Does the presence of systemic artery–pulmonary circulation shunt during bronchial arterial embolization increase the recurrence of noncancer-related hemoptysis? A retrospective cohort study

We queried the baseline information, preoperative computed tomography (CT) and angiographic data of 436 consecutive adult patients who underwent arterial embolization for hemoptysis at our institution between January 2015 and December 2020. The exclusion criteria were as follows: (1) cancer-related hemoptysis (n = 59); (2) technical failure (n = 3); (3) clinical failure (n = 8); (4) history of BAE or lobectomy (n = 12); (5) incomplete clinical information (n = 3); and (6) unavailable follow-up date (n = 25). Ultimately, 134 patients were enrolled in the SPS-present group, while 192 patients were enrolled in the SPS-absent group. Figure 1 shows the patient enrollment flowchart. The presence of SPS was identified by the presence of feeding arteries (bronchial arteries and NBSAs) and pathological communicating and drainage vessels (Fig. 2) on dynamic angiography by two doctors independently; the decision was discussed with a senior doctor, and an agreement was reached, ensuring the reliability of the assessment.

The covariates in the present study included baseline information (age, sex, underlying lung disease, smoking, hypertension, duration and volume of hemoptysis), preoperative CT findings (number of affected lobes, presence of pleural thickening, and lung destruction), and angiographic data (number and diameter of culprit bronchial arteries, presence of NBSAs, and embolization materials). Hemoptysis severity was graded and classified into three levels according to the volume of hemoptysis: mild (< 100 ml/d), moderate (100–300 ml/d), and massive (≥ 300 ml/d) [17]. Eight patients underwent bronchoscopy, CT and CT angiography (CTA) were performed for every patient during hospitalization. They could show underlying lung disease, locate the bleeding source, identify origins and courses of bronchial arteries and NBSAs, which provide high possibility for clinical success after BAE. The underlying lung disease included bronchiectasis, tuberculosis sequelae, chronic pneumonia, and cryptogenic hemoptysis. Cryptogenic hemoptysis indicated a lack of specific parenchymal or vascular abnormalities in the lung, as noted on preoperative CTA [18]. Pleural thickening > 3 mm was diagnosed as pathological [19]. Irreversible parenchymal destruction characterized by diffuse adhesions and large cavities was defined as lung destruction [20].

All patients received standard medical care, including vital sign monitoring, hypoxemia correction, and hemostasis. The angiographic machines used included the Artis Zeego Digital Subtraction Angiography (DSA) (Siemens, Germany) and UNIQ FD20 DSA (PHILIPS, Netherlands) devices. The BAE procedure was performed by two interventional physicians with 8 and 10 years of experience. Before the procedure, they reviewed CT and CTA images to observe anatomy of the culprit artery and searched suspicious NBSAs according to the location of lung lesion, in particular, inferior phrenic arteries for inferior lobe lesion, internal mammary or esophageal arteries for medial lung lesion and superior thoracic arteries for superior lobe lesion, lateral thoracic arteries for lateral lung lesion, etc.. All procedures were performed via the femoral artery approach. A 5-F angiographic catheter (Cobra, RLG, MIK; Cook, USA) was inserted into suspicious culprit vessels (bronchial and nonbronchial arteries) to perform angiography with a total volume of 6–10 ml contrast agent (iodixanol 320 mgI/ml, GE Healthcare, United States or iopromide 370 mgI/ml, BAYER, Germany) injected at a speed of 1.5–2.0 ml/s. The abnormal angiographic findings included contrast agent extravasation, hypertrophic and tortuous vessels, hypervascularity, and presence of an SPS [21]. Then, a microcatheter (2.7F; Terumo, Tokyo, Japan; or 2.4F; Merit Maestro, Utah, USA) was advanced as distally as possible to avoid ectopic embolization. The embolic materials were polyvinyl alcohol (PVA) particles (300–500 μm; Cook, USA), microspheres (500–700 μm; Merit Maestro, Utah, USA), and gelatin sponge particles (350–560 μm; Hangzhou Alicon Pharmaceutical Co., Ltd., Zhejiang, China). Microcoils (Cook, USA) were used for large vessel diameters or aneurysmal dilatation of culprit vessels after initial embolization with particles. The endpoint of embolization was complete occlusion of all the culprit arteries.

Technical success was reflected by immediately successful embolization of all culprit vessels; otherwise, the procedure was considered a technical failure [22]. Clinical success was defined as the resolution of hemoptysis within 24 h after the procedure; otherwise, the procedure was defined as a clinical failure [22]. Severe procedure-related complications resulted in prolonged hospitalization, advanced care, unscheduled admission for therapy after discharge, permanent sequelae or death; all other complications were considered minor complications [23].

After discharge, follow-up evaluations in an outpatient clinic were scheduled at approximately 1–3 months. Subsequently, the patient was followed up by telephone interview approximately every six months for the first two years. If there was no recurrence, the follow-up calls were reduced to once a year. The follow-up assessed the general condition of the patient, queried details of hemoptysis recurrence (date of relapse, volume of hemoptysis, and management details) and provided healthy lifestyle education, including on smoking cessation, precautions according to the season of the year, abdominal respiration, and controlling pulmonary infections with low-dose macrolide therapy. Recurrence was defined as relapse with a hemoptysis volume ≥ 30 ml per day, the need for repeated BAE or lobectomy, or death due to recurrent hemoptysis after clinical success [11]. According to the angiographic findings during repeated BAE, the cause of the recurrence was also documented; these causes included missed culprit arteries, recanalization and new collateral arteries. The end date of follow-up was May 2021 or the date of death.

All data analyses were performed with the Statistical Package for the Social Sciences (SPSS, version 22.0, Armonk, NY, USA). Patients with complete follow-up information were included in the final analysis. Continuous variables are described as the means and standard deviations (SD), and categorical variables are expressed as numbers (%). We compared the baseline characteristics of patients in the SPS-absent and SPS-present groups. Categorical variables were compared with the χ² test or Fisher’s exact test. Continuous variables were compared with the t test or the Wilcoxon test. Cumulative hemoptysis-free curves were estimated by the Kaplan–Meier method. The impact of SPSs on recurrence was assessed by four different Cox proportional hazards regression models. Model 1 was a univariate Cox proportional hazards regression model. Model 2 was the full model that integrated all potential factors. Then, multivariate Cox analysis was performed to identify the statistically significant variables (P < 0.1) in Model 2, which was described as Model 3. In Model 4, the presence of SPS was the only factor maintained in the model, and the other variables were screened in a forward stepwise manner. A P value < 0.05 was considered to indicate statistical significance. A forest plot was generated with GraphPad Software (Prism 8.0.1, San Diego, California) according to the hazard ratio (HR) and 95% confidence interval (CI) of different models.

The baseline characteristics of the study cohort are provided in Table 1. The SPS-present group had more female patients (P = 0.001), a different composition of underlying lung disease (P < 0.001), a longer duration of hemoptysis (P < 0.001), more affected lobes (P < 0.001), culprit arteries with larger diameters (P < 0.001), and a higher incidence of pleural thickening (P < 0.001), lung destruction (P = 0.001) and culprit NBSAs (P < 0.001) than the SPS-absent group. The other variables did not show significant differences between groups.

In total, we embolized 832 culprit arteries, including 733 bronchial arteries (401 in the right lung, 332 in the left lung) and 99 NBSAs, with an average of 2.6 arteries per patient. Culprit NBSAs were identified in 57 (42.5%) patients in the SPS-present group and 25 (13.0%) patients in the SPS-absent group. There were no significant differences in the number of culprit bronchial arteries and embolization materials (P = 0.677 and P = 0.273, respectively). Microcoils were used to treat high-level shunts in 10 patients (bronchial artery: 9 patients; NBSAs: 1 patient) and for aneurysmal dilatation of culprit arteries in 6 patients (bronchial artery: 5 patients; NBSAs: 1 patient).

Minor complications were observed in 60 patients, including chest or shoulder pain (n = 32), fever (n = 20), vomiting (n = 4), abdominal pain (n = 3) and puncture site discomfort (n = 1), all of which were relieved by conservative treatment. One patient in the SPS-present group suffered cerebral infarction after BAE with 300–500 μm PVA. There were no significant differences in either the minor or major complication rates between the two groups: 19.4% (26/134) and 0.7% (1/134) for the SPS-present group and 17.7% (34/192) and 0 for the SPS-absent group (P = 0.698 and P = 0.856, respectively).

During the median follow-up time of 39.8 months, recurrence was observed in 75 (23.0%) patients, 51 (38.1%) of whom were in the SPS-present group and 24 (12.5%) of whom were in the SPS-absent group. There was no difference in the median follow-up time between the two groups (38.6 vs. 42.6 months, P = 0.271). The number of recurrence events in the SPS-present group, there were 27, 11, 8, 4 and 1 recurrence events in the first, second, third, fourth and fifth years, while the corresponding numbers in the SPS-absent group were 10, 9, 2, 2 and 1. The 1-month, 1-year, 2-year, 3-year and 5-year hemoptysis-free survival rates of 91.8%, 79.7%, 70.6%, 62.3%, and 52.6% in the SPS-present group were significantly lower than the rates of 97.9%, 94.7%, 89.0%, 87.1%, and 82.3% in the SPS-absent group (P < 0.001) (Fig. 3). In the SPS-present group, 24 patients underwent repeated BAE, 2 patients underwent segmentectomy, 19 patients received medical therapy for recurrent hemoptysis, and 6 patients died due to recurrent hemoptysis; in the SPS-absent group, 8 patients underwent repeated BAE, and 16 patients received medical therapy. According to the angiography results from repeated BAE, the causes of relapse included missed culprit arteries (4 in the SPS-present group; 2 in the SPS-absent group, P = 0.601) for early recurrence, new collateral artery formation (7 in the SPS-present group; 5 in the SPS-absent group, P = 0.092) and recanalization (13 in the SPS-present group; 1 in the SPS-absent group, P = 0.040) for later recurrence.

The adjusted HRs of SPSs in the four models were 3.37 (95% CI, 2.07–5.47, P < 0.001 in model 1), 1.96 (95% CI, 1.11–3.49, P = 0.021 in model 2), 2.29 (95% CI, 1.34–3.92, P = 0.002 in model 3), and 2.39 (95% CI, 1.44–3.97, P = 0.001 in model 4) (Table 2). Based on these results, we generated a forest plot (Fig. 4).