Short-term prognostic value of clinical data in hospitalized patients with intermediate-risk acute pulmonary embolism

Abstract

Background: Intermediate-risk APE patients usually defined as hemodynamically stable, comprehending a great therapeutic dilemma , since some can deteriorate and eventually require reperfusion therapy .To evaluate the predictive values of short-term prognosis for intermediate-risk acute pulmonary embolism (APE) patients based on clinical data.

Methods: A retrospective cohort of 74 intermediate-risk APE patients confirmed by computed tomography pulmonary angiography (CTPA) was analyzed in the present study. Adverse clinical events outcomes included PE-related in-hospital deaths, critical systolic blood pressure consistently under 90 mmHg, refractory to volume loading and vasopressor infusion requirements, mechanical ventilation, and cardiopulmonary resuscitation. APE patients were stratified into two groups based on their adverse outcomes (n = 25) and controls (n = 49). Then, the clinical data of the two groups were compared. The receiver operating characteristic (ROC) curve was employed to explore the predictive value of white blood cell (WBC) counts and the ratio of right to left ventricular short-axis (RV/LV).

Results: Brain natriuretic peptide, WBC count, and the RV/LV were higher in patients with adverse outcomes compared to controls. The APE patients with adverse outcomes presented significantly higher rates of syncope, Negative T waves (TWI) in V1-V3, intermediate-high risk, thrombolytic therapy, and low arterial oxygen saturation (SaO₂) compared to controls. In the multivariate logistic regression analysis, the SaO₂＜90%, [odds ratio (OR) 5.343, 95% confidence interval (CI) 1.241-23.008; p = 0.024], RV/LV ratio (OR 7.429, 95% CI 1.145-48.209; p = 0.036), Syncope (OR 12.309, 95% CI 1.702-89.032; p = 0.013) ,TWI in V1-V3 (OR 5.617, 95% CI 1.228-25.683; p = 0.026), and WBC count (OR 1.212, 95% CI 1.035-1.419; p = 0.017) were independent predictors of in-hospital adverse outcomes among APE patients. The ROC curves indicated that the RV/LV ratio can be used to predict adverse outcomes (AUC = 0.748, p＜0.01). Moreover, an RV/LV > 1.165 was predictive for adverse outcomes with sensitivity and specificity of 88.00 and 59.20%, respectively. The WBC counts were also able to predict adverse outcomes (AUC = 0.752, p＜0.01). A WBC count > 9.05 was predictive for adverse outcomes with sensitivity and specificity of 68.00 and 73.50%, respectively.

Conclusion: Overall, a SaO₂＜90%, RV/LV ratio, Syncope, TWI in V1-V3, and WBC counts could independently predict adverse outcomes in intermediate-risk APE patients.

Introduction

Acute pulmonary embolism (APE) is a clinical and pathophysiological syndrome caused by the obstruction of pulmonary circulation. This obstruction is promoted by the blockage of the trunk or branch of pulmonary arteries by endogenous or exogenous emboli. APE is the third most common acute vascular disease worldwide, with a mortality rate behind only myocardial infarction and stroke. The European Union epidemiological model estimates that about 34% of APE patients suddenly die within hours before treatment even begins or becomes effective. 

Risk stratification is considered a critical step to select APE treatment strategies during short-term prognosis [1]. Usually, the PE severity index (PESI) and simplified PESI scores are used to predict the 30-day mortality of APE [2]. Two clinical prognostic scores are used to identify patients with a low risk of death within 30 days of treatment. However, clinical treatments should be based on broader results, such as cardiopulmonary resuscitation, mechanical ventilation, as well as vasopressor infusion requirement, not only PE-related deaths [3]. Clinicians should pay special attention and choose reperfusion treatment for PE patients with hemodynamic instability and high risk. Partial or complete outpatient treatments might be used for low-risk APE patients based on their early complications [1]. In the present study, we focused on intermediate-risk APE patients, usually defined as hemodynamically stable, comprehending a great therapeutic dilemma. According to current guidelines, these patients should be rigorously monitored for any sign of hemodynamic instability, since some can deteriorate and eventually require reperfusion therapy [4]. Therefore, better risk stratification strategies are required. Herein, we evaluated the predictive values of the differences in clinical data for the short-term prognosis of intermediate-risk APE patients.

Patients And Methods

Clinical data collection

 A total of 74 APE patients treated in the First Affiliated Hospital of Wannan Medical College from January 2017 to December 2021 were enrolled in the present study. The inclusion criteria were defined according to the 2019 ESC/ERS Guidelines for the Diagnosis and Management of Acute Pulmonary Embolism [1]. All patients were verified by computed tomography pulmonary angiography (CTPA) and underwent ECG examination within 6 h before and after PE diagnosis. Other clinical data, such as gender, age, disease history, onset signs, D-dimer, cardiac ultrasound, BNP, and troponin I were also recorded in detail. Patients with chronic thromboembolic pulmonary hypertension, acute coronary syndrome, valvular heart disease, cardiomyopathy, myocarditis, pulmonary artery tumor, electrolyte disturbance, clinical history, and incomplete auxiliary examination data were excluded. Patients with echocardiographic signs of right ventricular dysfunction and/or positive biomarkers were classified with intermediate risk according to the 2019 ESC/ERS Guidelines for the Diagnosis and Management of Acute Pulmonary Embolism [1]. In-hospital deaths related to PE, hemodynamic instability and vasopressor infusion requirements,mechanical ventilation, as well as cardiopulmonary resuscitation were considered as adverse outcomes. After diagnosis, routine blood samples were collected for blood cell analysis, and brain natriuretic peptide (BNP), troponin I, and arterial blood gas analysis.

Electrocardiography and CTPA

The paper walking speed of conventional 12-lead ECG was 25mm/s, and the standard voltage was 10 mV. ECG signs were analyzed for right ventricular strain considering the following features: (1) sinus tachycardia; (2) S1Q3T3; (3) Complete or incomplete right bundle branch block (RBBB); (4) supraventricular tachycardia; (5) prolonged QTC interval; (6) Negative T waves (NTW) of lead V1-V3; (7) V1 is Qr; and (8) Clock transposition. Sinus tachycardia was defined as sinus heart rate > 100 beats/min. The S1Q3T3 was defined as S wave in lead I > 1.5 mm, and Q in lead III > 1.5mm associated with an NTW in lead III[5]. The RBBB and clock transposition were consistent with traditional diagnostic criteria[5, 6]. The V1 in Qr was defined as Q wave amplitude ≥ 0.2 mV and width < 120 ms[7]. The NTW was defined as negative T wave amplitude ≥ 0.5 mV[8]. The QTC interval prolongation was defined as QTC ≥ 460 ms[9]. Finally, the cardiac axial CT image was used to measure the RV and LV short-axis diameters at their widest point[10, 11].

Statistical analyses

The SPSS 18.0 statistical software was used to process the data. Data with normal distribution are presented as  . Comparisons between two groups were conducted using t-tests. Data with non-normal distribution are presented as M (P25; P75) and were compared using Mann-Whitney U rank tests. Fisher’s exact and χ² tests were used to evaluate categorical variables. To identify the markers used to predict and estimate in-hospital adverse outcomes, we conducted multivariate logistic regression analysis. Then, ROC curves were employed to confirm the value of continuous data to predict adverse outcomes. A p < 0.05 was considered statistically significant.

Results

A total of 49 (66.2%) controls and 25 (33.8%) APE patients with adverse outcomes were enrolled in this study. The laboratory findings, predisposing factors, as well as the baseline demographic characteristics are presented in Table 1. Brain natriuretic peptide (648.66 ± 478.70 vs 393.25 ± 374.87 pg/mL; p = 0.014), WBC count [10.30 (8.30; 13.30) vs 7.60 (5.85; 8.95) × 109/L; p＜0.05] and RV/LV ratio (1.51 ± 0.52 vs 1.17 ± 0.48; p = 0.006) were significantly higher in patients with adverse outcomes compared to control APE patients. The patients with adverse otucomes also showed higher Syncope [7 (28.0%) vs 4 (8.2%); p = 0.039)], TWI in V1-V3 [12 (48.0%) vs 8 (16.3%); p = 0.006], intermediate high risk [20 (80.0%) vs 25 (51.0%); p = 0.023], and thrombolytic therapy [14 (56.0%) vs 6 (12.2%); p < 0.05)] rates. On the other hand, these patients presented lower SaO₂ [10 (40.0%) vs 8 (16.3%); p = 0.043] compared to controls. 

Next, a binary logistic regression analysis was carried out with all patients to determine the independent factors for in-hospital adverse outcome prediction. According to the univariate analysis, a SaO₂ < 90%, RV/LV ratio, Syncope, TWI in V1-V3, intermediate high-risk, BNP, and WBC count were considered as potential independent predictors of adverse outcomes among APE patients. After the multivariate logistic regression, the SaO₂ < 90%, [OR 5.343, 95% CI 1.241-23.008; p = 0.024], RV/LV ratio (OR 7.429, 95% CI 1.145-48.209; p = 0.036), Syncope (OR 12.309, 95% CI 1.702-89.032; p = 0.013), TWI in V1-V3 (OR 5.617, 95% CI 1.228-25.683; p = 0.026), and WBC count (OR 1.212, 95% CI 1.035-1.419; p = 0.017) remained independent predictors of in-hospital adverse outcomes (Table 2). Consistently, the predictive value of the RV/LV ratio was confirmed by its ROC curve (AUC = 0.748, p < 0.01; Fig. 1A). Moreover, an RV/LV ratio > 1.165 was predictive for adverse outcomes with sensitivity and specificity of 88.00 and 59.20%, respectively. The predictive value of WBC counts was also confirmed by its ROC curve (AUC = 0.752, p < 0.01; Fig. 1B). A WBC count > 9.05 was predictive for adverse outcomes with sensitivity and specificity of 68.00 and 73.50%, respectively.

Discussion

In this retrospective study, we identified the differences regarding the clinical data and electrocardiography between control and adverse outcome intermediate-risk APE patients. We showed that TWI in V1-V3, Syncope, and SaO2 < 90% were more common in the adverse outcome group. Increased BNP, WBC count, and RV/LV ratio were also observed in the adverse outcome group compared to controls. The regression analysis showed that a SaO₂ < 90%, RV/LV ratio, Syncope, TWI in V1-V3, and WBC count were independent predictors of in-hospital adverse outcomes among the APE patients enrolled in the present study.

Previously, integrating independent predictors, such as echocardiographic RV dysfunction or CT, blood biomarkers, as well as clinical prediction scores, were used to obtain a risk-stratification for PE [1]. Currently, SaO₂＜90%, RV/LV ratio, Syncope, TWI in V1-V3, WBC count, as well as ECG findings are not incorporated in the guidelines of PE risk-stratification criteria. The PESI and simplified PESI scores are the most frequent and validated scores used to predict the 30-day mortality of PE [2]. However, besides mortality, short-term adverse outcomes can not be predicted by these indicators. Hence, PE patients need additional measures to predict the incidence of adverse outcomes besides mortality. Thus, intermediate-risk PE patients who are more likely to deteriorate can benefit from more intensive monitoring, as well as more aggressive therapeutic approaches, including thrombolysis and/or mechanical thrombectomy [4, 12, 13]. 

Subramanian et al. [14] found that hypoxia was an independent predictor for adverse outcomes in PE patients, similar to our current results. Among the possible mechanisms of arterial hypoxia in APE, previous studies considered that the impaired oxygen transfer was caused by the mismatch of perfusion and ventilation. Other mechanisms, such as diffusion impairment, low cardiac output (as a result of RV dysfunction), as well as right-to-left shunt, could also be involved [15].

In PE patients, RV dysfunction is indicated by ECG findings, including RBBB, S1Q3T3, and TWI in V1-V3. For example, Choi and Park showed that TWI in the precordial leads was the strongest independent predictor of right ventricular dysfunction in APE patients [16]. However, the pathophysiological mechanisms of TWI in V1-V3 of APE patients remained unclear. This can be mainly explained by acute cor pulmonale due to RV dilatation followed by rapid RV pressure overload, besides RV dysfunction inducing TWI, impairing myocardial perfusion, as well as reducing the left ventricle preload. Moreover, cellular ischemia caused by chemical mediators, including histamine and catecholamine, is also associated with TWI development [8]. In recent studies, the RBBB, S1Q3T3, and TWI in V1-V3 were frequently observed in the adverse outcome group compared to controls and regardless of the APE risk stratification. Since these indicators are surrogate markers for short-term prognosis, they were used to predict adverse outcomes [2]. In the present study, TWI in V1-V3 was an independent predictor of in-hospital adverse outcomes among intermediate-risk APE patients. However, S1Q3T3 and RBBB were not significantly more frequent in the adverse outcome group than in controls. 

Recently, the WBC count was considered as an independent predictor for hospital readmission and short-term mortality in APE patients [17]. Consistent with previous reports, we also indicated that the WBC count can be used as an independent predictor for short-term adverse outcomes. Meanwhile, the ROC curve (AUC = 0.752, p < 0.01) analysis in our study showed that WBC count has a high accuracy to assess adverse outcomes with cut-off values of 9.05 in intermediate-risk acute pulmonary embolism. Right heart dysfunction is a known predictive factor for adverse prognosis and might be indicated by elevated WBC counts in APE patients. The correlations between the levels of factors VIII and VII, as well as fibrinogen and WBC count, were observed by some previous studies. Therefore, elevated WBC count can be used as a marker of hypercoagulability, which might lead to worse prognoses [18, 19].

 Here, significantly more prominent parameters that indicate RV dilatation and dysfunction were observed in the population with adverse outcomes compared to controls. The ROC curve (AUC = 0.748, p < 0.01)analysis in our study showed that RV/LV ratio has a high accuracy to assess adverse outcomes with cut-off values of 1.165 in intermediate-risk acute pulmonary embolism.The RV enlargement, characterized by RV/LV ratio ≥ 0.9, was previously reported as an independent predictor of adverse in-hospital outcomes, both in the overall PE population and in hemodynamically stable patients [10]. In a meta-analysis, positive correlations were previously observed between five-fold risk PE-related mortality and/or 2.5-fold increased risk for all-cause mortality and increased RV/LV ratio ≥ 1.0 on CT from 49 studies and > 13000 PE patients [20]. It is worth mentioning that RV/LV ratio in this study was measured by the short axial views rather than four-chamber reconstruction.A study have shown that RV/LV ratio obtained from four-chamber views are superior to those from axial views for identifying high-risk PE patients[21]. However, compared with short axial views, this method is more time-consuming and requires specific software tools, which is disadvantageous in emergency situations.

Although the detailed mechanism about syncopes in APE patients is not completely understood, it is considered a concerning feature in these patients. The neurogenic syncope and associated dysrhythmias derived from Bezold–Jarisch type vasovagal reflexes, as well as acute right ventricular failure, are considered the main mechanisms to explain PE-related syncopes. However, perfusion or ventilation abnormalities caused by hypoxemia might be significantly involved in the development of syncopes. Due to transient depressions in cardiac output, main pulmonary or lobar artery obstructions are also associated with syncope [22, 23]. In intermediate-risk PE patients with right ventricular involvement, the presence of syncope is associated with a more complicated in-hospital course [4]. Similar to previous reports, we demonstrated that intermediate-risk APE patients with syncope were at higher risk for clinical deterioration during hospitalization, compared with those without syncope. Although syncope has been suggested as a marker for adverse outcomes in these patients, data remain scarce. Overall, intermediate-risk PE patients are a heterogeneous group.

Study limitations 

Our current study is limited by its retrospective design. Hence, selection bias was inevitable, and can only be addressed as hypothesis-generating. Prospective randomized studies are required to evaluate whether more aggressive therapeutic approaches in APE patients are warranted.

Conclusions

Although anticoagulation therapy is sufficient for most intermediate-risk PE patients, some can present a poorer prognosis in the acute phase, thereby requiring advanced and reperfusion therapies, compared with their low-risk PE counterparts. In the present study, we showed that SaO₂ < 90%, RV/LV ratio, Syncope, TWI in V1-V3, and WBC count could independently predict adverse outcomes in intermediate-risk APE patients. These patients might benefit from interim intensive surveillance, including continuous monitoring and ongoing assessment to select treatment strategies beyond anticoagulation.

Declarations

Acknowledgements 

The authors appreciated all participants in this article for their contributions.

Authors’ contributions 

Concept/design: J-CL,Y-YL.  Data collection and/or compilation :J-CL, F-LZ, PF,CF,YL.  Data analysis and interpretation :Y-QW, J-FW, X-HW, HY.  Manuscript writing: J-Cl, Y-YL,X-RX.  All authors reviewed the manuscript, and revised and approved the content of the final version for publication.  

Funding

This study was funded by the Key Construction Project of Medical and Health Specialty in Anhui Province and Wannan Medical College Youth Fund(WK2020F09).  Funders play a vital role in data analysis and manuscript preparation  

Availability of data and materials 

The original data supporting the conclusions of this paper will be provided by the corresponding authors without undue reservation.  

Ethics approval and consent to participate

The author is responsible for all aspects of the work to ensure that issues related to the accuracy or completeness of any part of the work are properly investigated and resolved. This study was in accordance with the Heksinki Declaration.All experimental protocols and methods were approved by the Institutional Review Board of The First Affiliated Hospital of Wannan Medical College. Informed consent was waived as it was retrospective study,which was approved by the Institutional Review Board of The First Affiliated Hospital of Wannan Medical College. 

Consent for publication 

Not applicable. 

Competing interests 

The authors declare that there is no conflict of interest in the publication of this paper.

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Tables

Table1.Clinical, electrocardiographic, laboratory, and computed tomographic findings

DVT, deep venous thrombosis,COPD,chronic obstructive pulmonary disease,CAD,coronary artery disease,Bp,Blood pressure, SaO₂,arterial oxygen saturation , BNP,brain natriuretic peptide, RV/LV,right ventricular short-axis to left ventricular shor-taxis, NTW ,Negative T waves.WBC,white blood cell.

^a Chi-squared, ^bindependent-samples t test,^cMann–Whitney U test .

p<0.05 indicates statistical significance and was shown in bold characters.

Table 2.Univariate and multivariate analysis for in-hospital Adverse outcome in patients with intermediate risk pulmonary embolism

RV/LV,right ventricular short-axis to left ventricular short-axis, BNP,brain natriuretic peptide, NTW ,Negative T waves, WBC,white blood cell, SaO₂,arterial oxygen saturation.

p<0.05 indicates statistical significance and was shown in bold characters.