Emergency (****); * (*): *-* This open-access article distributed under the terms of the Creative Commons Attribution Noncommercial 3.0 License (CC BY-NC 3.0). Copyright © 2016 Shahid Beheshti University of Medical Sciences. All rights reserved. Downloaded from: www.jemerg.com 140 Emergency (2016); 4 (3): 140-144 ORIGINAL ARTICLE Bedside Ultrasonography versus Brain Natriuretic Peptide in Detecting Cardiogenic Causes of Acute Dyspnea Keihan Golshani, Mehrdad Esmailian, Aniseh Valikhany*, Majid Zamani Emergency Department, Al-Zahra Hospital, Isfahan University of Medical Sciences, Isfahan, Iran. *Corresponding Author: Aniseh Valikhany; Emergency Department, Al-Zahra Hospital, Soffeh Blvd, Isfahan, Iran. EmailDr.valikhany@yahoo.com, Tel: 09135342151. Received: May 2015; Accepted: September 2015 Abstract Introduction: Acute dyspnea is a common cause of hospitalization in emergency departments (ED).Distinguishing the cardiac causes of acute dyspnea from pulmonary ones is a major challenge for responsible physicians in EDs. This study compares the characteristics of bedside ultrasonography with serum level of blood natriuretic peptide (BNP) in this regard. Methods: This diagnostic accuracy study compares bedside ultrasonography with serum BNP levels in differentiating cardiogenic causes of acute respiratory distress. Echocardiography was considered as the reference test. A checklist including demographic data (age and sex), vital signs, medical history, underlying dis- eases, serum level of BNP, as well as findings of chest radiography, chest ultrasonography, and echocardiography was filled for all patients with acute onset of dyspnea. Screening characteristics of the two studied methods were calculated and compared using SPSS software, version 20. Results: 48 patients with acute respiratory distress were evaluated (50% female). The mean age of participants was 66.94 ± 16.33 (28-94) years. Based on the results of echocardiography and final diagnosis, the cause of dyspnea was cardiogenic in 20 (41.6%) cases. Bedside ultraso- nography revealed the cardiogenic cause of acute dyspnea in 18 cases (0 false positive) and BNP in 44 cases (24 false positives). The area under the ROC curve for bedside ultrasonography and BNP for differentiating the cardio- genic cause of dyspnea were 86.4 (95% CI: 74.6-98.3) and 66.3 (95% CI: 49.8-89.2), respectively (p = 0.0021). Conclusion: It seems that bedside ultrasonography could be considered as a helpful and accurate method in dif- ferentiating cardiogenic causes of acute dyspnea in emergency settings. Nevertheless, more study is needed to make a runaway algorithm to evaluate patients with respiratory distress using bedside ultrasonography, which leads to rapid therapeutic decisions in a short time. Keywords: Ultrasonography; natriuretic peptide, brain; dyspnea; echocardiography; emergency service, hospital Cite this article as: Golshani K, Esmailian M, Valikhany A, Zamani M. Bedside ultrasonography versus brain natriuretic peptide in detecting cardiogenic causes of acute dyspnea. Emergency. 2016; 4(3):140-144. Introduction: cute dyspnea is a common cause of hospitaliza- tion in emergency departments (ED) (1). There are some clinical and para clinical measures such as patients’ history, physical examination and bedside ultrasonography that help physicians differentiate car- diac causes of acute respiratory distress from pulmonary ones. Some have introduced diagnostic rules such as the Framingham heart failure criteria. But, due to their low sensitivity and high specificity, they cannot distinguish acute heart failure from non-cardiac causes well (2). On the other hand, the sensitivity of electrocardiography (ECG) and bedside ultrasonography are not high enough to exclude the presence of cardiogenic pulmonary edema, as well (2, 3). Conventional echocardiography is an important diagnostic tool for screening and diagnos- ing heart failure but it is not available 24 hours a day and 7 days a week, additionally it needs many training time for skillful application. Brain natriuretic peptide (BNP) or N-terminal of the pro-hormone brain natriuretic pep- tide (NT-pro-BNP) has been shown to be able to rule out or establish the diagnosis of cardiogenic causes of acute respiratory distress (1). But, some diseases such as renal failure, critical illness, pulmonary heart disease, arrhyth- mia, anemia, valvular heart diseases and muscular dis- eases can affect the results of BNP measures (1, 4). Now- adays, bedside ultrasonography is integrated into the daily practice of emergency physicians, which helps them ameliorate the accuracy of their diagnoses and managements. Pulmonary ultrasonography helps us find A mailto:Dr.valikhany@yahoo.com This open-access article distributed under the terms of the Creative Commons Attribution Noncommercial 3.0 License (CC BY-NC 3.0). Copyright © 2016 Shahid Beheshti University of Medical Sciences. All rights reserved. Downloaded from: www.jemerg.com 141 Emergency (2016); 4 (3): 140-144 lung pathologies in a short period of time, by interpret- ing the artifacts such as comet tails. These artifacts have high sensitivity, but low specificity in diagnosing pulmo- nary edema (5-7). In this study, we compare bedside ul- trasonography with BNP in differentiating cardiogenic causes of acute dyspnea. Methods: Study Design This diagnostic accuracy study compares bedside ultra- sonography with serum BNP levels in differentiating car- diogenic cause of acute respiratory distress from pulmo- nary sources. Echocardiography was considered as the reference test. The study was conducted in the emer- gency department of Al-Zahra Hospital, Isfahan, Iran, with more than 80000 patients admitted to the ED annu- ally and a 40% admission rate. Before the initiation of the study, a 10-day local workshop was taught by a board-certified attending emergency medicine physician and a cardiologist, focusing on bedside ultrasonography with both didactic and hands-on trainings. At the time of admission, we obtained a written informed consent from participants or their legal guardians. The research was approved by institutional review board of ethic commit- tee. Participants The study population consisted of those who were ad- mitted to the ED with acute onset of dyspnea between November 2013 and April 2014. Intubated and trau- matic patients as well as patients with myocardial in- fraction and history of end stage renal disease were ex- cluded. In addition, cases with the serum creatinine level above the normal range during laboratory evalua- tion were excluded. A checklist including demographic data (age and sex), vital signs, medical history, under- lying diseases, serum level of BNP, as well as findings of chest radiography, chest ultrasonography, and echo- cardiography was filled for all participants. Procedure Patients were enrolled with convenience sampling method. On admission, after history taking and physical examination, an echocardiogram and a bedside ultraso- nography were performed, and a blood sample was drawn for laboratory examinations (including BNP lev- els) during the first 15 minutes of admission. For meas- uring BNP level (by Bayer Diagnostic ADVIA centaur BNP assay method) 2 ml of peripheral venous blood sample was sent to the laboratory in a vacuum tube containing EDTA. Bedside ultrasonography was done with an (MyLab 25 Gold 2009) ultrasound machine (Bi- osound Esaote, Inc., Indianapolis, IN) using a CA430 Curved Array (3.5-5 MHz) and a LA523 Linear Array transducer (5.0 to 13.0 MHz) by trained emergency medicine residents within 30 minutes of admission. The majority of patients were in sitting or supine posi- tion in accordance with their comfort position. At first, ejection fraction (EF) of heart was estimated visually, via four-chamber, two-chamber, long axis and short axis views of the heart. EF was classified as good in case of EF ≥ 40% and low when EF was less than 40%. For performing ultrasonography, each hemi thorax was di- vided into 2 anterior (upper and lower) and 2 lateral zones. Anterior zone was the area between sternum and anterior axillary line while lateral zone was be- tween anterior and posterior axillary lines. These zones were divided into upper and lower zones by the third intercostal space as a border. Lungs were scanned for presence of pleural sliding, B-Lines and A-Lines. Pleural sliding is the back and forth movement of visceral and parietal pleura. B-Lines are vertical pleural-based dis- crete, laser-like, hyper-echoic reverberation artifacts. They move with respiration simultaneously and extend to the bottom of the screen without fading. A -Lines are horizontal hyper-echoic reverberation lung artifacts that are separated from each other by an equal dis- tance. For differentiating diastolic heart failure from pulmonary causes of acute respiratory distress, inferior vena cava (IVC) collapsibility index was measured. IVC collapsibility was defined as follows: maximum axial di- ameter of IVC minus minimum axial diameter of IVC di- vided by maximum axial diameter of IVC (IVC max- IVCmin/IVCmax). IVC diameters were measured at 2-3 centimeters from the right atrium, during expiration (IVCmax) and inspiration (IVCmin) with a curvilinear probe located longitudinally on sub-xyphoid area. Dias- tolic dysfunction was considered as source of acute dyspnea if EF was lower than 40% or EF was more than 40% but IVC collapsibility index was lower than 50%. Ultrasonography performance took 6 minutes for each patient. All echocardiography were performed by an expert cardiologist, who was blinded to clinical situa- tion of patients. Final diagnosis of patients was decided based on clinical, laboratory, imaging and response to treatment findings by an expert cardiologist together with an internist. Statistical analysis Total sample size of this study was estimated 48 cases (Zα = 95%, p= 50%, d =15%). Data analysis was per- formed using SPSS software, version 20. Quantitative data were reported as frequency and percentage, and qualitative ones as mean and standard deviation. Sen- sitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of bedside ultrasonog- raphy compared to BNP in differentiating cardiogenic causes of acute dyspnea were calculated. In addition, area under the receiver operating characteristic (ROC) curve with 95% confidence interval (CI) was calculated for the two diagnostic tests. Chi-square, Fisher’s exact test, and t-test were used for comparing the discrete This open-access article distributed under the terms of the Creative Commons Attribution Noncommercial 3.0 License (CC BY-NC 3.0). Copyright © 2016 Shahid Beheshti University of Medical Sciences. All rights reserved. Downloaded from: www.jemerg.com Golshani et al 142 and continuous variables. P-value < 0.05 was consid- ered statistically significant. Results: 48 patients with acute respiratory distress were evalu- ated (50% female). The mean age of participants was 66.94 ± 16.33 (28-94) years. Table 1 compares baseline characteristics of the studied patients. Based on the re- sults of echocardiography and final diagnosis, the cause of dyspnea was cardiogenic in 20 (41.6%) cases. Bedside ultrasonography revealed the cardiogenic cause of acute dyspnea in 18 cases (0 false positive) and BNP in 44 cases (24 false positives). Table 2 summarizes final diagnosis of patients based on imaging, laboratory, and clinical findings. Final diagnosis of patients regarding the source of dysp- nea was 100% compatible with echocardiographic re- sults. The area under the ROC curve for bedside ultraso- nography and BNP for differentiating the cardiogenic cause of dyspnea were 86.4 (95% CI: 74.6-98.3) and 66.3 (95% CI: 49.8-89.2), respectively (Figure 1, p = 0.0021). Table 3 summarizes the screening performance charac- teristics of the two studied diagnostic tests. Discussion: Based on the results of the present study, bedside ultra- sonography had better screening performance charac- teristics compared to BNP in detection of cardiogenic causes of dyspnea. The comparison of area under the ROC curve for the two tests showed significant accuracy of bedside ultrasonography in this regard. The causes of acute dyspnea divide into major categories of cardiac and non-cardiac. Distinguishing between these two cat- egories is the first step in choosing therapeutic approach and still remains as one of the frequent challenges of emergency physicians. In this regard, some facilities such as BNP measurement and echocardiography can be helpful (8). Multiple studies have shown high diagnostic accuracy of serum BNP in ruling out heart failure as a cause of acute dyspnea (9-12). Yet, the high rate of car- diac and renal dysfunction in critically ill patients limits the discriminative role of BNP. In the present study, the sensitivity of BNP in 703 pg/ml cut-off was 70% while Arques et al. showed 86.4% and 68% sensitivity of BNP in 253 pg/ml and 480 pg/mL cut-offs, respectively (13). Serum BNP ≥ 22 pmol/L precisely reflected the final di- agnosis of heart failure with 93% sensitivity and 90% specificity in Davis et al. study (14). In contrast to several studies in this regard, the accuracy of BNP in the present study was slightly low (15-18). This could be explained by the different cut-offs used for BNP in different studies. The accuracy of bedside ultrasonography in prediction of cardiac origin of dyspnea was known to be high (1). Table 1: Baseline characteristics of participants based on cause of dyspnea Characteristics Cause of dyspnea P-value Cardiogenic Non-Cardiogenic Age (year) 64.7±21.2 68.1±13.8 0.6 Sex Male 9 (37.5) 15 (62.5) 0.55 Female 11 (45.8) 13 (54.2) History of CHF* Yes 5 (35.7) 9 (64.3) 0.748 No 15 (45.5) 18 (54.5) Coronary artery disease Yes 14 (43.8) 18 (56.3) 0.763 No 6 (37.5) 10 (62.5) COPD* Yes 4 (44.4) 5 (55.6) 1.000 No 16 (41) 23 (59) Asthma Yes 1 (33.3) 2 (66.7) 1.000 No 19 (42.2) 26 (57.8) Hypertension Yes 6 (40) 9 (60) 1.000 No 14 (42.4) 19 (57.6) Jugular venous distension Yes 3 (30) 7 (70) 0.488 No 17 (44.7) 23 (55.3) Brain natriuretic peptide (pg/ml) 2819±4095 1433±3029 0.184 Ejection fraction (%) 48±12 40±13 0.04 Table 2: Final diagnosis of patients based on imaging, la- boratory, clinical findings, and response to treatment Diagnosis Number (%) Asthma 3 (3.6) Pulmonary edema 19 (39.6) Pulmonary thromboembolism 10 (20.8) Pneumonia 4 (8.3) Myocardial infraction 3 (6.3) COPD* 5 (10.4) Pleural effusion 1 (2.1) Emotional 1 (2.1) *COPD: Chronic obstructive pulmonary disease. This open-access article distributed under the terms of the Creative Commons Attribution Noncommercial 3.0 License (CC BY-NC 3.0). Copyright © 2016 Shahid Beheshti University of Medical Sciences. All rights reserved. Downloaded from: www.jemerg.com 143 Emergency (2016); 4 (3): 140-144 Ultrasonography is more accurate in distinguishing free pleural effusion (19). In the majority of studies, bedside ultrasonography was performed by experienced opera- tors within 10 minutes, and many studies claim comple- tion of the exam within 3-5 minutes (20). In a study by Gargani et al. bedside ultrasonography in patients with acute dyspnea significantly correlated with their BNP val- ues (1). Ultrasonography was shown to be accurate for differentiating cardiogenic acute dyspnea from those caused by primary pulmonary disease in the emergency setting (21). Multiple B-lines have been 100% sensitive and 92% specific in the diagnosis of pulmonary edema (22). In addition, the finding of diffuse multiple B-lines in bedside ultrasonography has had 95% specificity and 97% sensitivity in diagnosis of cardiogenic pulmonary edema (23). If these findings are confirmed in a large number of patients, bedside ultrasonography could be- come a valuable tool for situations where BNP is not avail- able or in settings where other techniques are not readily available such as remote area, or even in out-of-hospital settings. If we use BNP along with bedside ultrasonogra- phy in order to optimize its diagnostic potential, we could reach the final diagnosis in less time. Yet, in addition to op- erator dependency, ultrasonography has some limitations such as application difficulties in obese patients, ribcage, and presence of subcutaneous emphysema (24). Conclusion: It seems that bedside ultrasonography could be consid- ered as a helpful and accurate method in differentiating cardiogenic causes of acute dyspnea in emergency set- tings. Nevertheless, more study is needed to make a run- away algorithm to evaluate patients with respiratory distress using bedside ultrasonography, which leads to rapid therapeutic decisions in a short time. Acknowledgment: The contributions of all emergency department staffs of Alzahra Hospital, Isfahan, is appreciated. Conflict of interest: None Funding support: None Authors’ contributions: All authors passed four criteria for authorship contribu- tion based on recommendations of the International Committee of Medical Journal Editors. References: 1. Gargani L, Frassi F, Soldati G, Tesorio P, Gheorghiade M, Picano E. Ultrasound lung comets for the differential diagnosis of acute cardiogenic dyspnoea: A comparison with natriuretic peptides. European journal of heart failure. 2008;10(1):70-7. 2. Fonseca C, Oliveira AG, Mota T, et al. Evaluation of the performance and concordance of clinical questionnaires for the diagnosis of heart failure in primary care. European journal of heart failure. 2004;6(6):813-20. 3. Peacock WF. The evolving role of BNP in the diagnosis and treatment of CHF: a summary of the BNP consensus panel report. Emergency Medicine Cardiac Research and Education Group International (1). 2005. 4. Copetti R, Soldati G, Copetti P. Chest sonography: a useful tool to differentiate acute cardiogenic pulmonary edema from acute respiratory distress syndrome. Cardiovascular Ultrasound. 2008;6(1):16. 5. Lichtenstein D, Meziere G, Biderman P, Gepner A, Barre O. The comet-tail artifact: an ultrasound sign of alveolar- Figure 1: The area under the receiver-operating characteristic (ROC) curve for bedside ultrasonography and brain natriuretic peptide (BNP) for differentiating the cardiogenic causes of acute dyspnea (P = 0.0021). 0 .0 0 0 .2 5 0 .5 0 0 .7 5 1 .0 0 S e n si ti v it y 0.00 0.25 0.50 0.75 1.00 1-Specificity BNP ROC area: 0.6634 Ultrasonography ROC area: 0.8643 Reference Table 3: Screening performance characteristics of bedside ultrasonography and brain natriuretic peptide (BNP) Characteristics Test (95% Confidence Interval) P-value Ultrasonography BNP5 Sensitivity 80 (55.7-93.4) 70 (50.5-90.4) 0.0021 Specificity 92.8(75-98.7) 75 (54.7-88.5) PPV1 88.9 (63.9-98) 68.1 (45.1-85.2) NPV2 86.7 (68.3-95.6) 80.7 (60-92.6) PLR3 8 (2.1-29.8) 2.1 (1.09-4.2) NLR4 0.15(0.06-0.36) 0.23 (0.1-0.53) Accuracy 87.5 (74.75-95.27) 75 (60.4-86.36) 1. Positive predictive value; 2. Negative predictive value; 3. Positive likelihood ratio; 4. Negative likelihood ratio. 5. BNP’s characteristics were calculated in 703 pg/ml cut-offs. This open-access article distributed under the terms of the Creative Commons Attribution Noncommercial 3.0 License (CC BY-NC 3.0). Copyright © 2016 Shahid Beheshti University of Medical Sciences. All rights reserved. Downloaded from: www.jemerg.com Golshani et al 144 interstitial syndrome. American Journal of Respiratory and Critical Care Medicine. 1997;156(5):1640-6. 6. Stevenson LW, Perloff JK. The limited reliability of physical signs for estimating hemodynamics in chronic heart failure. Jama. 1989;261(6):884-8. 7. Soldati G, Copetti R, Sher S. Sonographic interstitial syndrome the sound of lung water. Journal of Ultrasound in Medicine. 2009;28(2):163-74. 8. Ziskin M, Thickman D, Goldenberg N, Lapayowker M, Becker J. The comet tail artifact. Journal of Ultrasound in Medicine. 1982;1(1):1-7. 9. Wang CS, FitzGerald JM, Schulzer M, Mak E, Ayas NT. Does this dyspneic patient in the emergency department have congestive heart failure? Jama. 2005;294(15):1944-56. 10. Maisel AS, Krishnaswamy P, Nowak RM, et al. Rapid measurement of B-type natriuretic peptide in the emergency diagnosis of heart failure. N Engl J Med. 2002;347(3):161-7. 11. McCullough PA, Nowak RM, McCord J, et al. B-type natriuretic peptide and clinical judgment in emergency diagnosis of heart failure: analysis from Breathing Not Properly (BNP) Multinational Study. Circulation. 2002;106(4):416-22. 12. Doust JA, Glasziou PP, Pietrzak E, Dobson AJ. A systematic review of the diagnostic accuracy of natriuretic peptides for heart failure. Arch Intern Med. 2004;164(18):1978-84. 13. Arques S, Roux E, Sbragia P, et al. Usefulness of Bedside Tissue Doppler Echocardiography and B-Type Natriuretic Peptide (BNP) in Differentiating Congestive Heart Failure from Noncardiac Cause of Acute Dyspnea in Elderly Patients with a Normal Left Ventricular Ejection Fraction and Permanent, Nonvalvular Atrial Fibrillation: Insights from a Prospective, Monocenter Study. Echocardiography. 2007;24(5):499-507. 14. Davis M, Espiner E, Yandle T, et al. Plasma brain natriuretic peptide in assessment of acute dyspnoea. The Lancet. 1994;343(8895):440-4. 15. Morrison LK, Harrison A, Krishnaswamy P, Kazanegra R, Clopton P, Maisel A. Utility of a rapid B-natriuretic peptide assay in differentiating congestive heart failure from lung disease in patients presenting with dyspnea. Journal of the American College of Cardiology. 2002;39(2):202-9. 16. Cabanes L, Richaud-Thiriez B, Fulla Y, et al. Brain natriuretic peptide blood levels in the differential diagnosis of dyspnea. CHEST Journal. 2001;120(6):2047-50. 17. Berdagué P, Caffin P-Y, Barazer I, et al. Use of N-terminal prohormone brain natriuretic peptide assay for etiologic diagnosis of acute dyspnea in elderly patients. American heart journal. 2006;151(3):690-8. 18. Lainchbury JG, Campbell E, Frampton CM, Yandle TG, Nicholls MG, Richards AM. Brain natriuretic peptide and n- terminal brain natriuretic peptide in the diagnosis of heart failure in patients with acute shortness of breath. Journal of the American College of Cardiology. 2003;42(4):728-35. 19. Zanobetti M, Poggioni C, Pini R. Can chest ultrasonography replace standard chest radiography for evaluation of acute dyspnea in the ED? CHEST Journal. 2011;139(5):1140-7. 20. Ang S-H, Andrus P. Lung ultrasound in the management of acute decompensated heart failure. Current cardiology reviews. 2012;8(2):123. 21. Kajimoto K, Madeen K, Nakayama T, Tsudo H, Kuroda T, Abe T. Rapid evaluation by lung-cardiac-inferior vena cava (LCI) integrated ultrasound for differentiating heart failure from pulmonary disease as the cause of acute dyspnea in the emergency setting. Cardiovasc Ultrasound. 2012;10(1):49. 22. Lichtenstein D, Meziere G. A lung ultrasound sign allowing bedside distinction between pulmonary edema and COPD: the comet-tail artifact. Intensive Care Med. 1998;24(12):1331-4. 23. Lichtenstein DA, Meziere GA. Relevance of lung ultrasound in the diagnosis of acute respiratory failure: the BLUE protocol. Chest. 2008;134(1):117-25. 24. Gargani L. Lung ultrasound: a new tool for the cardiologist. Cardiovascular ultrasound. 2011;9(1):6.