Predictors of Severe Bleeding During Endobronchial Biopsy: Experience of 537 Cases : Journal of Bronchology & Interventional Pulmonology

Journal Logo

Journal of Bronchology & Interventional Pulmonology

Predictors of Severe Bleeding During Endobronchial Biopsy

Experience of 537 Cases

Muthu, Valliappan MD, DM*; Ram, Babu MSc*; Sehgal, Inderpaul S. MD, DM*; Dhooria, Sahajal MD, DM*; Prasad, Kuruswamy T. MD, DM*; Bal, Amanjit MD; Aggarwal, Ashutosh N. MD, DM*; Agarwal, Ritesh MD, DM*

Author Information
Journal of Bronchology & Interventional Pulmonology: October 2019 - Volume 26 - Issue 4 - p 273-279
doi: 10.1097/LBR.0000000000000593

Abstract

Flexible bronchoscopy is a commonly performed diagnostic procedure for the evaluation of suspected lung cancer.1,2 The availability of endobronchial ultrasound and ultrathin bronchoscopes have enabled sampling of peripherally located lesions, which were conventionally subjected to percutaneous procedures. However, the diagnostic evaluation of centrally located endobronchial visible lesions has remained unchanged. Endobronchial biopsy (EBB) remains the most commonly performed diagnostic technique for these lesions.

Diagnostic flexible bronchoscopy is safe, and few complications are encountered. The complications include transient hypoxemia, bronchospasm, minor bleeding, and pneumothorax.3 Contemporary literature focuses mainly on the safety of advanced endoscopic procedures and their complications.4 Data on the more common and widely practiced procedures such as EBB is lacking. Data pertaining to the bleeding complications following EBB and its impact on the diagnostic yield, remains poorly studied. We retrospectively reviewed our bronchoscopy database to identify subjects who underwent EBB with a suspicion of malignancy. Herein, we present the incidence and the degree of bleeding after EBB, the predictors of bleeding and its impact on the histopathologic diagnosis.

METHODS

This was a retrospective analysis of prospectively collected data between May 2015 and November 2017, at the bronchoscopy suite of our institute. All subjects who underwent EBB for a clinically suspected malignant endobronchial lesion were included. Our institute is a tertiary referral centre in North India performing diagnostic bronchoscopy for the past 30 years.1 Currently, we perform ∼2500 flexible bronchoscopies every year. The study protocol was approved by the Institutional Ethics Committee. A consent waiver was granted due to the retrospective study design involving analysis of anonymous patient data. A procedural consent was, however, obtained from all the study participants.

All subjects underwent flexible bronchoscopy under local anesthesia, as previously described, without the use of sedation.5 Evaluation for coagulopathy and thrombocytopenia were performed only if there were risk factors for abnormal coagulation (chronic liver disease, anticoagulant therapy, history of bleeding tendency, and others). EBB was deferred if the platelet count was <50,000 cells/mm3 or prolonged prothrombin time ≥4 seconds or activated partial thromboplastin time >10 seconds than the control value, respectively. Antiplatelet drugs other than low-dose aspirin (75 to 150 mg/d) were discontinued at least 5 to 7 days before the procedure.6 For subjects on anticoagulation, we performed the procedure after discontinuing the drug and ensuring that the international normalized ratio was <1.5. The procedures were performed by consultants or by fellows under the close supervision of the consultants. After preliminary assessment, the subjects were administered 10% lignocaine spray (10 puffs) over the oropharynx. Topical 2% lignocaine jelly was then instilled into the nasal cavity. The procedure was performed through the nasal route (orally if nasal insertion failed). We used 1% lignocaine (instilled as aliquots of 2 mL) for anesthetizing the vocal cords, carina, and the main bronchi using the spray-as-you-go technique.5 The heart rate and oxygen saturation were monitored throughout the procedure. An airway examination was performed, and the endobronchial lesion was localized. This was followed by EBB using the cup, alligator, spur, cryoprobe, electrocoagulation-enabled, or a combination of forceps. The number of biopsies to be performed was left at the discretion of the operator. In general, 6 biopsies were obtained from each patient. Bleeding during EBB was managed by placing the affected side dependent (tilting the operating table to the ipsilateral side), instillation of ice-cold saline or adrenaline (1:10000 dilution), and endotracheal intubation, if required. We observed the subjects for 4 hours following the procedure. In case of persisting hypoxemia or bleeding, the subjects were admitted to the hospital. The samples obtained were transported in formalin for histopathologic examination.

We retrieved the following data: (1) demographic profile; (2) smoking status; (3) presence of features suggesting superior vena cava (SVC) syndrome; (4) the details of radiologic imaging (location of the lesion, unilateral or bilateral lesions, mediastinal masses, lymph nodes, presence of lung mass, consolidation, nodules or collapse, presence of an endoluminal growth in the airways visualized on computed tomography); (5) the operator (fellow, consultant, or both); (6) the site and the appearance of the endobronchial lesion (endobronchial growth, endobronchial infiltration, nodules, mucosal edema, or a combination of the above); (7) the forceps used for biopsy (alligator, cup, spur, cryoprobe, electrocoagulation-enabled, or >1 forceps); (8) the vascularity of the endobronchial lesion as judged by the bronchoscopist; (9) the number of attempts and the number of biopsies obtained; (10) the duration of the procedure; (11) the need for oxygen supplementation following the procedure; and (12) the final histologic diagnosis.

We classified bleeding during EBB as (i) none: no bleeding; (ii) mild: bleeding that did not require suctioning; (iii) moderate: needed clearing of the airways by suctioning or spilled over to contralateral side; (iv) severe: required instillation of ice-cold saline, local adrenaline or tamponade for the control of bleeding; and (v) life-threatening: bleeding that required endotracheal intubation or resulted in mortality. The location of the lesion was classified as “central” (if it was present in the trachea, either of the main bronchi or the bronchus intermedius) or peripheral. The operator rated the intensity of patient’s cough on a visual analogue scale of 100 mm (0 and 100 represented the best and worst possible rating, respectively).

Statistical Analysis

We used the commercial statistical package (SPSS for Windows, version 22.0; IBM SPSS Inc., Armonk, NY) for data analysis. Continuous data was expressed as mean [standard deviation (SD) or 95% confidence interval (CI)] or median (interquartile range), and frequencies were expressed as numbers (percentage). We compared the outcomes of subjects with severe and nonsevere bleeding following EBB. The difference between continuous and categorical data were analyzed using Mann-Whitney U test and χ2 test, respectively. The factors associated with severe bleeding were assessed using a multivariate logistic regression analysis. A P-value of <0.05 was considered statistically significant.

RESULTS

A total of 537 subjects underwent EBB for suspected malignancy. The mean (SD) age of the study population was 59.7 (11.4) years (Table 1), and the majority were men (n=452, 84.2%). Severe bleeding was encountered in 45 subjects (8%), while the majority had mild (n=306, 57%) or moderate bleeding (n=111, 21%). No bleeding was encountered in 12% (n=62), while the data were missing in 2% (n=13) of the subjects. EBB was not withheld in any subject due to perceived risk of bleeding. Prophylactic instillation of topical adrenaline or cold saline was not used in any of the study participants. Clinical features to suggest SVC syndrome were present in 25 subjects (4.7%). The proportion of subjects with SVC syndrome was significantly higher in those with severe bleeding than those without (11.1% vs. 4.1%, P=0.049). On computed tomography (CT) of the thorax, the most common abnormality (Supplemental Table 1, Supplemental Digital Content 1, https://links.lww.com/LBR/A178) was a mass lesion (n=348, 64.8%), followed by lobar/segmental collapse (n=112, 20.9%), and mass with cavitation (n=25, 4.7%).

T1
TABLE 1:
Clinical Features, Bronchoscopy Findings, Procedural Details, and Histopathology Results of the Study Population Undergoing Endobronchial Biopsy

In the entire cohort, bronchoscopic abnormalities were most commonly seen in the right upper lobe, followed by the left upper lobe, and the left main bronchus (Supplemental Table 1, Supplemental Digital Content 1, https://links.lww.com/LBR/A178). The severe bleeding group had a significantly larger proportion of central airway lesion than the nonsevere bleeding group (57.8% vs. 32.7%, P=0.002). Majority of the subjects had either an exophytic endobronchial growth (n=306, 57%) or mucosal infiltration (n=194, 36.1%). Subjects with a severe bleed had a higher proportion of vascular growth, as judged by the operator (46.7% vs. 21.5%, severe vs. nonsevere bleeding; P<0.0001). A total of 75.6% of the procedures were performed by the fellows, and the remainder were performed either by the consultant alone or both (Table 1). Alligator forceps (n=395, 73.6%), followed by the cup forceps (n=83, 15.5%) were most frequently employed for performing EBB (Table 1). A median (interquartile range) of 4 (3 to 5) and 6 (5 to 7) biopsies were obtained in subjects with severe and nonsevere bleeding, respectively. The visual analogue scale score for cough, and transient requirement of oxygen supplementation was significantly higher in the group with severe bleeding (Table 1). One patient developed acute exacerbation of chronic obstructive pulmonary disease following EBB and died following hospitalization. However, this patient had only mild bleeding. None of the other study participants required hospitalization or endotracheal intubation.

A final histologic diagnosis was available for 500 (93.1%) study participants (Table 1). Malignancy was diagnosed in 429 (85.8%), while the results were nondiagnostic in 44 subjects (8.8%). Benign diseases were identified on biopsy in the remaining 27 subjects (5.4%); of this tuberculosis accounted for 37% (n=10). Squamous cell carcinoma (n=236, 43.9%) followed by small cell lung cancer (n=87, 16.2%) was the most common malignancy in our cohort. There was no significant difference in the distribution of the various histologic subtypes of lung cancer, between the 2 study groups. However, the proportion of nondiagnostic biopsies was higher in the group experiencing severe bleed following EBB than without (20% vs. 7.1%, P=0.004).

On a multivariate logistic regression, a centrally located growth [odds ratio (OR) (95% CI), 3.01 (1.52-5.96)] and the bronchoscopist’s judgment of tumor vascularity [OR (95% CI), 2.68 (1.38-5.19)] were the only factors associated with a higher risk of severe bleeding after adjusting for other covariates (Table 2). The presence of SVC syndrome did not predict the risk of severe bleeding. Severe bleeding was also associated with an odds of obtaining lesser number of biopsies [OR (95% CI), 0.70 (0.59-0.83)]. The type of forceps used for biopsy and the histopathology of the endobronchial lesion were not associated with the severity of bleeding.

T2
TABLE 2:
Multivariate Logistic Regression Analysis Showing the Factors Associated With a Higher Risk of Severe Bleeding During Endobronchial Biopsy

DISCUSSION

The results of this study suggest that most patients (70%) who undergo EBB experience only mild or no bleeding at all. However, if severe bleeding occurs, it is associated with a significantly lesser number of biopsies obtained, and a higher chance of obtaining a nondiagnostic biopsy. The bronchoscopic appearance of a vascular lesion, and a central location of the lesion were predictors of an increased risk of severe bleeding following EBB.

Endobronchial biopsies are the standard diagnostic modality for evaluating lesions visualized on bronchoscopy.2,7,8 Bleeding is a common complication after EBB and the degree of endobronchial bleeding is generally assessed based on the level of intervention required to control it, as done in our study.7,9–11 Quantification by measuring the amount of blood suctioned during bronchoscopy and patient’s baseline hemoglobin in blood has been used only in a few studies.12,13 Although bleeding is common after EBB, in majority of the cases it is minimal or mild.7,10,13 Most of these previous studies were, however, not performed exclusively on subjects undergoing EBB. Rather, they included subjects undergoing a variety of flexible bronchoscopic procedures, including transbronchial needle aspiration, and transbronchial lung biopsy, in addition to EBB. For instance, in a cohort of 234 subjects undergoing bronchoscopy (only 14.9% of these were EBB), 90% subjects experienced a blood loss of <5 mL, and none experienced severe blood loss (>100 mL).13 A recent study of subjects with lung cancer diagnosed by EBB reported a 30.5% incidence of bleeding. They recorded the incidence of “bleeding” and “not bleeding” from the bronchoscopy report.11 Two studies evaluating the role of electrocoagulation forceps in EBB showed that the interventions to control bleeding (such as instillation of ice-cold saline or topical adrenaline) were required in 7.6% to 17% of subjects.7,9 No incidence of severe bleeding was reported in both these studies.7,9 EBB when performed using a cryoprobe can yield larger tissue (depending on the time used to freeze the tissue) and a randomized trial showed that cryoprobe had a better diagnostic yield compared with conventional forceps biopsy (95% vs. 85.1%, P<0.001).14 However, there was also a significantly higher incidence of bleeding (80.1% vs. 69.4%). Although no complications were attributed to bleeding, it should be noted that all subjects in that study underwent EBB after securing the airway using an endotracheal tube or a rigid bronchoscope.14

Massive bleeding following EBB can result in flooding of the airways resulting in asphyxiation. The latter can compromise patient safety much earlier than a measurable drop in serum hemoglobin occurs. Hence, it is essential to predict the lesions, which are likely to bleed profusely following EBB. The vascular appearance and the location of the tumor on bronchoscopy were risk factors associated with massive bleeding in our study. This is consistent with a previous study that suggested that the central location of the lesion was independently associated with an increased risk of bleeding.11 This study also found that the histopathology (squamous and small cell cancers were more likely to bleed than adenocarcinoma) was an independent factor predicting bleeding, a finding contrary to ours. In other studies, none of the risk factors studied (including deranged coagulation profile, use of aspirin, presence of pulmonary hypertension, or SVC syndrome) have been consistently identified to be associated with an increased risk of bleeding during bronchoscopy.10,13,15–17 However, most of these studies reported the safety of transbronchial lung biopsy.

Bleeding following EBB can compromise further bronchoscopic examination and reduce the diagnostic yield of the procedure. One study suggested that performing at least 3 biopsies from an endobronchial mass was adequate to diagnose malignancy in majority of the cases.18 However, this may not hold true in the current era of personalized cancer therapy, where molecular profiling of tumors would require more tissue.19 In our study, the median number of attempts as well as biopsies were significantly less in subjects with severe bleeding. The occurrence of severe bleeding precluded further attempts to biopsy the lesion. This might be one of the reasons for a higher proportion of nondiagnostic biopsies in subjects experiencing severe bleeding.

What does the current study add to our existing knowledge? Our study reinforces the safety and efficacy of a commonly performed diagnostic bronchoscopy procedure. The diagnostic yield in our study was 85% [similar to the published literature (76% to 92%)],2,7,8 despite the fact the procedure was done without sedation or general anesthesia, and performed by trainees (75% were performed by fellows under direct supervision of consultants). Also, the procedure duration in our study was short [mean (SD) of 11 (3.5) min]. Thus, a vast majority of patients can have their diagnosis established safely by conventional EBB (85%). The shorter duration of procedure, and the lack of general anesthesia substantially reduces the cost. The central location and the vascular appearance of the endobronchial lesion should alert the operator regarding the possibility of a severe bleeding. The bronchoscopist can then take preventive measures such as instillation of cold saline or adrenaline before biopsy or may consider using electrocoagulation-enabled forceps. While 2 previous studies on electrocoagulation-enabled EBB found no benefit, they did not specifically include subjects at a higher risk of bleeding. Future studies should consider performing electrocoagulation-enabled EBB in vascular-appearing centrally located tumors.

Our study has a few limitations. Although the bleeding was prospectively categorized according to severity, the study was a retrospective analysis of data, with its inherent disadvantages. Thus, our findings require validation in larger multicenter studies. The bronchoscopy practices in the current study may be different from several other centers, including the use of sedation and artificial airway. The complication rates may vary with the use of sedation. In fact, some of the previous studies evaluating EBB-related bleeding were performed under general anesthesia.11,14 The influence of comorbid illnesses including chronic kidney disease, pulmonary hypertension and others, have also been not addressed in the current study. Lastly, we did not have any objective definition for a “vascular”-appearing tumor and the bronchoscopic appearance of the tumor was not recorded. Interobserver rating of the “vascular appearance” from recorded images would have added more strength to our observations. Further, we did not use narrow-band imaging in our study. Whether the use of narrow-band imaging has additional advantage over white light bronchoscopy in predicting the risk of bleeding remains unclear. Future studies should prospectively note the occurrence of bleeding, the presence of comorbid illnesses and should record the appearance of endobronchial lesions. The definition of vascular-appearing lesion should be reported by multiple operators and the study should provide inter-rater agreement of this finding.

In conclusion, EBB is safe and severe bleeding is uncommon. The operator defined vascular appearance and central location of the tumor during bronchoscopy were the only significant predictors of severe bleeding. Severe bleeding reduces the number of biopsies performed and lowers the diagnostic yield.

REFERENCES

1. Gupta AA, Sehgal IS, Dhooria S, et al. Indications for performing flexible bronchoscopy: trends over 34 years at a tertiary care hospital. Lung India. 2015;32:211–215.
2. Zavala DC. Diagnostic fiberoptic bronchoscopy: techniques and results of biopsy in 600 patients. Chest. 1975;68:12–19.
3. Leiten EO, Martinsen EM, Bakke PS, et al. Complications and discomfort of bronchoscopy: a systematic review. Eur Clin Respir J. 2016;3:33324.
4. Dhooria S, Sehgal IS, Gupta N, et al. Diagnostic yield and complications of EBUS-TBNA performed under bronchoscopist-directed conscious sedation: single center experience of 1004 subjects. J Bronchology Interv Pulmonol. 2017;24:7–14.
5. Kaur H, Dhooria S, Aggarwal AN, et al. A randomized trial of 1% vs 2% lignocaine by the spray-as-you-go technique for topical anesthesia during flexible bronchoscopy. Chest. 2015;148:739–745.
6. Du Rand IA, Blaikley J, Booton R, et al. British Thoracic Society guideline for diagnostic flexible bronchoscopy in adults: accredited by NICE. Thorax. 2013;68(suppl 1):i1–i44.
7. Khan A, Aggarwal AN, Agarwal R, et al. A randomized controlled trial of electrocoagulation-enabled biopsy versus conventional biopsy in the diagnosis of endobronchial lesions. Respiration. 2011;81:129–133.
8. Mak VH, Johnston ID, Hetzel MR, et al. Value of washings and brushings at fibreoptic bronchoscopy in the diagnosis of lung cancer. Thorax. 1990;45:373–376.
9. Tremblay A, Michaud G, Urbanski SJ. Hot biopsy forceps in the diagnosis of endobronchial lesions. Eur Respir J. 2007;29:108–111.
10. Herth FJ, Becker HD, Ernst A. Aspirin does not increase bleeding complications after transbronchial biopsy. Chest. 2002;122:1461–1464.
11. Wang S, Ye Q, Tu J, et al. The location, histologic type, and stage of lung cancer are associated with bleeding during endobronchial biopsy. Cancer Manag Res. 2018;10:1251–1257.
12. Bjortuft O, Brosstad F, Boe J. Bronchoscopy with transbronchial biopsies: measurement of bleeding volume and evaluation of the predictive value of coagulation tests. Eur Respir J. 1998;12:1025–1027.
13. Carr IM, Koegelenberg CF, von Groote-Bidlingmaier F, et al. Blood loss during flexible bronchoscopy: a prospective observational study. Respiration. 2012;84:312–318.
14. Hetzel J, Eberhardt R, Herth FJ, et al. Cryobiopsy increases the diagnostic yield of endobronchial biopsy: a multicentre trial. Eur Respir J. 2012;39:685–690.
15. Wahidi MM, Garland R, Feller-Kopman D, et al. Effect of clopidogrel with and without aspirin on bleeding following transbronchial lung biopsy. Chest. 2005;127:961–964.
16. Diette GB, Wiener CM, White P Jr. The higher risk of bleeding in lung transplant recipients from bronchoscopy is independent of traditional bleeding risks: results of a prospective cohort study. Chest. 1999;115:397–402.
17. Diaz-Fuentes G, Bajantri B, Adrish M. Safety of bronchoscopy in patients with echocardiographic evidence of pulmonary hypertension. Respiration. 2016;92:182–187.
18. Shure D, Astarita RW. Bronchogenic carcinoma presenting as an endobronchial mass. Chest. 1983;83:865–867.
19. Kalemkerian GP, Narula N, Kennedy EB, et al. Molecular testing guideline for the selection of patients with lung cancer for treatment with targeted tyrosine kinase inhibitors: American Society of Clinical Oncology Endorsement of the College of American Pathologists/International Association for the Study of Lung Cancer/Association for Molecular Pathology Clinical Practice Guideline Update. J Clin Oncol. 2018;36:911–919.
Keywords:

lung cancer; bronchoscopy; electrocoagulation; cryobiopsy; SVC syndrome

Supplemental Digital Content

Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.