This article aims to describe a stepwise approach to performing robotic-assisted bronchoscopy combined with fluoroscopy, radial endobronchial ultrasound, and cone beam computed tomography to obtain targeted transbronchial lung cryobiopsies.
Robotic-assisted bronchoscopy (RAB) allows for targeted bronchoscopic biopsy in the lung. A robotic-assisted bronchoscope is navigated through the airways under direct vision after establishing a pathway to a target lesion based on mapping performed on a 3-dimensional (3D) lung and airway reconstruction obtained from a pre-procedure thin-slice computed tomography chest. RAB has maneuverability to distal airways throughout the lung, precise catheter tip articulation, and stability with the robotic arm. Adjunct imaging tools such as fluoroscopy, radial endobronchial ultrasound (r-EBUS), and cone beam computed tomography (CBCT) can be used with RAB. Studies using shape-sensing robotic-assisted bronchoscopy (ssRAB) have shown favorable diagnostic outcomes and safety profiles in both malignant and non-malignant processes for the biopsy of peripheral pulmonary lesions (PPLs). A 1.1 mm cryoprobe combined with ssRAB has been shown to be safe and effective for the diagnosis of PPLs compared to a traditional bronchoscopy with forceps biopsy. This technique can also be used for targeted lung sampling in benign processes. The aim of this article is to describe a stepwise approach to performing RAB combined with fluoroscopy, r-EBUS, and CBCT to obtain targeted transbronchial lung cryobiopsies (TBLC).
Flexible bronchoscopy with transbronchial lung biopsy (TBBX) is a diagnostic modality used for the evaluation of abnormal chest imaging, including masses, nodules, non-resolving infiltrates, or parenchymal lung diseases1. Diffuse parenchymal lung diseases (DPLD) can often be characterized by fibrosis and/or inflammation. While some patients can be diagnosed noninvasively with a thorough history, physical examination, relevant serologies, high-resolution computed tomography (HRCT) findings, and multi-disciplinary discussion (MDD), many patients need an invasive procedure to establish a diagnosis2. Conventional transbronchial lung biopsies with forceps are limited due to small biopsy size and crush artifacts; as a result, surgical lung biopsy has been considered the gold standard, although it has significant morbidity and mortality3,4.
Transbronchial lung cryobiopsy (TBLC) is a technique that can be used to diagnose interstitial lung disease (ILD) or diffuse parenchymal lung disease (DPLD) and might serve as an alternative to surgical lung biopsy (SLB)5. According to the European Respiratory Society guidelines, TBLC is recommended as a substitute for SLB in eligible patients6. Similarly, the American Thoracic Society guidelines offer a conditional recommendation for TBLC as an alternative to SLB in medical centers with the necessary expertise in performing and interpreting TBLC results7. TBLC has historically provided good accuracy in diagnosis compared to SLB but is limited by complications, including bleeding and pneumothorax8. A recent meta-analysis showed an overall diagnostic yield of 77% that improved to 80.7% with MDD, and reported a pneumothorax rate of 9.2% and bleeding rate of 9.9%9. TBLC is also used in the evaluation of PPLs10.
The development of robotic-assisted bronchoscopy (RAB) allows for targeted sampling in the lung by navigating through the airways under direct vision with easy catheter maneuverability, precise catheter tip articulation, stability, and the ability to maintain a bronchoscopic wedge in distal airways with the catheter using a robotic arm. The Ion endoluminal system utilizes shape-sensing technology for navigation to access specific targeted areas in the lung. Studies using shape-sensing robotic-assisted bronchoscopy (ssRAB) have shown favorable diagnostic outcomes and safety profile, primarily for PPLs suspicious of malignancy11,12,13,14. A 1.1 mm cryoprobe for TBLC combined with ssRAB has been shown to be safe and effective for the diagnosis of pulmonary nodules compared to transbronchial biopsy with forceps15. This technique can be used to obtain targeted lung biopsies larger than conventional transbronchial biopsies using forceps that are relatively free of crush artifacts.
Radial endobronchial ultrasound (r-EBUS) and cone beam computed tomography are used in conjunction with conventional bronchoscopy, electromagnetic, or robotic navigational systems for real-time confirmation prior to sampling PPLs16,17,18,19,20,21,22. R-EBUS has also been utilized during TBLC for DPLD to increase the pathologic confidence of lung specimens, decrease bleeding, and have a shorter procedure time23. The addition of CBCT has improved the safety profile of TBLC for DPLD by confirming the probe tip is in a safe zone for biopsy, allowing objective measurement of the distance from the pleura with the ability to visualize and avoid vasculature24,25,26.
This protocol will describe a procedure to obtain targeted TBLC in the setting of parenchymal lung disease for patients who are able to tolerate and benefit from the procedure using the Ion endoluminal system in conjunction with fluoroscopy, r-EBUS, and CBCT in a clinical setting under general anesthesia. This multimodal approach allows for precise sampling of targeted areas of interest.
The protocol described in this article outlines standard clinical practice. The University of Texas Southwestern Medical Center Institutional Review Board approved the prospective data collection of patients undergoing standard-of-care bronchoscopy with ssRAB (STU-2021-0346), and individual consent is waived for inclusion in our database. Routine procedure consent is obtained from the patient prior to the procedure. Patients who have DPLD radiographically and are acceptable candidates for bronchoscopic biopsy are referred for this procedure5,27. Patients over 18 years of age are deemed able to undergo the procedure by the referring and performing physicians. Exclusion criteria include bleeding disorders (elevated INR >1.3, thrombocytopenia <100,000/µL), hypoxia with pulse oximetry <90% on 2 L/min supplemental oxygen, pulmonary hypertension (echocardiographically measured systemic pulmonary artery pressure >50 mmHg), or severe cardiac disease. The details of the equipment used in this study are listed in the Table of Materials.
1. Pre-procedural planning
2. Patient preparation
3. Conventional bronchoscopy
4. Robotic-assisted bronchoscopy
5. Conventional bronchoscopy
6. Procedure conclusion
7. Follow-up post procedure
The described technique allows for targeted transbronchial lung cryobiopsies via RAB with fluoroscopy, r-EBUS, and CBCT guidance. Compared to conventional bronchoscopy with random TBLC, this technique allows for targeting specific areas of DPLD or PPLs of interest while assessing surrounding structures prior to biopsy. This technique can be used with r-EBUS and fluoroscopy only or with a combination of CBCT. While this technique had been devised for PPLs, it can be utilized in benign and diffuse parenchymal lung diseases to ensure the sampling of precise, targeted areas.
Historically, TBLC has been performed with larger cryoprobes (1.7 mm, 1.9 mm, 2.4 mm)9,10. Evaluation of the smaller, disposable 1.1 mm cryoprobe is ongoing. A recent prospective, randomized controlled trial evaluating 1.1 mm versus 1.9 mm cryoprobes for patients undergoing bronchoscopy with TBLC in the evaluation of DPLD reported no difference in specimen quality or diagnostic rate but a smaller sample size with the 1.1 mm cryoprobe32. The FROSTBITE-2 trial, a study to compare the effectiveness of transbronchial biopsy done by a 1.1 mm cryoprobe versus standard 2.0 mm forceps for a variety of lung processes (evaluation of lung transplant allograft, DPLD or PPL) is currently enrolling.
There is limited data on DPLD using navigational bronchoscopy guidance to obtain TBLC. Kronborg et al.33 reported a pilot study on the use of electromagnetic navigational bronchoscopy-guided TBLC in 18 patients with DPLC using a 1.7 mm or 1.9 mm touch cryoprobe. They reported that biopsies contributed to the diagnosis in 11 patients, with pneumothorax in 3 and mild-moderate hemorrhage in 733.
We have previously published our outcomes for patients undergoing this multi-modality technique (using ssRAB with fluoroscopy, r-EBUS, and CBCT) for targeted lung sampling in both benign and malignant diseases21,22. To date, from the initial manuscript submission, we have had ten patients who have undergone RAB with fluoroscopy, CBCT, and R-EBUS for TBLC in DPLD, which are not included in these data sets. Among this cohort, there were no episodes of bleeding requiring intervention. One patient required admission for observation, followed by chest tube placement for an enlarging but asymptomatic pneumothorax. Eight patients had biopsy in one lobe (1 right upper lobe, 5 right lower lobe, 1 left upper lobe, 1 left lower lobe) and 2 patients in multiple lobes (right upper and right lower lobes). The mean total biopsies obtained was 7 ± 1.2. The mean largest dimension of biopsies was 0.32 mm ± 0.1 mm. Bronchoscopy results contributed to diagnosis in 70% of patients. Data collection is ongoing.
Figure 1: CT chest slices in axial, coronal, and sagittal views with airway reconstruction and selected biopsy site in right upper lobe with planned pathway. Please click here to view a larger version of this figure.
Figure 2: Views on ssRAB console with fluoroscopy at left anterior oblique (LAO) 30 degrees and digital zoom. (A) Top with r-EBUS extended with no significant vasculature noted at the biopsy site. (B) 1.1 mm touch cryoprobe extended. Please click here to view a larger version of this figure.
Figure 3: Cone beam CT performed with r-EBUS probe visible. Biopsy area segmented for use with augmented fluoroscopy. Note significant motion artifact and atelectasis when CBCT spin performed without breath hold. Please click here to view a larger version of this figure.
Figure 4: Post-procedure chest radiograph in anteroposterior view. Bilateral interstitial densities noted with no pneumothorax or pleural effusion. Please click here to view a larger version of this figure.
This manuscript provides a stepwise approach for performing RAB with fluoroscopy, r-EBUS, and cone beam CT to obtain targeted TBLC.
There are several critical steps in this protocol. First, patient selection is imperative to ensure patients are both appropriate candidates (the biopsy procedure may have a direct impact on diagnosis and further care) and medically able to undergo the procedure5,6. Pre-procedure preparation includes discussion with the referring physician and/or radiologist to determine differential diagnosis and optimal biopsy areas that may yield diagnostic material. This combination of techniques (CBCT and r-EBUS) is helpful in patients who have DPLD but may have focal areas of disease such as nodularity or ground glass opacities amenable to targeted sampling, and/or if the optimal biopsy sites are adjacent to critical structures (pleura, vasculature) or a technically challenging area of the lung to access bronchoscopically due to airway angulation or anatomy. If CBCT is unavailable, then the addition of r-EBUS can be helpful in determining the pleural border and allowing r-EBUS visualization of the planned biopsy area to identify areas of ground glass and to avoid vasculature to decrease bleeding risk.
It is important to plan to sample multiple lesions and account for various pathways to the target areas if possible, as numerous variables such as narrowed distal airways, mucus impaction, or airway angulation can make navigation challenging. The benefits of using the ssRAB catheter, with a 3.5 mm outer diameter, is that the flexibility and stability allow access throughout the lung to areas that may have previously been inaccessible bronchoscopically.
After navigation, adjunct imaging such as r-EBUS and CBCT serves to verify the potential biopsy site is acceptable. R-EBUS with 2-dimensional fluoroscopy is used to visualize the pleural border, parenchyma, and any vasculature structures at the potential biopsy site. CBCT serves to further ensure the biopsy site is appropriate without surrounding critical structures, approach direction for sampling, and assist with later clinical-pathologic correlation at MDD if the intra-procedure imaging is uploaded to PACS.
When obtaining the TBLC, It is vital to maintain continued depression of the pedal while withdrawing the probe using the 1.1 mm touch cryoprobe, as early release can lead to premature defrosting and tissue loss. Modifications are based on patient characteristics, including body habitus distribution of disease, and can include adjusting areas targeted for biopsy, the number of TBLC obtained in each target site, or adjustment of freeze cycle depending on tissue size obtained.
Given the current size of the ssRAB catheter and the described technique, this protocol is limited to the use of a 1.1 mm touch cryoprobe. The combination of a smaller cryoprobe compared to larger probes (1.7 mm, 1.9 mm, or 2.4 mm) and the reliability of ssRAB to maintain a distal wedge position has decreased the risk of bleeding and potentially obviated the need for an endobronchial blocker. This technique may be helpful in patients who otherwise may not be able to undergo a non-targeted TBLC given patient characteristics or available procedure expertise, and would otherwise have undergone standard bronchoscopy with TBBX or no procedure. Further research is needed on this technique in non-malignant parenchymal lung disease.
This combination of techniques may currently have limited generalizability given the cost, availability, and training required with the multi-modality approach and equipment necessary: ssRAB, fluoroscopy, CBCT, and r-EBUS. However, given the increasing use and availability of these techniques to biopsy PPLs15,34, this may allow for increased use in non-malignant diseases. Reproducibility of these techniques should be performed in centers with high volume and experience in peripheral bronchoscopy with the ability to handle complications (pneumothorax and airway bleeding), in addition to access to MDD and thoracic surgery if used for the evaluation of DPLD. Other novel techniques that may be additive in the bronchoscopic evaluation of DPLD in the future include optical coherence tomography (OCT), confocal laser endomicroscopy (CLE), rapid onset evaluation (ROSE) to assess specimen adequacy, and immunohistochemistry and genomic classifier (GC) testing35,36,37,38,39.
In summary, the multimodal approach using ssRAB with adjunct advanced imaging and 1.1 mm cryoprobe in obtaining targeted lung biopsies for those with malignant or benign pulmonary processes and abnormal chest CTs may provide a safer modality to obtain lung tissue and aid in establishing a diagnosis. Further evidence is required regarding diagnostic yield and safety for these combined techniques for both benign and malignant diseases.
The authors have nothing to disclose.
The authors want to thank the interventional pulmonology team, endoscopy staff, anesthesia team, cytopathology team, and hybrid operating room radiology technicians at UT Southwestern Medical Center.
0.9% normal saline, 1000 mL | Any make | ||
10 mL Leuer lock syringes | Any make | ||
20 mL slip tip syringes | Any make | ||
Bronchoscope | Intuitive | ||
Bronchoscope processor and video screens | Intuitive | ||
Carbon dioxide gas tank | |||
Cone beam computed tomography system with c-arm and controller console | |||
Disposable valve for biopsy channel | |||
Disposable valve for suction | |||
ERBECRYO 2 1-pedal footswitch AP & IP X8 Equipment US | Erbe | 20402-201 | |
ERBECRYO 2 Cart | Erbe | 20402-300 | |
ERBECRYO 2 Cryosurgical unit | Erbe | 10402-000 | |
ERBECRYO 2 System | Erbe | ||
Flexible Cryoprobe, OD 1.1 mm, L1.15 m with oversheath, OD 2.6 mm, L817 mm | Erbe | 20402-401 | |
Flexible gas hose; L 1m for Erbokryo CA/AE/ERBECRYO 2 | Erbe | 20410-004 | |
Gas bottle adapter H; CO2; Pin index | Erbe | 20410-011 | |
Ion endoluminal system with robotic arm, controller console | Intuitive | ||
Ion fully articulating catheter | Intuitive | 490105 | |
Ion instruments and accessories | |||
Ion peripheral vision probe | Intuitive | 490106 | |
Laptop with PlanPoint planning software | Intuitive | ||
Probe driving unit | Olympus | MAJ-1720 | |
Radial EBUS Probe | Olympus | UM-S20-17S or UM-S20-20R-3 | |
Radial endobronchial ultrasound system | |||
Specimen containers with fixative per institution standards | |||
Sterile disposable cups | |||
Suction tubing | |||
Topical 1:10,000 epinephrine, 10 mL | |||
Topical tranexamic acid 1000mg, 10 mL | |||
Universal ultrasound processor | Olympus | EU-ME2 | |
Wire basket; 339 x 205 x 155 / 100 mm | Erbe | 20180-010 |
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