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.