key: cord-0683607-h45i1m8s authors: Szekely, Yishay; Lichter, Yael; Hochstadt, Aviram; Taieb, Philippe; Banai, Ariel; Sapir, Orly; Granot, Yoav; Lupu, Lior; Merdler, Ilan; Ghantous, Eihab; Borohovitz, Ariel; Sadon, Sapir; Oz, Amir Gal; Ingbir, Merav; Arbel, Yaron; Laufer-Perl, Michal; Banai, Shmuel; Topilsky, Yan title: The predictive role of combined cardiac and lung ultrasound in Coronavirus Disease 2019 date: 2021-02-09 journal: J Am Soc Echocardiogr DOI: 10.1016/j.echo.2021.02.003 sha: 58a690fe4e0135eade37c135413fc35ac88c7397 doc_id: 683607 cord_uid: h45i1m8s Background and Objectives We aimed to evaluate sonographic features that may aid in risk stratification and propose a focused cardiac and lung ultrasound (LUS) algorithm in patients with COVID-19 Methods Two hundred consecutive hospitalized patients with COVID-19 underwent comprehensive clinical and echocardiographic examination, as well as LUS, irrespective of clinical indication, within 24 hours of admission as part of a prospective predefined protocol. Assessment included calculation of the Modified Early Warning Score (MEWS), left ventricular (LV) systolic and diastolic function, hemodynamic and right ventricular (RV) assessment and a calculated LUS score. We performed outcome analysis to identify echocardiographic and LUS predictors of mortality or the composite event of mortality or need for invasive mechanical ventilation, and to assess their adjunctive value on top of clinical parameters and MEWS. Results A simplified echocardiographic risk score comprised of LV ejection fraction< 50% combined with TAPSE< 18 mm, was associated with mortality (p=0.0002) and with the composite event (p=0.0001). Stepwise analyses evaluating echocardiographic and LUS parameters on top of existing clinical risk scores showed that addition of TAPSE and SVI improved prediction of mortality when added to clinical variables but not when added to MEWS. Once echocardiography was added, and patients re-categorized as high risk only if having both high risk MEWS, and high-risk cardiac features, the specificity increased from 63% to 87%, positive predictive value from 28% to 48% and accuracy improved from 66% to 85%. Although LUS was not associated with incremental risk prediction for mortality above clinical and echocardiographic criteria, it improved prediction of need for invasive mechanical ventilation. Conclusions In hospitalized patients with COVID-19, a very limited echocardiographic exam is sufficient for outcome prediction. The addition of echocardiography in patients with high risk MEWS score decreases the rate of falsely identifying patients as high risk to die, and may improve resource allocation in case of high patient load.background Both the European and the American Societies of Echocardiography recognize the prognostic significance and clinical implications of the cardiac complications of COVID-19. 1 ,2 Yet, both Societies recommend limiting the echocardiographic assessment of COVID-19 patients to a "focused cardiac ultrasound (FoCUS) approach" in order to reduce the exposure of medical personnel and thus decrease their risk of contamination. 2, 3 Importantly, the suggested FoCUS algorithm in these Consensus Documents is based on expert opinion and lacks supporting outcome data. Similarly, whereas lung ultrasound (LUS) is increasingly used as a diagnostic tool in critically ill patients, [4] [5] [6] little is known about its role in COVID-19. 7 Combining LUS with bedside echocardiography allows for a rapid and thorough assessment of both the cardiovascular and respiratory status of critically ill patients. 8, 9 We therefore adopted the combined use of bedside echocardiography and LUS during the initial assessment of consecutive patients hospitalized with COVID-19 infection. 7, 10 The aims of the study were: 1) To identify echocardiographic and LUS features that are useful in risk stratification of hospitalized patients with COVID-19 and 2) to assess the adjunctive use and added value of these tests, on top of routine clinical parameters and risk scores. J o u r n a l P r e -p r o o f 6 Philips Medical Systems, Bothell, WA). In accordance to present guidelines, 3 the following measures were undertaken to minimize the risk of inadvertent infection: 1) All studies were performed at the designated COVID-19 units; 2) All exams were performed with small dedicated scanners; 3) Personal protection included airborne precautions comprising of N-95 masks, fluid resistant gowns, two sets of gloves, head-covers, eye shields and shoe covers; 4) Electrocardiographic monitoring during imaging was omitted and all measurements were performed offline to reduce exposure time and contamination. 13, 14 Analysis of all echocardiographic findings was performed by a senior cardiologist with expertise in echocardiography. Suboptimal image quality was identified in 22 patients (11%), nevertheless all examinations were diagnostic. Left ventricular (LV) diameters, and ejection fraction (LVEF) were measured as recommended. 15 Measurements of mitral inflow included the peak early filling (E-wave) and late diastolic filling (A-wave) velocities, and the E/A ratio. Early diastolic mitral septal and lateral annular velocities (e′) were measured in the apical 4chamber view. 16 Left atrial (LA) volume was calculated using the biplane area length method at end-systole. Forward stroke volume (SV) was calculated from LV outflow tract (LVOT) Doppler time velocity interval multiplied by LVOT cross sectional area with subsequent calculation of cardiac output and index. From 4-chamber views encompassing the entire right ventricle (RV), end-systolic and end-diastolic RV areas and tricuspid annulus were measured. RV function was evaluated by tricuspid annular plane systolic excursion (TAPSE), systolic tricuspid lateral annular velocity (RV S') measured in the apical 4-chamber view, and fractional area change (FAC). 15, 17 Hemodynamic right sided assessment included the measurement of the pulmonic flow acceleration time (PAT) velocity to assess pulmonary vascular resistance and estimated right atrial pressure using the inferior vena cava. 18 Estimation of systolic J o u r n a l P r e -p r o o f We performed LUS on all patients with COVID-19 using a 6-zone method for each lung, including a scan of the anterior, antero-lateral, and postero-lateral aspects of the thorax. Examinations were performed by cardiologists with expertise in LUS recording and interpretation using the same equipment (CX 50, Philips Medical Systems, Bothell, WA), with the same phased-array probe used for echocardiography. Each LUS lasts between 2-3 minutes, with the patient supine or semi-supine, omitting the need for position change during the examination. A standard point scoring system was employed for each region and ultrasound pattern: A-lines (normal reverberation artifacts of the pleural line that when accompanied by lung sliding correspond to normal aeration of the lung) were graded as 0 points; B-lines (hyperechoic lines vertical to the pleura line, arising from it and reaching the edge of the screen erasing A-lines), which represent reverberation artifact through edematous interlobular septa or alveoli, were classified as B1 (separated B-lines that correspond to moderate lung aeration loss) that were graded as 1 point, or as B2 (coalescent B-lines that correspond to severe lung aeration loss) and graded as 2 points. Finally, lung consolidation received 3 points. Thus, a LUS score of 0 was normal, and 36 was the worst score possible. 19 (Supplemental Figure I) . We also qualitatively documented the presence of pleural thickening and defined a homogenous vs. patchy pattern of each examination. Clinical follow-up was obtained prospectively. Outcome analysis started at time of baseline echocardiographic and LUS exam. The study endpoints were: 1) All-cause mortality, 2) need for invasive mechanical ventilation and 3) the composite event of J o u r n a l P r e -p r o o f death or need for invasive mechanical ventilation (excluding patients already invasively mechanically ventilated during baseline ultrasound exam). Patients who needed invasive mechanical ventilation and eventually died were censored at the time of initiating invasive mechanical ventilation. Inter-observer and intra-observer variability for SV, TAPSE and LUS score were determined by a second independent blinded observer, and by the same observer, who measured the parameters at least a month apart, in 15 randomly selected patients. They were assessed using the Bland-Altman method and the within-subject coefficient of variation, calculated as the ratio of the standard deviation of the measurement difference to the mean value of all measurements. Continuous normally distributed parameters were presented as means± SD and compared using the Student's t-test. Non-normally distributed data were presented by median, 1 st and 3 rd quartiles and compared using the Wilcoxon rank sum test. Categorical data were compared between groups using the χ 2 test, or Fisher's exact for all patients. Analyses for the composite event were done excluding those who were mechanically ventilated at presentation, before baseline echocardiographic and LUS evaluation. To assess the independent echocardiographic and LUS parameters associates of outcome, we used multivariable Cox proportional hazard models for the endpoints. The first step was to group the variables into LV and LA, Doppler, RV and LUS parameters. The second step was to select for each group all the variables with P<0.05 in a univariable analysis. The third step was to assess correlations between the selected variables within each group to avoid co-linearity (R 2 >0.7; p<0.0001). In the fourth step, cutoff values for continuous parameters affecting survival were derived using the maximally selected rank statistics method. Although LVEF was not significantly associated with mortality as a continuous variable, because it was previously reported to be associated with mortality and cardiac events, 10 it was forced into the Cox Hazard model. Covariates were entered in a stepwise forward multivariable. We performed separate analyses for mortality or the composite event adjusted for routine clinical parameters, MEWS or SOFA. For the routine clinical parameters, we selected only clinical variables that are known associates of adverse events in COVID-19 infection (age, gender, systolic blood pressure, heart rate, oxygen saturation, baseline Troponin, D-dimer and BNP levels). The variables assessing clinical associates were entered first, the echocardiographic significant dichotomous parameters second and the LUS score last. We performed the same process to assess if a "super-simple" echocardiographic score calculated by multiplying the HRs for LVEF and TAPSE, and multiplying the two together, The study population consisted of 234 consecutive patients; 34 patients were excluded because they did not undergo cardiac and lung ultrasound assessment within the first 24 hours. The reasons for not performing the cardiac and lung ultrasound were hospital discharge in <24 hours (21 patients), patient refusal (6 patients) and a "do not resuscitate/intubate" status (7 patients). Thus, the final study group consisted of 200 patients (Table 1) Results of univariate analysis for mortality, and the composite event for echocardiographic parameters are shown in Table 2 . Results of univariate analysis for LUS parameters are presented in supplementary Table 2 . The median follow-up was 59 days with an interquartile range (IQR) of 12-86 days. A total of 29 patients (14.5%) died and 43 (21.5%) reached the composite endpoint. Echocardiographic parameters significantly associated with higher rates of both mortality and the composite endpoint mortality were LVEF <50%, SVI, PAT, and TAPSE. Increased LUS score, presence of pleural effusion and pleural thickening at baseline LUS were each associated with higher rates of both` mortality and the composite endpoint ( Supplementary Figures 2A and 2B ). In nested models the best associate of mortality between the pulmonary parameters was LUS score. SVI and TAPSE were the only echocardiographic parameters independently J o u r n a l P r e -p r o o f associated with mortality ( Table 3 ). The addition of LUS score consecutively to the echocardiographic multivariable analysis for mortality resulted in improved prediction (AIC decreased from 218 to 216; p=0.01). SVI, TAPSE and PAT were the only echocardiographic parameters independently associated with the composite event. The addition of LUS score to the echocardiographic multivariable analysis for the composite event resulted in improved prediction (AIC decreased from 303 to 292; p<0.0001). The prevalence of abnormal TAPSE, LVEF, and SVI were 18%, 14% and 28%, respectively. The remaining 126 (63%) patients did not have any of the echocardiographic parameters associated with adverse outcome. Outcome of patients stratified into patients with normal or abnormal cardiac or lung ultrasound are described in Figure 1 and in the supplementary results. Step-wise analyses evaluating the significant echocardiographic and LUS parameters and either pre-selected combination of clinical parameters or existing clinical risk scores (SOFA and MEWS) are presented in Table 4 . Addition of TAPSE and SVI improved prediction of mortality when added to SOFA or clinical variables but not when added to MEWS. LUS did not have additive predictive value for mortality on top of clinical and echocardiographic parameters. The results of contingency tables for models incorporating MEWS score with or without echocardiography or LUS are shown in Table 5 . The addition of echocardiography, so patients were categorized as high risk only if having both high risk MEWS and high-risk imaging features, reclassified more individuals without events as low risk and improved specificity, positive predictive value, and accuracy of the models compared with MEWS alone. J o u r n a l P r e -p r o o f 13 The addition of either LUS, or echocardiography, so patients were categorized as high risk if having either high risk MEWS or high-risk imaging features, reclassified more individuals with events as high risk, increasing sensitivity, but came with the expense of decreasing accuracy, specificity and positive predictive value. "Super-simple" echocardiography risk score We assessed a simplified echocardiographic approach using a calculated "supersimple" echocardiographic risk score. The "super-simple" score was valuable, We evaluated different models using the "super-simple" risk score, LUS and either pre-selected clinical parameters or existing clinical risk scores (SOFA score and MEWS), and presented them in Table 4 . Addition of the "super-simple" risk score Results of inter-and intra-observer variability are presented in supplementary Table 4 . This study analyzes the predictive value of combined echocardiographic and LUS in LUS may be useful for identifying individuals at risk for mechanical ventilation but not useful for mortality prediction above-and-beyond clinical and echocardiographic criteria. Although the American and European Societies recognize the importance of echocardiographic assessment of patients with COVID-19, the amount of data collected prospectively is limited to several reports. [20] [21] [22] [23] [24] [25] [26] Half of the patients in the present cohort appeared in our previous publication, 10 where we reported on the echocardiographic results of the first 100 patients with COVID-19 admitted to our institution. Doubling the number of studied patients, the addition of LUS parameters and the longer follow-up period in the present study, allow us to evaluate the independent predictive ability of echocardiography combined with LUS and clinical parameters for mortality or need for invasive mechanical ventilation. The only echocardiographic parameters associated with adverse outcome in non-adjusted analyses are LVEF, SVI, PAT and TAPSE. The cut-off values for TAPSE and LVEF were within the lower normal range, thus unlikely to be discriminatory in other populations. However, due to the heightened adrenergic tone in patients with respiratory failure, a "lower normal range" TAPSE or LVEF may reflect early cardiac deterioration. In our center, the same cardiologist performing the echocardiographic assessment also routinely performs LUS. We show that survival drops with an abnormal LUS score in line with those achieved by chest computed tomography. 9, 27, 28 This study is the first to combine results of LUS with echocardiographic evaluation. We show that neither echocardiography, nor LUS significantly improved the sensitivity or negative Echocardiography have recommended a FoCUS approach in patients with COVID-19. 2,3 Since these guidelines were based on expert opinion rather than on outcome data, we aimed to assess whether an even more limited approach is sufficient. We found that an optimal model including only two echocardiographic parameters, TAPSE and SVI, provides information that is potentially valuable for clinical management. Recent advances in ultrasound technology have led to the miniaturization of machines to the size of a mobile phone that do not provide Spectral J o u r n a l P r e -p r o o f Doppler functions. 29 We show that in the context of patients with COVID-19 infection, assessment of LVEF and TAPSE from the 4-chamber view alone, carries significant prognostic data. Nevertheless, because the echocardiographic model including Doppler data was superior to the "super-simple" approach, we recommend the first and not the latter, if possible. Our study included only patients with COVID-19 infection who were hospitalized. infection. In view of the low number of events, the algorithms presented in the manuscript are liable to overfitting, thus, their prognostic value will need external validation prior to clinical use. Echocardiography was performed by cardiologists with expertise in echocardiography using a mobile system and not a pocket-size handheld device. Thus, our hypothesis regarding the use of hand-held device and very limited exams by non-cardiologists should serve as incentive to explore the issue of "super-simple" echocardiographic exams in patients with COVID-19 infection in larger prospective series. The fact that in some cases echocardiographic and LUS parameters were measured by the cardiologist caring for the patient may lead to bias. We describe a cohort of combined echocardiographic and LUS studies in COVID-19 patients. To achieve maximal clinical value for risk stratification, a very limited echocardiogram in patients with high risk clinical criteria is sufficient. LUS is possibly useful for identifying individuals at risk for mechanical ventilation but not useful for prediction of mortality above clinical and echocardiographic criteria. Importantly, MEWS provides most of the prognostic information needed for risk assessment. Overall survival in patients with COVID-19 infection comparing patients with "good-lung" (LUS score≤ 18) and "good-heart" (red line), "good-lung" (LUS score≤ 18) , and "bad-heart" (at least one cardiac parameter associated with adverse outcome; blue line); "bad-lung" (LUS score> 18) with "good-heart" (no cardiac parameter associated with adverse outcome; green line), and "bad-lung" (LUS score> 18) combined with "bad-heart" (black line). Freedom from the composite event of mortality or need for invasive mechanical ventilation in patients with COVID-19 infection comparing patients with "good-lung" (LUS score≤ 18) and "good-heart" (red line), "good-lung" (LUS score≤ 18) , and "bad-heart" (at least one cardiac parameter associated with adverse outcome; blue line); "bad-lung" (LUS score> 18) with "good-heart" (no cardiac parameter associated with adverse outcome; green line), and "bad-lung" (LUS score> 18) combined with "bad-heart" (black line). 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