Complications of linear endobronchial ultrasound guided biopsies: narrative review

Introduction

Background

Endobronchial ultrasound (EBUS) is a technique that combines bronchoscopy with ultrasound to evaluate lung pathology beyond the airways. Transbronchial needle aspiration (TBNA) is used along with EBUS to biopsy lung lesions and lymph nodes. TBNA was first developed in 1949 and was used with rigid bronchoscopy (1). In 1978, Yang et al. designed a prototype needle for flexible bronchoscopy (1). TBNA with flexible bronchoscopy, also called conventional TBNA (C-TBNA) is considered a blind technique since it is dependent on the operator’s knowledge of anatomy and extent of training. A limited number of procedures and the need for supervisor expertise led to lower yields causing decreased use by physicians. Literature has shown the yield for C-TBNA to be from 14% to 100% (1). In 2002, the convex probe for linear EBUS was created, which was a major advancement in the field of bronchoscopy (1). Linear EBUS combines bronchoscopy with ultrasound to help in the visualization of lesions and lymph nodes adjacent to the airway. This advancement allowed bronchoscopists to use TBNA in real time for mediastinal and hilar lesions and lymph nodes for lung cancer staging, and extra thoracic malignancies. In the last 20 years, EBUS has evolved significantly and has become a vital instrument in the field of pulmonary diseases. Linear EBUS-TBNA has a high diagnostic yield in diagnosing both non-malignant and malignant conditions. For mediastinal staging of non-small lung cancer, the sensitivity is around 93% with a specificity of around 100% (2). Techniques including intranodal forceps biopsy and cryo-biopsy guided by EBUS have been developed to improve diagnostic accuracy and obtain larger tissue samples. Other uses include intra-tumoral therapy, positioning fiducial markers, and facilitating the drainage of pleural or pericardial effusions.

Rationale and knowledge gap

As the prevalence of EBUS has increased, those complications which were once considered theoretical or not previously appreciated are now being documented and published. These complications are rare and most of the data is from case reports, and few published studies.

Objective

This narrative review article reports the published data on the complications that have been reported to date. We present this article in accordance with the Narrative Review reporting checklist (available at https://med.amegroups.com/article/view/10.21037/med-24-33/rc).

Methods

A literature search was performed in April 2024. We included the year 2009–2024 using PubMed and Google Scholar databases using the following terms: ‘endosonography’, ‘EBUS’, ‘endoscopic ultrasound’, ‘ultrasound-guided’ combined with ‘biopsy’, ‘fine-needle’ combined with ‘fine-needle aspiration’, ‘FNA’, ‘transbronchial needle aspiration’, ‘TBNA’, ‘cryobiopsy’, ‘forceps biopsy’, and ‘complications’ (Table 1). All case reports, retrospective and prospective studies that reported a complication with the use of linear EBUS with TBNA, cryobiopsy, or forceps biopsy were included. Results from complications from radial EBUS or endoscopic ultrasound (EUS) were excluded.

Discussion

Overall complications

Overall complications reported in prospective and retrospective studies range from 0.04% to 17% and are listed in Table 2. The largest published retrospective study by Asano et al. which included 7,345 patients reported 1.23% complications (3). The largest prospective study by Eapen et al. with 1,317 patients reported 1.44% complications (4). Common complications include infectious, anesthesia-related, equipment-related, respiratory failure, cardiac, neurological, bleeding, and rarely death.

Infectious complications

The incidence of infectious complications from linear EBUS has been reported from 0.04% to 4%. There have been multiple prospective studies, retrospective studies, and case series of infectious complications (5-14). Table 3 shows the case reports of infectious complications reported. A possible mechanism of post-procedure infection is the inoculation of oropharyngeal bacteria into the target tissue during the transbronchial passage of the needle. The needle can get contaminated when passing through the bronchoscope or the airway wall, especially if the bronchoscope is used to clear secretions by suctioning before passing the needle sheath (15). Transient bacteremia and fever are commonly seen post-procedure which typically resolves without intervention (5). Death is rare and has been reported in a single case of bacterial pericarditis (16).

Infectious complications are noted to be higher in patients with risk factors including >10 nodal sampling, known immunosuppression, bronchial colonization, and cavitated or necrotic lesions. Serra Mitjà et al. looked at 370 patients (245 with risk factors and 125 without risk factors). Overall, 15 patients (4.05%) presented with acute infectious complications: 14 in high-risk factor groups (5.7%) and 1 in controls (0.8%). There was an increased risk of complication in patients with risk factors and in patients with necrosis (P=0.018) (6). History of diabetes mellitus has also been proposed as a risk factor for infection, likely due to the overall decreased immune response (17). The most common reported complications include pneumonia, mediastinitis, pericarditis, tumor bed infection, lung abscess, empyema, and cyst infection, which can lead to septic shock and prolonged hospitalization.

Bacteremia/fever

Transient bacteremia can be seen after EBUS-TBNA, but it is usually clinically insignificant (5). A study looked at 43 patients who underwent EBUS-TBNA of mediastinal and hilar lymph nodes. Blood cultures were performed within 60 s of EBUS-TBNA. Sterile washings of the TBNA needle were also sent for cultures. Three/43 (7%) patients were bacteremic with oropharyngeal organisms and 15/43 (35%) had positive needle-washing cultures. None of the patients had clinical symptoms of infection. The isolated bacteria were Actinomyces, Streptococcus salivarius, and Streptococcus mitis (5). The exact cause of bacteremia following EBUS-TBNA remains uncertain. The three patients who developed bacteremia had negative TBNA needle-washing cultures. This may be due to reduced culture sensitivity, or the bacteremia being caused by the bronchoscope rather than the TBNA. Bacteremia rates after routine flexible bronchoscopy range from 0% to 6%, with no link to specific procedures (e.g., brushings or biopsy). It is thought that bacteremia may result from bacterial penetration above the vocal cords or bronchial trauma from bronchoscope insertion. Studies in both humans and animals show that rigid bronchoscopy, which causes more mucosal trauma, has a >30% bacteremia rate. The EBUS-TBNA bronchoscope, being larger, less maneuverable, and equipped with different video optics, likely increases pharyngeal and glottic contact during insertion, explaining its higher bacteremia rate compared to C-TBNA (5).

Transient bacteremia is not only unique to EBUS but can be seen in any procedure that is causing damage to the mucosa leading to the translocation of bacteria into the bloodstream. In colonoscopies incidence of bacteremia is seen in 0% to 25% of cases, with a mean frequency of 4.4%, and in 8% of cases in upper endoscopies (52,53). Fiberoptic bronchoscopies have shown the incidence of bacteremia to be 6.5% (54).

Fever can develop after EBUS-TBNA and is seen 20% of the time. A study with 684 patients who underwent EBUS-TBNA were evaluated for the development of a fever (defined as an increase in axillary body temperature over 37.8 ℃). One hundred and ten/552 (20%) of patients developed a fever after around 7 hours (range, 0.5–32 hours) and lasted 7 hours (range, 1–52 hours), usually not more than 24 hours. No risk factors were found to be associated with developing a fever. There were 6 cases (1.1%) that lasted longer than 24 hours from which 3 patients (0.54%) developed complications (pneumonia-2, mediastinal abscess-1). One possible cause of post-EBUS-TBNA fever is transient bacteremia resulting from the introduction of oropharyngeal bacteria during transbronchial aspiration. Another possible cause of fever may be due to a systemic inflammatory response triggered by physical irritations, such as suctioning, TBNA, or fluid instillation. If the fever lasts more than 24 hours then further workup is required (8).

Mediastinitis

Mediastinitis is inflammation or infection of the connective tissues and structures contained within the mediastinum. It is associated with high morbidity and mortality (55).

There have been multiple case reports and studies reporting mediastinitis as a complication of EBUS-TBNA. The incidence is around 0.10–0.50% (3,9,10). The proposed mechanism is inoculation of oropharyngeal flora into the mediastinal tissue during biopsy especially if the bronchoscope is used to suction secretions before putting in the needle sheath (5).

Organisms that have been identified in patients with mediastinitis are Streptococcus pneumoniae, Pseudomonas, methicillin-resistant Staphylococcus aureus (MRSA), Eikenella corrodens, Streptococcus mitis, Streptococcus intermedius, alpha Streptococcus, Streptococcus milleri, and Gemella sanguinis. These organisms were isolated from either biopsies or drainage of the infected site or from blood. Time to infection from the time of procedure ranged from a few hours to up to 50 days. Most biopsied lymph nodes were right paratracheal and subcarinal and a 22-gauge needle was used in most of the cases.

Necrotic and cystic lesions are at higher risk of developing infections. Necrotic lesions are avascular, thus creating an environment with decreased bacterial clearance (5,9,18). Kang et al. reported that necrotic lesions had a three-fold higher risk of infection (9). Cystic lesions are also avascular and if bacteria are introduced, it can lead to uninhibited bacterial growth since the immune system cannot reach and fight the pathogens there due to lack of blood supply (19-22). Mediastinitis can present as just an infection of the mediastinum which is treated with antibiotics, or it can develop into an abscess which requires drainage either by computed tomography (CT) guidance or surgical incision and drainage (18,23-25). If the abscess is large it can lead to airway obstruction by external compression of enlarged infected lymph node. Jahoor et al. presented a case of EBUS-TBNA of a para-tracheal lymph node causing infection and enlargement of the lymph node leading to tracheal obstruction and requiring rigid bronchoscopy with stent placement, debulking, and antibiotics (23). Mediastinitis can present along with infective pericarditis with or without tamponade, pneumonia, empyema, and lung abscess. A case of mediastinitis leading to the formation of tracheo-mediastinal fistula has also been reported (26). Severe cases can lead to septic shock and most cases of septic shock are seen in patients who developed pericarditis as well (21,27,28).

Pericarditis

Pericarditis has been reported as a rare complication of EBUS-TBNA. In a Japanese survey of 7,345 cases, pericarditis was seen in 1 case (0.01%) from a total of 90 complications (1.23%) (3). In a retrospective survey by Çağlayan et al. that included 3,123 patients, there were five reported cases of complications from which one was of pericarditis, which was in a patient with drainage of a bronchogenic cyst (11). Another retrospective study by Marty et al. which included 4,619 patients, reported three infectious complications from which one was pericarditis (12).

Multiple mechanisms have been proposed. Haas et al. reported a case that did not develop mediastinitis but only pericarditis by two oral organisms, Actinomyces odontolyticus and Streptococcus mutans. He proposed that direct penetration of the pericardium occurred with the entry of the needle tip into the pericardial space leading to pericardial contamination. It can be hard to identify the pericardial sac because the pericardial recess is hard to differentiate from a lymph node (15) (Figure 1). Superior aortic recess correlates with paratracheal lymph nodes (4R and 4L), right and left pulmonic recesses correlate with para-bronchial nodes (10R and 10L) and oblique sinus recess correlates with subcarinal node (56). Pericarditis can occur without direct penetration of pericardium but just from a tissue prick adjacent to the pericardium especially if there is necrotic tissue. This was described by Lee et al. who reported two cases of pericarditis. Both cases had biopsies of a 4R lymph node which is close to the pericardial recess, and both nodes had large necrotic lesions (16). Another mechanism is extension from infection of the surrounding tissue which is seen in most of the reported cases (21,24,25,27,29,30). Organisms that have been identified as causing pericarditis are mostly oral flora. The most commonly biopsied lymph nodes were the right paratracheal, subcarinal, and right hilar. In reported cases, pericarditis often led to pericardial tamponade, typically requiring pericardiocentesis or a pericardial window for drainage. However, one case resolved with antibiotics without needing drainage due to minimal fluid. About half of the cases involving the pericardium also developed septic shock.

Figure 1 EBUS image with Doppler (A) and without Doppler (B) showing superior aortic recess between ascending aorta and the left pulmonary artery which can be mistaken for 4R or 4L lymph node. A: EBUS view of ascending aorta; P: EBUS view of pulmonary artery; B: bronchoscopic view of the airway; R: superior aortic recess. EBUS, endobronchial ultrasound.

Pneumonia

Pneumonia, empyema, and lung abscess can occur as a complication of EBUS-TBNA. The pathophysiology of developing parenchymal lung infections is the same as mentioned above. A retrospective study by Kang et al. with 6,826 patients reported 33 (0.48%) infectious complications from which 18 (0.26%) were pneumonia (9). A prospective study by Serra Mitjà et al. reported 4 (1%) cases of pneumonia from 375 patients (6). The Japanese study which had an incidence of 1.23% complications, pneumonia was seen in 4 patients (0.05%) (3). A study by Souma et al. that had 47/1,045 (0.04%) infectious complications, pneumonia was seen in 24 cases, lung abscess in three cases, and pleuritis in three cases (7). Another case of lung abscess is reported in a patient who had developed empyema and mediastinal abscess (31). Cases of obstructive pneumonia and obstructive pneumonitis have also been reported, which can occur after biopsy of the lesion with airway obstruction due to the tumor (10).

Tumor bed infection

Direct infection of the tumor bed is also possible. Haas et al. presented a case where a patient developed expansion of the lung mass with formation of air pockets 9 days after EBUS-TBNA with enlargement of new reactive paratracheal lymph nodes (15). A retrospective study by Souma et al. included 1,045 patients, and 47 patients developed infectious complications, 14 of these were tumor bed infections (7).

Non-infectious complications

Non-infectious complications have also been reported and are summarized in Table 4. These include bleeding (57-61), fistula formation (62-65), air leakage (66-74), and issues related to EBUS equipment, such as needle breakage (75,76), balloon dislodgment, or breakage of other parts of the bronchoscope. Additionally, complications related to anesthesia can occur as well. All types of complications are summarized in Table 5.

Bleeding complications

Bleeding complications during or after EBUS can range from mild to massive hemoptysis and mediastinal hematoma formation that may lead to airway obstruction. It occurs due to a puncture of an artery during the procedure and may be worse if the patient is on anti-thrombotics. In a Japanese nationwide survey that looked at complications of EBUS-TBNA in 7,345 cases, hemorrhage was reported in 42 cases. One case was of massive hemorrhage possibly due to damage of blood vessels after puncture of 11L lymph node, requiring prolonged hospitalization. None of the 42 cases were on antiplatelet therapy. A 22-gauge needle was used in 30 cases and a 21-gauge needle in five cases with hemorrhage (3). Eapen et al. reported 3 cases of bleeding (0.2%), one case was severe enough to cause death (4). Few cases of bleeding in patients on anticoagulation has been reported. There is a case of hemoptysis and hematoma formation in a patient who was being changed from low molecular weight heparin to antivitamin K treatment and underwent a biopsy of the subcarinal lymph node. He developed hemoptysis a few days after the procedure and a CT chest showed subcarinal hematoma. The patient improved with conservative management. Puncture of the bronchial artery was thought to have occurred during biopsy and being on anticoagulation led to hematoma formation (57). Another case of mediastinal hematoma due to anticoagulation is reported in a patient with mechanical aortic valve. Prior to his procedure, the vitamin K antagonist was held and bridged with low molecular weight heparin until the international normalized ratio (INR) was less than 1.2. Biopsy of 4R and subcarinal lymph node was done, the patient tolerated the procedure well and was discharged the next day with instructions to restart anticoagulation. The patient presented 3 weeks later with cough, fever, and shortness of breath and had a supratherapeutic INR of 5.3. CT chest with intravenous (IV) contrast showed right paratracheal fluid collection consistent with hematoma. The cause was thought to be due to supratherapeutic INR (58). A study that compared the risk of bleeding complications in patients in whom anti-thrombotic therapy (antiplatelet and anticoagulation) was held sufficiently vs. insufficiently showed no risk of increased bleeding if on anti-thrombotic therapy. Only one bleeding complication occurred in the sufficient discontinuation group (1/102, 1%) and one in the insufficient discontinuation group (1/396, 0.3%). This shows that the procedure can be safely performed in patients who are not able to hold the anti-thrombotic therapy before the procedure (77). A case of excessive bleeding has been reported in a patient with fibrosing mediastinitis (13). Hematoma formation in mediastinum can lead to airway narrowing and obstruction. A case is reported of tracheal narrowing after a biopsy of a 4L lymph node due to bleeding and the development of a hematoma. It was thought to be due to injury to the aorta by the needle. Even though the operator could clearly see the aortic border, the image was blurred during the procedure. Rapid swelling in the tracheal wall led to a narrowing of the tracheal lumen. The procedure was aborted, and an urgent CT chest showed mediastinal hematoma with no contrast leak. The patient improved with conservative management (59). Massive hemoptysis that led to death is reported in a patient with metastatic disease and thrombocytopenia who underwent EBUS-TBNA of right hilar and subcarinal lymph nodes. Six hours later patient developed hemoptysis that continued to worsen. Labs were done that revealed mildly prolonged prothrombin time (PT) and activated partial thromboplastin time (APTT). The family did not want further intervention and the patient died. The cause of bleeding was thought to be due to low platelets and prolonged PT/APTT (60).

There has been no observed increase in bleeding complications related to needle size. In a study by Hsu et al., which compared bleeding complications between 19- and 21/22-gauge needles in two groups with 25 patients in each group, the bleeding rate was 20% for the 19-gauge needle and 4% for the 21/22-gauge needles. However, this difference was not statistically significant. All bleeding events were successfully managed with cold saline and compression (78). Another prospective randomized trial comparing 19- and 22-gauge needles for diagnostic yield showed an equal number of bleeding incidents in both groups (79). In a study by Webb et al., 42 patients taking aspirin and Plavix underwent EBUS-TBNA of 92 lymph nodes under general anesthesia. Three passes were made with a 22-gauge needle, followed by three additional passes with a 21-gauge needle if no complications arose. Only one patient required cold saline to achieve hemostasis (80). Even transvascular biopsies using a 22-gauge needle have shown no bleeding risk. In a retrospective study by Kazakov et al., EUS biopsies were performed using a 22-gauge needle on 14 patients through branches of the pulmonary artery and 19 through the aorta. EUS-guided fine-needle aspiration (EUS-FNA) involves using an endoscope with ultrasound guidance through the esophagus to obtain biopsies from lymph nodes. No immediate or follow-up complications were documented after 12 months (81). A case series by Perathur et al. reported that eight patients underwent transvascular needle aspiration during EBUS using a 21-gauge needle through the main or major branches of the pulmonary artery with no immediate or 6-month post-procedure bleeding complications (82).

It is unclear whether the risk of bleeding varies based on the station of the lymph node biopsied. In our study, there were six case reports of bleeding, involving biopsies of lymph nodes at station 7, right hilar, 4R, 4L, 11L, with most cases involving station 7. In the Japanese study by Asano et al., the most frequently punctured lymph node was station 7, biopsied in 34 patients (43.0%), followed by station 4R in 24 patients (30.4%) (3). While station 7 appears to have the highest rate of bleeding complications, this may be because it is the most frequently biopsied lymph node.

Fistula formation

Esophageo-bronchial artery fistula

Jadeja et al. reported a case of a patient with a history of human immunodeficiency virus and acid reflux who presented with cough and dyspnea on exertion. Chest CT had bilateral pulmonary nodules, and fibrosis with mediastinal and hilar lymphadenopathy (62). EBUS- TBNA of the right hilar and subcarinal lymph nodes was done. One month after her EBUS-TBNA, she presented with hemoptysis and hematemesis with a hemoglobin drop from 10 to 8 g/dL. Chest CT revealed foci of gas in the posterior mediastinum and adenopathy adjacent to the esophagus suspicious of esophageal fistula formation (62). Bronchoscopy did not have evidence of active bleeding. EUS showed a 13 mm × 15 mm circular anechoic structure in the mediastinum anterior to the esophagus with visible arterial Doppler flow suggestive of a pseudoaneurysm at the level of the subcarinal region, a small fistula in the middle third of the esophagus, and abnormal lymph nodes in the paratracheal region (62). The needle puncture likely caused injury to the arterial wall, which weakened over time, thus resulting in the formation of an aneurysm. The aneurysm within the high-pressure system of the bronchial arteries was thought to be responsible for the patient’s hematemesis and hemoptysis. Transversion of the subcarinal lymph nodes during needle aspiration caused a fistula formation between the pseudoaneurysm and the esophagus. This defect led to the reflux of gastrointestinal contents into the mediastinum resulting in mediastinitis and mediastinal lymphoid hyperplasia resulting in the focal pockets of gas seen on CT. No evidence of bronchial fistulation was seen. Coil embolization was done. Post-embolization CT had resolution of pseudoaneurysm and mediastinitis (62).

Tracheo-mediastinal fistula

Development of fistulous tracts of the tracheobronchial tree is a serious and possibly fatal complication. Higher incidence is seen in patients treated with bevacizumab due to its antiangiogenic properties that cause impaired wound healing of the mucosal injury as well as bleeding and thrombotic events (63). When EBUS-TBNA is done in these patients, the perforation of the mucosa can create a fistula. There are two reported cases of this complication after EBUS-TBNA in patients who received bevacizumab. Wong et al. reported a case of stage 4 non-small cell lung cancer (NSCLC) who received chemotherapy with bevacizumab after a biopsy of station 4L. Two months later, he presented with massive hemoptysis and bronchoscopy showing blood at the biopsy site. He underwent embolization of five bronchial and intercostal arteries and stabilized. A month later, he presented again with massive hemoptysis and bronchoscopy had fresh blood and a mucosal defect at the site of sampling. CT scan confirmed a bronchomediastinal fistula with an aberrant tract between the aortic arch and left pulmonary artery at station 4L. The patient denied further treatment and died after being made comfortable (64). Castro-Varela et al. reported a case of EBUS-TBNA performed on a large right paratracheal mass causing superior vena cava syndrome. The patient was diagnosed with metastatic poorly differentiated NSCLC with mediastinal involvement and started chemotherapy including bevacizumab. Three weeks later, a mediastinal air-filled cavity/fistula developed at 4R. Bevacizumab was discontinued, and antibiotics were administered, but the patient died 6 days later from massive hemoptysis (63). Other risk factors for fistula formation are infection, radiation, and squamous cell carcinoma (26). Jang et al. reported a case of a patient who had EBUS of the right paratracheal lymph nodes and later presented with cough, fever, and CT findings of enlarged lymph nodes and pericardial effusion. Flexible bronchoscopy revealed pus through a fistula in the right lateral trachea. The patient underwent a thoracotomy for drainage and received antibiotics. The fistula closed in 2 weeks, and the patient was discharged (26).

Air leakage

Pneumothorax

The risk of pneumothorax after EBUS-TBNA is reported to be 0.03% (2 cases) as reported by Asano et al., one of which required chest tube drainage (3). A prospective study by Eapen et al. of 1,317 patients had complications incidence of 1.44% with 7 (0.53%) of those being pneumothorax (4). Four of these patients required tube thoracostomy and in three patients it resolved without intervention. Only transbronchial biopsy was associated with increased risk of pneumothorax which occurred in 2.7% of patients. The use of positive pressure ventilation with transbronchial biopsy was not associated with an increased risk of pneumothorax in this population who did not have underlying respiratory failure. Higher station lymph nodes (2R, 2L) were also not associated with pneumothorax (4).

Pneumomediastinum and pneumopericardium

Pneumomediastinum is the presence of free air in the mediastinum and pneumopericardium is the presence of free air in the pericardium. EBUS-TBNA-related pneumomediastinum is rare, with only a few cases reported. Potential mechanisms include barotrauma from ventilation leading to leakage of alveolar air into the tissues (Macklin effect), bronchial wall defects from sampling, or tracheal leaks from forceful coughing (66). In a study by Çağlayan et al. of 3,123 patients, 0.16% developed complications, with only one case of pneumomediastinum (11). If the air leaks into the pericardium, it can cause pneumopericardium. Pneumopericardium can potentially cause tamponade which would then require pericardial drainage (67).

There are two reported cases of pneumomediastinum after EBUS-TBNA due to forceful coughing, both occurring 24 hours post-procedure. One patient had a biopsy of 11R under conscious sedation and developed a cough post-procedure with screening CT chest 24 hours later showing pneumomediastinum (66). Another case had an EBUS-TBNA of stations 4R, 4L, 7, 11 due to suspected malignancy. The patient, under general anesthesia with a laryngeal mask airway (LMA), initially did well but returned 24 hours later with severe cough, chest, and neck pain, and swelling. Imaging showed pneumomediastinum with subcutaneous emphysema (68). Even without coughing, needle trauma can cause air leaks. For instance, a patient who had EBUS-TBNA of 4R, 7, 10R, 10L and a left lower lobe lesion, developed pneumomediastinum and subcutaneous emphysema after the procedure despite no cough or high-pressure ventilation, likely due to blunt needle trauma (69). Another case of a patient who underwent EBUS-TBNA of 4R, 7, and 10R using a 21-gauge needle under general anesthesia, presented to the hospital after discharge due to chest pain with shortness of breath. Pneumomediastinum with extension of the air to the base of the neck was seen on imaging (83). Both patients did well with conservative management. Patients with chronic obstructive pulmonary disease (COPD) or interstitial lung disease (ILD) have a higher risk of pneumomediastinum. A case report of a patient with severe paraseptal emphysema who underwent EBUS-TBNA of stations 4R and 7 developed chest pain and neck crepitus an hour after the procedure. Despite no post-procedure cough, the patient developed pneumomediastinum, pneumopericardium, and subcutaneous emphysema, likely due to needle trauma (67). Three cases of pneumomediastinum have also been reported in patients with ILD who underwent mediastinal lymph node biopsy (70).

Patients can develop respiratory distress if pneumomediastinum leads to subcutaneous emphysema at the base of the neck, leading to respiratory compromise. Treatment options include blowhole incisions, subcutaneous angio-catheters, or tunneled drains to evacuate air (84).

Pneumoperitoneum

Pneumoperitoneum is an extremely rare complication of EBUS-TBNA, with only three reported cases, typically due to issues with oxygen delivery rather than the procedure itself. Two cases are of isolated pneumoperitoneum and one of pneumoperitoneum with pneumothorax and pneumomediastinum. Causes may include unrecognized esophageal intubation, gastric rupture, pulmonary barotrauma with the passage of air through micro-perforations of the diaphragm into the peritoneum, or excessive ventilation with air entering the peritoneal space. Söyler et al. presented a patient with bilateral hilar lymphadenopathy who underwent EBUS-TBNA under deep sedation with a nasal cannula. The procedure had to be stopped twice due to coughing and hypoxia, the scope was withdrawn, and bag-mask ventilation was performed. Biopsies of the subcarinal and right interlobar lymph nodes were done using a 22-gauge needle, and the procedure was completed without requiring bag-mask ventilation after the biopsy. Within minutes after the procedure, the patient developed chest pain, abdominal distension, hypoxia, and tachycardia. An urgent chest and abdomen CT was done that had subcutaneous emphysema, bilateral pneumothorax, pneumomediastinum, and pneumoperitoneum. An abdominal CT with oral contrast did not show any leakage, so the only possible mechanism to cause this was likely the bag-mask ventilation leading to barotrauma (71). In the second case, the procedure was interrupted three times because of repeated episodes of desaturation requiring vigorous face mask ventilation, and the patient became hypotensive, tachycardic, and tachypneic after the procedure. CT abdomen showed tension pneumoperitoneum, without pneumomediastinum or pneumopericardium. No leaks were seen on oral contrast imaging. Decompression was done by a needle and the patient was discharged (72). In both of these cases, there was the use of a face mask for oxygenation which could have led to air in the stomach and bowel, causing leakage into the peritoneum. The third reported case is also of isolated pneumoperitoneum where EBUS-TBNA was done to biopsy paratracheal lymph nodes using deep sedation and oxygen delivered using a nasopharyngeal catheter at 15 L/min. The patient tolerated the procedure well, but a few minutes after the procedure he became hypoxic with tongue swelling and bronchospasm, it was thought to be an allergic reaction. Mask ventilation was not effective, so he was intubated which first went into the esophagus and then repositioned into the trachea. Bronchoscopy did not show any lesions. He started to develop abdominal distention, hypotension, and bradycardia. Abdominal ultrasound revealed massive pneumoperitoneum, with no pneumothorax or pneumomediastinum. Emergent decompression was done after which the patient improved. No gastrointestinal perforation was found, and the cause was likely the passage of air into the peritoneal cavity from gastric or bowel micro-perforations (73). Once pneumoperitoneum occurs, the patient would show dramatic hemodynamic and respiratory failure.

EBUS-TBNA equipment complications

Needle breakage

Needle breakage is a rare complication but has been reported. Japan Society for Respiratory Endoscopy did a nationwide survey and reported needle breakage in 15 (0.20%) cases (3). The first case of needle breakage was reported by Özgül et al. of possible migration of the needle to the gastrointestinal tract and expelled in the feces. The patient had excessive coughing during the procedure so it is possible the needle was expectorated and swallowed (85). There are few reports where fragments migrated to the dependent lobes of the lung and were eventually expelled by coughing (86-88). Attempting to remove the needle can cause complications, like endobronchial hemorrhage, a case of extensive hemorrhage causing hypoxemia and intubation has been reported (87). Vial et al. observed a retained needle fragment within the lymph node after it broke into the lymph node during the left paratracheal biopsy. Needle removal from the lymph node was unsuccessful and the procedure terminated. A positron emission tomography (PET) scan done for staging showed the needle in the lymph node. Flexible bronchoscopy had mucosal thickening and inflammatory changes in the region. The consequences of needle retention without removal are not known but possibly an inflammatory response requiring thoracotomy or vascular disruption or embolization (89).

Breakage of other EBUS bronchoscope parts

The nationwide Japanese survey by Asano et al. reported damage to the bronchoscope in 98 cases (1.33%). Breakage of the working channel for needle insertion was in 71 cases (74%), breakage of the fiber owing to external compression such as biting by the patient in 15 cases (15.6%), breakage of the ultrasound probe in 7 cases (7.3%) and breakage of other portions in 3 cases (3.1%) (3).

Dislodged air balloon in the bronchus

The balloon attached to the probe can slip off and, if left in the airway, may cause complications like atelectasis and post-obstructive pneumonia. Here’s a reported case of a patient with squamous cell lung cancer, post right upper lobectomy and chemotherapy, who underwent EBUS to evaluate an enlarged right paratracheal lymph node for tumor recurrence. Due to difficulty with LMA placement, the patient was intubated. After inflating the balloon and taking biopsies, the EBUS scope was advanced to the left hilar area, but balloon inflation failed, and the small crescent was not seen. The scope was withdrawn, and the balloon was found at the orifice of the right lower lobe bronchus. It was successfully retrieved using suction. The balloon may have rubbed against the endotracheal tube (ETT) during the right paratracheal lymph node biopsy and slipped into the right lower lobe. It’s crucial to confirm the balloon’s presence at the end of the procedure to prevent complications (90).

Anesthesia-related complications

A prospective study by Casal et al. compared sedation-related complications in patients receiving general anesthesia vs. moderate sedation during EBUS. Among 149 cases, 25 complications were noted: four under general anesthesia (all hypotension) and 21 under moderate sedation (including one hypotension, six hypertension, two hypoxemia, four excessive cough, three arrhythmia, one aspiration, four inadequate sedation). All were resolved by the end of the procedure without affecting diagnostic yield (13). A retrospective study evaluated respiratory complications in 586 patients under general anesthesia during EBUS-TBNA. Complications occurred in 79 (13.5%) patients, including severe hypoxia with oxygen saturation less than 85%, prolonged hypoxemia, bronchospasm, and postoperative ventilation. These were more common in patients with pre-existing respiratory disease, those on home oxygen, or who received albuterol intraoperatively (91).

A case of pulmonary edema due to negative pressure during EBUS was reported in a patient with an enlarged 4R lymph node causing tracheal narrowing. The patient underwent moderate sedation with a high-flow nasal cannula. Three minutes after the insertion of the EBUS, oxygen saturation dropped to below 90%. EBUS bronchoscope was removed but the patient dropped to 30% oxygen saturation. Bag-mask ventilation was started but inspiratory pressure was high, and end-tidal carbon dioxide was consistent with inappropriate ventilation. The patient was intubated, and a large amount of pink frothy fluid was regurgitated from the ETT. Flexible bronchoscopy was performed, and a large amount of pink frothy fluid was suctioned, after which oxygenation and peak pressures improved. Chest X-ray showed bilateral infiltrates. Passing the EBUS scope sealed the trachea and suctioning during the EBUS caused negative pressure leading to pulmonary edema and hypoxia (92).

EBUS-intranodal forceps biopsy (EBUS-IFB) complications

EBUS-IFB is a technique where linear EBUS is used to guide mini forceps into the desired lymph node or lesion to obtain tissue biopsy (93). When EBUS-TBNA is performed in combination with EBUS-IFB, it improves the diagnostic yield. It is most useful in non-malignant mediastinal lesions. Combining the two increases the diagnostic yield for lymphoma from 30% to 86% and for sarcoidosis from 58% to 93%. Overall diagnostic yield improves from 67% to 92% (94).

The overall complication rate for EBUS-IFB is 1.5%. When done in combination with EBUS-TBNA it does not increase the complication rate (95). In a meta-analysis by Agrawal et al., complications for EBUS-IFB were reported in combination with EBUS-TBNA and included pneumomediastinum (1%), bleeding (0.8%), and respiratory failure (0.6%) (94). A prospective case series of 50 patients where combined technique was used, there were three cases of bleeding controlled with epinephrine and one case of pneumomediastinum and one case of atrial fibrillation (96). Since this is a relatively newer procedure, the data for its complications is much less robust, and the actual risks may not be completely known yet.

EBUS-transbronchial cryobiopsy (EBUS-TBCB) complications

EBUS-TBNA has excellent diagnostic yield for primary lung malignancies, but it does not give adequate tissue for mediastinal diseases that require histopathological samples and require overall background architecture. Cryoprobes have been used to debulk endobronchial lesions through freezing and thawing. But since it can give a large amount of pulmonary tissue, cryobiopsy has recently been used to obtain tissue for diffuse lung disease and mediastinal sampling. In diffuse lung disease, it is superior to forceps biopsy to obtain sufficient sample without architectural distortion. But like EBUS-IFB, it is also a newer procedure and not enough data is available to know the actual risks and complications.

In a randomized trial by Zhang et al. with 197 patients, the overall diagnostic yield for mediastinal TBNA was 79.9% and for TBCB was 91.8% (97). If used in combination with EBUS-TBNA, EBUS-TBCB has a similar diagnostic yield for mediastinal metastasis as EBUS-TBNA alone, but better sensitivity in benign disorders (94% vs. 67%) and better tissue sample for molecular and immunological analysis for NSCLC (98). An open-label, randomized trial at three hospitals in Europe and Asia where 271 patients were divided into EBUS-TBNA combined with mediastinal cryobiopsy vs. EBUS-TBNA alone for diagnosis of mediastinal disease. The incidence of complications did not differ in both groups. Three (2%) cases of grade 3–4 airway bleeding were seen in the combined group and 2 (1%) in the control group. No severe complications were seen (98). A prospective study of 50 patients with mediastinal lymphadenopathy who underwent EBUS-TBNA and EBUS-TBCB in a single procedure reported six mild complications that resolved during the same procedure (99). Another prospective study of 50 patients who underwent both EBUS-TBNA and EBUS-TBCB for mediastinal lymph node biopsy had no reported complications (100).

Safety of EBUS in geriatrics

Studies have been done to analyze the safety of EBUS-TBNA in the elderly. When comparing the risk of complications for patients between the ages 65–69 vs. ≥70 years, there was no difference in the frequency and type of complications, even though the group ≥70 years had more comorbidities and lower overall performance status (101). In a prospective study in the United Kingdom including 451 patients who underwent EBUS-TBNA were divided into groups of ≥70 and <70 years of age. Older patients had a worse performance status and required significantly lower sedation but had similar overall complication rates (8.7% <70 vs. 5.1% ≥70 years, P=0.13) and tolerated the procedure better (P=0.036). Diagnostic accuracy was higher in the older group (102). Older age increases perioperative risks related to anesthesia, so a study by Tunç et al. evaluated the use of deep sedation with EBUS-TBNA in elderly patients. This was a retrospective study that included 280 patients who were divided into two groups, 156 were >65 years and 124 were <45 years. There was no difference in the body mass index, procedure duration, and recovery time in both groups. ASA classification, frequency of comorbidities, and initial mean arterial pressure were higher in the older group, but complication rates were similar in both groups. Respiratory depression was the major complication and occurred in 1 patient in each group (103).

Safety of EBUS in the pediatric population

EBUS-TBNA is used in children as well. The diagnostic yield is around 98% for mediastinal lymphadenopathy and 84% for pulmonary nodules (104,105). Most of the published studies are retrospective, case series, or case reports. A meta-analysis looked at complications of EBUS-TBNA/EUS-B-FNA (transesophageal bronchoscopic ultrasound-guided FNA) for mediastinal lymphadenopathy in children <18 years of age and included 173 patients. Combined results were published and a procedure-related major complication was seen in 1 patient (1/173, 0.6%) and minor complications occurred in 6 patients (6/173, 3.5%) (104).

Mortality

The mortality rate after EBUS-TBNA is 0.01% to 0.04% (3,14). The Japanese study with 7,345 cases had 90 complications, death occurred in one patient due to severe cerebral infarction (3). A study by von Bartheld et al. looked at 2,675 EBUS procedures with 2 reported deaths (0.04%) (14). A death has been reported in a patient who developed pericarditis and pericardial effusion that grew Viridans streptococcus who died despite pericardiocentesis (16). Death from massive hemoptysis has been reported in two patients on bevacizumab for NSCLC who developed tracheo/broncho-mediastinal fistula after EBUS-TBNA that led to hemorrhage and death (63,64). Death after massive hemoptysis has also been reported in a patient who underwent a biopsy of subcarinal and right hilar lymph nodes and developed hemoptysis 6 hours post-procedure. It was thought to be due to low platelets from marrow infiltration due to metastatic adenocarcinoma (60). The AQuIRE study also reported one death that occurred due to bleeding (4).

Limitations

This study has limitations, including its retrospective nature, the possibility of author bias, and the possibility of missing cases.

Conclusions

EBUS-TBNA has been supported by literature as a safe, minimally invasive procedure with a high diagnostic yield. However, as the use of EBUS increases, the incidence of complications is also expected to rise, particularly rare complications that now have more opportunities to occur.

Risk factors for infectious complications should be kept in mind which include multiple nodal samplings, immunosuppression, bronchial colonization, necrotic lesions, cystic lesions, diabetes, and airway stenosis. While prophylactic antibiotics are not generally recommended, meticulous techniques—such as minimizing needle contamination, deliberate puncture/biopsy of the target, and caution during biopsy—are crucial in high-risk patients. Contamination can be minimized by using an LMA or endotracheal intubation to bypass the mouth and oral flora. Although post-EBUS bacteremia and fever are typically self-limiting, clinicians should remain vigilant for severe outcomes to ensure timely intervention. Patients with underlying infection, receiving radiation, or on bevacizumab are at increased risk of developing fistulas at the biopsy site so caution should be taken.

Performing EBUS under general anesthesia may carry a lower risk of complications compared to moderate sedation. The latter is associated with higher risks of hypoxemia and arrhythmias. In certain cases, moderate sedation may be suitable, but the decision should be left to the discretion of the bronchoscopist. However, it is reasonable to avoid moderate sedation in cases with central airway stenosis.

The risk of bleeding during EBUS procedures varies. While EBUS can often be performed without stopping anti-thrombotic therapy, extra caution is required for patients on anticoagulation. Needle size did not increase the risk of bleeding, even in individuals receiving dual antiplatelet therapy. Additionally, transvascular biopsy did not show an increased bleeding risk related to needle size as well. However, these studies have involved small sample sizes, and caution is still necessary. We recommend these higher-risk procedures be conducted by experienced bronchoscopists.

Clinicians should ensure equipment integrity both before and after the procedure, watching for signs of retained or dislodged components, and retrieving them promptly if detected. Needle breakage can result in migration and inflammation, while attempts to retrieve broken needles may cause hemorrhage. Dislodged air balloons may obstruct airways, leading to atelectasis or pneumonia. Severe cough post-procedure, barotrauma, and history of ILD or COPD increases the risk of developing pneumothorax or pneumomediastinum. Post-procedural medications to control coughing may help reduce the risk, and additional care is warranted in patients with COPD or ILD.

EBUS should not be avoided based solely on age, as it is safe for both geriatric patients over 70 years and pediatric patients under 18 years. Clinicians performing EBUS must be aware of the potential complications, closely monitor patients’ post-procedure, and ensure rapid diagnosis and treatment to prevent fatal outcomes. Additional research is required to gain a clearer understanding of the complications associated with EBUS.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://med.amegroups.com/article/view/10.21037/med-24-33/rc

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Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://med.amegroups.com/article/view/10.21037/med-24-33/coif). G.C. received Harvard patent on SLIPS from BIDMC, and other patent pending, and received consulting fees from Intuitive, Ajax, Olympus, Cook, Pinnicle Biologics, Siemens, Leadoptiks. G.C. also has a leadership role in AABIP board of directors and in ACCP. N.M.P. received consulting proctoring fees from Intuitive Surgical and support for meeting attendance from European Respiratory Society. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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