Endobronchial Ultrasound

Endobronchial ultrasound (EBUS) is a technique that uses ultrasound along with bronchoscopy to visualize the airway wall and structures adjacent to it. The clinical application and diagnostic benefit of EBUS have been established in many studies. EBUS has been incorporated into routine practice in many centers because of its high diagnostic value and low risk. Endoscopic ultrasound was first used in the field of gastroenterology for staging esophageal and gastric malignancies. Ultrasound use within the airways was developed in the early 1990s. These small ultrasound probes, “miniprobes,” were the first generation of radial probe EBUS (RP-EBUS). The first report of using RP-EBUS to guide transbronchial biopsies for the assessment of lung nodules was published in 2002 ^[1] .

Transbronchial needle aspiration (TBNA) was first described in 1949 to use with the rigid bronchoscope, ^[2]  and Wang et al designed a prototype needle for the flexible bronchoscope in 1978 ^[3] . TBNA to sample beyond the wall of the central airways gained great attention of chest physicians. Subsequently, convex probe endobronchial ultrasound (CP-EBUS), with the ability to perform real-time endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) was developed in 2002. EBUS allowed TBNA of mediastinal and hilar structures and parabronchial lung masses, and it became popular quickly.  EBUS can access a wide range of mediastinal and hilar lymph nodes (2R, 2L, 3p, 4R, 4L, 7, 10R, 10L, 11R, 11L) but cannot sample subaortic (stations 5 and 6), paraesophageal (station 8), and pulmonary ligament (station 9) lymph nodes. The addition of EUS-FNA allows access to stations 8 and 9. CP-EBUS and EBUS-TNBA achieved widespread use because they are minimally invasive, are less expensive, and have a lower rate of complications as compared to mediastinoscopy. With the use of EBUS-TBNA, median rates of mediastinoscopy performed in the United States dropped from 21.6% to 10% between 2006 and 2010 ^[4] .

Indications of CP-EBUS

Diagnosis and staging of non-small cell lung cancer (NSCLC)

EBUS-TBNA is highly sensitive to staging and diagnosing lung cancer, and it is the preferred first-step procedure when nodal involvement is suspected. The meta-analysis published by Gu et al covering 11 studies with 1299 lung cancer patients showed that EBUS-TBNA had a pooled sensitivity of 0.93 and a pooled specificity of 1.00. ^[5]  EBUS-TBNA has higher diagnostic yield than conventional TBNA (c-TBNA) in all accessible lymph node stations except subcarinal lymph nodes in determining the lymph node involvement in NSCLC. ^[6]  In a study of 209 patients who underwent sampling of hilar/mediastinal lymph nodes for the diagnosis/staging of lung cancer (99 EBUS-TBNA and 110 c-TBNA), EBUS-TBNA was found to have significantly better results than c-TBNA in terms of diagnostic accuracy (94.2% vs 89.7%), sample adequacy (70.3% vs 42%), and sensitivity (93% vs 86.4%) for lymph nodes less than 2 cm. There were no significant differences in diagnostic accuracy, adequacy, and sensitivity for lymph nodes 2 cm or greater. ^[7]  EBUS-TBNA can also be used to restage lung cancer in the mediastinum. ^[8]

Lymphoma 

EBUS-TBNA can be used for diagnosis of lymphoma, but the diagnostic accuracy for lymphoma is significantly lower than it is for lung cancer diagnosis and staging. It may be reasonable to consider using EBUS-TBNA initially in a patient suspected of having lymphoma with isolated mediastinal lymphadenopathy. In one study, the sensitivity of EBUS-TBNA for the detection of lymphoma was 76%; however, the sensitivity for the definitive diagnosis of lymphoma was only 57%. ^[9]  Another study found an overall sensitivity of 85% but 91% for detection of recurrence. ^[10]  The American College of Chest Physicians (ACCP) has stated that EBUS-TBNA is an acceptable initial, minimally invasive diagnostic test for a patient with suspected lymphoma. The British Thoracic Society said that “at present, there is insufficient evidence to recommend EBUS-TBNA for routine use in the diagnosis of lymphoma.” ^[11]

Sarcoidosis

EBUS-TBNA is useful for evaluating benign causes of thoracic lymphadenopathy. It provides diagnostic information in patients with early stage sarcoidosis who have adenopathy but minimal changes in the lung parenchyma. In the GRANULOMA study, endosonographic (EUS-FNA or EBUS-TBNA) diagnosis of lower stage (I and II) sarcoidosis was higher than conventional bronchoscopic biopsy (transbronchial or endobronchial). ^[12]  The diagnostic yield of granuloma detection was 80% in the endosonographic group versus 53% in the standard bronchoscopy group. The American Thoracic Society recommends EBUS-guided lymph node sampling, rather than mediastinoscopy, as the initial mediastinal and/or hilar lymph node sampling procedure for patients with suspected sarcoidosis and mediastinal and/or hilar lymphadenopathy for whom tissue sampling is necessary ^[13] .

TB and infectious disease

EBUS-TBNA has also been found to be useful in the diagnosis of TB that presents with intrathoracic lymphadenopathy. In a meta-analysis of 8 studies involving 809 patients with TB, the pooled sensitivity and specificity of EBUS-TBNA for the diagnosis of intrathoracic TB was 80% and 100%, respectively. ^[14]  EBUS-TBNA is useful in identifying the cause of granulomatous inflammation within intra-thoracic lymph nodes. In a study of 210 patients who underwent EBUS-TBNA, 56 were found to have granulomatous inflammation on histocytologic evaluation. Twenty of these patients were found to have caseating granulomas of varying etiologies: histoplasma, blastomyces, or mycobacterium TB. ^[15]  The role of EBUS-TBNA in diagnosis of an infectious etiology is not as unequivocally proven as it is for lung and other cancers. In a retrospective evaluation of 86 patients, EBUS-TBNA samples did not appear to be sufficiently sensitive to rule out infectious causes of adenopathy. Bacterial cultures were positive in 52% of samples. However, all but one were considered contaminants, and 2 more patients had a positive mycobacterial culture (both for Mycobacterium avium-intracellulare); fungal cultures were negative. ^[16]

Mediastinal lesions

A variety of mediastinal lesions can be accessed or sampled by EBUS-TBNA. Careful review of the chest CT (location, Hounsfield units) can help formulate a differential diagnosis of the lesion prior to procedure. In a retrospective study of 140 patients with mediastinal masses of unknown etiology and no evidence of lung cancer or other pulmonary malignancy, EBUS-TBNA was diagnostic in 131 (93.6%) of patients. ^[17]  EBUS-TBNA can be used as a therapeutic intervention as well. Drainage of mediastinal cyst may be possible. ^[18]  There are several case reports outlining the use of CP-EBUS for draining mediastinal lesions, such as esophageal duplication cysts, bronchogenic cysts, and pericardial effusions. It is important to note that these therapeutic applications of CP-EBUS are yet to be supported by robust data; complete therapeutic success is uncommon.

Contraindications

Contraindications to endobronchial ultrasound are similar to contraindications to flexible bronchoscopy and include following:

• Life-threatening cardiac arrhythmias

• Current or recent myocardial ischemia

• Poorly controlled heart failure

• Severe hypoxemia

• Uncooperative patient

Additional contraindications to EBUS-TBNA are related to bleeding risk and include following:

• Current antiplatelet agents ^[19]

• Current anticoagulant therapy

• Coagulopathy

• Thrombocytopenia

• Elevated blood urea nitrogen or serum creatinine

Anesthesia

In the United States, EBUS-TNBA procedures are most often performed under deep sedation. Moderate sedation can be utilized for EBUS bronchoscopy in a fashion similar to that for flexible bronchoscopy. ^[20] .The use of moderate sedation or deep sedation during EBUS-TBNA and outcome are conflicting. In a retrospective study of EBUS performed under moderate or deep sedation, there was statistically significant benefit of deep sedation on diagnostic yield. ^[21]  However, a prospective, randomized, controlled study of EBUS-TBNA under moderate sedation and general anesthesia found no difference in the diagnostic yield, rate of major complications, and patient tolerance. ^[22]

Equipment

RP-EBUS probe

The RP-EBUS probe has an ultrasound processor and a balloon catheter that is fixed at the tip of the probe. Three radial ultrasound probe are available (20 MHz miniature, 30 MHz miniature, and 20 MHz ultra-miniature). The 20 MHz and 30 MHz miniature radial probes have a diameter of 2.5 mm; therefore, a flexible bronchoscope with a working channel of 2.8 mm is required to use it. The 20 MHz ultra-miniature radial probe has a smaller diameter and can be inserted through the 2 mm working channel of a bronchoscope and can extend further into subsegmental bronchi than the miniature radial probe. RP-EBUS provides 360-degree images of the airway wall and surrounding structures and has the ability to visualize the layers of the airway wall in detail. RP-EBUS is used for visualization of peripheral lung nodules and assists during transbronchial biopsies. 

CP-EBUS bronchoscope

The CP-EBUS bronchoscope has a linear, curved-array ultrasonic transducer of 7.5 MHz at the distal tip, which has the capability of displaying B-mode and color Doppler mode. ^[23]

(See the images below.)

The transducer forms a gray-scale image that is parallel to the insertion of the bronchoscope. Three CP-EBUS bronchoscopes are available: Olympus (United States), Pentax (Tokyo), and Fujifilm (Tokyo). These 3 bronchoscopes have similar designs, with each having some unique features. The angle and direction vary with different CP-EBUS types of equipment. The Olympus EBUS bronchoscope has a field of view of 80 degrees, and the direction of view is 35 degrees forward oblique. The outer diameter of the bronchoscope is 6.2 mm, and the inner channel diameter is 2 mm. 

 

Positioning

EBUS is usually performed with the patient in the supine position, with the operator standing at the head end of the bed. The monitoring devices are placed on the patient, and intravenous access is established before the procedure is started. The patient's eyes should be covered to prevent splashing of normal saline, secretions, or blood into the eyes.

RP-EBUS

RP-EBUS is performed by placing the tip of a conventional bronchoscope in the area of interest, and the radial probe, with or without the working channel extended, is inserted through the working channel. The probe is positioned at the target level, and the balloon is filled with water until it has achieved firm contact with the airway. A complete circular image of the airway wall and surrounding structures is obtained once the balloon has firm contact with the airway wall. Once the target lesion is identified, the radial probe is removed from the working channel of the bronchoscope, and the  sampling instrument is introduced through the guide sheath. RP-EBUS does not permit sampling in real-time. It can be combined with a virtual bronchoscopic navigation system. RP-EBUS has the ability to precisely visualize the airway wall invasion and helps to differentiate airway wall infiltration and compression in mass next to the trachea or within the tracheobronchial angles. EBUS has been shown to be superior to CT in distinguishing infiltration and compression. ^[24]

Real-time TBNA

The EBUS bronchoscope can be inserted through the nose, mouth, laryngeal mask airway, endotracheal tube, and tracheostomy tube. The size of the endotracheal tube should be at least No. 8 to accommodate the CP-EBUS bronchoscope and to ensure adequate ventilation. Lymph node stations 2R, 2L, and 3P will not be accessible with the use of an endotracheal tube and should be avoided if these lymph nodes are the sampling target.

Real-time TBNA is simultaneous sonographic visualization and sampling of the lesion. The endobronchial view image quality of CP-EBUS is lower than that of regular bronchoscopy. One must be careful while passing the EBUS bronchoscope through the vocal cord if EBUS is being done with conscious sedation or with the use of a laryngeal mask airway. Position the tip of the bronchoscope anteriorly to prevent the EBUS bronchoscope from sticking to the posterior part of the vocal cords. Once the bronchoscope is in the airway, systemic examination of the mediastinal lymph nodes should be done. If in doubt, Doppler ultrasound can be used to differentiate lymph nodes and vascular structures. The subcarinal lymph node can be visualized from either the right main or the left main bronchus. The bronchoscopic and ultrasound views can be toggled alternatively, or a 2-screen display can be used for simultaneous viewing. The ultrasound image can be frozen, allowing lesions to be measured. Ultrasonic features of lymph nodes, such as round shape, distinct margins, heterogeneous echogenicity, central necrosis, and increased vascularity are findings suggestive of, but not definitive for, malignancy.

(See the image below.)

EBUS scopes allow the attachment of disposable balloons at the distal ultrasound tips of the EBUS scope. This can be filled with saline to improve contact between the ultrasound probe and the bronchial wall, so as to enhance visualization of the target lesion. Balloons are commonly used when the target lymph nodes are located in the paratracheal areas (2R, 2L, 4R, and 4L), particularly the slightly challenging angle of the left paratracheal lymph node (4L), and hilar stations (10R and 10L).

(See the image below.)

Balloons are usually not needed in lymph node stations 7 and 11. Balloons are made of latex and therefore should not be used in patients with latex allergies. In this situation, a water-based lubricant can be used to improve ultrasound visualization. ^[25]  Once the target lesion is identified, keep the bronchoscope in a neutral position and insert the EBUS-TBNA needle system through the working channel of the bronchoscope, and secure it on the scope. Unlock the sheath adjuster knob, and adjust the tip of sheath to be visualized in the endoscopic view and tighten the screw. Flex the scope to re-engage with the airway wall, and locate the target lymph node on the ultrasound view. Release the needle adjuster and advance the needle into the target. 

Once the needle is in the target, move the stylet up and down at least once to dislodge the bronchial epithelium that passed into the needle, and then pull back the stylet about 15 cm or completely remove it. Data have shown that the stylet does not improve the diagnostic yield of CP-EBUS. ^[26]  Inserting and removing a metal stylet in the biopsy needle may be an unnecessary step during EBUS-TBNA. Eliminating use of the stylet during EBUS-TBNA will reduce procedural complexity and may save time. EBUS-TBNA can be performed with or without the use of suction (capillary sampling). To apply suction, use a prepared 20 ml syringe attached on the aspiration port, turning the stopcock to the parallel position on the syringe. In a randomized, clinical trial in which EBUS-TBNA with suction was compared with EBUS-TBNA without suction, there were no significant differences in specimen adequacy, diagnosis rate, or specimen quality regardless of node size. ^[27]  The operator should consider not using suction if intranodal blood vessels are visualized on sonographic images and if samples being obtained are bloody. if suction was used, it should be released before retracting the needle into the sheath.

To obtain a sample, move the needle slider back and forth several times in the target area. A “pass" is entry and exit of the needle through the airway wall, and each pass usually involves 5-15 agitations of the needle within the target site. After this, retract the needle into the sheath until it clicks, and then push the lever to lock the needle adjuster. Place the scope in the neutral position. Release the connecting slider to unlock the needle from the scope and remove. The tissue core is then removed from the needle lumen by reinserting the stylet or blowing air with a syringe. The EBUS-TBNA aspirated specimen is smeared onto glass slides (air dry), along with cell block preparation.

Commercially available EBUS-TBNA needle sizes are 25G, 22G, 21G, and 19G. The size of the needle may affect the quantity of sample and aspirated blood, sample quality, and diagnostic yield, as well as result in tissue trauma. Generally, it is thought that the 22G and 21G needles are sufficient for cytology, whereas a 19G needle may be used to obtain a tissue core for histopathologic evaluation. The theoretical advantage of a larger needle is that it will provide more tissue. Trials comparing 21G and 22G needles found no significant difference in sample adequacy or diagnostic yield. ^[28] .

The American College of Chest Physicians (ACCP) recommends using either a 21G or a 22G needle in patients undergoing EBUS-TBNA. The possible advantages of a 25G needle include better penetration, reduced specimen contamination with blood, and decreased deformity of the needle. If there is a suspicion of granulomatous disease or lymphoma, using a 19G needle is reasonable. At this time, there are no data to suggest needle size during EBUS-TBNA. Some factors influencing choice of needle size may include location and accessibility of a lymph node in station 4L (known for its slightly angulated location), vascularity of the node, and presence of intranodal vessels. 

EBUS-TBNA can be performed with or without rapid onsite evaluation (ROSE). ROSE reduces the number of needle passes and the number of other procedures required but does not affect the diagnostic yield in EBUS-TBNA procedures. In a prospective, randomized clinical trial of 120 patients, ROSE decreased the number of punctures and reduced the need for additional diagnostic procedures. ^[29]  In a retrospective review of 780 patients, ROSE reduced the number of aspirates per procedure but did not improve the diagnostic yield. ^[30]  The number of needle aspirations per site can impact the yield. In a study to evaluate how many aspirations per lymph node are needed in the evaluation of lung cancer, specimen adequacy was obtained in 90.1% on the first pass, 98.1% after 2 passes, and 100% after 3 passes. The first pass has the highest yield. It is reasonable to obtain at least 3 separate needle passes in each lymph node when evaluating lung cancer adenopathy in the absence of ROSE.

Samples obtained with EBUS-TBNA are adequate for molecular marker testing in non-small cell lung cancer, according to prospective trials. ^{[31, 32, 33]}  It appears that more than 3 passes are needed to obtain adequate sampling for molecular testing. In a retrospective study, a median of 4 EBUS-TBNA passes were needed to obtain adequate samples for molecular testing. ^[34]

With EBUS, intranodal forceps biopsy (IFB) can be performed, whereby a mini forcep is advanced into the target lesion and core biopsy specimens are obtained under real-time EBUS view. Several reports on IFB have been published, and this technique may improve the overall utility of bronchoscopy to provide diagnostic information, staging, and specimen acquisition. ^[35]

If the TBNA is being done for staging of NSCLC, the sampling should be started from N3 lymph nodes, followed by N2 and N1 nodes, to avoid contamination and upstaging.

EBUS training

Education in EBUS procedures is necessary to improve competency and patient outcome. Physicians should have knowledge of mediastinal lymph node stations and the airway wall. The ACCP recommends that trainees perform at least 50 procedures in a supervised setting to establish basic competency in analyzing anatomic structures and handling the instrument. To maintain competency, dedicated operators should perform at least 20 examinations per year. ^[36]  However, the volume-based competency for EBUS-TBNA is debatable. For physicians wishing to learn how to perform EBUS, there are several different educational approaches. Short (1-2 days) EBUS training programs and advanced programs are available. EBUS training can be done directly on patients or simulated. Simulation-based training has been shown to be effective and can be an important first line in credentialing before proceeding to supervised performance on patients. ^{[37, 38]}  The ACCP recommends the use of simulators (low or high fidelity) and objectively validated EBUS skills assessment tests. ^[39]  The EBUS Skills and Task Assessment Tool (EBUS-STAT) is validated and is commonly used for objective assessment of EBUS skill level. ^[40]  EBUS-STAT scores the EBUS-TBNA operator's skills on ultrasound image acquisition and optimization, as well as identification of mediastinal nodal and vascular structures.

 

Following completion of the procedure, the bronchoscope should be disinfected and hung upright to prevent the accumulation of moisture. EBUS and EBUS-TBNA are usually safe procedures. In a systematic review of effectiveness and safety, no serious complications were found for CP-EBUS or EBUS-TBNA of regional lymph nodes ^[41] . Reported complications have included agitation, sore throat, cough, hypoxia, laryngeal injury, fever, bacteremia and infection, bleeding, pneumothorax, and broken equipment becoming stuck in the airway. Mediastinal abscess has also been reported. Complications related to upper airway local anesthesia include laryngospasm, laryngeal edema, bronchospasm, methemoglobinemia, and cardiac arrhythmias. ^[42]  Complications attributable to procedural sedation include respiratory depression, cardiovascular instability, vomiting, and aspiration.

Monitoring

Cardiac rhythm, heart rate, respiratory rate, oxyhemoglobin saturation, and blood pressure are continuously monitored after the procedure until the effects of sedation and upper airway anesthesia have worn off. Patients should be monitored closely for 1-4 hours after the test. Eating and drinking can be resumed once the patient is fully awake and the gag reflex returns. A routine chest radiograph is not needed after the procedure to look for complications. Patients who have undergone outpatient procedures must have stable vital signs and be alert and oriented with baseline ambulation before discharge.

Patient education

Do not eat or drink anything 6-8 hours prior to the procedure. Someone must be available to drive or accompany the patient home. The patient may have a mild sore throat, hoarseness, cough, or fever following the procedure. If the patient experiences increasing chest pain or shortness of breath or coughs up more than a few tablespoons of blood after being discharged, a physician should be contacted immediately.