Utility of pulmonary echography with a handheld ultrasound device in patients with acute coronary syndrome

Internal and Emergency Medicine UTILITY OF PULMONARY ECHOGRAPHY WITH A HANDHELD ULTRASOUND DEVICE IN PATIENTS WITH ACUTE CORONARY SYNDROME. --Manuscript Draft-- Manuscript Number: IAEM-D-22-00592R3 Full Title: UTILITY OF PULMONARY ECHOGRAPHY WITH A HANDHELD ULTRASOUND DEVICE IN PATIENTS WITH ACUTE CORONARY SYNDROME. Article Type: ORIGINAL Section/Category: EM - ORIGINAL Keywords: acute coronary syndrome; heart failure; mechanical ventilation; myocardial infarction; pulmonary echography Corresponding Author: Juan C Garcia-Rubira, PhD, MD Hospital Universitario Virgen Macarena Sevilla, SPAIN Corresponding Author Secondary Information: Corresponding Author's Institution: Hospital Universitario Virgen Macarena Corresponding Author's Secondary Institution: First Author Secondary Information: First Author: María J Cristo Ropero Order of Authors: María J Cristo Ropero Francisco J Rivera Rabanal Tania Seoane García Luis Madrona Jimenez Alvaro Izquierdo Bajo Rafael Hidalgo Urbano Juan C Garcia-Rubira, PhD, MD Angel Vilches Arenas Order of Authors Secondary Information: Funding Information: Abstract: OBJECTIVES : To establish the usefulness of lung ultrasound with a handheld device to predict the risk of developing heart failure with the need for mechanical ventilation (MV) in acute coronary syndrome (ACS). METHODS: This is a prospective study of consecutive patients admitted because of ACS-type myocardial infarction, without data of HF at admission in a tertiary hospital, between February 2017 and February 2018. Lung ultrasounds were performed with a hand-held cardiologic device in the first 24 hours, and defined as echo-positive (PE+) when exams revealed 3 or more B-lines in 2 or more bilateral quadrants. We related this finding to the need for MV during admission. RESULTS: We included 119 patients (65,1 ±12,8 year; 75.6% male, 24.4% female; 87.4% in Killip class I, 12.6% in Killip class II). Pulmonary echography was positive (PE+) in 21 patients (17,6%). The sensitivity of PE+ to predict MV was 93.3%, the specificity 93.3%, and the area under the curve 0.93. In Cox-regression analysis adjusted by CRUSADE score and Killip class, PE+ patients had a hazard ratio of 64.55 (CI 7.87; 529,25, p<0.001) of needing MV. PE+ was associated to more frequent use of inotropes and mortality.  Powered by Editorial Manager® and ProduXion Manager® from Aries Systems Corporation CONCLUSIONS : Pulmonary ultrasonography with a handheld echocardiograph was predictive of severe heart failure and the need for mechanical ventilation in ACS with high specificity and sensitivity. Response to Reviewers: ANSWER TO REVIEWERS Reviewer #2: Q: This Reviewer, personally, would soften the sentence in the Discussion that boldly states that the accuracy data is "nearly perfect." The prior sentence makes the point. A: We agree, and changed to “Very High” Q: In the Title, there's mispelling of echocardiograph. Personally, this reviewer would use "hand held ultrasound device" as the Vscan is not just for cardiac imaging and the lung ultrasound is not a part of echocardiography. A: We agree in changing the title. Q: In the Kaplan Meier, the labeling of the Y axis is unclear. Is it really "survival" without MV, or isn't it the "proportion" without MV? A: It is the percentage of patients free of MV. We have changed the label. Thank you for your comments. Powered by Editorial Manager® and ProduXion Manager® from Aries Systems Corporation ANSWER TO REVIEWERS Reviewer #2: Q: This Reviewer, personally, would soften the sentence in the Discussion that boldly states that the accuracy data is "nearly perfect." The prior sentence makes the point. A: We agree, and changed to “Very High” Q: In the Title, there's mispelling of echocardiograph. Personally, this reviewer would use "hand held ultrasound device" as the Vscan is not just for cardiac imaging and the lung ultrasound is not a part of echocardiography. A: We agree in changing the title. Q: In the Kaplan Meier, the labeling of the Y axis is unclear. Is it really "survival" without MV, or isn't it the "proportion" without MV? A: It is the percentage of patients free of MV. We have changed the label. Thank you for your comments. Authors' Response to Reviewers' Comments Click here to access/download;Authors' Response to Reviewers' Comments;answer to reviewers.docx 1 UTILITY OF PULMONARY ECHOGRAPHY WITH A HANDHELD ULTRASOUND DEVICE IN PATIENTS WITH ACUTE CORONARY SYNDROME. AUTHORS: Cristo Ropero, María José (a) Rivera Rabanal, Francisco Javier (a) Seoane García, Tania (a) Madrona Jiménez, Luis (a) Izquierdo Bajo, Álvaro (a) Hidalgo Urbano, Rafael (a) Garcia-Rubira, Juan Carlos (a) Vilches Arenas, Angel (b) Institution: (a) Servicio de Cardiología. Hospital Virgen Macarena. Avenida Dr Fedriani, sn, 41009 Sevilla. España (b) Departamento de Medicina Preventiva y Salud Pública de la Universidad de Sevilla. Plaza del Dr Barraquer, 1. 41009, Sevilla. España. Correspondence author: Juan Carlos Garcia-Rubira Address: Unidad Coronaria. Hospital Virgen Macarena. Avenida Dr Fedriani sn, 41009, Sevilla. Email: [email protected] Manuscript clean Click here to access/download;Manuscript;ecografiapulmonar_Revision3.do 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 2 Tlf +34619973837. This work has been previously published as an abstract in ESC Congress 2020 - The Digital Experience 29 August - 1 September. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 3 SUMMARY OBJECTIVES: To establish the usefulness of lung ultrasound with a handheld device to predict the risk of developing heart failure with the need for mechanical ventilation (MV) in acute coronary syndrome (ACS). METHODS: This is a prospective study of consecutive patients admitted because of ACS-type myocardial infarction, without data of HF at admission in a tertiary hospital, between February 2017 and February 2018. Lung ultrasounds were performed with a hand-held cardiologic device in the first 24 hours, and defined as echo-positive (PE+) when exams revealed 3 or more B- lines in 2 or more bilateral quadrants. We related this finding to the need for MV during admission. RESULTS: We included 119 patients (65,1 ±12,8 year; 75.6% male, 24.4% female; 87.4% in Killip class I, 12.6% in Killip class II). Pulmonary echography was positive (PE+) in 21 patients (17,6%). The sensitivity of PE+ to predict MV was 93.3%, the specificity 93.3%, and the area under the curve 0.93. In Cox-regression analysis adjusted by CRUSADE score and Killip class, PE+ patients had a hazard ratio of 64.55 (CI 7.87; 529,25, p<0.001) of needing MV. PE+ was associated to more frequent use of inotropes and mortality. CONCLUSIONS: Pulmonary ultrasonography with a handheld echocardiograph was predictive of severe heart failure and the need for mechanical ventilation in ACS with high specificity and sensitivity. Keywords: Acute coronary syndrome; heart failure; mechanical ventilation; myocardial infarction; pulmonary echography. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 4 INTRODUCTION. Despite early revascularization strategies, cardiovascular disease is the most frequent cause of mortality in the world, being responsible for more than 8 million deaths per year (1,2). The development of acute heart failure in the postinfarction period is related to an increase in mortality (3–5). Several prognostic scores have been developed, with the GRACE score being widely used and recommended in acute coronary syndrome (ACS). This score includes the exploratory findings of congestion through the 4 degrees of the Killip classification (6,7). On the other hand, pulmonary examination by ultrasound, as described by D. Lichtenstein, is capable of detecting data of pulmonary congestion and interstitial occupation in different pathologies (8–12), with good inter- and intraobserver reproducibility in some studies, although the interpretation of the ultrasound findings can vary significantly in relation to the transducer used for the study (12–15). Numerous studies confirm the ability of lung ultrasound to estimate the degree of congestion (16). The implementation of this technique in different clinical scenarios requires confirming its validity in different clinical algorithms, whether in emergencies or in regular hospital admission or consultation assessments. The objectives of the current study were to determine the usefulness of lung ultrasound using a portable handheld device in the acute phase of ACS and to assess the validity of this examination to detect early pulmonary congestion and the risk of mechanical ventilation (MV) during admission. METHODS This was an observational, analytical study of prospective cohorts, which consecutively included patients admitted to the emergency department of our center between February 2017 and February 2018 who had clinical judgments of ACS-type myocardial infarction (17), who were in Killip I-II situations, and who agreed to participate voluntarily and freely in the study. Those with a Killip scale greater than II, pneumothorax, total or partial pneumonectomy, pleural 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 5 drainage, recent major chest trauma, primary or secondary pleuropulmonary malignancy, active pneumonia, advanced chronic lung disease (emphysematous or chronic bronchitis GOLD IIIIV), pregnancy, and severe obesity, or those who required intubation as part of anesthesia in the case of surgical revascularization, were excluded. The sample size at the end of the recruitment period was 119 patients (Figure 1). MV was defined as the application of positive pressure through a mechanical device to support the ventilation of the patient, either through a noninvasive interface (noninvasive MV) or with intubation of the airway (invasive MV). The noninvasive MV applied modes were continuous positive airway pressure (CPAP) and bilevel positive airway pressure (BiPAP). The ultrasound images were obtained with a handheld ultrasound machine (V-SCAN®) with a protocol based on the abbreviated Volpicelli protocol (18). Each hemithorax was divided into 4 quadrants (horizontal line in the fifth intercostal space and vertical line in the anterior axillary line). Patients with 3 or more B lines in 2 or more bilateral quadrants were considered to have positive ultrasounds (PE+) and otherwise considered to have negative ones (PEN). All the exams were obtained by MJCR, who developed a previous training in the Coronary Unit of the University Hospital Virgen Macarena in Seville. Analysis of the pulmonary echography was made blinded to the clinical evolution. The medical treatment of the patients was carried out in accordance with current protocols and clinical guidelines, based on clinical criteria by their responsible physicians, not on pulmonary ultrasound. The reliability of lung ultrasound was estimated by randomly presenting 40 recordings with a 50% prevalence of positive results to 6 cardiologists. These images were duplicated in random order in such a way that each observer evaluated the recorded exams twice, without knowing it. The research project was approved by the Biomedical Research Ethics Coordinating Committee of Hospital Virgen Macarena, Sevilla, Spain. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 6 Statistical analysis: A database was created in the statistical package SPSS-IBM SPSS version 24 (June 2016). Numerical variables were expressed as the mean and standard deviation (SD) or median and percentiles (P25 and P75). The relationship between qualitative variables was determined with the chi-square test with continuity correction or with Fisher’s test. The relationship between dichotomous qualitative variables and each quantitative variable was determined using Student's T test. All significant results are presented with 95% confidence intervals (CI). MV- free survival was analyzed using the Kaplan-Meier curve, and the effect of PE+ was analyzed using the log-rank test and Cox regression analysis. The sensitivity, specificity, and area under the curve (AUC) of PE+ were analyzed to predict MV. To choose the best MV-free survival model, logistic regression analyses were performed with MV as the dependent variable. The following models were included in successive models: anthropometric and anamnesis data; admission examination and analysis; and a third model, which included the variables that were significant in the previous models, together with the GRACE and CRUSADE scores (Supplemental Data). With the resultant variables independently related to MV, a multivariate Cox regression model was used to calculate the hazard ratio (HR) of PE+ to MV. RESULTS We included 119 patients aged between 41 and 89 years (65.1 ± 12.8), 90 (75.6%) of whom were men and 29 (24.4%) of whom were women. One hundred and three (86.6%; CI 79.1 to 91.7%) patients were in Killip I status at admission. Twenty-one patients (17.6%, CI 11.3 to 25.7%) met the criteria for PE+. Among PEN patients, 16 (16.3%) had 1 to 3 positive quadrants on lung ultrasound (supplemental data). 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 13 The clinical scenario is that of patients presenting in the emergency room with an acute coronary syndrome, and all the patients included in the study had analytical and angiographic confirmation of type 1 AMI, so our results cannot be extrapolated to other clinical situations with a more uncertain diagnosis. This is especially relevant in patients who meet the exclusion criteria for our study, especially active pneumonia or advanced chronic lung disease, pathologies that represent a significant percentage of medical emergencies, and for which other protocols are more advisable (15,30). Our study was performed with an ultrasound probe suitable for cardiological studies, so the results cannot be directly applied to studies performed with linear or abdominal probes. CONCLUSIONS Our study shows that bedside lung ultrasound using a handheld echocardiograph has a high predictive value for the development of severe heart failure and the need for MV in patients hospitalized for acute coronary syndrome. These findings are applicable even to patients without any initial signs of pulmonary congestion. The inclusion of lung ultrasound in the initial assessment of patients with acute coronary syndrome and elevated markers of myocardial necrosis is recommended. 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Intensive Care Med. 2019 Sep 1;45(9):1200–11. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 16 30. Johannessen Ø, Myhre PL, Omland T. Assessing congestion in acute heart failure using cardiac and lung ultrasound - a review. Expert Review of Cardiovascular Therapy 2021;19(2):165–76. 31. Miglioranza, M. H. et al. Pulmonary congestion evaluated by lung ultrasound predicts decompensation in heart failure outpatients. Int. J. Cardiol. 240, 271–278 (2017). 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 17 TABLES Table 1: Clinical and analytical characteristics. PE+ (n=21) PEN (n=98) CI 95% CI 95% p Anthropometric and history data Female 8 (38.1%) 18.1 to 61.6 21 (21.4%) 12.8 to 30.1 0.182 Age 73.5 ±11.2 68.4 to 78.6 63.3 ±12.4 60.8 to 65.8 0.001 BMI 28.7 ±3.7 27.0 to 30.4 28.8 ±3.8 28.0 to 29.5 0.950 Family CAD 5 (23.8%) 8.2 to 47.2 15 (15.3%) 7.7 to 22.9 0.345 Diabetes 9 (42.9%) 19.3 to 66.4 34 (34.7%) 24.8 to 44.6 0.648 Hypertension 15 (71.4%) 47.8 to 88.7 55 (56.1%) 45.8 to 66.5 0.294 Dyslipidemia 8 (38.1%) 18.1 to 61.6 42 (42.9%) 32.5 to 53.2 0.875 Smoker 5 (23.8%) 8.2 to 47.2 40 (40.8%) 30.6 to 51.1 0.226 Sedentary 17 (81.0%) 58.1 to 95.5 62 (63.3%) 53.2 to 73.3 0.193 Aspirine 7 (33.3%) 14.6 to 57.0 14 (14.3%) 6.8 to 21.7 0.056 Diuretics 4 (19.0%) 0.1 to 23.8 8 (8.2%) 2.2 to 14.1 0.221 Stroke 3 (14.3%) 3.0 to 36.3 7 (7.1%) 1.5 to 12.7 0.379 AF 3 (14.3%) 3.0 to 36.3 1 (1.0%) 0.0 to 5.5 0.017 CKD 5 (23.8%) 8.2 to 47.2 1 (1.0%) 0.0 to 5.5 0.001 Vascular disease 5 (23.8%) 8.2 to 47.2 7 (7.1%) 1.5 to 12.7 0.037 Chronic CAD 6 (28.6%) 11.3 to 52.2 12 (12.2%) 5.2 to 19.2 0.078 HF 4 (19.0%) 5.4 to 41.9 1 (1.0%) 0.0 to 5.5 0.003 Cancer 1 (4.8%) 0.1 to 23.8 6 (6.1%) 0.9 to 11.4 0.999 Anemia 3 (14.3%) 3.0 to 36.3 2 (2.0%) 0.2 to 7.2 0.038 OSAS 0 (0.0%) 0.0 to 16.1 5 (5.1%) 1.7 to 11.5 0.585 Clinical findings at admission NSTEMI 13 (61.9 %) 38.4 to 81.9 41 (41.8 %) 31.6 to 52.1 0.151 STEMI 8 (38.1 %) 18.1 to 61.6 57 (58.2 %) 47.9 to 68.4 Killip I 13 (61.9 %) 38.4 to 81.9 90 (91.8%) 84.6 to 96.4 0.001 Killip II 8 (38.1%) 18.1 to 61.6 8 (8.2 %) 3.6 to 15.5 Systolic BP(mmHg) 133.8 ±28.2 121.0 to 146.7 137.5 ±29.0 131.7 to 143.4 0.596 Diastolic BP (mmHg) 74.8 ±19.7 65.8 to 83.8 79.6 ±17.2 76.2 to 83.1 0.257 HR (bpm) 83.9 ±21.1 74.3 to 93.5 73.7 ±15.8 70.5 to 76.9 0.013 O2 Saturation (%) 95.3 ±3.1 93.9 to 96.8 96.8 ±1.7 96.5 to 97.2 0.045 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 18 GFR (ml/min/1.73m²) 59.4 ±31.3 45.1 to 73.6 95.7 ±30.4 89.7 to 101.8 <0.001 GRACE score 147.0 ±38.9 129.3 to 164.7 119.6 ±29.7 113.6 to 125.5 0.005 CRUSADE score 42.7 ±20.6 33.3 to 52.1 22.3 ±14.6 19.4 to 25.2 <0.001 Hematocrito. (% ) 40.2 ±5.6 37.6 to 42.7 44.4 ±5.3 43.3 to 45.5 0.001 Creatinine (mg/dl) 1.6 ±1.6 0.9 to 2.4 0.9 ±0.2 0.9 to 1.0 0.080 Glucose (mg/dl) 175.2 ±40.1 157.0 to 193.5 153.4 ±56.2 142.1 to 164.7 0.094 TnT Us (ng/ml) 7138.3 ±8721.8 3168.2 to 11108.4 2848.7 ±4146.2 2017.4 to 3680.0 0.039 PE+: positive lung echography; PEN: negative lung echography; BMI: body mass index; CAD: coronary artery disease; AF: atrial fibrillation; CKD: chronic kidney disease; HF: heart failure; OSAS: obstructive sleep apnea syndrome; NSTEMI: myocardial infarction without ST segment elevation; STEMI: myocardial infarction with ST segment elevation; BP: blood pressure; HR: heart rate; GFR: glomerular filtration rate; TnT Us: maximal value of ultrasensible troponin-T during admission. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 19 Table 2: In hospital events PE+ (n=21) PEN (n=98) CI 95% CI 95% p Congestion in XR 9 (42.9%) 19.3 to 66.4 2 (2.0%) 0.2 to 7.2 <0.001 MV 14 (66.7%) 43.0 to 85.4 1 (1.0%) 0.0 to 5.5 <0.001 Non invasive MV 11 (52.4%) 28.6 to76.1 0 (0.0%) 0.0 to 3.7 <0.001 Invasive MV 7 (33.3%) 14.6 to 57.0 1 (1.0%) 0.0 to 5.5 <0.001 Amines 10 (47.6%) 23.9 to 71.4 4 (4.1%) 1.1 to 10.1 <0.001 Diuretics 18 (85.7%) 63.7 to 96.9 18 (18.4%) 10.2 to 26.5 <0.001 Death 9 (42.9%) 19.3 to 66.4 0 (0.0%) 0.0 to 3.7 <0.001 PE+: positive lung echography; PEN: negative lung echography; XR: Chest X-ray; MV: mechanical ventilation. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 20 FIGURES Figure 1: Flowchart of inclusion of patients. ACS: acute coronary syndrome; AMI: acute myocardial infarction; PTE: pulmonary embolism; MINOCA: non obstructive coronary disease myocardial infarction, Figure 2: Survival without mechanical ventilation. MV: Mechanical ventilation; PEN: negative pulmonary echography; PE+: positive pulmonary echography. Kaplan-Meier log-rank p<0.001. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 1 UTILITY OF PULMONARY ECHOGRAPHY WITH A HANDHELD ECOCARDIOGRAPHULTRASOUND DEVICE IN PATIENTS WITH ACUTE CORONARY SYNDROME. AUTHORS: Cristo Ropero, María José (a) Rivera Rabanal, Francisco Javier (a) Seoane García, Tania (a) Madrona Jiménez, Luis (a) Izquierdo Bajo, Álvaro (a) Hidalgo Urbano, Rafael (a) Garcia-Rubira, Juan Carlos (a) Vilches Arenas, Angel (b) Institution: (a) Servicio de Cardiología. Hospital Virgen Macarena. Avenida Dr Fedriani, sn, 41009 Sevilla. España (b) Departamento de Medicina Preventiva y Salud Pública de la Universidad de Sevilla. Plaza del Dr Barraquer, 1. 41009, Sevilla. España. Correspondence author: Juan Carlos Garcia-Rubira Address: Unidad Coronaria. Hospital Virgen Macarena. Avenida Dr Fedriani sn, 41009, Sevilla. Manuscript marked Click here to access/download;Manuscript;ecografiapulmonar_Revision_ma 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 2 Email: [email protected]m Tlf +34619973837. This work has been previously published as an abstract in ESC Congress 2020 - The Digital Experience 29 August - 1 September. Field Code Changed 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 9 vascular disease, history of infarction, and anemia) and 5 variables from laboratory tests or physical examination at admission (Killip class, heart rate, glomerular filtration rate, glucose, and left ventricular ejection fraction). Logistic regression analysis identified 2 variables independently related to MV: Killip class at admission and glomerular filtration rate. These variables were analyzed in a new logistic regression together with the CRUSADE and GRACE scores, and finally, the Killip class and the CRUSADE score were chosen for the multivariate survival analysis together with positive pulmonary echography (supplemental material). With these 2 variables and the PE+, the Cox multivariate regression model was built. The adjusted HR of PE+ to predict MV was 64.55 (CI 7.87, 529.25, p<0.001). Figure 2 shows the adjusted survival curve. DISCUSSION We found that 21 of 119 patients in our series had PE+ (17.6%), an incidence higher than expected if it is considered a surrogate of heart failure, compared with other series of contemporary ACS, in which coronary revascularization is the standard treatment (19). In the series by Kaul et al., significant heart failure developed in 13.6% of STEMI patients and 14.8% of NSTEMI patients. In the Diocles registry, representative of patients with ACS in Spain, severe heart failure at admission was 7.8% in STEMI and 4.8% in NSTEMI, but the development of heart failure after admission was not reported. As part of the inclusion criteria, all our patients had a significant increase in myocardial necrosis markers compared to 77.6% of the patients in the Diocles registry. This is one of the greatest predictors of heart failure in ACS (20) and can explain some differences. RECALCAR (2) showed significant heterogeneity between the different centers treating ACS patients, with our center being one of the most complex. The patients included in our study had a median troponin level of 1649, more than 100 times the reference 99th percentile in our laboratory, which implies a large infarct size in 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 10 many of these patients. These characteristics of our cohort explain the high percentage of heart failure in evolution. The incidence of heart failure during hospital stay because of ACS is quite variable among different publications, but there is general agreement that it is related to early myocardial revascularization and that it is a fundamental long-term prognostic factor (21). Our study found a clear relationship between the findings of pulmonary ultrasound on admission and the worsening of Killip class, the need for MV, and in-hospital mortality in patients admitted for ACS, despite the absence of significant heart failure on admission. Thus, it shows the validity of lung ultrasound to predict MV needs with good sensitivity, specificity, and likelihood ratio. The sensitivity, specificity, area under the curve, and likelihood ratio obtained were almost perfectvery high, although the confidence intervals were wide due to the sample size. The results suggest that the detection of abundant and extensive bilateral B lines is sensitive and specific for predicting pulmonary edema that may require MV. These results were obtained with a pocket ultrasound machine adapted for echocardiography, and the protocol was reinforced by excellent inter- and intraobserver agreement, which supports the clinical reliability of applying a simplified method using these devices in an acute coronary syndrome care setting. The Cox multivariate analysis included the CRUSADE scale and the Killip class at admission in addition to the PE+. The CRUSADE scale, initially designed to predict bleeding events (22), is based on 8 clinical variables that give a very complete profile of general risk: heart rate, systolic pressure, hematocrit, glomerular filtration rate, sex, data on congestion, peripheral vascular disease, and diabetes mellitus. It has recently been seen that the scale is a predictor of risk that complements the GRACE (23) scale, and in fact, in our study, the CRUSADE was a better predictor of MV than the GRACE. Our analysis of CXR revealed that only 43% of patients with PE+ showed some findings suggestive of pulmonary congestion. In addition, none of the patients with CXR suggestive of 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 11 congestion and PEN required VM. This finding reinforces our hypothesis of the usefulness of pulmonary echography with a hand-held echocardiograph in the scenario of ACS in the emergency department. It can be especially useful in the case of pulmonary flash edema because of its fast bedside applicability (24,25). There are no large trials in the literature relating pulmonary ultrasound to MV in ACS. Bedetti et al applied a risk stratification protocol in myocardial infarction through multiple ultrasound parameters, finding that ejection fraction, movement of the tricuspid annulus, and the presence of B lines were independent predictors of prognosis (26). Our study establishes a predictive value of severe heart failure and the need for MV. Therefore, we consider that our study is the first to demonstrate the incremental value of lung ultrasound over exploration in patients with ACS Killip <II to predict the need for MV. PE+ patients more often had 3-vessel or left main disease and less often had successful PCI, which suggests that this finding is related to more extensive ischemic myocardium. Flash pulmonary edema can be the presentation of extensive myocardial ischemia, and pulmonary echography has an increasing role in early diagnosis and management (27). We suggest that patients who are PE+ at the time of admission for ACS could be classified as advanced Killip II, benefiting from intensive care unit admission, due to their higher risk of developing severe heart failure. The pioneering study by Killip and Kimball (28) established a classification based on auscultation that is still used in the stratification of myocardial infarction. Our study proposes a further step in this classification. Ultrasound is now becoming more widely available, so the results of this study support the hypothesis that the era of the Killip scale is giving way to the era of lung ultrasound. We therefore consider it essential to incorporate lung ultrasound into ACS urgent care protocols, which will allow us to better stratify patients. Our results also support the suitability of handheld devices for 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 12 echocardiography in this type of patient. In other types of clinical scenarios, a greater variability of the observations has been found, and the most appropriate type of probe is not unanimous (29). While Haaksma et al found the convex abdominal probe more appropriate (15), Johannessen recommended the use of the cardiac probe to perform a global approach to cardiac function and pulmonary congestion in patients with acute heart failure (30). Our study strongly supports the systematic use of lung ultrasound in the assessment of pulmonary congestion, which should also be enhanced in clinical scenarios of heart or kidney failure(16). The final message is that in a patient with ACS presenting with disseminated B lines throughout both lung fields, one should be alert to the imminent need for respiratory support through MV. Conversely, the finding of only 1 to 3 quadrants with B-lines does not seem to indicate a risk of needing MV. LIMITATIONS Although the sample size in our study is small, the results are highly significant and have great physiological plausibility. The physician who obtained the pulmonary echography images was not blinded to the initial clinical data, so some bias could not be excluded, but the analysis of these images was totally blinded to the clinical evolution. Other limitation to the universalization of our findings comes from the fact that only one investigator obtained the lung ultrasound. However it guarantees that careful search for B-lines have been made in each thoracic sector, a key point in the usefulness of this technique, and this approach has been adopted in previous publications (31). Furthermore, the blind analysis of inter- and intraobserver variability showed very good agreement. The exclusion of patients with a Killip scale greater than II creates a restricted scenario for obtaining events. Instead, our results demonstrate the value of lung ultrasound in those apparently stable but with incipient or doubtful signs of heart failure at admission. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 13 The clinical scenario is that of patients presenting in the emergency room with an acute coronary syndrome, and all the patients included in the study had analytical and angiographic confirmation of type 1 AMI, so our results cannot be extrapolated to other clinical situations with a more uncertain diagnosis. This is especially relevant in patients who meet the exclusion criteria for our study, especially active pneumonia or advanced chronic lung disease, pathologies that represent a significant percentage of medical emergencies, and for which other protocols are more advisable (15,30). Our study was performed with an ultrasound probe suitable for cardiological studies, so the results cannot be directly applied to studies performed with linear or abdominal probes. CONCLUSIONS Our study shows that bedside lung ultrasound using a handheld echocardiograph has a high predictive value for the development of severe heart failure and the need for MV in patients hospitalized for acute coronary syndrome. These findings are applicable even to patients without any initial signs of pulmonary congestion. The inclusion of lung ultrasound in the initial assessment of patients with acute coronary syndrome and elevated markers of myocardial necrosis is recommended. The finding of extensive B-lines through the lung fields detects patients with large areas of ischemic myocardium and at risk of pulmonary edema. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 14 REFERENCES 1. Mortality and global health estimates [Internet]. [cited 2022 May 11]. Available from: https://www.who.int/data/gho/data/themes/mortality-and-global-health-estimates 2. Rodríguez-Padial L, Bertomeu V, Elola FJ, Anguita M, Fernández Lozano I, Silva L, et al. Quality Improvement Strategy of the Spanish Society of Cardiology: The RECALCAR Registry. J Am Coll Cardiol. 2016;68(10):1140–2. 3. Arrigo M, Gayat E, Parenica J, Ishihara S, Zhang J, Choi DJ, et al. Precipitating factors and 90- day outcome of acute heart failure: a report from the intercontinental GREAT registry. 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Formatted: Spanish (Spain) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 16 30. Johannessen Ø, Myhre PL, Omland T. Assessing congestion in acute heart failure using cardiac and lung ultrasound - a review. Expert Review of Cardiovascular Therapy 2021;19(2):165–76. 31. Miglioranza, M. H. et al. Pulmonary congestion evaluated by lung ultrasound predicts decompensation in heart failure outpatients. Int. J. Cardiol. 240, 271–278 (2017). Formatted: English (United States) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 17 TABLES Table 1: Clinical and analytical characteristics. PE+ (n=21) PEN (n=98) CI 95% CI 95% p Anthropometric and history data Female 8 (38.1%) 18.1 to 61.6 21 (21.4%) 12.8 to 30.1 0.182 Age 73.5 ±11.2 68.4 to 78.6 63.3 ±12.4 60.8 to 65.8 0.001 BMI 28.7 ±3.7 27.0 to 30.4 28.8 ±3.8 28.0 to 29.5 0.950 Family CAD 5 (23.8%) 8.2 to 47.2 15 (15.3%) 7.7 to 22.9 0.345 Diabetes 9 (42.9%) 19.3 to 66.4 34 (34.7%) 24.8 to 44.6 0.648 Hypertension 15 (71.4%) 47.8 to 88.7 55 (56.1%) 45.8 to 66.5 0.294 Dyslipidemia 8 (38.1%) 18.1 to 61.6 42 (42.9%) 32.5 to 53.2 0.875 Smoker 5 (23.8%) 8.2 to 47.2 40 (40.8%) 30.6 to 51.1 0.226 Sedentary 17 (81.0%) 58.1 to 95.5 62 (63.3%) 53.2 to 73.3 0.193 Aspirine 7 (33.3%) 14.6 to 57.0 14 (14.3%) 6.8 to 21.7 0.056 Diuretics 4 (19.0%) 0.1 to 23.8 8 (8.2%) 2.2 to 14.1 0.221 Stroke 3 (14.3%) 3.0 to 36.3 7 (7.1%) 1.5 to 12.7 0.379 AF 3 (14.3%) 3.0 to 36.3 1 (1.0%) 0.0 to 5.5 0.017 CKD 5 (23.8%) 8.2 to 47.2 1 (1.0%) 0.0 to 5.5 0.001 Vascular disease 5 (23.8%) 8.2 to 47.2 7 (7.1%) 1.5 to 12.7 0.037 Chronic CAD 6 (28.6%) 11.3 to 52.2 12 (12.2%) 5.2 to 19.2 0.078 HF 4 (19.0%) 5.4 to 41.9 1 (1.0%) 0.0 to 5.5 0.003 Cancer 1 (4.8%) 0.1 to 23.8 6 (6.1%) 0.9 to 11.4 0.999 Anemia 3 (14.3%) 3.0 to 36.3 2 (2.0%) 0.2 to 7.2 0.038 OSAS 0 (0.0%) 0.0 to 16.1 5 (5.1%) 1.7 to 11.5 0.585 Clinical findings at admission NSTEMI 13 (61.9 %) 38.4 to 81.9 41 (41.8 %) 31.6 to 52.1 0.151 STEMI 8 (38.1 %) 18.1 to 61.6 57 (58.2 %) 47.9 to 68.4 Killip I 13 (61.9 %) 38.4 to 81.9 90 (91.8%) 84.6 to 96.4 0.001 Killip II 8 (38.1%) 18.1 to 61.6 8 (8.2 %) 3.6 to 15.5 Systolic BP(mmHg) 133.8 ±28.2 121.0 to 146.7 137.5 ±29.0 131.7 to 143.4 0.596 Diastolic BP (mmHg) 74.8 ±19.7 65.8 to 83.8 79.6 ±17.2 76.2 to 83.1 0.257 HR (bpm) 83.9 ±21.1 74.3 to 93.5 73.7 ±15.8 70.5 to 76.9 0.013 O2 Saturation (%) 95.3 ±3.1 93.9 to 96.8 96.8 ±1.7 96.5 to 97.2 0.045 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 18 GFR (ml/min/1.73m²) 59.4 ±31.3 45.1 to 73.6 95.7 ±30.4 89.7 to 101.8 <0.001 GRACE score 147.0 ±38.9 129.3 to 164.7 119.6 ±29.7 113.6 to 125.5 0.005 CRUSADE score 42.7 ±20.6 33.3 to 52.1 22.3 ±14.6 19.4 to 25.2 <0.001 Hematocrito. (% ) 40.2 ±5.6 37.6 to 42.7 44.4 ±5.3 43.3 to 45.5 0.001 Creatinine (mg/dl) 1.6 ±1.6 0.9 to 2.4 0.9 ±0.2 0.9 to 1.0 0.080 Glucose (mg/dl) 175.2 ±40.1 157.0 to 193.5 153.4 ±56.2 142.1 to 164.7 0.094 TnT Us (ng/ml) 7138.3 ±8721.8 3168.2 to 11108.4 2848.7 ±4146.2 2017.4 to 3680.0 0.039 PE+: positive lung echography; PEN: negative lung echography; BMI: body mass index; CAD: coronary artery disease; AF: atrial fibrillation; CKD: chronic kidney disease; HF: heart failure; OSAS: obstructive sleep apnea syndrome; NSTEMI: myocardial infarction without ST segment elevation; STEMI: myocardial infarction with ST segment elevation; BP: blood pressure; HR: heart rate; GFR: glomerular filtration rate; TnT Us: maximal value of ultrasensible troponin-T during admission. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 Supplementary File revised Click here to access/download Supplementary File (audio/video attachments) Supplemental data reviewed.docx