Jeffrey A. Kline

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https://hdl.handle.net/1805/6677

Facial Expression as a Diagnostic Tool for Pulmonary Embolism

Jeffrey Kline studies blood clots, the people they affect, and the providers who care for those people. His diagnostic research interests focus on human affect analysis, pretest probability, and novel breath-based instruments to reduce medical imaging. His human treatment research includes randomized trials of fibrinolysis and inhaled nitric oxide to reduce heart damage from blood clots in the lungs. He derived and validated a decision rule to help emergency physicians reduce unnecessary diagnostic tests for low-risk patients with symptoms of blood clots in the lungs.

Dr. Kline’s current work focuses on using the human face as a diagnostic instrument to further help doctors make informed decisions about diagnostic testing for blood clots. His laboratory work focuses on mechanisms and treatment of acute pulmonary hypertension from pulmonary embolism (PE), animal models of pulmonary embolism, and a nanoparticle-delivered enzyme, plasmin, to promote clot lysis without increasing risk. He helped set up an advanced hospital treatment program to treat patients with severe PE, and he also created and runs a clinic specifically to allow patients diagnosed with blood clots in the emergency department to treat themselves at home, rather than in the hospital.

Dr. Kline’s work using the human face as a diagnostic instrument is another example of how IUPUI’s faculty members are TRANSLATING their RESEARCH INTO PRACTICE.

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High Rate Of Right Ventricular Dysfunction After Negative Computed Tomographic Pulmonary Angiography
(American Thoracic Society, 2014-05) Kline, Jeffrey A.; Lahm, T; Russell, F
Background: Prior work found that 20% of patients with persistent dyspnea have right ventricular (RV) dysfunction. Many patients with suspected pulmonary embolism (PE) who have a negative CTPA have persistent yet unexplained dyspnea. We hypothesized that a substantial proportion of these patients have unrecognized RV dysfunction. We sought to estimate this proportion and develop criteria to predict RV dysfunction on echocardiography after CTPA negative for PE. Methods: This was a four-center, prospective study of patients with ≥one symptom or sign and ≥one risk factor for PE, and CTPA scan performed. To assess potential predictors of RV dysfunction, we recorded 82 clinical predictors in real time. These included clinical findings, 12-lead electrocardiography (ECG), exhaled volumetric CO2/O2, plasma D-dimer and fibrinogen measurements. Patients underwent echocardiography within one week. Isolated RV dysfunction was defined as normal LV function with either moderate-severe RV hypokinesis, or estimated RV systolic pressure >35 mmHg. To assess if RV dysfunction led to symptoms that prompted reevaluation, we compared the frequency of repeat CTPA within 90 days. CTPA scans were interpreted by two independent radiologists. Predictors of RV dysfunction were assessed using a univariate (P<0.1)-multivariate (P<0.05) statistical approach. Results: 647 patients were enrolled; 120 with CPTA positive for PE were excluded, and 97 were excluded because of lack of persistent dyspnea. Of the 430 remaining patients, 184 underwent echocardiography, which demonstrated isolated RV dysfunction in 34% (95% CI: 30-41%). 27% of patients with isolated RV dysfunction had repeat CTPA within 90 days, a significantly higher rate than in patients without echocardiography (4%, P=0.03, Chi Square) or a normal echocardiogram (5%, P=0.02). No repeat CTPA scan showed PE. Of 82 candidate predictors of examined, univariate analysis found only 6 significant: active malignancy, normal CTPA, right bundle branch block on ECG, T-wave inversion in V1-V2 on ECG, history of COPD, and fibrinogen concentration. Of these six, multivariate logistic regression analysis found only normal CTPA as a significant predictor of isolated RV dysfunction. Conclusion: Patients with persistent dyspnea who have a normal CTPA performed for suspected PE have a high rate of unexplained isolated RV dysfunction on echocardiography. These patients are more likely to have persistent symptoms leading to unnecessary repeat CTPA in the short term. These findings form the starting point for a screening protocol to select patients with negative CTPA scanning for formal echocardiography and specialist referral to evaluate for pulmonary hypertension or other treatable causes of RV dysfunction.
A soluble guanylate cyclase stimulator, BAY 41-8543, preserves pulmonary artery endothelial function in experimental pulmonary embolism
(European Respiratory Journal, 2013-09) Watts, John; Gellar, Michael; Fulkerson, Mary-Beth; Quach, Hugh; Kline, Jeffrey A.
Background: BAY 41-8543 reduces pulmonary vascular resistance and right ventricle injury in experimental PE. Objective: Test if BAY 41-8543 protects pulmonary artery (PA) endothelial function in PE. Methods: PE was induced (anesthetized, Sprague-Dawley rats, 25 µm polystyrene microspheres, 1.95 million/100g, IV) with BAY 41-8543 (50 ug/kg, IV) or solvent treatment. Controls had vehicle for microspheres. Rings isolated from primary PA branches (5hr. PE) were contracted (phenylephrine, 10-6M) and dilation was endothelium-dependent (acetylcholine, 10-7M – 10-5M) or with BAY 41-8543 (10-8M – 10-6M). Oxidant stress was assessed: PA tissue 4-hydroxynoneal (4-HNE) immunohistochemistry; plasma malondialdehyde (MDA). Other Control rings received red blood cell (RBC) lysate. Results: PE inhibited dilation to acetylcholine vs. Control (dose x group interaction p=0.001), while dilation to BAY 41-8543 was minimally changed. PE raised plasma hemoglobin (30-fold, p=0.003), 4-HNE stain and plasma MDA (2.2-fold, p=0.009). Treating PE rats with BAY 41-8543 reduced plasma hemoglobin, 4-HNE and MDA to levels not different from Control. Dilation to acetylcholine significantly improved in PE + BAY 41-8543 rats vs. PE (dose x group interaction p=0.04). Addition of RBC lysate to Control rings reduced dilation to acetylcholine, while BAY 41-8543 responses remained strong. Conclusion: PE caused PA endothelial dysfunction, elevated plasma hemoglobin and oxidant stress. Treating rats with BAY 41-8543 lowered plasma hemoglobin, oxidant stress and endothelial dysfunction in PE. Treating isolated rings with BAY 41-8543 bypassed endothelial dysfunction with PE or RBC lysate.
Effectiveness of the Chest Pain Choice decision aid in emergency department patients with low-risk chest pain: study protocol for a multicenter randomized trial
(BioMed Central, 2014) Anderson, Ryan T; Montori, Victor M; Shah, Nilay D; Ting, Henry H; Pencille, Laurie J; Demers, Michel; Kline, Jeffrey A.; Diercks, Deborah B; Hollander, Judd E; Torres, Carlos A; Schaffer, Jason T; Herrin, Jeph; Branda, Megan; Leblanc, Annie; Hess, Erik P
Background: Chest pain is the second most common reason patients visit emergency departments (EDs) and often results in very low-risk patients being admitted for prolonged observation and advanced cardiac testing. Shared decision-making, including educating patients regarding their 45-day risk for acute coronary syndrome (ACS) and management options, might safely decrease healthcare utilization. Methods/Design: This is a protocol for a multicenter practical patient-level randomized trial to compare an intervention group receiving a decision aid, Chest Pain Choice (CPC), to a control group receiving usual care. Adults presenting to five geographically and ethnically diverse EDs who are being considered for admission for observation and advanced cardiac testing will be eligible for enrollment. We will measure the effect of CPC on (1) patient knowledge regarding their 45-day risk for ACS and the available management options (primary outcome); (2) patient engagement in the decision-making process; (3) the degree of conflict patients experience related to feeling uninformed (decisional conflict); (4) patient and clinician satisfaction with the decision made; (5) the rate of major adverse cardiac events at 30 days; (6) the proportion of patients admitted for advanced cardiac testing; and (7) healthcare utilization. To assess these outcomes, we will administer patient and clinician surveys immediately after each clinical encounter, obtain video recordings of the patient-clinician discussion, administer a patient healthcare utilization diary, analyze hospital billing records, review the electronic medical record, and conduct telephone follow-up. Discussion: This multicenter trial will robustly assess the effectiveness of a decision aid on patient-centered outcomes, safety, and healthcare utilization in low-risk chest pain patients from a variety of geographically and ethnically diverse EDs. Trial registration: NCT01969240.
Urinary Metabolomic Analysis to Detect Changes After Intravenous, Non-ionic, Low Osmolar Iodinated Radiocontrast for Computerized Tomographic Imaging
(2014-03) Diercks, Deborah B; Owen, Kelly P; Tolstikov, Vladimir; Sutter, Mark E; Kline, Jeffrey A.
Contrast-induced nephropathy is a result of injury to the proximal tubules caused by oxidative stress and ischemia. Metabolomics is a novel technique that has been used to identify renal damage from drug toxicities. The objective of this study is to analyze the metabolic changes in the urine after dosing with intravenous (IV) contrast for computed tomograph (CT) of the chest Methods A convenience sample of patients undergoing a chest CT with IV contrast who had at least one of the following: age ≥50 years, diabetes, heart failure, chronic kidney disease, coronary artery disease, or diastolic blood pressure >90 mmHg -- were eligible for enrollment. Urine samples were collected prior to imaging and 4–6 hours post imaging. Samples underwent gas chromography/mass spectrometry profiling. We measured peak metabolite values and log transformed data. Paired T tests were calculated. We used significance analysis of microarrays (SAM) to determine the most significant metabolites. Results The cohort comprised 14 patients with matched samples; 9/14 (64.3) were males, and the median age was 61 years (IQR 50–68). A total of 158 metabolites were identified. Using SAM we identified 9 metabolites that were identified as significant using a delta of 1.6. Conclusion Changes in urinary metabolites are present soon after contrast administration. This change in urinary metabolites may be potential early identifiers of contrast-induced nephropathy and could identify patients at high-risk for developing this condition.
Identification of Reduced Circulating Haptoglobin Concentration as a Biomarker of the Severity of Pulmonary Embolism: A Nontargeted Proteomic Study
(2014-06) Insenser, Maria; Montes-Nieto, Rafael; Martinez-Garcia, M Ángeles; Durán, Elena Fernandez; Santiusta, Carmen; Gómez, Vicente; Kline, Jeffrey A.; Escobar-Morreale, Héctor F; Jiménez, David
Risk stratification of patients with pulmonary embolism (PE) may identify patients at high risk of early death who may benefit from more intensive surveillance or aggressive therapy. Nontargeted proteomics may identify biomarkers useful for the risk stratification of patients with acute symptomatic pulmonary embolism (PE). We studied 6 patients presenting with low-risk PE and 6 patients presenting with intermediate (n = 3) or high-risk (n = 3) PE. Two-dimensional difference gel electrophoresis was used to compare their plasma protein abundances. Candidate protein markers were identified by matrix assisted laser desorption ionization time-of-flight mass spectrometry. A panel of four biomarkers (haptoglobin, hemopexin, α2-macroglobulin, and Ig α1-chain C region) showed differences in plasma abundance among patients with acute symptomatic PE of different severity. Haptoglobin and hemopexin were decreased, whereas α2-macroglobulin and Ig α1-chain C region were increased, in patients with high or intermediate-risk PE compared with low-risk PE patient. In a separate clinical population consisting of 104 adults with acute PE, serum haptoglobin concentrations had an 85% chance of correctly identifying patients with high-risk PE according to receiving operating characteristics curve analysis. Moreover, serum haptoglobin concentrations ≤1 g/l showed an 80% sensitivity and a 96% specificity for the diagnosis of high-risk PE. Nontargeted proteomics identified protein biomarkers for the severity of PE that are involved in iron metabolism pathways and acute-phase response. Among them, reduced serum haptoglobin concentrations show a high accuracy for the biochemical detection of high-risk PE.
Computer-based device and model for predicting probability of death from thrombosis
(2012-08) Kline, Jeffrey A.
A computer-based device and predictive model executable by computer software for use with the device to predict or estimate a percentage probability of death from thrombosis in a patient with active cancer.
Randomized Trial of Tenecteplase or Placebo with Low Molecular Weight Heparin for Acute Submassive Pulmonary Embolism: Assessment of Patient-Oriented Cardiopulmonary Outcomes at Three Months
(2013-03) Kline, Jeffrey A.; Hernandez, Jackeline; Kabrhel, Christopher; Courtney, Daniel M; Jones, Alan E; Nordenholtz, Kristen; Diercks, Deborah; Klinger, Jame
Background: Acute submassive pulmonary embolism (PE) with right ventricular (RV) injury and/or concomitant deep venous thrombosis can cause persistent symptoms that degrade quality of life. We tested the hypothesis that intravenous tenecteplase would improve the probability of a favorable outcome at three months after submassive PE. Methods: Multicenter randomized double-blind, placebo controlled trial. Eligible patients were ambulatory at baseline, had image-proven acute PE, a systolic blood pressure > 90 mm Hg and RV dysfunction (abnormal echocardiography, troponin or brain natriuretic peptide). Patients received anticoagulation with low molecular weight heparin (LMWH) and either tiered-dose tenecteplase or saline in an opaque syringe. Composite favorable outcome: 5 day survival to hospital discharge without shock, intubation, or major hemorrhage (any intracranial bleed or need for surgical or medical intervention for acute anemia), and at 90 days, normal RV on resting echocardiography, 6 minute walk distance>330 m, no dyspnea at rest, and no recurrent PE or DVT. Self-perception of wellness was assessed by the SF-16, VEINES-QOL and rank on 1-10 ordinal scale. Results: 83 patients were enrolled, including 33 women, 52 Caucasians, mean age 55+/-14 years, 43 received placebo, 40 received tenecteplase, and 38 had concomittant DVT. A favorable composite outcome occurred in 17/43(40%, 95% CI: 25-56%) treated with placebo, versus 26/40 (65%, 95% CI: 48-79%) treated with tenecteplase, p=0.02 Fisher’s exact. Acute deterioration occurred in 3 patients treated with placebo: fatal PE (1), intubation (1), thrombectomy (1) and in one patient treated with tenecteplase who had a fatal intracranial hemorrhage. At three months, a nonfavorable outcome was found in 23 additional patients treated with placebo, versus 13 patients treated with tenecteplase. Assessments of wellness were consistently higher in the tenecteplase group (e.g., p=0.03 for ordinal scale rank). Conclusions: In this randomized trial, patients with submassive PE treated with LMWH and tenecteplase were more likely to have a favorable patient-oriented outcome at three months than patients treated with LMWH and saline placebo.
Utilizing lipopolysaccharide in exhaled breath condensate to diagnose gram negative pneumonia
(2010-11) Kline, Jeffrey A.; Hernandez, Jackeline; Watts, John Albert Jr
A device for collecting exhaled breath condensate from a subject. The device comprises a plunger assembly and a stopper. The stopper is connected to the plunger disk of the plunger assembly by a plurality of support pins and is configured for sealing engagement. The device is utilized to collect exhaled breath condensate from both spontaneously breathing and mechanically ventilated subjects and the devices utilized to determine whether lipopolysaccharide is present in the collected exhaled breath condensate.
High Discordance of Chest X-ray and CT for Detection of Pulmonary Opacities in ED Patients: Implications for Diagnosing Pneumonia
(2013-02) Self, Wesley H; Courtney, D Mark; McNaughton, Candace D; Wunderink, Richard G; Kline, Jeffrey A.
Objective To evaluate the diagnostic performance of chest x-ray (CXR) compared to computed tomography (CT) for detection of pulmonary opacities in adult emergency department (ED) patients. Methods We conducted an observational cross-sectional study of adult patients presenting to 12 EDs in the United States from July 1, 2003, through November 30, 2006, who underwent both CXR and chest CT for routine clinical care. CXRs and CT scans performed on the same patient were matched. CXRs and CT scans were interpreted by attending radiologists and classified as containing pulmonary opacities if the final radiologist report noted opacity, infiltrate, consolidation, pneumonia, or bronchopneumonia. Using CT as a criterion standard, the diagnostic test characteristics of CXR to detect pulmonary opacities were calculated. Results The study cohort included 3423 patients. Shortness of breath, chest pain and cough were the most common complaints, with 96.1% of subjects reporting at least one of these symptoms. Pulmonary opacities were visualized on 309 (9.0%) CXRs and 191 (5.6 %) CT scans. CXR test characteristics for detection of pulmonary opacities included: sensitivity 43.5% (95% CI, 36.4%-50.8%); specificity 93.0% (95% CI, 92.1%-93.9%); positive predictive value 26.9% (95% CI, 22.1%-32.2%); and negative predictive value 96.5% (95% CI, 95.8%-97.1%). Conclusion In this multicenter cohort of adult ED patients with acute cardiopulmonary symptoms, CXR demonstrated poor sensitivity and positive predictive value for detecting pulmonary opacities. Reliance on CXR to identify pneumonia may lead to significant rates of misdiagnosis.
Characteristics and Outcomes of Patients with Vasoplegic Versus Tissue Dysoxic Septic Shock
(2013-07) Sterling, Sarah A; Puskarich, Michael A; Shapiro, Nathan I; Trzeciak, Stephen; Kline, Jeffrey A.; Summers, Richard L; Jones, Alan E
Background: The current consensus definition of septic shock requires hypotension after adequate fluid challenge or vasopressor requirement. Some patients with septic shock present with hypotension and hyperlactatemia greater than 2 mmol/L (tissue dysoxic shock), whereas others have hypotension alone with normal lactate (vasoplegic shock). Objective: The objective of this study was to determine differences in outcomes of patients with tissue dysoxic versus vasoplegic septic shock. Methods: This was a secondary analysis of a large, multicenter randomized controlled trial. Inclusion criteria were suspected infection, two or more systemic inflammatory response criteria, and systolic blood pressure less than 90 mmHg after a fluid bolus. Patients were categorized by presence of vasoplegic or tissue dysoxic shock. Demographics and Sequential Organ Failure Assessment scores were evaluated between the groups. The primary outcome was in-hospital mortality. Results: A total of 247 patients were included, 90 patients with vasoplegic shock and 157 with tissue dysoxic shock. There were no significant differences in age, race, or sex between the vasoplegic and tissue dysoxic shock groups. The group with vasoplegic shock had a lower initial Sequential Organ Failure Assessment score than did the group with tissue dysoxic shock (5.5 vs. 7.0 points; P = 0.0002). The primary outcome of in-hospital mortality occurred in 8 (9%) of 90 patients with vasoplegic shock compared with 41 (26%) of 157 in the group with tissue dysoxic shock (proportion difference, 17%; 95% confidence interval, 7%–26%; P < 0.0001; log-rank test P = 0.02). After adjusting for confounders, tissue dysoxic shock remained an independent predictor of in-hospital mortality. Conclusions: In this analysis of patients with septic shock, we found a significant difference in in-hospital mortality between patients with vasoplegic versus tissue dysoxic septic shock. These findings suggest a need to consider these differences when designing future studies of septic shock therapies.

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