUND: Blood biomarkers for ischemic and hemorrhagic stroke diagnosis remain elusive. Recent investigations suggested that apolipoprotein (Apo), matrix metalloproteinase (MMP), and paraoxonase-1 may be associated with stroke. We hypothesized that Apo A-I, Apo C-I, Apo C-III, MMP-3, MMP-9, and paraoxonase-1 are differentially expressed in ischemic stroke, hemorrhagic stroke, and controls. METHODS: In a single-center prospective observational study, consecutive stroke cases were enrolled if blood samples were obtainable within 12 hours of symptom onset. Age- (±5 years), race-, and sex-matched controls were recruited. Multiplex assays were used to measure protein levels. The Wilcoxon signed-rank test and the Mann-Whitney U-test were used to compare biomarker values between ischemic stroke patients and controls, hemorrhagic stroke patients and controls, and ischemic and hemorrhagic stroke patients. The 95% confidence intervals (CIs) for the difference of 2 medians were calculated. RESULTS: Fourteen ischemic stroke case-control pairs and 23 intracerebral hemorrhage (ICH) case-control pairs were enrolled. Median Apo A-I levels were lower in ischemic stroke cases versus controls (140 mg/dL versus 175 mg/dL, difference of 35 mg/dL, 95% CI -54 to -16) and in ischemic stroke versus ICH cases (140 mg/dL versus 180 mg/dL, difference of 40 mg/dL, 95% CI -57 to -23). Median paraoxonase-1 was lower in ischemic stroke cases than in both ICH cases and matched controls. Median Apo C-I was slightly lower in ischemic stroke cases than in ICH cases. There were no differences between groups for MMP-3, MMP-9, and Apo C-III. CONCLUSION: Apo A-I and paraoxonase-1 levels may be clinically useful for ischemic stroke diagnosis and for differentiating between ischemic and hemorrhagic strokes.

Prevalence of Diagnosed and Undiagnosed Hepatitis C in a Midwestern Urban Emergency Department.

BACKGROUND: Targeted hepatitis C virus (HCV) screening is recommended. Implementation of screening in emergency department (ED) settings is challenging and controversial. Understanding HCV epidemiology in EDs could motivate and guide screening efforts. We characterized the prevalence of diagnosed and undiagnosed HCV in a Midwestern, urban ED. METHODS: This was a cross-sectional seroprevalence study using de-identified blood samples and self-reported health information obtained from consecutively approached ED patients aged 18-64 years. Subjects consented to a "study of diseases of public health importance" and were compensated for participation. The Biochain ELISA kit for Human Hepatitis C Virus was used for antibody assay. Viral RNA was isolated using the Qiagen QIAamp UltraSens Virus kit, followed by real-time reverse transcription polymerase chain reaction using a Bio-Rad CFX96 SYBR Green UltraFast program with melt-curve analysis. RESULTS: HCV antibody was detected in 128 of 924 (14%; 95% confidence interval [CI], 12%-16%) samples. Of these, 44 (34%) self-reported a history of HCV or hepatitis of unknown type and 103 (81%; 95% CI, 73%-87%) were RNA positive. Two additional patients were antibody negative but RNA positive. Fully implemented birth cohort screening for HCV antibody would have missed 36 of 128 (28%) of cases with detectable antibody and 26 of 105 (25%) of those with replicative HCV infection. CONCLUSIONS: HCV infection is highly prevalent in EDs. Emergency departments are likely to be uniquely important for HCV screening, and logistical challenges to ED screening should be overcome. Birth cohort screening would have missed many patients, suggesting the need for complementary screening strategies applied to an expanded age range.

Identification of Emergency Department Patients With Acute Heart Failure at Low Risk for 30-Day Adverse Events: The STRATIFY Decision Tool.

OBJECTIVES: No prospectively derived or validated decision tools identify emergency department (ED) patients with acute heart failure (AHF) at low risk for 30-day adverse events who are thus potential candidates for safe ED discharge. This study sought to accomplish that goal. BACKGROUND: The nearly 1 million annual ED visits for AHF are associated with high proportions of admissions and consume significant resources. METHODS: We prospectively enrolled 1,033 patients diagnosed with AHF in the ED from 4 hospitals between July 20, 2007, and February 4, 2011. We used an ordinal outcome hierarchy, defined as the incidence of the most severe adverse event within 30 days of ED evaluation (acute coronary syndrome, coronary revascularization, emergent dialysis, intubation, mechanical cardiac support, cardiopulmonary resuscitation, and death). RESULTS: Of 1,033 patients enrolled, 126 (12%) experienced at least one 30-day adverse event. The decision tool had a C statistic of 0.68 (95% confidence interval: 0.63 to 0.74). Elevated troponin (p < 0.001) and renal function (p = 0.01) were significant predictors of adverse events in our multivariable model, whereas B-type natriuretic peptide (p = 0.09), tachypnea (p = 0.09), and patients undergoing dialysis (p = 0.07) trended toward significance. At risk thresholds of 1%, 3%, and 5%, we found 0%, 1.4%, and 13.0% patients were at low risk, with negative predictive values of 100%, 96%, and 93%, respectively. CONCLUSIONS: The STRATIFY decision tool identifies ED patients with AHF who are at low risk for 30-day adverse events and may be candidates for safe ED discharge. After external testing, and perhaps when used as part of a shared decision-making strategy, it may significantly affect disposition strategies. (Improving Heart Failure Risk Stratification in the ED [STRATIFY]; NCT00508638).

Prevalence of undiagnosed acute and chronic HIV in a lower-prevalence urban emergency department.

OBJECTIVES: We estimated the seroprevalence of both acute and chronic HIV infection by using a random sample of emergency department (ED) patients from a region of the United States with low-to-moderate HIV prevalence. METHODS: This cross-sectional seroprevalence study consecutively enrolled patients aged 18 to 64 years within randomly selected sampling blocks in a Midwestern urban ED in a region of lower HIV prevalence in 2008 to 2009. Participants were compensated for providing a blood sample and health information. After de-identification, we assayed samples for HIV antibody and nucleic acid. RESULTS: There were 926 participants who consented and enrolled. Overall, prevalence of undiagnosed HIV was 0.76% (95% confidence interval [CI] = 0.30%, 1.56%). Three participants (0.32%; 95% CI = 0.09%, 0.86%) were nucleic acid-positive but antibody-negative and 4 (0.43%; 95% CI = 0.15%, 1.02%) were antibody-positive. CONCLUSIONS: Even when the absolute prevalence is low, a considerable proportion of undetected HIV cases in an ED population are acute. Identification of acute HIV in ED settings should receive increased priority.

Randomized comparison of universal and targeted HIV screening in the emergency department.

OBJECTIVE: Universal HIV screening is recommended but challenging to implement. Selectively targeting those at risk is thought to miss cases, but previous studies are limited by narrow risk criteria, incomplete implementation, and absence of direct comparisons. We hypothesized that targeted HIV screening, when fully implemented and using maximally broad risk criteria, could detect nearly as many cases as universal screening with many fewer tests. METHODS: This single-center cluster-randomized trial compared universal and targeted patient selection for HIV screening in a lower prevalence urban emergency department. Patients were excluded for age (<18 and >64 years), known HIV infection, or previous approach for HIV testing that day. Targeted screening was offered for any risk indicator identified from charts, staff referral, or self-disclosure. Universal screening was offered regardless of risk. Baseline seroprevalence was estimated from consecutive deidentified blood samples. RESULTS: There were 9572 eligible visits during which the patient was approached. For universal screening, 40.8% (1915/4692) consented with 6 being newly diagnosed [0.31%, 95% confidence interval (CI): 0.13% to 0.65%]. For targeted screening, 37% (1813/4880) had no testing indication. Of the 3067 remaining, 47.4% (1454) consented with 3 being newly diagnosed (0.22%, 95% CI: 0.06% to 0.55%). Estimated seroprevalence was 0.36% (95% CI: 0.16% to 0.70%). Targeted screening had a higher proportion consenting (47.4% vs. 40.8%, P < 0.002), but a lower proportion of ED encounters with testing (29.7% vs. 40.7%, P < 0.002). CONCLUSIONS: Targeted screening, even when fully implemented with maximally permissive selection, offered no important increase in positivity rate or decrease in tests performed. Universal screening diagnosed more cases, because more were tested, despite a modestly lower consent rate.

Risk stratification in acute heart failure: rationale and design of the STRATIFY and DECIDE studies.

BACKGROUND: A critical challenge for physicians facing patients presenting with signs and symptoms of acute heart failure (AHF) is how and where to best manage them. Currently, most patients evaluated for AHF are admitted to the hospital, yet not all warrant inpatient care. Up to 50% of admissions could be potentially avoided and many admitted patients could be discharged after a short period of observation and treatment. Methods for identifying patients that can be sent home early are lacking. Improving the physician's ability to identify and safely manage low-risk patients is essential to avoiding unnecessary use of hospital beds. METHODS: Two studies (STRATIFY and DECIDE) have been funded by the National Heart Lung and Blood Institute with the goal of developing prediction rules to facilitate early decision making in AHF. Using prospectively gathered evaluation and treatment data from the acute setting (STRATIFY) and early inpatient stay (DECIDE), rules will be generated to predict risk for death and serious complications. Subsequent studies will be designed to test the external validity, utility, generalizability and cost-effectiveness of these prediction rules in different acute care environments representing racially and socioeconomically diverse patient populations. RESULTS: A major innovation is prediction of 5-day as well as 30-day outcomes, overcoming the limitation that 30-day outcomes are highly dependent on unpredictable, post-visit patient and provider behavior. A novel aspect of the proposed project is the use of a comprehensive cardiology review to correctly assign post-treatment outcomes to the acute presentation. CONCLUSIONS: Finally, a rigorous analysis plan has been developed to construct the prediction rules that will maximally extract both the statistical and clinical properties of every data element. Upon completion of this study we will subsequently externally test the prediction rules in a heterogeneous patient cohort.

Galectin 3 complements BNP in risk stratification in acute heart failure.

BACKGROUND: Galectin 3 (G3) is a mediator of fibrosis and remodeling in heart failure. METHODS: Patients diagnosed with and treated for Acute Heart Failure Syndromes were prospectively enrolled in the Decision Making in Acute Decompensated Heart Failure multicenter trial. RESULTS: Patients with a higher G3 had a history of renal disease, a lower heart rate and acute kidney injury. They also tended to have a history of HF and 30-day adverse events compared with B-type natriuretic peptide. CONCLUSION: In Acute Heart Failure Syndromes, G3 levels do not provide prognostic value, but when used complementary to B-type natriuretic peptide, G3 is associated with renal dysfunction and may predict 30-day events.

Elevated urinary neutrophil gelatinase-associated lipocalcin after acute heart failure treatment is associated with worsening renal function and adverse events.

AIMS: Reliable detectors of worsening renal function (WRF) in Emergency Department (ED) patients with acute heart failure (AHF) are limited. We hypothesized that initial urinary neutrophil gelatinase-associated lipocalcin (NGAL) levels, and changes in urinary NGAL levels after initial ED AHF therapy, would be associated with WRF and adverse events. METHODS AND RESULTS: Urinary NGAL upon ED presentation and 12-24 h after ED treatment was measured in a cohort of ED patients with AHF. NGAL was corrected for urinary creatinine (uCr). WRF was defined as RIFLE stages 1, 2, or 3, or a creatinine increase of ≥0.3 mg/dL. Patients were prospectively followed for 5- and 30-day adverse cardiovascular events. The 399 patients had a median age of 63 years, 50% were Caucasian, and 62% were male. Those with WRF at 72-96 h were more likely to have a higher initial NGAL value (71 vs. 32 ng NGAL/mg uCr) (P = 0.005), and a higher NGAL level at 12-24 h after ED therapy (107 vs. 25ng NGAL/mg uCr, P < 0.001). In a multivariable model, NGAL at 12-24 h remained a significant predictor of WRF (P = 0.012). Of all variables available 12-24 h after initial therapy, the only significant predictor of 30-day events was an elevated urinary NGAL level (P = 0.02). CONCLUSIONS: Urinary NGAL levels determined 12-24 h after ED therapy are significantly associated with both WRF at 72-96 h and 30-day adverse events. This suggests that early management strategies may have an impact on subsequent WRF and outcomes. If confirmed, NGAL may have a role for guiding therapeutic decisions.

Biomarker changes during acute heart failure treatment.

Biomarker changes may provide physicians with objective evidence of treatment efficacy in patients with acute decompensated heart failure (ADHF) and facilitate early hospital discharge. The authors hypothesize that mid-regional-pro-adrenomedullin (MR-proADM), C-terminal-pro-endothelin-1 (CT-pro-ET-1), and mid-regional-pro-atrial natriuretic peptide (MR-proANP) change during the first 24 hours of ADHF therapy. Eligible patients had an emergency department diagnosis of ADHF and fulfilled modified Framingham criteria. Clinical data, serum, and plasma values were collected at enrollment, 2 to 4 hours, and 12 to 24 hours after treatment. Changes in biomarker concentrations from baseline to 2 to 4 hours, baseline to 12 to 24 hours, and 2 to 4 to 12 to 24 hours were calculated. Fisher exact and Kruskal-Wallis tests were used for comparisons. Forty-eight patients were included. The median age was 62 years (range 40-88), 54% were men and 50% were white. More patients had changes in MR-pro-ANP levels in the first 2 to 4 hours after ADHF therapy compared with MR-proADM or CT-pro-ET-1 (36% vs 16% and 24%). However, 12 to 24 hours after therapy, similar proportions of patients had changes in MR-proANP, MR-proADM, and CT-proET-1 levels (47%, 41%, and 49%). In this preliminary study, patients with ADHF had measurable changes in MR-proANP, MR-proADM, and CT-pro-ET-1 24 hours after initial therapy. A study of association with clinical course and outcomes to determine the role of these markers in risk-stratification is warranted.

Long-term stability of recombinant tissue plasminogen activator at -80 C.

BACKGROUND: Recombinant tissue plasminogen activator (tPA) is a thrombolytic widely used clinically in the treatment of acute thrombotic disease such as ischemic stroke, myocardial infarction, and deep venous thrombosis. This has led to much interest in tPA based lytic therapies leading to laboratory based in-vitro and in-vivo investigations using this drug. However, tPA reconstituted in solution exhibits full activity for only 6-8 hours, according to the manufacturer. Therefore, methods to store reconstituted tPA for long durations while maintaining activity would be of assistance to laboratories using this enzyme. FINDINGS: In this work, the enzymatic activity of tPA stored at -80 C over time was measured, using an ELISA technique that measured the amount of active tPA bound to plasminogen activator inhibitor 1 (PAI-1) in a given sample. Sample of tPA solution mixed to a concentration of 1 (mg/ml) were stored in cryogenic vials at -80 C for up to 7 years. For a given sample, aliquots were assayed for tPA activity, and compared with a tPA standard to determine relative enzymatic activity. Results are reported as means with standard errors, and 12 measurements were performed for each sample age. CONCLUSION: There was no decrease in tPA activity for samples stored up to 7 years. Such cryogenic storage is a viable method for the preservation of tPA solution for laboratory investigations of tPA-based lytic therapies.