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Cryptogenic Hemoptysis: Effectiveness of Bronchial Artery Embolization Using N-Butyl Cyanoacrylate
CLINICAL STUDY
Cryptogenic Hemoptysis: Effectiveness of Bronchial Artery Embolization Using N-Butyl Cyanoacrylate Hyukjoon Lee, MD, MPH, Chang Jin Yoon, MD, PhD, Nak Jong Seong, MD, PhD, Chang Ho Jeon, MD, Ho Il Yoon, MD, PhD, and Joongseok Go, MS ABSTRACT Purpose: To describe angiographic findings and assess safety and effectiveness of bronchial artery embolization (BAE) with N-butyl cyanoacrylate (NBCA) in patients with cryptogenic hemoptysis (CH). Materials and Methods: Between May 2003 and March 2014, 26 patients who underwent BAE for CH were enrolled. A retrospective review was conducted for angiographic findings and clinical outcomes of BAE, including technical and clinical success, complications, and recurrent hemoptysis. Results: Selective arteriograms were abnormal in 22 patients (85%), showing hypertrophied bronchial arteries (n ¼ 19), parenchymal hypervascularity (n ¼ 18), and bronchial-to-pulmonary shunting (n ¼ 8). All abnormal bronchial and nonbronchial collateral arteries (n ¼ 36) were successfully embolized with NBCA. Hemoptysis ceased within 24 hours in all patients. There were no procedure-related complications. During 11–117 months of follow-up (median, 60.2 mo), 1 patient (4%) experienced recurrent hemoptysis at 5 months after initial BAE, which was treated with repeat BAE. The 5-year hemoptysis-free survival rate was 96%. Conclusions: Bronchial arteries were angiographically abnormal in most patients with CH (85%). BAE is a safe and effective treatment with excellent short- and long-term results in patients with CH. NBCA appears to be a useful embolic material for this application.
ABBREVIATIONS BAE ¼ bronchial artery embolization, CH ¼ cryptogenic hemoptysis, NBCA ¼ N-butyl cyanoacrylate, PVA ¼ polyvinyl alcohol
Hemoptysis has a wide clinical spectrum, ranging from a benign self-limited bleeding event to a life-threatening condition, with associated mortality rates of 4.7%–13.5% depending on severity (1). The most common causes of hemoptysis are bronchiectasis, chronic bronchitis, tuberculosis, and bronchopulmonary malignancy (2,3). However, despite the use of modern diagnostic tools such as bron-
From the Division of Vascular and Interventional Radiology, Department of Radiology (H.L., C.J.Y., N.J.S., C.H.J., J.G.), and Division of Pulmonology, Department of Internal Medicine (H.I.L.), Seoul National University Bundang Hospital, 82, Gumi-ro 173 beon-gil, Bundang-gu, Seongnam-si, Gyeonggi-do, South Korea, 13620. Received January 20, 2017; final revision received March 7, 2017; accepted March 20, 2017. Address correspondence to C.J.Y.; E-mail: [email protected] None of the authors have identified a conflict of interest. © SIR, 2017 J Vasc Interv Radiol 2017; ▪:1–6 http://dx.doi.org/10.1016/j.jvir.2017.03.029
choscopy and computed tomography (CT), the cause of hemoptysis cannot be determined in 7%–25% of cases (4), which are termed cryptogenic. Bronchial artery embolization (BAE) is now considered to be the most effective treatment for massive and recurrent hemoptysis. Numerous studies have demonstrated its safety and efficacy in patients with hemoptysis caused by various pulmonary diseases (5,6). CT angiography is essential for identification of the cause of bleeding and localization of the bleeding focus. It also provides information on bronchial and nonbronchial vascular abnormalities and facilitates the decision to perform BAE. However, in cases of cryptogenic hemoptysis (CH) in which no specific lung parenchymal or vascular abnormality is seen on CT angiography and bronchoscopy, it is difficult to decide whether to proceed with BAE or to undertake conservative management. To date, few studies with limited populations have addressed this issue (7,8). Hence, the present study was performed to describe angiographic findings and determine long-term outcomes of BAE in patients with CH.
2 ▪ Bronchial Artery NBCA Embolization for Cryptogenic Hemoptysis
MATERIALS AND METHODS This retrospective study was approved by the institutional review board of Seoul National University Bundang Hospital. The requirement to obtain informed consent was waived.
Study Population A retrospective review of our institution’s database identified 641 patients who had undergone BAE for hemoptysis between May 2003 and March 2014. Diagnosis of CH was made based on the following criteria: (i) no history of specific pulmonary disease, (ii) no endobronchial and parenchymal abnormality (except for ground-glass opacity or consolidation as a result of aspirated blood) on bronchoscopy and CT, (iii) no late diagnosis of lung cancer during follow-up, (iv) no clinical or laboratory findings of concomitant infection, and (v) no anticoagulation medication. Thirty-two patients (5%) fulfilled these criteria. Six patients were excluded as a result of short follow-up duration (< 6 mo). Therefore, a total of 26 patients were included in the study. There were 20 men and six women, with a mean age of 45 years (age range, 21–74 y). Mean smoking history was 14.7 pack-years (range, 0–60 packyears). Thirteen patients were active smokers with a mean history of 29.4 pack-years, and the others were nonsmokers. All patients had major hemoptysis defined as a single event of massive bleeding (240 mL/d; n ¼ 11), mild to moderate recurrent bleeding (100 mL/d), and/or bleeding for several days (n ¼ 15) (9). All patients underwent chest radiography, CT angiography, and fiberoptic bronchoscopy to identify the cause of hemoptysis and localize the bleeding foci. All patients were hospitalized and initially treated in a conservative manner to stop hemoptysis (eg, administration of tranexamic acid), and those whose condition did not respond to medical management underwent embolization procedures.
BAE All angiographic procedures were performed by an interventional radiologist with 10 years of experience with BAE. After femoral arterial access was obtained with a 5-F vascular sheath, aortography covering the thoracic and upper abdominal aorta was performed with a 5-F pigtail catheter with the tip positioned at the ascending aorta. Selective angiograms of the bronchial and nonbronchial systemic collateral arteries, in which identification was aided by CT and aortography, were obtained with 5-F angiographic catheters (Torcon NB; Cook, Bloomington, Indiana). The following findings were regarded as pathologic: abnormal vessel enlargement, parenchymal hypervascularity, bronchial-to-pulmonary shunting, and extravasation of contrast agent (10). Abnormal vessel enlargement was determined based on the experience of the operator. All pathologic bronchial and nonbronchial systemic collateral arteries were embolized with the use of N-butyl cyanoacrylate (NBCA; Histoacryl; B. Braun, Melsungen, Germany). When no vascular abnormality was
Lee et al ▪ JVIR
Table 1. Angiographic Findings of Bronchial and Nonbronchial Systemic Arteries Angiographic Finding
No. of Vessels
No. of Patients
Selective angiogram
84
26
Bronchial artery
78
26
Right
36
Left
42
Aberrant bronchial artery
4
4
Nonbronchial systemic artery
2
2
31 (40) 29 (37)
22 (85) 19 (73)
Abnormal findings of bronchial artery Bronchial arterial enlargement Parenchymal hypervascularity
27 (35)
19 (73)
Bronchial-to-pulmonary shunting
6 (8)
6 (23)
Pseudoaneurysm or extravasation
0
0
n¼6
–
Arterial enlargement Parenchymal hypervascularity
5 (83) 5 (83)
– –
Bronchial-to-pulmonary shunting
2 (33)
–
Pseudoaneurysm or extravasation
0
–
36 (44)
22 (85)
Abnormal findings of aberrant bronchial/ nonbronchial systemic artery
Overall abnormal finding
Note–Values in parentheses are percentages.
detected on angiography, the bronchial arteries were embolized based on CT and/or bronchoscopic findings. A 2-F microcatheter (Progreat; Terumo, Tokyo, Japan) was introduced coaxially into the angiographic catheter and advanced as distal as possible to avoid spinal feeder vessels and reflux of the embolic material into the aorta. NBCA was mixed with iodized oil (Lipiodol Ultra Fluide; Guerbet, Roissy, France) at a ratio of 1:3 or 1:4. After the microcatheter was flushed with 5% dextrose solution to avoid gluing and occlusion of the lumen during injection of NBCA, 0.5–1 mL of the mixture was carefully injected under fluoroscopic monitoring. The ratio, volume, and injection rate of the mixture were based on the size and flow of the embolized vessels. To avoid adhesion of the catheter tip to the vessel wall, the microcatheter was quickly removed after injection. Immediately after withdrawal, the microcatheter was flushed with 5% dextrose solution for subsequent embolization of the remaining pathologic arteries. After completion of embolization, aortography was performed to confirm the absence of any other residual pathologic arteries.
Assessment and Follow-up Medical records and images of the 26 patients were retrospectively reviewed regarding angiographic findings, embolized vessels, technical and clinical success, recurrent hemoptysis, and complications. We correlated the angiographically pathologic arteries with the presumed bleeding foci on CT angiograms. Technical success was defined as the complete embolization of bronchial and nonbronchial systemic collateral vessels in which embolization was attempted (11). Clinical success was defined as cessation of
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Figure 1. Images from a 32-year-old man with massive hemoptysis. (a) CT angiography shows ground-glass opacity, which is suggestive of aspirated blood, in the right lower lobe (arrows). There is no other parenchymal abnormality possibly related to hemoptysis. (b) Selective angiogram of intercostobronchial artery shows mildly engorged right bronchial artery (arrow) and focal bronchial-topulmonary shunting (arrowhead). The right bronchial artery was embolized with NBCA mixed with iodized oil at a ratio of 1:3. (c) Radiograph obtained immediately after embolization shows NBCA/iodized oil mixture in the right bronchial artery (arrow). (d) Followup CT scan obtained 9 years after embolization reveals clearance of the ground-glass opacity (arrow). No other pulmonary disease was found during the follow-up period.
hemoptysis within 24 hours of BAE (11,12). After discharge, the patients visited the outpatient department every 3–4 months. Follow-up CT at 3–6-month intervals was recommended for late diagnosis of pulmonary disease. The hemoptysis-free survival rates were estimated by Kaplan–Meier method. Complications that required extended hospitalization or an advanced level of care or resulted in permanent adverse sequelae or death were classified as major complications (13); the remaining complications were considered minor. The follow-up period was defined as the duration between BAE and the last hospital visit or date of death.
arteries are summarized in Table 1. The most common abnormalities were arterial enlargement (29 arteries in 19 patients) and parenchymal hypervascularity (27 in 18 patients). No patient showed pseudoaneurysm or contrast agent extravasation. Overall, 22 patients (85%) had at least one abnormal angiographic finding. The contributory territories of abnormal arteries were in accordance with the location of aspirated blood on CT (ie, ground-glass opacity) in 22 patients (85%). Among these, five patients showed abnormal angiographic findings in the contralateral lung as well. Four patients (15%) showed no vascular abnormality on angiography despite hemorrhagic findings on CT (ie, ground-glass opacity).
RESULTS Angiographic Findings
Outcomes of BAE
Selective angiograms of 78 bronchial arteries (36 right and 42 left) were obtained in 26 patients. Four patients had aberrant bronchial arteries arising from the aortic arch (n ¼ 2) or thyrocervical artery (n ¼ 2). Angiograms of two nonbronchial systemic arteries were also obtained (right and left inferior phrenic arteries). Angiographic findings of those
Technical success was achieved in all patients. A total of 36 arteries (mean, 1.4 arteries per patient) were selectively embolized: 31 bronchial arteries (20 right and 11 left), three aberrant bronchial arteries, and two inferior phrenic arteries (Fig 1). BAE was clinically successful in all patients. Hemoptysis stopped within 24 hours after all procedures.
4 ▪ Bronchial Artery NBCA Embolization for Cryptogenic Hemoptysis
Lee et al ▪ JVIR
Figure 2. Images from a 20-year-old man with recurrent hemoptysis. (a) CT angiogram shows ground-glass opacity in the right lower lobe (arrows). (b) Selective angiogram reveals engorgement of right bronchial artery (arrow) and bronchial-to-pulmonary shunting (arrowhead). The right bronchial artery was successfully embolized with NBCA. However, the patient experienced recurrent hemoptysis 5 months after embolization. (c) Angiogram demonstrates a right bronchial artery (arrow) other than the previously embolized one. There is focal bronchial-to-pulmonary shunting (arrowhead) at the same territory as the first event. The right bronchial artery was embolized with NBCA mixed with iodized oil at a ratio of 1:4. (d) Radiograph obtained immediately after embolization shows NBCA/ iodized oil mixture in the embolized right bronchial artery (arrows).
There were no major complications or procedure-related deaths. Seven patients reported chest pain, which was controlled with narcotic analgesic agents. The mean follow-up duration was 60.2 months (range, 11–117 mo; median, 54.6 mo). One patient experienced recurrent hemoptysis at 5 months after BAE. A repeat angiogram was obtained, which showed that the bronchial artery embolized in the previous procedure was still occluded. There was another right bronchial artery enlargement and parenchymal hypervascularity in the same territory as the previous event. The abnormal bronchial artery was successfully embolized with NBCA, and the patient did not experience recurrent hemoptysis thereafter (Fig 2). Twenty patients (77%) underwent follow-up CT and/or bronchoscopy. The ground-glass opacity was completely cleared on CT in all patients. There were no abnormal findings on CT and bronchoscopy suggestive of late diagnosis of any pulmonary disease or late complication. No patient died during follow-up. The estimated hemoptysisfree survival rates at 1, 3, and 5 years were all 96% (95% confidence interval, 104.1%–120.5%; Fig 3).
DISCUSSION Even with the advent of modern diagnostic tools such as multidetector CT and flexible bronchoscopy, as many as 25% of patients presenting with hemoptysis remain classified as having CH. The clinical presentation of CH is usually minor and chronic bleeding with a benign course. However, recent studies (4,14,15) demonstrated that CH may present as a lifethreatening condition. Savale et al (4) reported that one third of their patients had hemoptysis greater than 200 mL on admission. In the present study, 11 patients (42%) presented with massive hemoptysis (240 mL/d). Therefore, in contrast to the traditional concept, a substantial portion of patients with CH require an immediate hemostatic procedure. BAE has been accepted as the first-line nonsurgical treatment of massive or recurrent hemoptysis of various etiologies. In 90% of cases, embolization stops the bleeding immediately, and 70% of patients do not experience recurrences during 1 year of follow-up (16,17). However, in contrast to hemoptysis with known etiologies, a limited number of studies have evaluated the role of BAE in CH. To
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Figure 3. Hemoptysis-free survival rate in 26 patients who underwent BAE. The 5-year hemoptysis-free survival rate was 96.2%.
Table 2. Previously Published Studies on BAE in the Treatment of CH (4,8,14,18) Study, Year
No. of Patients*
Success
Recurrence† ‡
Clinical Follow-up
Technical
Clinical
Early
Late
Mean ± SD
Range
Savale et al (4), 2007
50
43 (86)
39 (78)
None
3 (8)
47.3 mo
0.1–133 mo
Menchini et al (8), 2009 Delage et al (18), 2010
35 21
34 (97) 20 (95)
29 (83) 20 (95)
5 (17) 1 (5)
2 (7) 2 (10)
7.01 y ± 6.8 5 y ± 3.4
1.6–26.8 y NA
Kervancioglu et al (14), 2015
26
26 (100)
26 (100)
1 (4)
2 (8)
29.2 mo
6–61 mo
Present study
26
26 (100)
26 (100)
None
1 (4)
60.2 mo
11–117 mo
Note–Values in parentheses are percentages. BAE ¼ bronchial artery embolization; CH ¼ cryptogenic hemoptysis. * Number of patients in whom BAE was attempted. † Numbers in parentheses are percentages of patients in whom clinical success was achieved. ‡ Within 3 mo after BAE.
our knowledge, only four published studies of this issue enrolled more than 10 subjects (Table 2) (4,8,14,18). They reported that successful control of bleeding was achieved in 78%–100% of cases (8,14,18), with recurrence rates of 7.6%–24%. Similar to previous publications, the present study supports the effectiveness of BAE in CH. Control of hemoptysis was achieved after a single session of BAE in all patients, and recurrent hemoptysis occurred in only one patient during a mean follow-up of 60.2 months. In the present study, 85% of patients showed abnormal angiographic findings. The most common vascular abnormalities were bronchial artery enlargement and hypervascularity, which was consistent with previous reports (8,14). An important finding of the present study was that 23% of patients (six of 26) had abnormal bronchial arteries not only on the bleeding side but also on the contralateral side. Previous studies (8,14) reported that bilateral vascular abnormalities were detected on 70%–76% of bronchial arteriograms.
Menchini et al (8) suggested that bilateral involvement of vascular abnormalities may be caused by bronchial hyperemia secondary to smoking. All patients in their study (8) had clinical symptoms of chronic bronchitis related to smoking, whereas only half of the patients in the present study had a smoking history, which can explain the relatively low rate of bilateral vascular abnormalities in the present study. Angiographic findings in the present study showed that the culprit arteries of CH were mainly bronchial arteries. Previous studies (19,20) reported that 30%–45% of cases of hemoptysis of known etiology were caused by a nonbronchial systemic artery. However, nonbronchial systemic arteries contributed hemoptysis in only two patients (8%) in the present study. The primary bronchial artery supply seems to be one of the angiographic features of CH. Another noteworthy finding of the present study was that 15% of patients had angiographically normal bronchial arteries on the side of bronchial bleeding. In such cases, it is
6 ▪ Bronchial Artery NBCA Embolization for Cryptogenic Hemoptysis
difficult to decide whether to perform embolization. Because hemoptysis was not responsive to medication before the embolization procedure, embolization of the ipsilateral bronchial artery was performed based on bleeding localization by CT, and immediate cessation of bleeding was achieved. Therefore, it is surmised that even angiographically normal bronchial arteries can be responsible for hemoptysis, and BAE is an effective treatment in such cases. One distinctive feature of the procedure performed in the present study was the use of NBCA as an embolic material. Traditionally, particulate agents have been standard embolic materials in BAE. Likewise, previous studies on CH used polyvinyl alcohol (PVA) particles (8,14) or, more recently, tris-acryl gelatin microspheres (15). NBCA has been avoided in BAE because of the concern that it carries a high risk of severe complications such as tissue necrosis and nontarget embolization from uncontrolled reflux (21). However, recent studies (10) demonstrated that BAE with the use of NBCA is a safe and effective treatment of hemoptysis. NBCA can reach and occlude the distal parts of target vessels as a result of its semifluid characteristics, which might be especially useful in treating CH. In patients with CH, bronchial artery hypertrophy is usually mild, and even a normal bronchial artery should be embolized in some cases. In such cases, PVA particles frequently aggregate and form plugs prematurely, which can lead to early recanalization. Menchini et al (8) reported frequent “immediate recurrence” after BAE in patients with CH (15%) in the form of early recanalization of embolized vessels, requiring repeat embolization. On the contrary, NBCA provides a more durable embolic effect, which leads to less recanalization of embolized vessels (9). In the present study, only one patient experienced recurrent hemoptysis, which was caused by a missed abnormal bronchial artery. There was no recanalization of embolized vessels. These findings suggest potential advantages of NBCA over PVA in treatment of CH. Several limitations should be acknowledged in the present study. First, this was a retrospective study with all its inherent limitations. Only patients who were referred to our department were included for endovascular treatment, which can cause a potential selection bias. To prove the effectiveness of BAE, it is desirable to compare patients treated with BAE versus patients treated with other methods. Second, the study population (N ¼ 26) is too small to confirm the results of the study because of the relative rarity of CH. A third limitation concerns the long patient inclusion period of 11 years. However, all procedures were performed by one interventionist, and the device and technique were essentially the same throughout the study period. In conclusion, bronchial arteries are angiographically abnormal in most patients with CH, with bronchial artery dilation and parenchymal hypervascularization the most common abnormalities. BAE is a safe and effective treatment in patients with CH, with excellent short-term and long-term results. NBCA appears to be a useful embolic material in this application, with a potential advantage over traditional particulate embolic agents.
Lee et al ▪ JVIR
ACKNOWLEDGMENTS This study was supported by a grant from the Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea (HI14C2175).
REFERENCES 1. Lee MK, Kim SH, Yong SJ, et al. Moderate hemoptysis: recurrent hemoptysis and mortality according to bronchial artery embolization. Clin Respir J 2015; 9:53–64. 2. Shigemura N, Wan IY, Yu SC, et al. Multidisciplinary management of lifethreatening massive hemoptysis: a 10-year experience. Ann Thorac Surg 2009; 87:849–853. 3. Kalva SP. Bronchial artery embolization. Tech Vasc Interv Radiol 2009; 12: 130–138. 4. Savale L, Parrot A, Khalil A, et al. Cryptogenic hemoptysis: from a benign to a life-threatening pathologic vascular condition. Am J Respir Crit Care Med 2007; 175:1181–1185. 5. Tom LM, Palevsky HI, Holsclaw DS, et al. Recurrent bleeding, survival, and longitudinal pulmonary function following bronchial artery embolization for hemoptysis in a U.S. adult population. J Vasc Interv Radiol 2015; 26:1806–1813.e1. 6. Garcia-Olive I, Sanz-Santos J, Centeno C, et al. Results of bronchial artery embolization for the treatment of hemoptysis caused by neoplasm. J Vasc Interv Radiol 2014; 25:221–228. 7. Samara KD, Tsetis D, Antoniou KM, Protopapadakis C, Maltezakis G, Siafakas NM. Bronchial artery embolization for management of massive cryptogenic hemoptysis: a case series. J Med Case Reports 2011; 5:58. 8. Menchini L, Remy-Jardin M, Faivre JB, et al. Cryptogenic haemoptysis in smokers: angiography and results of embolisation in 35 patients. Eur Respir J 2009; 34:1031–1039. 9. Woo S, Yoon CJ, Chung JW, et al. Bronchial artery embolization to control hemoptysis: comparison of N-butyl-2-cyanoacrylate and polyvinyl alcohol particles. Radiology 2013; 269:594–602. 10. Yoo DH, Yoon CJ, Kang SG, Burke CT, Lee JH, Lee CT. Bronchial and nonbronchial systemic artery embolization in patients with major hemoptysis: safety and efficacy of N-butyl cyanoacrylate. AJR Am J Roentgenol 2011; 196:W199–W204. 11. Dave BR, Sharma A, Kalva SP, Wicky S. Nine-year single-center experience with transcatheter arterial embolization for hemoptysis: mediumterm outcomes. Vasc Endovasc Surg 2011; 45:258–268. 12. Thompson AB, Teschler H, Rennard SI. Pathogenesis, evaluation, and therapy for massive hemoptysis. Clin Chest Med 1992; 13:69–82. 13. Sacks D, McClenny TE, Cardella JF, Lewis CA. Society of Interventional Radiology clinical practice guidelines. J Vasc Interv Radiol 2003; 14(suppl): S199–S202. 14. Kervancioglu S, Bayram N, Gelebek Yilmaz F, Sanli M, Sirikci A. Radiological findings and outcomes of bronchial artery embolization in cryptogenic hemoptysis. J Kor Med Sci 2015; 30:591–597. 15. Samara KD, Tsetis D, Antoniou KM, Protopapadakis C, Maltezakis G, Siafakas NM. Bronchial artery embolization for management of massive cryptogenic hemoptysis: a case series. J Med Case Rep 2011; 5:58. 16. Mal H, Rullon I, Mellot F, et al. Immediate and long-term results of bronchial artery embolization for life-threatening hemoptysis. Chest 1999; 115:996–1001. 17. Tsoumakidou M, Chrysofakis G, Tsiligianni I, Maltezakis G, Siafakas NM, Tzanakis N. A prospective analysis of 184 hemoptysis cases: diagnostic impact of chest X-ray, computed tomography, bronchoscopy. Respiration 2006; 73:808–814. 18. Delage A, Tillie-Leblond I, Cavestri B, Wallaert B, Marquette CH. Cryptogenic hemoptysis in chronic obstructive pulmonary disease: characteristics and outcome. Respiration 2010; 80:387–392. 19. Keller FS, Rosch J, Loflin TG, Nath PH, McElvein RB. Nonbronchial systemic collateral arteries: significance in percutaneous embolotherapy for hemoptysis. Radiology 1987; 164:687–692. 20. Yoon W, Kim YH, Kim JK, Kim YC, Park JG, Kang HK. Massive hemoptysis: prediction of nonbronchial systemic arterial supply with chest CT. Radiology 2003; 227:232–238. 21. Yoon W. Embolic agents used for bronchial artery embolisation in massive haemoptysis. Expert Opin Pharmacother 2004; 5:361–367.
Cryptogenic Hemoptysis: Effectiveness of Bronchial Artery Embolization Using N-Butyl Cyanoacrylate Hyukjoon Lee, MD, MPH, Chang Jin Yoon, MD, PhD, Nak Jong Seong, MD, PhD, Chang Ho Jeon, MD, Ho Il Yoon, MD, PhD, and Joongseok Go, MS ABSTRACT Purpose: To describe angiographic findings and assess safety and effectiveness of bronchial artery embolization (BAE) with N-butyl cyanoacrylate (NBCA) in patients with cryptogenic hemoptysis (CH). Materials and Methods: Between May 2003 and March 2014, 26 patients who underwent BAE for CH were enrolled. A retrospective review was conducted for angiographic findings and clinical outcomes of BAE, including technical and clinical success, complications, and recurrent hemoptysis. Results: Selective arteriograms were abnormal in 22 patients (85%), showing hypertrophied bronchial arteries (n ¼ 19), parenchymal hypervascularity (n ¼ 18), and bronchial-to-pulmonary shunting (n ¼ 8). All abnormal bronchial and nonbronchial collateral arteries (n ¼ 36) were successfully embolized with NBCA. Hemoptysis ceased within 24 hours in all patients. There were no procedure-related complications. During 11–117 months of follow-up (median, 60.2 mo), 1 patient (4%) experienced recurrent hemoptysis at 5 months after initial BAE, which was treated with repeat BAE. The 5-year hemoptysis-free survival rate was 96%. Conclusions: Bronchial arteries were angiographically abnormal in most patients with CH (85%). BAE is a safe and effective treatment with excellent short- and long-term results in patients with CH. NBCA appears to be a useful embolic material for this application.
ABBREVIATIONS BAE ¼ bronchial artery embolization, CH ¼ cryptogenic hemoptysis, NBCA ¼ N-butyl cyanoacrylate, PVA ¼ polyvinyl alcohol
Hemoptysis has a wide clinical spectrum, ranging from a benign self-limited bleeding event to a life-threatening condition, with associated mortality rates of 4.7%–13.5% depending on severity (1). The most common causes of hemoptysis are bronchiectasis, chronic bronchitis, tuberculosis, and bronchopulmonary malignancy (2,3). However, despite the use of modern diagnostic tools such as bron-
From the Division of Vascular and Interventional Radiology, Department of Radiology (H.L., C.J.Y., N.J.S., C.H.J., J.G.), and Division of Pulmonology, Department of Internal Medicine (H.I.L.), Seoul National University Bundang Hospital, 82, Gumi-ro 173 beon-gil, Bundang-gu, Seongnam-si, Gyeonggi-do, South Korea, 13620. Received January 20, 2017; final revision received March 7, 2017; accepted March 20, 2017. Address correspondence to C.J.Y.; E-mail: [email protected] None of the authors have identified a conflict of interest. © SIR, 2017 J Vasc Interv Radiol 2017; ▪:1–6 http://dx.doi.org/10.1016/j.jvir.2017.03.029
choscopy and computed tomography (CT), the cause of hemoptysis cannot be determined in 7%–25% of cases (4), which are termed cryptogenic. Bronchial artery embolization (BAE) is now considered to be the most effective treatment for massive and recurrent hemoptysis. Numerous studies have demonstrated its safety and efficacy in patients with hemoptysis caused by various pulmonary diseases (5,6). CT angiography is essential for identification of the cause of bleeding and localization of the bleeding focus. It also provides information on bronchial and nonbronchial vascular abnormalities and facilitates the decision to perform BAE. However, in cases of cryptogenic hemoptysis (CH) in which no specific lung parenchymal or vascular abnormality is seen on CT angiography and bronchoscopy, it is difficult to decide whether to proceed with BAE or to undertake conservative management. To date, few studies with limited populations have addressed this issue (7,8). Hence, the present study was performed to describe angiographic findings and determine long-term outcomes of BAE in patients with CH.
2 ▪ Bronchial Artery NBCA Embolization for Cryptogenic Hemoptysis
MATERIALS AND METHODS This retrospective study was approved by the institutional review board of Seoul National University Bundang Hospital. The requirement to obtain informed consent was waived.
Study Population A retrospective review of our institution’s database identified 641 patients who had undergone BAE for hemoptysis between May 2003 and March 2014. Diagnosis of CH was made based on the following criteria: (i) no history of specific pulmonary disease, (ii) no endobronchial and parenchymal abnormality (except for ground-glass opacity or consolidation as a result of aspirated blood) on bronchoscopy and CT, (iii) no late diagnosis of lung cancer during follow-up, (iv) no clinical or laboratory findings of concomitant infection, and (v) no anticoagulation medication. Thirty-two patients (5%) fulfilled these criteria. Six patients were excluded as a result of short follow-up duration (< 6 mo). Therefore, a total of 26 patients were included in the study. There were 20 men and six women, with a mean age of 45 years (age range, 21–74 y). Mean smoking history was 14.7 pack-years (range, 0–60 packyears). Thirteen patients were active smokers with a mean history of 29.4 pack-years, and the others were nonsmokers. All patients had major hemoptysis defined as a single event of massive bleeding (240 mL/d; n ¼ 11), mild to moderate recurrent bleeding (100 mL/d), and/or bleeding for several days (n ¼ 15) (9). All patients underwent chest radiography, CT angiography, and fiberoptic bronchoscopy to identify the cause of hemoptysis and localize the bleeding foci. All patients were hospitalized and initially treated in a conservative manner to stop hemoptysis (eg, administration of tranexamic acid), and those whose condition did not respond to medical management underwent embolization procedures.
BAE All angiographic procedures were performed by an interventional radiologist with 10 years of experience with BAE. After femoral arterial access was obtained with a 5-F vascular sheath, aortography covering the thoracic and upper abdominal aorta was performed with a 5-F pigtail catheter with the tip positioned at the ascending aorta. Selective angiograms of the bronchial and nonbronchial systemic collateral arteries, in which identification was aided by CT and aortography, were obtained with 5-F angiographic catheters (Torcon NB; Cook, Bloomington, Indiana). The following findings were regarded as pathologic: abnormal vessel enlargement, parenchymal hypervascularity, bronchial-to-pulmonary shunting, and extravasation of contrast agent (10). Abnormal vessel enlargement was determined based on the experience of the operator. All pathologic bronchial and nonbronchial systemic collateral arteries were embolized with the use of N-butyl cyanoacrylate (NBCA; Histoacryl; B. Braun, Melsungen, Germany). When no vascular abnormality was
Lee et al ▪ JVIR
Table 1. Angiographic Findings of Bronchial and Nonbronchial Systemic Arteries Angiographic Finding
No. of Vessels
No. of Patients
Selective angiogram
84
26
Bronchial artery
78
26
Right
36
Left
42
Aberrant bronchial artery
4
4
Nonbronchial systemic artery
2
2
31 (40) 29 (37)
22 (85) 19 (73)
Abnormal findings of bronchial artery Bronchial arterial enlargement Parenchymal hypervascularity
27 (35)
19 (73)
Bronchial-to-pulmonary shunting
6 (8)
6 (23)
Pseudoaneurysm or extravasation
0
0
n¼6
–
Arterial enlargement Parenchymal hypervascularity
5 (83) 5 (83)
– –
Bronchial-to-pulmonary shunting
2 (33)
–
Pseudoaneurysm or extravasation
0
–
36 (44)
22 (85)
Abnormal findings of aberrant bronchial/ nonbronchial systemic artery
Overall abnormal finding
Note–Values in parentheses are percentages.
detected on angiography, the bronchial arteries were embolized based on CT and/or bronchoscopic findings. A 2-F microcatheter (Progreat; Terumo, Tokyo, Japan) was introduced coaxially into the angiographic catheter and advanced as distal as possible to avoid spinal feeder vessels and reflux of the embolic material into the aorta. NBCA was mixed with iodized oil (Lipiodol Ultra Fluide; Guerbet, Roissy, France) at a ratio of 1:3 or 1:4. After the microcatheter was flushed with 5% dextrose solution to avoid gluing and occlusion of the lumen during injection of NBCA, 0.5–1 mL of the mixture was carefully injected under fluoroscopic monitoring. The ratio, volume, and injection rate of the mixture were based on the size and flow of the embolized vessels. To avoid adhesion of the catheter tip to the vessel wall, the microcatheter was quickly removed after injection. Immediately after withdrawal, the microcatheter was flushed with 5% dextrose solution for subsequent embolization of the remaining pathologic arteries. After completion of embolization, aortography was performed to confirm the absence of any other residual pathologic arteries.
Assessment and Follow-up Medical records and images of the 26 patients were retrospectively reviewed regarding angiographic findings, embolized vessels, technical and clinical success, recurrent hemoptysis, and complications. We correlated the angiographically pathologic arteries with the presumed bleeding foci on CT angiograms. Technical success was defined as the complete embolization of bronchial and nonbronchial systemic collateral vessels in which embolization was attempted (11). Clinical success was defined as cessation of
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Figure 1. Images from a 32-year-old man with massive hemoptysis. (a) CT angiography shows ground-glass opacity, which is suggestive of aspirated blood, in the right lower lobe (arrows). There is no other parenchymal abnormality possibly related to hemoptysis. (b) Selective angiogram of intercostobronchial artery shows mildly engorged right bronchial artery (arrow) and focal bronchial-topulmonary shunting (arrowhead). The right bronchial artery was embolized with NBCA mixed with iodized oil at a ratio of 1:3. (c) Radiograph obtained immediately after embolization shows NBCA/iodized oil mixture in the right bronchial artery (arrow). (d) Followup CT scan obtained 9 years after embolization reveals clearance of the ground-glass opacity (arrow). No other pulmonary disease was found during the follow-up period.
hemoptysis within 24 hours of BAE (11,12). After discharge, the patients visited the outpatient department every 3–4 months. Follow-up CT at 3–6-month intervals was recommended for late diagnosis of pulmonary disease. The hemoptysis-free survival rates were estimated by Kaplan–Meier method. Complications that required extended hospitalization or an advanced level of care or resulted in permanent adverse sequelae or death were classified as major complications (13); the remaining complications were considered minor. The follow-up period was defined as the duration between BAE and the last hospital visit or date of death.
arteries are summarized in Table 1. The most common abnormalities were arterial enlargement (29 arteries in 19 patients) and parenchymal hypervascularity (27 in 18 patients). No patient showed pseudoaneurysm or contrast agent extravasation. Overall, 22 patients (85%) had at least one abnormal angiographic finding. The contributory territories of abnormal arteries were in accordance with the location of aspirated blood on CT (ie, ground-glass opacity) in 22 patients (85%). Among these, five patients showed abnormal angiographic findings in the contralateral lung as well. Four patients (15%) showed no vascular abnormality on angiography despite hemorrhagic findings on CT (ie, ground-glass opacity).
RESULTS Angiographic Findings
Outcomes of BAE
Selective angiograms of 78 bronchial arteries (36 right and 42 left) were obtained in 26 patients. Four patients had aberrant bronchial arteries arising from the aortic arch (n ¼ 2) or thyrocervical artery (n ¼ 2). Angiograms of two nonbronchial systemic arteries were also obtained (right and left inferior phrenic arteries). Angiographic findings of those
Technical success was achieved in all patients. A total of 36 arteries (mean, 1.4 arteries per patient) were selectively embolized: 31 bronchial arteries (20 right and 11 left), three aberrant bronchial arteries, and two inferior phrenic arteries (Fig 1). BAE was clinically successful in all patients. Hemoptysis stopped within 24 hours after all procedures.
4 ▪ Bronchial Artery NBCA Embolization for Cryptogenic Hemoptysis
Lee et al ▪ JVIR
Figure 2. Images from a 20-year-old man with recurrent hemoptysis. (a) CT angiogram shows ground-glass opacity in the right lower lobe (arrows). (b) Selective angiogram reveals engorgement of right bronchial artery (arrow) and bronchial-to-pulmonary shunting (arrowhead). The right bronchial artery was successfully embolized with NBCA. However, the patient experienced recurrent hemoptysis 5 months after embolization. (c) Angiogram demonstrates a right bronchial artery (arrow) other than the previously embolized one. There is focal bronchial-to-pulmonary shunting (arrowhead) at the same territory as the first event. The right bronchial artery was embolized with NBCA mixed with iodized oil at a ratio of 1:4. (d) Radiograph obtained immediately after embolization shows NBCA/ iodized oil mixture in the embolized right bronchial artery (arrows).
There were no major complications or procedure-related deaths. Seven patients reported chest pain, which was controlled with narcotic analgesic agents. The mean follow-up duration was 60.2 months (range, 11–117 mo; median, 54.6 mo). One patient experienced recurrent hemoptysis at 5 months after BAE. A repeat angiogram was obtained, which showed that the bronchial artery embolized in the previous procedure was still occluded. There was another right bronchial artery enlargement and parenchymal hypervascularity in the same territory as the previous event. The abnormal bronchial artery was successfully embolized with NBCA, and the patient did not experience recurrent hemoptysis thereafter (Fig 2). Twenty patients (77%) underwent follow-up CT and/or bronchoscopy. The ground-glass opacity was completely cleared on CT in all patients. There were no abnormal findings on CT and bronchoscopy suggestive of late diagnosis of any pulmonary disease or late complication. No patient died during follow-up. The estimated hemoptysisfree survival rates at 1, 3, and 5 years were all 96% (95% confidence interval, 104.1%–120.5%; Fig 3).
DISCUSSION Even with the advent of modern diagnostic tools such as multidetector CT and flexible bronchoscopy, as many as 25% of patients presenting with hemoptysis remain classified as having CH. The clinical presentation of CH is usually minor and chronic bleeding with a benign course. However, recent studies (4,14,15) demonstrated that CH may present as a lifethreatening condition. Savale et al (4) reported that one third of their patients had hemoptysis greater than 200 mL on admission. In the present study, 11 patients (42%) presented with massive hemoptysis (240 mL/d). Therefore, in contrast to the traditional concept, a substantial portion of patients with CH require an immediate hemostatic procedure. BAE has been accepted as the first-line nonsurgical treatment of massive or recurrent hemoptysis of various etiologies. In 90% of cases, embolization stops the bleeding immediately, and 70% of patients do not experience recurrences during 1 year of follow-up (16,17). However, in contrast to hemoptysis with known etiologies, a limited number of studies have evaluated the role of BAE in CH. To
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Figure 3. Hemoptysis-free survival rate in 26 patients who underwent BAE. The 5-year hemoptysis-free survival rate was 96.2%.
Table 2. Previously Published Studies on BAE in the Treatment of CH (4,8,14,18) Study, Year
No. of Patients*
Success
Recurrence† ‡
Clinical Follow-up
Technical
Clinical
Early
Late
Mean ± SD
Range
Savale et al (4), 2007
50
43 (86)
39 (78)
None
3 (8)
47.3 mo
0.1–133 mo
Menchini et al (8), 2009 Delage et al (18), 2010
35 21
34 (97) 20 (95)
29 (83) 20 (95)
5 (17) 1 (5)
2 (7) 2 (10)
7.01 y ± 6.8 5 y ± 3.4
1.6–26.8 y NA
Kervancioglu et al (14), 2015
26
26 (100)
26 (100)
1 (4)
2 (8)
29.2 mo
6–61 mo
Present study
26
26 (100)
26 (100)
None
1 (4)
60.2 mo
11–117 mo
Note–Values in parentheses are percentages. BAE ¼ bronchial artery embolization; CH ¼ cryptogenic hemoptysis. * Number of patients in whom BAE was attempted. † Numbers in parentheses are percentages of patients in whom clinical success was achieved. ‡ Within 3 mo after BAE.
our knowledge, only four published studies of this issue enrolled more than 10 subjects (Table 2) (4,8,14,18). They reported that successful control of bleeding was achieved in 78%–100% of cases (8,14,18), with recurrence rates of 7.6%–24%. Similar to previous publications, the present study supports the effectiveness of BAE in CH. Control of hemoptysis was achieved after a single session of BAE in all patients, and recurrent hemoptysis occurred in only one patient during a mean follow-up of 60.2 months. In the present study, 85% of patients showed abnormal angiographic findings. The most common vascular abnormalities were bronchial artery enlargement and hypervascularity, which was consistent with previous reports (8,14). An important finding of the present study was that 23% of patients (six of 26) had abnormal bronchial arteries not only on the bleeding side but also on the contralateral side. Previous studies (8,14) reported that bilateral vascular abnormalities were detected on 70%–76% of bronchial arteriograms.
Menchini et al (8) suggested that bilateral involvement of vascular abnormalities may be caused by bronchial hyperemia secondary to smoking. All patients in their study (8) had clinical symptoms of chronic bronchitis related to smoking, whereas only half of the patients in the present study had a smoking history, which can explain the relatively low rate of bilateral vascular abnormalities in the present study. Angiographic findings in the present study showed that the culprit arteries of CH were mainly bronchial arteries. Previous studies (19,20) reported that 30%–45% of cases of hemoptysis of known etiology were caused by a nonbronchial systemic artery. However, nonbronchial systemic arteries contributed hemoptysis in only two patients (8%) in the present study. The primary bronchial artery supply seems to be one of the angiographic features of CH. Another noteworthy finding of the present study was that 15% of patients had angiographically normal bronchial arteries on the side of bronchial bleeding. In such cases, it is
6 ▪ Bronchial Artery NBCA Embolization for Cryptogenic Hemoptysis
difficult to decide whether to perform embolization. Because hemoptysis was not responsive to medication before the embolization procedure, embolization of the ipsilateral bronchial artery was performed based on bleeding localization by CT, and immediate cessation of bleeding was achieved. Therefore, it is surmised that even angiographically normal bronchial arteries can be responsible for hemoptysis, and BAE is an effective treatment in such cases. One distinctive feature of the procedure performed in the present study was the use of NBCA as an embolic material. Traditionally, particulate agents have been standard embolic materials in BAE. Likewise, previous studies on CH used polyvinyl alcohol (PVA) particles (8,14) or, more recently, tris-acryl gelatin microspheres (15). NBCA has been avoided in BAE because of the concern that it carries a high risk of severe complications such as tissue necrosis and nontarget embolization from uncontrolled reflux (21). However, recent studies (10) demonstrated that BAE with the use of NBCA is a safe and effective treatment of hemoptysis. NBCA can reach and occlude the distal parts of target vessels as a result of its semifluid characteristics, which might be especially useful in treating CH. In patients with CH, bronchial artery hypertrophy is usually mild, and even a normal bronchial artery should be embolized in some cases. In such cases, PVA particles frequently aggregate and form plugs prematurely, which can lead to early recanalization. Menchini et al (8) reported frequent “immediate recurrence” after BAE in patients with CH (15%) in the form of early recanalization of embolized vessels, requiring repeat embolization. On the contrary, NBCA provides a more durable embolic effect, which leads to less recanalization of embolized vessels (9). In the present study, only one patient experienced recurrent hemoptysis, which was caused by a missed abnormal bronchial artery. There was no recanalization of embolized vessels. These findings suggest potential advantages of NBCA over PVA in treatment of CH. Several limitations should be acknowledged in the present study. First, this was a retrospective study with all its inherent limitations. Only patients who were referred to our department were included for endovascular treatment, which can cause a potential selection bias. To prove the effectiveness of BAE, it is desirable to compare patients treated with BAE versus patients treated with other methods. Second, the study population (N ¼ 26) is too small to confirm the results of the study because of the relative rarity of CH. A third limitation concerns the long patient inclusion period of 11 years. However, all procedures were performed by one interventionist, and the device and technique were essentially the same throughout the study period. In conclusion, bronchial arteries are angiographically abnormal in most patients with CH, with bronchial artery dilation and parenchymal hypervascularization the most common abnormalities. BAE is a safe and effective treatment in patients with CH, with excellent short-term and long-term results. NBCA appears to be a useful embolic material in this application, with a potential advantage over traditional particulate embolic agents.
Lee et al ▪ JVIR
ACKNOWLEDGMENTS This study was supported by a grant from the Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea (HI14C2175).
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