Indocyanine Green in Thoracic and Esophageal Surgery: What Anesthesiologists Need to Know

Indocyanine Green in Thoracic and Esophageal Surgery: What Anesthesiologists Need to Know As thoracic and esophageal surgical procedures evolve to become more minimally invasive, the evaluation of lymph nodes, small nodules, and gastric conduit perfusion has become more challenging. Recently, the use of indocyanine green dye (ICG) dye with near infrared spectroscopy (NIR) (ICG/NIR) has been evaluated as a marker for lymphatic and vascular flow, as well as for the detection of small pulmonary nodules. ICG/NIR fluorescence has the potential to facilitate surgical planning, to stage disease, and to reduce postoperative complications.1 In the April 2023 issue of the Annals of Thoracic Surgery, Ng et al reported the proposed recommendations developed from an expert panel for the use of ICG/NIR fluorescence in thoracic and esophageal procedures. The expert panel was composed of 12 thoracic and gastrointestinal surgeons from Asian-Pacific countries and these recommendations were formulated during a consensus meeting in an attempt to adopt, optimize and standardize the use of this technique in thoracic and esophageal surgery, including the indications, the route of administration, the dose required, and the contraindications, based on the most current surgical literature. Indocyanine green dye is a lyophilized green powder containing 25 mg of ICG dye with no more than 5% sodium iodide that is reconstituted with sterile water and administered intravenously, intrabronchially, or interstitially, to mark surgical sites.2 After administration, the dye is actively bound to plasma proteins, with approximately 95% being bound to albumin. ICG dye undergoes no significant extrahepatic or enterohepatic recirculation and there is negligible renal, peripheral, lung, or cerebrospinal uptake of the dye. Excretion occurs after uptake by the hepatic parenchymal cells and is secreted entirely into the bile. With biliary obstruction, the dye appears in the hepatic lymphatic system, making ICG dye a useful index of hepatic function.2 Other indications for the use of ICG/NIR fluorescence include ophthalmologic angiography, visualization of micro- and macrovascular blood flow and tissue perfusion before, during, and after vascular, gastrointestinal, organ transplant and micro- and macro reconstructive surgeries in adults and pediatric patients one month of age and older, the visualization of extrahepatic biliary ducts, and visualization of lymph nodes and lymphatic vessels during lymphatic mapping for gynecologic cancers .2 The recommended single intravenous dose for the visualization of vessels, blood flow, and tissue perfusion is 5 mg in adults, 2.5 mg in children, and 1.25 mg in infants, with a maximum dose of 2 mg/kg. Since the effects of ICG dye on pregnancy and lactation are unknown, ICG dye should be avoided in pregnant or lactating women unless clearly indicated. The only absolute contraindication is a hypersensitivity to the dye but since the ICG dye formulation contains sodium iodide, it should be used with caution in patients with a history of iodide allergy. Reactions such as urticaria and anaphylaxis have been reported.3,4 In the ophthalmologic literature, severe reactions to ICG dye occur in 0.05% to 0.07%, of patients, moderate reactions in 0.2%, and mild reactions in 0.15%.5 The peak spectral absorption of ICG dye is between 800-810 nm and the emission wavelength is 835 nm.2 Since this wavelength is invisible to the human eye, a near-infrared fluorescent light with a wavelength between 700-900 nm is necessary to produce visible images.3 The first reports of the use of ICG/NIR fluoroscence in thoracic surgery were published in 2004 by Nimura et al, who utilized this technique to detect sentinel lymph nodes (SLNs) in patients with gastric cancer6 and by Ito et al to detect SLNs in patients with lung cancer.7 Over time, the use of ICG/NIR fluorescence has been expanded to include pulmonary nodule and solid tumor identification, the assessment of gastric conduit perfusion during esophagectomy, pulmonary intersegmental plane identification during sublobar resections, particularly segmentectomy, bullous lesion detection, and thoracic duct imaging. 8,9 ICG/NIR fluorescence has been used to detect thoracic duct injury causing chylothorax. Kaburagi et al, using ICG/NIR fluorescence was able to determine the location of a chyle leak when ICG dye was injected into the mesentery of the small bowel.10 Chang et al reported similar results using bilateral inguinal region ICG dye injection.11 Due to the increased utilization of ICG/NIR fluorescence imaging in thoracic surgery, the expert panel, searching the PubMed database, developed recommendations addressing the feasibility, safety, and optimal indications for the its use based on the most current evidence available. This panel focused on 7 areas: intersegmental plane identification for sublobar resections; pulmonary nodule localization; lung tumor detection; bullous lesion detection; lymphatic mapping of lung tumors, evaluation of gastric conduit perfusion, and lymphatic mapping in esophageal procedures.1 (Table 1.) Their PubMed search yielded 2638 results including randomized trials, cohort studies, case series/reports, and review articles, of which 98 were used to develop these recommendations. Of the 7 clinical areas, the identification of the intersegmental plane for sublobar resections, localization of pulmonary nodules, lymphatic mapping in lung tumors, and the assessment of gastric conduit perfusion were applications with the most robust current evidence. The expert panel developed 9 consensus recommendations that were divided into 7 sections and each were assigned a level of evidence and a grade of recommendation. Table 2.Table 1Clinical areas of Focus for the Use of ICG Dye (my work)1Identification of the intersegmental plane during sublobar resections1Intraoperative localization of pulmonary nodules1Detection of lung tumors based on the enhanced permeability and retention effect1Detection of bullous lesions1Sentinel lymph node mapping of lung tumors1Evaluation of gastric conduit perfusion in esophagectomy1Lymphatic mapping in esophageal surgical procedures Open table in a new tab Table 2Finalized Consensus Recommendations (Reference 1 – Elsevier) Open table in a new tab Recently, sublobar resections, particularly segmentectomy, have been demonstrated to be a safe and effective alternative to lobectomy in the treatment of early-stage non-small cell lung cancer (NSCLC), especially in those patients with small peripheral nodules or those with poor cardiopulmonary function.1 One of the difficulties with these procedures is the accurate identification of the intersegmental lung plane. The main method used to identify the affected segment is the inflation-deflation technique. With the deflation technique, the target segmental bronchus, arteries and veins are ligated and when the lungs are inflated, the target segment remains deflated. With the inflation technique, the target segment is inflated using jet ventilation or direct intubation. The major limitations of the inflation-deflation technique are the presence of collateral circulation, which can inflate the segment that should be deflated, and with the inflation method, the inflated segment may obstruct surgical exposure, especially in those patients with obstructive lung disease.8,12 ICG/NIR fluorescence has the ability to facilitate real-time identification of the intersegmental plane.12 ICG dye can either be injected into the vasculature, where it has a half-life of 4 minutes2 or for a longer duration, interstitial, peritumoral, or transbronchial injections can be performed.1,13 An interstitial injection of ICG dye will drain into the lymphatic channels and concentrate in lymph nodes before entering the thoracic duct, then the vascular system and finally into the biliary system where it is excreted.6 Liu et al compared inflation-deflation to systemic intravenous ICG/NIR fluorescence and reported that the use of fluorescence reduced operative time, improved the ability to visualize the intersegmental plane, reduced hospital length of stay and postoperative complications, including a reduction in thoracostomy tube drainage duration and prolonged air leak.14 There are two techniques to determine intersegmental margins; negative staining, where the ICG dye is injected intravenously after ligation of the artery of the affected segment, causing the entire lung except for that segment to fluoresce and positive staining, where the dye is injected directly into the bronchus and only the affected segment lights up. While both techniques are effective, the advantage of negative staining is that it is easier to perform but the disadvantage is the short half-life of the intravenous dye. Performing a positive stain requires knowledge of intrabronchial dye injection, but has a much longer half-life, which is more advantageous in complex segmentectomies.1 The recommendations for the use of ICG dye to help delineate intersegmental boundaries for sublobar lung resections was graded as a level of evidence of B with a class of IIa (B/IIa). The panel further recommended that the negative staining technique had a recommendation level of B/IIa while a positive staining technique had a recommendation level of C/IIb.1 Standard methods for pulmonary nodule localization include the preoperative use of micro-coils, hook wires, or computer tomography (CT) guided methylene blue injection.8,15 These techniques come with risks of pneumothorax, hemothorax, and poor visibility in the presence of anthracosis.1 In an attempt to reduce these risks, several studies have reported the use of CT guided percutaneous ICG injection followed by NIR video assisted thoracic surgery (VATS) for the safe and accurate localization of pulmonary nodules. These nodules were defined as those with a median size and distance from the pleural surface of ≤1 cm, and included primary tumors, metastases, and benign nodules.16-18 NIR-ICG dye has the advantages of ease of use, allows for durable visualization of the target nodule, and has less effects on the pathologic diagnosis while preventing the complications of wire migration, pneumothorax and hemothorax. The limitations of this technique include the inability to detect nodules in blind areas such as the mediastinal pleura, interlobular fissures, and scapular cover and the risk of ICG diffusion through the lung parenchyma.19 ICG dye can be administered using electromagnetic navigation bronchoscopy (ENB) for the intraoperative localization of small pulmonary nodules near the pleural surface.19-21 Since the expert panel concluded that there is a benefit of using ICG/NIR fluorescence imaging for the localization of pulmonary nodules that are up to 2 cm from the pleural surface, the consensus group graded this recommendation as B/IIa. ICG dye has been used to detect lung tumors based on its enhanced permeability and retention in tumor tissues, compared to normal tissue. This is due to the increased vasculature and dysfunctional lymphatics of tumor tissue that is not present with normal tissue.1 Other mechanisms for the accumulation of ICG dye in tumor cells include the amphiphilic properties of the dye and the high endocytic activity of tumor cells due to the disruption of their tight junctions.1 The first use of NIRS/ICG fluorescence for the detection of lung tumors was reported by Okusanya et al.22 They performed preoperative 1mm CT scans before and after ICG dye injection 24 hours prior to open thoracotomy with NIR. Intraoperative NIR visualized malignant nodules that were not detected on plain CT or by palpation.22 This technique could detect nodules as small as 0.2 cm and as deep as 1/3 cm from the pleural surface. Although many centers have reported similar findings,1 Kim et al, reported 2 false positives that were actually areas of obstructive pneumonitis, suggesting the inability of ICG dye to differentiate tumors from inflammation.23 The expert panel recognized the safety and feasibility of ICG fluorescence for the detection of lung tumors but that the lesions detected should be confirmed with CT and clinical judgement and thus assigned the use of this technique as B/IIb. VATS bullectomy is the mainstay treatment for spontaneous pneumothorax but there is a significant recurrence rate if there are inadequate margins or undetected bullous lesions present.8,15 Although some small studies have reported success with the use of ICG/NIR fluorescence, the heterogenicity of these lesions may make it difficult to differentiate all bullous lesions from normal tissues. Well-designed controlled studies are needed to confirm the usefulness of ICG/NIR fluorescence in the detection of bullous lesions. The expert panel graded the use of ICG fluorescence to detect bullous lesions as C/III, or no benefit. A sentinel lymph node (SLN) is the first lymph node involved in the lymphatic drainage of a tumor and if malignant, can predict lymphatic metastatic spread, affecting disease staging, treatment, and prognosis.8,9 In selected patients, SLN biopsy may be an alternative to a more extensive lymphadenectomy, with its risks of prolonged air leak, hemothorax, chylothorax, recurrent laryngeal nerve injury, and bronchial fistula.24 The typical agents used for SLN mapping include methylene blue and technetium 99 (99Tc). Methylene blue yields a low detection rate because of anthracotic lymph nodes in the lung and mediastinum and 99Tc administration is associated with radiation exposure and is complex to administer.8 Based on studies with patients having early-stage NSCLC1, the use of ICG/NIR fluorescence yielded an SLN detection rate of ≥ 80%, comparable with that of 99Tc, and a ≤ 2.9% false negative rate. Other advantages were the ability of ICG dye to be visualized despite the presence of anthracosis, the ease of use, and the avoidance of radiation exposure.25 ICG dye can be injected around the tumor or into the staple line after resection, or it can be mixed with 20 ml of blood or albumin and injected under CT or ENB guidance to identify SLNs 10-30 minutes after injection. The expert panel recognized the potential of ICG/NIR fluorescence for intraoperative SLN mapping to improve staging in patients with early-stage NSCLC and graded it as a B/IIa recommendation. A major cause of morbidity and mortality following esophagectomy is related to the reconstruction and anastomosis of the gastric conduit.26 ICG angiography is an emerging imaging modality that can facilitate real-time intraoperative assessment of gastric conduit perfusion during esophagectomy, with the goal of reducing the risk of anastomotic leaks. Slooter et al, performed a systematic review of 20 studies demonstrating the feasibility and safety of ICG angiography for the evaluation of gastric conduit perfusion prior to anastomotic reconstruction.27 They reported that the pooled incidence of anastomotic leakage and graft necrosis in those procedures guided by ICG angiography was 11% and 8 studies reported that ICG angiography was associated with a change in surgical procedure in 25%. A meta-analysis of 5 of these studies demonstrated that ICG angiography was associated with a reduction in anastomotic leakage and necrosis (odds ratio, 0.30; 95% CI, 0.14-0.63) compared with other methods.27 The expert panel concluded that the use of ICG angiography for the intraoperative assessment of gastric conduit perfusion and anastomotic sites during esophagectomy is reasonable to reduce the risk of anastomotic leak and thus graded it as B/IIa. With esophageal cancer, even a 3-field lymphadenectomy may miss malignant lymph nodes and occult nodal metastases,28 while carrying additional risks such as bleeding, recurrent laryngeal nerve injury, and devascularization, all which may impair healing.29 The use of radioisotope tracers to improve intraoperative nodal staging in esophageal cancer had been previously attempted, but could not be validated as a technique to accurately detect malignant lymph nodes.30 The use of ICG/NIR fluorescence imaging has been investigated by two groups. Hachey et al reported the first use of ICG/NIR fluorescence for the intraoperative assessment of regional lymph nodes during minimally invasive esophagectomy and reported that the use of ICG/NIR fluorescence identified positive regional lymph nodes in 6/10 patients.31 Park et al demonstrated the safety and feasibility of ICG fluorescence lymphatic mapping for the assessment of bilateral recurrent laryngeal nerve nodes in early-stage esophageal squamous cell carcinoma. The ICG stained lymph basins were identified in 25 out of 29 patients and 6 patients had nodal metastases.32 In this study, the negative predictive value in the detection of nodal metastases for the right and left recurrent laryngeal nerve chains were 100% and 98.2% respectively. This technique looks promising but due to the lack of high-level evidence, the expert group assigned a grade of C/IIb. These consensus recommendations reflect the safety and feasibility of ICG/NIR fluorescence in thoracic and esophageal surgery. It appears to be most promising in the identification of the intersegmental plane for sublobar resections, intraoperative localization of superficial pulmonary nodules, SLN mapping in lung tumors and in the assessment of gastric conduit perfusion. Where the use of ICG dye is more uncertain or of no value is in the determination of margins for bullous disease, in the inability to locate deep nodules due to its inability to penetrate lung tissue, and the inability to differentiate lung tumors from benign or inflammatory nodules. Further research from randomized controlled trials or multicenter prospective studies are needed to determine the role of ICG/NIR fluorescence for SLN mapping for NSCLC and for esophageal cancer as well as to standardize the routine use of ICG/NIR fluorescence imaging in thoracic and esophageal surgery. But as those who will administer ICG dye, it is important to know the indications for its use, the pharmacokinetics, especially with the different routes of administration, and the adverse effects, particularly in those patients with a history of a severe iodide allergy. As the use of ICG/NIR fluorescence increases, will be interesting to see whether the iodide in the formulation will result in an increased incidence of allergic reactions, necessitating pretreatment similar to radiographic contrast dyes. 1Ng CS, Ong BH, Chao YK, et al. Use of Indocyanine Green Fluorescence Imaging in Thoracic and Esophageal Surgery. Ann Thorac Surg. Apr 2023;115(4):1068-1076. doi:10.1016/j.athoracsur.2022.06.0612Administration FaD. Highlights of Prescribing Information: Information about Spy Agent Green. Accessed June 20, 2023, https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/211580s000lbl.pdf3Frangioni JV. New technologies for human cancer imaging. J Clin Oncol. Aug 20 2008;26(24):4012-21. doi:10.1200/JCO.2007.14.30654Chu W, Chennamsetty A, Toroussian R, Lau C. Anaphylactic Shock After Intravenous Administration of Indocyanine Green During Robotic Partial Nephrectomy. Urol Case Rep. May 2017;12:37-38. doi:10.1016/j.eucr.2017.02.0065Meira J, Marques ML, Falcao-Reis F, Rebelo Gomes E, Carneiro A. Immediate Reactions to Fluorescein and Indocyanine Green in Retinal Angiography: Review of Literature and Proposal for Patient's Evaluation. Clin Ophthalmol. 2020;14:171-178. doi:10.2147/OPTH.S2348586Nimura H, Narimiya N, Mitsumori N, Yamazaki Y, Yanaga K, Urashima M. Infrared ray electronic endoscopy combined with indocyanine green injection for detection of sentinel nodes of patients with gastric cancer. Br J Surg. May 2004;91(5):575-9. doi:10.1002/bjs.44707Ito N, Fukuta M, Tokushima T, Nakai K, Ohgi S. Sentinel node navigation surgery using indocyanine green in patients with lung cancer. 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J Thorac Cardiovasc Surg. Aug 2016;152(2):546-54. doi:10.1016/j.jtcvs.2016.04.02532Park SY, Suh JW, Kim DJ, et al. Near-Infrared Lymphatic Mapping of the Recurrent Laryngeal Nerve Nodes in T1 Esophageal Cancer. Ann Thorac Surg. Jun 2018;105(6):1613-1620. doi:10.1016/j.athoracsur.2018.01.08333Ng CS, Ong BH, Chao YK, et al. Use of Indocyanine Green Fluorescence Imaging in Thoracic and Esophageal Surgery. Ann Thorac Surg. Apr 2023;115(4):1068-1076. doi:10.1016/j.athoracsur.2022.06.061 The author whose name is listed immediately below certifies that they have NO affiliations with or involvement in any organization or entity with any financial interest (such as honoraria; educational grants; participation in speakers’ bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements), or non-financial interest (such as personal or professional relationships, affiliations, knowledge or beliefs) in the subject matter or materials discussed in this manuscript.