Endobronchial ultrasound (EBUS) has become the most preferred technique for the assessment of mediastinal and hilar lymph node enlargement.1,2 It is not only the recommended initial modality for the staging of lung cancer but is also useful for the diagnosis of mediastinal disease both in adults and children.3–5 EBUS-guided transbronchial needle aspiration (TBNA) is performed with a dedicated echobronchoscope, which has a larger diameter compared with a flexible bronchoscope, and causes more discomfort to the patient than routine flexible bronchoscopy.6 Thus, flexible bronchoscopy can be routinely performed under light sedation or under local anesthesia alone,7 whereas EBUS generally requires moderate to deep sedation in spontaneously breathing subjects or general anesthesia.2 Although there are clear guidelines on the use of sedation and anesthesia during the performance of flexible bronchoscopy, the issues regarding anesthesia and sedation during EBUS-TBNA are an area of active research.8 Recently, there have been a few studies that have evaluated different protocols of sedation and anesthesia used during EBUS.9–11
One major issue regarding the use of sedation/anesthesia during EBUS is the choice between general anesthesia and conscious sedation. One study reported a higher diagnostic yield when the procedure was performed under general anesthesia, whereas a recent randomized controlled trial found the yield to be similar during moderate sedation or general anesthesia.9,12 Other studies have demonstrated that EBUS performed under conscious sedation is associated with good patient satisfaction and diagnostic yield.10,11 On the other hand, results of the multicenter American College of Chest Physicians Quality Improvement Registry, Evaulation and Education (AQuIRE) data registry suggest that escalation of care is required in about 0.4% with moderate sedation as compared with 1.4% of patients with general anesthesia.13 The recent American College of Chest Physicians guidelines suggest that either moderate or deep sedation is an acceptable approach for EBUS-TBNA.14 Another issue is whether sedation or anesthesia should be administered by trained anesthesia personnel or can be directed by a bronchoscopist.
In this retrospective study, we describe our experience of performing EBUS and the more recently described technique of transesophageal ultrasound with an echobronchoscope [endoscopic ultrasound with a bronchoscope-guided fine needle aspiration (EUS-B-FNA)] under bronchoscopist-directed conscious sedation.15,16
This is a retrospective analysis of data collected in the bronchoscopy suite of the Institute on EBUS-TBNA or EUS-B-FNA procedures performed between July 2011 and January 2016. The Institutional Ethics Committee approved the study protocol and waived the requirement for informed consent. However, procedural consent was obtained from all study subjects according to the institutional practice.
Consecutive subjects who underwent EBUS-TBNA or EUS-B-FNA were included in the study. The following information was retrieved from the bronchoscopy database: (a) demographic characteristics including age, sex, and clinical diagnosis; (b) sedative, analgesic, and antisecretory drugs administered before and during the procedure along with their doses; (c) the Ramsay scale score of the subject during the procedure; (d) operator assessment of the subject’s cough and respiratory secretions during the procedure assessed on a visual analog scale of 0 to 100; (e) duration of the procedure; (f) the lymph node stations (based on International Association for the Study of Lung Cancer (I classification) sampled, size of lymph nodes on EBUS, number of lymph node stations sampled and lymph node characteristics on EBUS, namely the presence of heterogeneous echotexture or coagulation necrosis sign17,18; (g) cytological diagnosis on TBNA; and, (h) complications associated with the procedure.
All subjects underwent complete blood count, coagulation profile, liver and kidney function tests, chest radiograph, and computed tomography of the chest.
Protocol for Sedation and Anesthesia
After an overnight fast, the subjects were administered intramuscular atropine (0.6 mg) and promethazine (25 mg), 15 minutes before the procedure. Subsequently, they were nebulized with 2.5 mL of 4% lignocaine for 15 minutes in the preparation room. Once shifted to the procedure table, 10% lignocaine solution was sprayed twice (10 mg/puff) over the oropharynx with an atomizer just before the procedure. The subjects were then administered IV midazolam (1 to 2 mg initially, and additional 1 mg doses) and pentazocine (30 mg initially with additional doses as required to maintain cough suppression) by the bronchoscopy technician, as directed by the bronchoscopist. An assistant (a fellow or a bronchoscopy consultant) supervised the administration of the sedative in consultation with the operator. The echobronchoscope was then introduced through the mouth and 2 mL aliquots of 2% lignocaine solution (1% solution was used beginning from January 2015) were delivered through the echobronchoscope using the “spray-as-you-go” technique. One aliquot each was instilled at the vocal cords, tracheal carina, and in the right and left main bronchus. Additional lignocaine aliquots were instilled as required to suppress cough, at the discretion of the operator. Subjects were routinely monitored for any adverse effects related to the use of the local anesthetic and sedative drugs. Heart rate, respiratory rate, blood pressure, and oxygen saturation (by pulse oximetry) were monitored throughout the procedure. All subjects received oxygen at the rate of 2 to 4 L/min by nasal cannula/face mask; the flow was increased to 6 to 8 L/min if the oxygen saturation fell below 88%.
Subjects were placed in the supine position and the EBUS scope was introduced transorally through a protective mouth guard. The procedure was performed by operators (consultants or fellows under direct supervision of the consultant) experienced in EBUS technique, as described previously.6 Lymph node stations were categorized according to the IASLC classification.19 The convex probe EBUS scope (BF-UC 180F; Olympus Medical Systems, Japan) with a 7.5 MHz convex transducer and a compatible endoscopic ultrasound scanner (EU-ME1; Olympus Medical Systems, Japan) were used. Lymph nodes were punctured using a disposable, 21 or 22 G, dedicated EBUS-TBNA needle (Vizishot, NA-201SX-4021/4022, Olympus Medical Systems, Japan) under sonographic and bronchoscopic visualization. The aspirate thus obtained was spread out on to a glass slide; both air dried and alcohol-fixed slides were prepared. On-site cytologic assessment facility was not available.
EUS-B-FNA was performed in cases with one or more of the following features: lymph node inaccessible by EBUS-TBNA, EBUS-TBNA technically difficult, if all areas of lymph node could not be accessed adequately by EBUS-TBNA, subject unfit for bronchoscopy or EBUS-TBNA not feasible due to hypoxemia, raised intracranial pressure, excessive coughing, or potential airway compromise. The procedure was performed in the supine position, as previously described.16,20 The scope was directed using vascular landmarks and lymph nodes were identified based on their location with respect to the heart and intrathoracic vessels. Aspiration of the lymph nodes and processing of the specimen were performed in a manner similar to EBUS-TBNA.
Assessment of Level of Sedation, Cough, and Airway Secretions
The depth of sedation was assessed using the Ramsay sedation scale (RSS). It is a numerical scale that describes 6 levels of consciousness from 1 (subject anxious, agitated, and/or restless) through 6 (subjects exhibiting no response to light glabella tap or loud auditory stimulus).21 The operator recorded the intensity of subject’s cough and amount of airway secretions during EBUS-TBNA/EUS-B-FNA using a visual analog scale (VAS), immediately after the procedure. The VAS for cough was rated on a horizontal line, 100 mm in length with “no cough” at one end, and “worst cough” affixed at the other. The amount of airway secretions was rated on a similar scale with “no secretions” and “copious secretions” anchored at the two ends of the line.
Complications Related to EBUS
All subjects were observed for a minimum of two hours after the procedure. Complications recorded after the procedure included: (i) fever and chills; (ii) excessive coughing; (iii) chest pain; (iv) bradycardia (heart rate <60/min); (v) sustained hypoxemia (fall in pulse oximetric saturation below 88% for >1 min); (vi) respiratory failure or arrest; (vii) pneumothorax; (viii) bleeding; and, (ix) escalation of the level of care. Bleeding was further classified as mild (required only suctioning), moderate (needed instillation of cold saline or epinephrine); and severe (associated with hypotension or necessitated blood transfusion, intubation or escalation of the level of care). The following complications were classified as major: hypotension, bradycardia, any arrhythmia, severe bleeding, respiratory failure or any complication requiring escalation of the level of care. All other complications were considered as minor complications.
A diagnostic procedure was defined as cytologic examination of the aspirate yielding a definite diagnosis (such as malignancy, sarcoidosis, tuberculosis, and others). An adequate sample was defined as an aspirate revealing a definite diagnosis or showing preponderance of lymphocytes.
Statistical analysis was performed using the commercial statistical package SPSS for MS-Windows (Version 22, IBM Inc, Chicago, IL). Data were expressed as mean±SD, or number with percentage. Differences between categorical variables between 2 groups were assessed using the χ2 test or Fisher exact test and continuous variables in the 2 groups were compared using Mann-Whitney U test. The effect of any complication on the diagnostic yield of the procedure was assessed using the χ2 test.
A total of 1005 procedures were performed during the study period, of which one was performed in a patient receiving mechanical ventilation. The 1004 subjects [378 (37.6%) females] included in the study had a mean (SD) age of 45.9 (15.8) years (Table 1). The most common indication for EBUS was diagnosis of sarcoidosis (48.6%). EUS-B-FNA was performed with/without EBUS in 79 (7.9%) patients. Additional procedures such as endobronchial and transbronchial biopsies were performed in 456 and 432 subjects respectively. A total of 2003 lymph nodes were sampled with a median [interquartile range (IQR)] of 2 (1 to 3) nodes per subject. The mean (SD) short-axis diameter of the lymph nodes as measured on EBUS was 16.5 (6.1) mm. A median (IQR) of 2 (2 to 3) aspirations were performed per node. The average duration of the procedure was 22.5 minutes.
A majority of the subjects (96.7%) received premedication with intramuscular atropine and promethazine (Table 2). IV sedation and analgesia were administered using midazolam (97.9%) and pentazocine (97.5%), respectively. The mean (SD) doses of midazolam and pentazocine used were 2.53 (1.84) mg and 30.9 (6.9) mg, respectively. The data regarding the level of sedation using the Ramsay score was available for 284 subjects, most (73.9%) were maintained at a RSS score of 3 or 4. The operator rated median (IQR) VAS for cough and secretions encountered during the procedure were 17 (8 to 35) and 14 (8 to 26), respectively.
Of the 1004 subjects, TBNA was not performed due to various reasons in 17 subjects, while the cytologic details were not available in 15 subjects. The diagnostic yield of the procedure in the remaining 972 subjects was 61.2%. An adequate sample was obtained in 94.9% of the subjects. Of the 595 diagnostic procedures, the majority of the diagnoses (80.0%) achieved using EBUS-TBNA/EUS-B-FNA were infectious and inflammatory disorders, with sarcoidosis [279 (46.9%) subjects] being the most common (Table 3). Tuberculosis was diagnosed in 193 (32.4%) subjects. Malignancies were diagnosed by EBUS-TBNA/EUS-B-FNA in 115 (19.7%) subjects with metastatic adenocarcinoma being the commonest. Lymphoma was diagnosed in 15 (2.5%) subjects. Other malignancies diagnosed on EBUS-TBNA/EUS-B-FNA included large cell anaplastic carcinoma (n=1), renal cell carcinoma (n=1), myeloma (n=1), and neuroendocrine carcinoma (n=2). Three subjects were diagnosed as having bronchogenic cysts; aspiration was performed in 2 of them. Peripheral nerve sheath tumor was diagnosed in 2 subjects. The aspirate demonstrated Aspergillus species in 4 subjects.
Sixty (5.9%) subjects had at least 1 complication, of these the procedure was abandoned without performing TBNA in 1 subject. There were 11 (1.1%) major complications. Respiratory failure requiring assisted ventilation occurred in 6 (0.6%) subjects. Hypotension occurred in 2 (0.2%) subjects, both the subjects recovered with a bolus of IV fluids. Escalation in the level of care (overnight observation in the medical ward or the intensive care unit) was required in 8 (0.8%) subjects. Bleeding occurred in 17 (1.7%) subjects and included mild or moderate bleeding in 13 and 4 cases, respectively (Table 4). Excessive coughing and hypoxia were the most common complications that occurred in 14 (1.4%) and 11 (1.1%) subjects, respectively. In 7 (0.7%) subjects, the procedure could not be satisfactorily performed (either inadequate number of passes or inadequate number of lymph node stations sampled) due to a complication.
The diagnostic yield of the procedure in subjects who had a complication was significantly lower (46.7%), as compared with that (62.2%) in subjects without any complications (P=0.02).
The results of this study show that EBUS-TBNA performed under bronchoscopist-directed conscious sedation is associated with a reasonable diagnostic yield and an acceptable safety profile. Although a number of minor complications were encountered, they were self-limiting. Few major complications occurred that required intervention or escalation of care, and importantly there was no mortality. The results of the present study lend further support to the recent observations in other studies that EBUS-TBNA performed under conscious sedation is safe and effective, even in a resource constrained setting.9–11,22
The diagnostic yield in this study is less than the yield reported in several randomized controlled trials of EBUS-TBNA (66.7% to 91%).9,23–25 The possible reason is that this is a retrospective analysis of an unselected cohort of subjects undergoing EBUS-TBNA in a real-world setting. Multiple operators including pulmonary fellows performed the procedure. Further, a large proportion of our patients had suspected sarcoidosis rather than malignancy, the yield of EBUS being much lower in sarcoidosis than malignancy.3,26 Rapid on-site cytologic examination was unavailable. However, the diagnostic yield and sample adequacy rates in this study, about 61% and 95%, respectively are closer to those reported in the AQuIRE registry (50% and 90%, respectively), as the registry has also presented data from a real-world scenario.27
Despite the fair overall diagnostic yield, the yield was significantly lower in patients who had a complication (47%) as compared with those who did not (62%). This is possibly because the occurrence of a complication led to either an abrupt termination of the procedure or prompted the bronchoscopist to complete the procedure quickly due to concerns of patient safety; both of which may have led to a less thorough sampling. Whether the use of general anesthesia would have increased the yield in these patients is a question that cannot be answered from the current study. In this context, a recent randomized study has demonstrated that the yield, major complications, and patient tolerance are similar between EBUS-TBNA performed under general anesthesia or moderate sedation.9
EBUS-TBNA performed under moderate sedation is safe. Complications occurred in about 6% of the patients in the present study; however, most were mild, requiring no further intervention. Significant complications such as hypotension, respiratory failure, and arrhythmias occurred in only 11 (1.1%) patients leading to an escalation of care in only 0.8% of the patients. The complication rate is similar to that reported in the AQuIRE registry, and lower than that in a randomized trial of moderate sedation.9,13 A recent multicenter study of 3123 patients from Turkey has also demonstrated the safety of EBUS-TBNA with a reported serious complication rate of only 0.16%.28 However, in that study, only the most serious complications have been reported.
Midazolam and pentazocine are used as the sedative agents at our center as they are available free of cost in the hospital formulary. Moreover, midazolam has good hypnotic, amnesic, anxiolytic, and hemodynamic properties.29 It is also easy to use, has a rapid onset of action that can be easily reversed with flumazenil. The British Thoracic Society guidelines for diagnostic flexible bronchoscopy recommend the use of midazolam as the preferred drug for sedation.8 Further, combining midazolam with pentazocine (opioid analgesic and cough suppressant), enhances the amnestic and sedative effects of midazolam, decreasing the required dose of midazolam and improves bronchoscopic tolerance.8,30 The subjects in the present study had a fair level of sedation as suggested by a RSS score of 3 (patient responding only to verbal command) or 4 (brisk response to light glabella tap or loud auditory stimulus) in three-fourths of the study population and low median VAS score for cough. We have previously shown that the use of anticholinergic medications is not beneficial (and may even be harmful) during routine diagnostic flexible bronchoscopy.31 However, there are little data on the use of anticholinergic medications in patients undergoing EBUS-TBNA. We have used atropine in all our EBUS procedures with an aim to reduce airway secretions, without any observed ill effects.
The use of bronchoscopist-guided moderate sedation at our center stems from many reasons. Our center is a public sector hospital performing about 2000 bronchoscopies and over 250 EBUS procedures annually. The services of anesthesia personnel are not routinely available for this reasonably large number of procedures. Also, the number of diagnostic EBUS procedures far outnumbers the lung cancer staging procedures at our center, thus requiring a shorter average procedure time (about 20 min) as compared with other reports (30 to 45 min).11,12,32 As the EBUS is now available even in low-income and middle-income countries and in smaller hospitals, the problems of availability of anesthesiologists and postprocedure monitoring facilities are real. The effectiveness and safety of EBUS-TBNA under moderate sedation makes the technology feasible even at the secondary levels of health care.
Finally, our study has a few limitations. Being a retrospective analysis, assessments such as patient satisfaction, amnesia, pain, discomfort, and readiness to undergo a repeat procedure were not performed as part of the study procedures. Also, the nonavailability of sedation scores in all patients is a major limitation. Rapid onsite cytologic evaluation was not available. A heterogeneous group of operators including pulmonary fellows performed the procedure, many of whom were in their learning curve. However, these factors also make the study more generalizable to everyday clinical practice in teaching institutions where pulmonary fellows or trainees are also performing the procedures along with experienced consultants. To our knowledge, this is the largest single-center experience of yield and complications of EBUS-TBNA performed under bronchoscopist-directed moderate sedation.
In conclusion, EBUS-TBNA/EUS-B-FNA performed under bronchoscopist-directed moderate sedation is not only safe but also has an acceptable diagnostic yield.
1. Gupta D, Dadhwal DS, Agarwal R, et al. Endobronchial ultrasound-guided transbronchial needle aspiration vs conventional transbronchial needle aspiration in the diagnosis of sarcoidosis. Chest. 2014;146:547–556.
2. Dhooria S, Sehgal IS, Aggarwal AN, et al. Convex-probe endobronchial ultrasound: a decade of progress. Indian J Chest Dis Allied Sci. 2016;58:21–35.
3. Gu P, Zhao YZ, Jiang LY, et al. Endobronchial ultrasound-guided transbronchial needle aspiration for staging of lung cancer: a systematic review and meta-analysis. Eur J Cancer. 2009;45:1389–1396.
4. Dhooria S, Madan K, Pattabhiraman V, et al. A multicenter study on the utility and safety of EBUS-TBNA and EUS-B-FNA
in children. Pediatr Pulmonol. 2016. DOI 10.1002/ppul.23415
5. Sehgal IS, Dhooria S, Aggarwal AN, et al. Endosonography vs mediastinoscopy in staging of lung cancer: systematic review and meta-analysis. Ann Thorac Surg. 2016. [In press]. doi: 10.1016/j.athoracsur.2016.05.110
6. Srinivasan A, Agarwal R, Gupta N, et al. Initial experience with real time endobronchial ultrasound guided transbronchial needle aspiration from a tertiary care hospital in north India. Indian J Med Res. 2013;137:803–807.
7. 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.
8. 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.
9. Casal RF, Lazarus DR, Kuhl K, et al. Randomized trial of endobronchial ultrasound-guided transbronchial needle aspiration under general anesthesia versus moderate sedation. Am J Respir Crit Care Med. 2015;191:796–803.
10. Chrissian AA, Bedi H. Bronchoscopist-directed continuous propofol infusion for targeting moderate sedation during endobronchial ultrasound bronchoscopy: a practical and effective protocol. J Bronchology Interv Pulmonol. 2015;22:226–236.
11. Jeyabalan A, Medford AR. Endobronchial ultrasound-guided transbronchial needle aspiration: patient satisfaction under light conscious sedation. Respiration. 2014;88:244–250.
12. Yarmus LB, Akulian JA, Gilbert C, et al. Comparison of moderate versus deep sedation for endobronchial ultrasound transbronchial needle aspiration. Ann Am Thorac Soc. 2013;10:121–126.
13. Eapen GA, Shah AM, Lei X, et al. Complications, consequences, and practice patterns of endobronchial ultrasound-guided transbronchial needle aspiration: results of the AQuIRE registry. Chest. 2013;143:1044–1053.
14. Wahidi MM, Herth F, Yasufuku K, et al. Technical aspects of endobronchial ultrasound guided transbronchial needle aspiration: CHEST Guideline and Expert Panel Report. Chest. 2016;149:816–835.
15. Dhooria S, Aggarwal AN, Gupta D, et al. Utility and safety of endoscopic ultrasound with bronchoscope-guided fine-needle aspiration in mediastinal lymph node sampling: systematic review and meta-analysis. Respir Care. 2015;60:1040–1050.
16. Dhooria S, Aggarwal AN, Singh N, et al. Endoscopic ultrasound-guided fine-needle aspiration with an echobronchoscope in undiagnosed mediastinal lymphadenopathy: first experience from India. Lung India. 2015;32:6–10.
17. Dhooria S, Agarwal R, Aggarwal AN, et al. Differentiating tuberculosis from sarcoidosis by sonographic characteristics of lymph nodes on endobronchial ultrasonography: a study of 165 patients. J Thorac Cardiovasc Surg. 2014;148:662–667.
18. Dhooria S, Agarwal R, Aggarwal AN, et al. Agreement of mediastinal lymph node size between computed tomography and endobronchial ultrasonography: a study of 617 patients. Ann Thorac Surg. 2015;99:1894–1898.
19. Rusch VW, Asamura H, Watanabe H, et al. The IASLC lung cancer staging project: a proposal for a new international lymph node map in the forthcoming seventh edition of the TNM classification for lung cancer. J Thorac Oncol. 2009;4:568–577.
20. Hwangbo B, Lee HS, Lee GK, et al. Transoesophageal needle aspiration using a convex probe ultrasonic bronchoscope. Respirology. 2009;14:843–849.
21. Ramsay MA, Savege TM, Simpson BR, et al. Controlled sedation with alphaxalone-alphadolone. Br Med J. 1974;2:656–659.
22. Dhooria S, Sehgal IS, Gupta N, et al. Yield of new versus reused endobronchial ultrasound-guided transbronchial needle aspiration needles: a retrospective analysis of 500 patients. Lung India. 2016;33:367–371.
23. Herth F, Becker HD, Ernst A. Conventional vs endobronchial ultrasound-guided transbronchial needle aspiration: a randomized trial. Chest. 2004;125:322–325.
24. Ernst A, Anantham D, Eberhardt R, et al. Diagnosis of mediastinal adenopathy-real-time endobronchial ultrasound guided needle aspiration versus mediastinoscopy. J Thorac Oncol. 2008;3:577–582.
25. Arslan Z, Ilgazli A, Bakir M, et al. Conventional vs. endobronchial ultrasound-guided transbronchial needle aspiration in the diagnosis of mediastinal lymphadenopathies. Tuberk Toraks. 2011;59:153–157.
26. Agarwal R, Srinivasan A, Aggarwal AN, et al. Efficacy and safety of convex probe EBUS-TBNA in sarcoidosis: a systematic review and meta-analysis. Respir Med. 2012;106:883–892.
27. Ost DE, Ernst A, Lei X, et al. Diagnostic yield of endobronchial ultrasound-guided transbronchial needle aspiration: results of the AQuIRE Bronchoscopy Registry. Chest. 2011;140:1557–1566.
28. Caglayan B, Yilmaz A, Bilaceroglu S, et al. Complications of convex-probe endobronchial ultrasound-guided transbronchial needle aspiration: a Multi-Center Retrospective Study. Respir Care. 2016;61:243–248.
29. Midtling JI. Midazolam: a new drug for intravenous sedation. Anesth Prog. 1987;34:87–89.
30. Newman M, Reves JG. Pro: midazolam is the sedative of choice to supplement narcotic anesthesia. J Cardiothorac Vasc Anesth. 1993;7:615–619.
31. Malik JA, Gupta D, Agarwal AN, et al. Anticholinergic premedication for flexible bronchoscopy: a randomized, double-blind, placebo-controlled study of atropine and glycopyrrolate. Chest. 2009;136:347–354.
32. Dal T, Sazak H, Tunc M, et al. A comparison of ketamine-midazolam and ketamine-propofol combinations used for sedation in the endobronchial ultrasound-guided transbronchial needle aspiration: a prospective, single-blind, randomized study. J Thorac Dis. 2014;6:742–751.