Safety and efficacy of thrombolytic therapy in the treatment of early pulmonary embolism after thoracic surgery

Introduction

Venous thromboembolism (VTE), which includes deep venous thrombosis (DVT) and pulmonary embolism (PE), is a manifestation of the same disease at different stages and in different body parts. PE significantly affects the lives of patients and can even lead to death (1). Compared to a similar study conducted ten years ago, there seems to be a general increase in DVT and PE incidences (2). This longitudinal survey showed that postoperative thromboembolic events were common, with DVT occurring in up to 0.2% of patients and PE in 0.12% of patients (2). Worldwide, in both sexes combined, lung cancer is the most commonly diagnosed cancer (11.6% of the total cases) and the leading cause of cancer-related death (18.4% of the total cancer-related deaths) (3). Esophageal cancer ranks seventh in terms of incidence (572,000 new cases) and sixth in mortality overall (509,000 deaths), and China ranks among the top five countries worldwide (3). The incidence of perioperative VTE is high in both lung and esophageal cancers (4,5).

The guidelines for prevention and management of perioperative VTE in patients with thoracic malignancies in China recommend that low-molecular-weight heparin (LMWH) or fondaparinux can be used to prevent perioperative VTE after evaluating the risk of VTE occurrence and bleeding (6). According to the diagnostic and treatment guidelines of DVT, thrombolytic therapy is recommended when PE occurs (1). However, early thrombolytic therapy in patients with PE after thoracic surgery may lead to massive bleeding, which is the reason why every thoracic surgeon is reluctant to implement it. Despite thrombolytic treatment having an increased total bleeding risk, there was no difference in the incidence of major bleeding events compared with patients receiving anticoagulation treatment (7). If anticoagulation is feasible, thrombolytic therapy is also feasible, and successful reports of thrombolytic therapy for PE after surgery do exist (8-10). Our thoracic surgery department also initiated thrombolytic therapy for PE occurring in the early postoperative period. Here, we analyze and summarize the safety and efficacy of urokinase thrombolytic therapy for patients with early postoperative PE in our department and discuss the treatment strategies for such patients. We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-782/rc).

Methods

Patients’ characteristics

The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by ethics board of Affiliated Hospital of North Sichuan Medical College (approval document No. 2022ER485-1), and individual consent for this retrospective analysis was waived. We retrospectively analyzed 40 patients who had PE early after surgery for esophageal cancer and lung tumor in the Department of Thoracic Surgery, Affiliated Hospital of North Sichuan Medical College from January 1, 2015 to November 1, 2022. Of these, three patients died suddenly after PE and had no time for anticoagulation or thrombolytic therapy. We analyzed the treatment of 37 patients with postoperative PE, including 20 with esophageal cancer, 17 with lung cancer, and 27 men and 10 women. For patients with PE, we recommend thrombolysis therapy, but there is a risk of bleeding in thrombolysis therapy. After informing the patient and their family members of the thrombolysis risk, whether to choose thrombolysis therapy was according to their wishes. Before thrombolysis therapy, a consent form for thrombolysis therapy must be signed. Among them, 21 patients were treated with thrombolytic + anticoagulant therapy and classified as group A (exposure group), whereas 16 patients were only treated with anticoagulant therapy and classified as group B (non-exposure group).

The general information gathered included sex, age, smoking and drinking history, body mass index (BMI), diabetes, hypertension, chronic obstructive examined were the operation method (endoscopy or thoracotomy), operation time, pulmonary disease, hyperlipidemia, and postoperative lung infection. Additional parameters amount of bleeding, tumor staging after the operation, time of PE, bleeding after thrombolytic and anticoagulant therapy, chest drainage volume, prognosis, postoperative D-dimer (D-D), post-treatment oxygen partial pressure (PO₂), and partial pressure of carbon dioxide (PCO₂).

It is difficult to establish a clear clinical diagnosis of PE after surgery. Most patients have an acute onset, obvious dyspnea, unstable hemodynamics, and are not easy to move. It is difficult to perform a computed tomographic pulmonary angiography (CTPA) examination. The diagnosis of PE is mainly based on the sudden occurrence of dyspnea, syncope, refractory hypoxemia, sudden chest pain, D-D levels, and color Doppler echocardiography of the heart and blood vessels when the patients get out of bed and move, which is also known as presumed PE. Five patients underwent CTPA or pulmonary angiography for the confirmation of PE.

Treatment method

After excluding absolute contraindications to anticoagulation and thrombolysis, anticoagulants and thrombolytics were administered. The anticoagulant drug was LMWH calcium (1 mL: 5,000 IU), and the thrombolytic drug was urokinase with a specification of 100,000 U/tube. The dosage of each thrombolytic treatment (200,000–1,000,000 U) and the number of times each treatment implemented (1–13 times) were variable. Our treatment was based on the recovery of oxygen saturation, reduction of D-D value, and no bleeding. When the symptoms of hypoxia improved significantly or there was significant bleeding, we stopped thrombolysis. The iterations of thrombolytic treatment were 1–3 in 16 patients, seven in four patients, and 13 in one patient; LMWH was injected subcutaneously every 12 h, and urokinase was administered diluted in 250 mL normal saline from the peripheral veins of the lower limbs. The infusion was completed within 2 h daily. There was no massive hemorrhage, and the end point of anticoagulant treatment was three months either when the patient died or when the patient was discharged from the hospital after rehabilitation (LMWH was used in the hospital and rivaroxaban was taken orally after discharge). Anticoagulant and thrombolytic drugs were discontinued in case of massive hemorrhage after treatment.

Statistical analyses

The SPSS 25.0 statistical software was used to analyze the data. Normally distributed measurement data were expressed as the mean ± standard deviation (x¯±s). An independent sample t-test was adopted, and the counting data were expressed as frequency/percentage. The Chi-squared test was used, but if the theoretical number was T<1 or the total number of samples was n<40, the Fisher exact probability method was used. All the statistical analyses were based on two-sided hypothesis tests. A test level of α=0.05 was used, and logistic regression analysis was implemented if the outcome variable was a binary variable.

Results

During the study period, there were 8,655 patients with esophageal cancer and lung cancer in our department: 40 patients (0.46%) had PE early after surgery; of those, 3 (7.5%), 19 (47.5%) and 14 (35%) cases had PE on the first, second and third day, respectively. PE occurred more than 3 days after surgery in 4 patients (10%). Among those, three patients died suddenly when PE occurred. Ninety percent of postoperative PE occurred within the first 3 days. There were three cases of PE due to a postoperative benign pulmonary tumor, and one patient died. There was no significant difference between the two groups in age, sex, preoperative complications, BMI, smoking, drinking, operation time, blood loss, and tumor stage after operation, as shown in Table 1.

The PO₂ in groups A and B on the third and fourth day after treatment was significantly different (P<0.05). The oxygen pressure in group A gradually increased, whereas the oxygen pressure in group B did not improve significantly, as shown in Figure 1. The change in the partial PCO₂ in groups A and B was not obvious after treatment, as shown in Figure 2. The D-D value was significantly different between groups A and B at the time of PE after operation and on the fourth day after treatment (P<0.05). The D-D level in group A showed a downward trend, while the D-D level in group B showed an upward trend after treatment, as shown in Figure 3. The mortality rate of group A was 19.0%, while that of group B was 81.3%, i.e., significantly different (P<0.001). This showed that thrombolytic + anticoagulant therapy could reduce the mortality of patients compared to anticoagulant therapy, as shown in Figure 4. The total mortality rate of the two groups plus three sudden deaths was 50%, and the total mortality rate of the two groups after treatment was 45.94%. There were no cases of massive hemorrhage in either group after the treatment. There was no significant difference in the time of PE, thoracic drainage volume after treatment, D-D value on the second and third days after treatment, PO₂ on the first and second days after treatment, and PCO₂ within the four days after treatment between the two groups (P>0.05), as shown in Table 2.

Figure 1 Changing in PO₂ after treatment. Day 1: the first day after surgery; Day 2: the second day after surgery; Day 3: the third day after surgery; Day 4: the fourth day after surgery. The partial pressure of oxygen in group A was significantly improved than that in group B. The partial pressure of oxygen in group A was significantly improved than that in group B. The partial pressure of group A increased gradually, while the partial pressure of group B did not improve. Group A: thrombolysis group; group B: non-thrombolysis group. PO₂, partial pressure of oxygen.

Figure 2 Changing in PCO₂ after treatment. Day 1: the first day after surgery; Day 2: the second day after surgery; Day 3: the third day after surgery; Day 4: The fourth day after surgery. The change of PCO₂ in group A and group B after treatment was not significant. But the PCO₂ of both groups is in the upper limit. Group A: thrombolysis group; group B: non-thrombolysis group. PCO₂, partial pressure of carbon dioxide.

Figure 3 Changing in D-D after treatment. Day 1: the first day after surgery; Day 2: the second day after surgery; Day 3: the third day after surgery; Day 4: the fourth day after surgery. At the beginning, both groups had higher D-D value. The higher the D-D value, the more clinicians will pay attention to it. The D-D value in Group A showed a decreasing trend after thrombolytic therapy. The D-D value in group B showed an increasing trend. Group A: thrombolysis group; group B: non-thrombolysis group. D-D, D-dimer.

Figure 4 The difference in the perioperative period survival rate between group A and group B. The survival rate of group A was significantly higher than that of group B in the perioperative period. Group A: thrombolysis group; group B: non-thrombolysis group.

A logistic regression model was generated and included age, thrombolysis, and diabetes. The results showed that the older the age, the higher the risk of death, with statistical significance [odds ratio (OR) 0.682, 95% confidence interval (CI): 0.477–0.975, P=0.04]. Compared with non-thrombolytic therapy, thrombolytic therapy could significantly improve the survival of postoperative PE (OR 72.17, 95% CI: 2.337–2,229.012, P=0.01). Additionally, the risk of death associated with diabetes was significantly increased (OR 0.015, 95% CI: 0.000–0.931, P=0.046), as shown in Table 3.

Discussion

The incidence rate of postoperative PE in patients has increased year by year and reached 0.16% in 2016 (11). PE is associated with higher mortality (11). This study found that the incidence of early postoperative PE was 0.46%. It was reported that the overall 30-day incidence of PE after thoracic surgery was 0.53% in Li et al.’s study, and the 30-day PE incidence without chemical prophylaxis was 0.57% (55/9,726) and the mortality rate was 10% (12). Among the 70 patients with esophagectomy, a total of 10 cases of VTE occurred within a 60-day window (9 within 30 days postoperatively), with a cumulative incidence of 14.3% (5). There were three DVTs and seven PEs (5). The rates were 2.0% for PE, 3.7% for DVT, and 5.1% for VTE (13). However, mortality was not reported. In a post-esophagectomy study, VTE was diagnosed in 84 patients (2.9%) and PE in 1.5% (44 patients) (14). Overall, the mortality rate reached 7.3% with a significantly higher rate difference between the VTE+ and VTE− groups (23% and 7%, respectively, P<0.001), while of note, in the VTE group, 5/19 recorded deaths (26.3%) were directly caused by PE (14). This study found that the total mortality rate after early postoperative PE treatment was 45.94%, but the mortality rate in the thrombolytic group A was only 19%. It can be seen that PE is a serious threat to the postoperative lives of patients, which requires great attention.

For the diagnosis of postoperative PE in patients, the 2019 European Society of Cardiology (ESC) guidelines for PE recommend the following diagnostic methods: clinical presentation (dyspnea, chest pain, syncope, or hemoptysis), assessment of clinical (pre-test) probability, D-D testing, CTPA, lung scintigraphy, pulmonary angiography, and echocardiography (15). CTPA is the preferred diagnosis for PE (16,17). However, it is difficult for patients with severe clinical symptoms to undergo CTPA when diagnosing PE after thoracic surgery. Even in patients not undergoing surgery (remaining 60 of the cases), the PE diagnosis was based on clinical findings (18). It is safe and fast to obtain the D-D value, so the D-D plays an important role in the diagnosis of PE. Monitoring D-D detection value is possible for concentrations of <1.0 µg/mL, which is helpful for excluding PE diagnosis (19,20). The diagnosis, treatment rate, and prognosis can be improved by monitoring indicators such as D-D (21). This study also found that the D-D level increased significantly and was >10 times higher than 1.0 μg/mL when PE occurred after surgery. The diagnosis of PE can be inferred from D-D levels and clinical manifestations. This study also found that the D-D value of group A after treatment showed a downward trend, while the D-D value of group B after treatment fluctuated greatly and showed an upward trend; therefore, the D-D value can be used to observe the treatment effect.

There are many therapy methods for PE such as thrombolysis treatment, surgical thrombectomy, mechanical thrombectomy, and percutaneous catheter therapies, etc. (22). Each type of treatment has its own characteristics or side effects. For example, surgical thrombectomy requires skilled surgeons and carries potential risks such as infection, bleeding, and haemodynamic instability, and this highly invasive procedure is rarely used (22), and percutaneous catheter-based therapies and mechanical thrombectomy carry potential risks such as arterial wall damage, access-related vascular complications, and formation of small thrombus, besides complications of percutaneous catheter-based therapies include contrast-associated kidney injury and device-specific complications (23,24). Of course, all of these treatments carry a risk of bleeding. Systemic thrombolysis is the standard of treatment in the treatment of high-risk PE (15), and systemic thrombolysis may also be considered for some intermediate-risk PE, and the most common risk of systemic thrombolytic therapy is bleeding (15). Therefore, in the treatment of postoperative PE, we give priority to systemic thrombolysis. In conclusion, the patients in this study were all patients who developed PE early after surgery. These patients are not patients with common PE. Our hospital has not tried the method of re-operation thrombectomy in patients after thoracic surgery. And the safety and effectiveness of Invasive therapy in these patients is more uncertain. Thrombolytic therapy was mainly used in this study.

For the prophylaxis and therapy of PE postoperatively in patients, the 2019 ESC guidelines for PE recommend that PE should be assessed for severity. First, high-risk PE requires systemic thrombolytic therapy, while intermediate-risk PE does not necessitate in-time thrombolytic therapy treatment. Low-risk PE can be treated at home as appropriate (15). It mainly consists of the following: maintenance of hemodynamic stability and respiratory support, anticoagulant therapy, thrombolytic therapy, percutaneous catheter-guided therapy, and surgical thrombectomy. The guidelines do not mention the evaluation of the bleeding risk with anticoagulant and thrombolytic therapy (15). Although the treatment suggestions for PE have been put forward, those for postoperative PE have not been mentioned. The 2021 USA guidelines for VTE point out that the drug prophylaxis for VTE in patients with cancer after surgery is better than that before surgery. For patients with cancer who undergo surgery, mechanical prophylaxis and drug prophylaxis [Low molecular weight heparin (LMWH) or fondaparinux] depend on their condition and it is mainly aim to assess the risk of VTE formation and bleeding risk of anticoagulation with drugs, focusing on the prophylaxis of VTE in the perioperative period (25). The 2022 China guidelines for perioperative VTE of thoracic surgery recommend that patients with esophagectomy or pulmonary resection who are at high risk of VTE use LMWH or fondaparinux to prevent anticoagulation for 7–35 days. This suggests that the risk of VTE formation, the risk of patient bleeding, and the high-risk factors of perioperative massive bleeding need to be assessed; however, the use of postoperative PE has not been mentioned. The highest risk of anticoagulant and thrombolytic therapy is extensive hemorrhage. Thrombolytic treatment for patients with intermediate-risk PE, if not contraindicated, could reduce the clinical deterioration and recurrence of PE, and trends towards a decrease in all-cause, 30-day mortality can be observed (7). Despite thrombolytic treatment having an increased total bleeding risk, there is no difference in the incidence of major bleeding events compared to patients receiving anticoagulation treatment (7). The results of this study showed that there were no cases of extensive hemorrhage after thrombolytic therapy. Multivariate logistic regression analysis showed that thrombolytic therapy significantly affected the survival rate of patients perioperatively, and it is recommended for high- or intermediate-risk postoperative PE after excluding thrombolytic contraindications. This study found that there were no cases of massive bleeding after thrombolytic therapy in patients with early PE after thoracic surgery, which may be related to postoperative hypercoagulability and cancer.

The main causes of death in this study were respiratory failure, cardiac arrest, and pulmonary infections. No patient died because of massive hemorrhage after thrombolysis. Among patients who were administered vasopressors, thrombolytics were not associated with hospital mortality (thrombolysis in 41% of the cases vs. no thrombolysis in 35% of the cases) (26). A previous study reported that a patient who underwent hepatectomy had no major bleeding after thrombolytic therapy for PE (27). Another patient was reported to have renal hemorrhage after PE and thrombolytic therapy after percutaneous nephrolithotomy and renal artery embolization on the third postoperative day (28). We suspect that the patient may have had active renal hemorrhage after the operation, which was aggravated during the thrombolytic therapy. In our thoracic surgery department, there was a case of bleeding after early PE thrombolytic therapy post-lung surgery (29). The initial dose for this patient was 20,000 U/kg, which was pumped into the peripheral vein within 2 h (29). The initial single dose was too high, which may have caused bleeding. Patients undergoing thrombolysis in this study did not exhibit active bleeding or other thrombolytic contraindications. The initial single dose of 200,000–300,000 U did not cause any massive bleeding.

The fibrinolysis and blood coagulation systems are regulated by many small molecules and are central to the hemostatic mechanism (30). When the effect of fibrinolysis is greater than that of blood coagulation, bleeding may occur. Therefore, we need to evaluate the bleeding risk, adjust the drug dose, and avoid using it when there are thrombolytic contraindications. This may also be the reason for the lack of bleeding with thrombolytic therapy in this study.

A recent study mentioned that systemic thrombolysis was administered despite 56% of patients having had contraindications to thrombolysis, with 26% experiencing major bleeding with no intracranial hemorrhage (31). Our study excluded the contraindication of thrombolysis, and the bleeding rate after thrombolytic therapy was not so high. Survival to hospital discharge was 65% for the patients with confirmed PE vs. 6% for those presumed to have PE (P<0.01) (31). We found that for patients with suspected PE, most thrombolytic therapy use was limited to cardiac arrest situations (90%), which could account for the dismal survival to discharge rate of 6% for these patients (31). Therefore, thrombolysis cannot be considered until cardiac arrest or hemodynamic instability, and timely thrombolytic treatment is very necessary. The in-hospital mortality of patients with confirmed acute PE has remained high (35%) in contemporary practice for those treated with systemic thrombolysis (31). In this study, contraindications to thrombolysis were excluded. The mortality rate of the thrombolytic group was only 19%, whereas that of the non-thrombolytic group was 81.3%. Therefore, timely thrombolytic therapy is effective for early PE after surgery.

Conclusions

This retrospective study demonstrates that, in the absence of absolute contraindications for anticoagulation and thrombolysis, urokinase can be used reasonably, and timely thrombolysis combined with anticoagulation treatment can significantly improve the perioperative survival rate of patients with early postoperative PE without massive bleeding. Thus, early postoperative PE should be treated using thrombolysis in a timely manner.

Acknowledgments

We sincerely thank the doctors of the Thoracic Surgery Department of the Affiliated Hospital of North Sichuan Medical College for their timely treatment of the patient with pulmonary embolism, and thank you for the cases provided by all teachers.

Funding: None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-782/rc

Data Sharing Statement: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-782/dss

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-782/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-782/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by ethics board of Affiliated Hospital of North Sichuan Medical College (approval document No. 2022ER485-1), individual consent for this retrospective analysis was waived.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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