吲哚靛氰绿荧光成像在胸腔镜肺切除术应用的专家共识（2022版）

Expert consensus on indocyanine green fluorescence imaging for thoracoscopic lung resection (The Version 2022)

The use of the white-light thoracoscopy is hampered by the low contrast between oncologic margins and surrounding normal parenchyma. As a result, many patients with in situ or micro-infiltrating adenocarcinoma have to undergo lobectomy due to a lack of tactile and visual feedback in the resection of solitary pulmonary nodules. Near-infrared (NIR) guided indocyanine green (ICG) fluorescence imaging technique has been widely investigated due to its unique capability in addressing the current challenges; however, there is no special consensus on the evidence and recommendations for its preoperative and intraoperative applications. This manuscript will describe the development process of a consensus on ICG fluorescence-guided thoracoscopic resection of pulmonary lesions and make recommendations that can be applied in a greater number of centers. Specifically, an expert panel of thoracic surgeons and radiographers was formed. Based on the quality of evidence and strength of recommendations, the consensus was developed in conjunction with the Chinese Guidelines on Video-assisted Thoracoscopy, and the National Comprehensive Cancer Network (NCCN) guidelines on the management of pulmonary lesions. Each of the statements was discussed and agreed upon with a unanimous consensus amongst the panel. A total of 6 consensus statements were developed. Fluorescence-guided thoracoscopy has unique advantages in the visualization of pulmonary nodules, and recognition and resection of the anterior plane of the pulmonary segment. The expert panel agrees that fluorescence-guided thoracoscopic surgery has the potential to become a routine operation for the treatment of pulmonary lesions.

The evidence base was provided for each item including expert recommendations, evidence quality, and evidence level grades were developed through group discussions (Table 1).

Table 1The 6 consensus opinions reached by the panel

Recommendations	Evidence level	Recommendation grade
Route 1: Percutaneous ICG injection
ICG percutaneous injection under CT guidance	High	Strong
Route 2: ICG injection via the vessels of the target lung segment
Blocking the vessels of the target lung segment and injecting ICG via a peripheral/central vein can reveal the intersegmental plane by reverse staining	Middle	Strong
In patients with bronchial stenosis or poor lung dilation/collapse, the vascular reverse staining method is preferred to display the intersegmental plane compared with the dilation and collapse method	High	Strong
Because of the short development time when using the vascular reverse staining method, the intersegmental plane boundary can be marked quickly or repeatedly staining with repeated injections of ICG; the pulmonary veins can also be clamped to extend the staining duration appropriately	Middle	Strong
Route 3: ICG injection via airway approach
Bronchoscopic guidance of ICG injection into the target lung segment via the bronchus to stain the target lung segment	Middle	Strong
ENB allows ICG to be injected and positioned around the target lesion through an ultra-thin bronchoscope	Middle	Strong

ICG, indocyanine green; CT, computed tomography; ENB, electromagnetic navigation bronchoscopy.

Localization of pulmonary lesions: ICG percutaneous injection under computed tomography guidance

Preoperative ICG injection was performed under computed tomography (CT)-guided puncture to locate pulmonary nodules. Precise preoperative localization of pulmonary nodules is a key prerequisite to the identification of lesions. Localization of small pulmonary nodules is challenging. Notably, when ground-glass nodules (GGNs) do not alter the surface of the visceral pleura, the elevation of tumors cannot be perceived sin the deflated lung during VATS, making localization difficult. Suzuki et al. observed a 54% overall conversion rate from VATS to thoracotomy which increased to 63% for nodules ≤10 mm in size and >5 mm from the pleural surface (23). A NIR thoracoscopy can detect ICG injected into the lungs as a marker (24). ICG can be topically administered into the nodules 24 hours before surgery (25). Both percutaneous and bronchoscopic injection techniques have been shown to be safe and reliable methods for lung nodule localization (26-28). As percutaneous marking is not dependent on bronchial branching, it can easily be performed by interventional radiologists, using the same technique as CT-guided biopsy. The success rate of a single marking using the CT-guided percutaneous approach is high, and there is minimal risk for retained foreign bodies or vascular embolism (16).

However, there are some details to heed when applying this technique. After ICG injection, negative pressure needle extraction is required to avoid ICG overflow resulting in extensive development of the pleura. The depth of the lung lesion also affects the result of ICG imaging. According to the experience of different institutions, the ICG imaging effect is best when the depth of the lung lesion is less than 3 cm or pulmonary nodules are located outside 1/3 of the lung tissue. For some patients with extensive chest adhesion, severe emphysema, or poor pulmonary perfusion, the time of ICG-enhanced staining is shortened, and ICG may not play a full role. ICG staining should be used with caution in these patients (29). Furthermore, complications may also occur during CT-guided percutaneous injection puncture due to improper operation, it may damage the visceral pleura and lead to pneumothorax.

Recommendation

Percutaneous marking is not dependent on bronchial branching, it can easily be performed by interventional radiologists, using the same technique as CT-guided biopsy. The success rate of a single marking using the CT-guided percutaneous approach was high. In terms of cost, the CT-guided percutaneous approach costs less than other methods because it involves only the expense of using the CT scanner unless complications, such as severe pneumothorax, occur.

ICG percutaneous injection under CT guidance.

Evidence level: high.

Recommendation grade: strong.

Localization of pulmonary lesions: ICG injection via targeted vascular occlusion

After occlusion of target arteries and veins, ICG was injected through the peripheral/central vein to image the unresected lung segment. The intravenous injection method should proceed as follows: based on the results of preoperative CT or three-dimensional (3D) reconstruction, the vessels in the diseased lung segment(s)/subsegment(s) are transected or temporarily occluded to dissect the diseased lung tissue. Next, a prepared sterile solution of ICG is intravenously administered. Ideally, by the ICG reverse staining, a visual boundary will appear between the preserved segment and the target segment (the target lung segment will be dark on negative contrast, while the other lung segments will be green because the fluorescent contrast agent cannot enter the segmental vessel after dissection) (17). The intersegmental planes (ISPs) between the target and preserved segments can be visualized by infrared thoracoscopy (IRT). After the target lung segment can be visually separated from the other segments, it is removed with a linear cutter/stapler (30). The ICG solution diffuses within 3–5 minutes. With the help of infrared light, the lines among lung segments can be seen clearly. The target lung segments can be removed along the boundaries (31). The lung tissue is endoscopically placed in a sterile bag, removed from the chest cavity, and immediately sent for pathological evaluation. The extent of surgical resection (lobectomy vs. segmentectomy) will depend on the histopathological findings of the frozen sectional analysis and institutional practices (15).

The intravenous injection method is simple and easy to perform but has the disadvantage of the ICG being rapidly metabolized by the liver through the bronchial circulation, which leads to a short visualization time. However, repeated angiographies can be performed and may be helpful; otherwise, intraoperative clamping of the pulmonary lobar veins may enable prolongation of washout time (32). In addition, previous literature reports have demonstrated that ICG-guided watershed analysis of the target pulmonary artery for nodule localization is safe and effective, especially in selected patients undergoing thoracoscopic wedge resection, which may be a feasible and attractive alternative method for localizing non-palpable pulmonary nodules (33).

In addition, when a patient has a combination of emphysema and underdeveloped lung fissures, the alveolar inflation-deflation method will make it difficult to perform lung ISP identification. The use of NIR fluorescence thoracoscopy is a potential solution to this challenge. The combination of NIR fluorescence imaging with the intravenous ICG method to generate ISPs has gained considerable momentum recently due to its simplicity and rapidity. Misaki et al. were among the early pioneers and described their experience with ICG for the first time in pulmonary segmentectomy in 8 patients (17). In a clinical trial performed by Kasai et al., a total of 30 consecutive patients who underwent NIR-guided segmentectomy were evaluated by 2- and 1-wavelength IRT; the rate of successful identification of ISPs was 93%; the 1-wavelength group (0.5 mg/kg) had a lower ICG dose than did the 2-wavelength group (3.0 mg/kg) and longer staining duration, although the image quality was relatively poorer (34). Additional studies have focused on the evaluation of the true success rate of IRT with ICG during VATS, with multiple studies reporting high rates of ISP identification. In particular, Tarumi et al. demonstrated a success rate of 84.6% (11/13) (35), Mun et al. 95% (19/20) (36), and Bédat et al. 88% (59/67 patients) (37). In a prospective trial by Motono et al., the ISP identification efficiency was 90% (18/20) (38). Pischik et al. successfully identified ISPs in 86 of 90 consecutive patients, with a success rate of 95.6% (29). The ISP identification efficiency even reached 100% in research conducted by Guigard et al. (22/22) (39) and Chen et al. (19/19) (40). In a prospective trial, Iizuka et al. successfully identified ISPs in 98.6% of patients and found that smoking index (SI) (SI >800) and low attenuation areas >1.0% on CT were strong predictors of unfavorable ICG visibility (41). Recent studies have demonstrated that NIR fluorescence thoracoscopy is non-inferior to the inflation-deflation method in ISP identification. Notably, a retrospective study by Sun et al. found that ISPs in the fluorescence group were consistent with those in the inflation-deflation group, with the former having significantly shorter in-plane generation time and operative time than the latter (42,43). In addition, Soo Chang et al. applied the combination of NIR fluorescence imaging and intraoperative CT for ISP identification, and complete resection was achieved in all 12 consecutive patients using this approach (44).

However, some details need to be taken into account when applying the technique. The use of an ICG diluent is recommended to reduce the chance of adverse effects (38,45). The optimal cutoff volume of diluted ICG (0.0125 mg/mL) for insufflation was 8.91% of the calculated targeted pulmonary segment volume (46). However, in some cases, no fluorescent imaging can be seen after ICG localization or no pulmonary nodules can be found after excision. In this case, either an expanded excision or an anatomic excision with 3D reconstruction should be performed. Furthermore, due to the shorter staining duration of transvascular ICG injection, it may cause some difficulty in separating intersegmental planes during the prolonged use of energy instruments. In addition, intravascular ICG reverse staining is not recommended for patients who are allergic to iodine.

Recommendation

In patients with bronchial stenosis or poor lung dilation/collapse, the vascular reverse staining method is preferred to display the intersegmental plane compared with the dilation and collapse method. During intravenous injection of ICG or other ICG-based tracers, the pulmonary lobar veins can be clamped after the visual boundaries appear, and the boundaries can be marked with electrocautery, which helps to avoid a second injection due to the short visualization time. The use of an ICG diluent is recommended to ensure the duration and effectiveness of the imaging while reducing the chance of adverse effects.

ICG injection via targeted vascular occlusion.

Evidence level: middle.

Recommendation grade: strong.

Localization of pulmonary lesions: ICG injection via airway approach

By marking the target bronchus under the bronchoscope, ICG was directly injected into the corresponding target bronchus to image the lung segment to be resected. Bronchoscopic marking enables the injection of ICG-fluorescence (ICG-FL) markers into multiple lung sections without injuring the visceral pleura. Additionally, the bronchoscopic approach is more feasible for regions of the lung that are difficult to reach using a percutaneous approach, such as the subscapular area (26). Several bronchoscopic localization techniques have been advocated and validated in clinical trials, which overcome these adverse events associated with percutaneous needle marking (47-50). The endobronchial injection method offers relatively adequate visualization time for resecting the lung segment (31). In addition, describing the ISP of the lung with ICG is feasible despite the type of lung segmental anatomy, and is commonly utilized during lung segmentectomy (51).

The electromagnetic navigation bronchoscopy (ENB) approach was used to locate pulmonary nodules near the visceral pleura, based on thin-section CT reconstructed images. In this way, the ENB system, using an ultrathin bronchoscope (outer diameter: 2.8–3.5 mm), enabled deeper visualization into the tracheobronchial tree to reach the right position around the target lesion. Subsequently, dye marking was performed to inject ICG under the guidance of ENB, which can mark the position of the target lesion (52). In addition, for patients with multiple pulmonary nodules and inconvenient percutaneous puncture localization, ICG fluorescence navigation under ENB guidance is considered, which has certain advantages (53).

However, there are some disadvantages of the bronchoscopic-assisted localization technique: Localization accuracy has some limitations, the locator procedure is complicated, and the localization costs are higher.

Recommendation

For patients with inconvenient percutaneous puncture localization and multiple pulmonary nodules, ENB-guided ICG injection is recommended. In addition, in patients with pulmonary lesions with secondary bronchial signs, lesion localization with ENB alone may be superior to CT-guided lung puncture localization because of similar accuracy but lower complication rates in the former (54).

ICG injection via airway approach.

Evidence level: middle.

Recommendation grade: strong.

Cui F, Liu J, Du M, Fan J, Fu J, Geng Q, He M, Hu J, Li B, Li S, Li X, Liao YD, Lin L, Liu F, Liu J, Lv J, Pu Q, Tan L, Tian H, Wang M, Wang T, Wei L, Xu C, Xu S, Xu S, Yang H, Yu BT, Yu G, Yu Z, Lee CY, Pompeo E, Azari F, Igai H, Kim HK, Andolfi M, Hamaji M, Bassi M, Karenovics W, Yutaka Y, Shimada Y, Sakao Y, Sihoe ADL, Zhang Y, Zhang Z, Zhao J, Zhong W, Zhu Y, He J. Expert consensus on indocyanine green fluorescence imaging for thoracoscopic lung resection (The Version 2022). Transl Lung Cancer Res. 2022 Nov;11(11):2318-2331. doi: 10.21037/tlcr-22-810. PMID: 36519017; PMCID: PMC9742622.

• Expert consensus on indocyanine green fluorescence imaging for thoracoscopic lung resection (The Version 2022)