Thoracic Duct Lymphography by Near-Infrared Indocyanine Green Fluorescence imaging in Thoracic Surgery. A Review

Abstract

Near-infrared (NIR) fluorescence imaging with indocyanine green dye (ICG) is an emerging technology in detecting the anatomy of the thoracic duct; hence, it can be useful for the identification of the thoracic duct in real time and prevention of its injury during thoracic surgery. It helps to localize thoracic duct injury, identifying chyle leaks in difficult, recurrent, and refractory cases. This review paper provides insights regarding the current applications, advantages, and potential developments of NIR fluorescence imaging with ICG in recognizing thoracic duct during thoracic surgery.

Introduction

Chylothorax after thoracic surgeries is an infrequent postoperative complication. Incidence of chylothorax ranges from 1.4% after transthoracic esophageal resection to 2.4% after transhiatal esophagectomy [1]. The incidence of chyle leak after prophylactic ligation of the thoracic duct (TD) after transthoracic Ivor Lewis esophagectomy is reported to be 1.9% [2]. It occurs in approximately 1–2% after pulmonary resection and mediastinal lymph node dissection (MLND) [3]. Postoperative chyle leak is a potentially morbid complication that significantly increases hospital stay, with high in-hospital mortality [2].

The thoracic duct is the biggest lymphatic vessel in the human body that conveys chyle and 75% of the body’s total lymph to the bloodstream [4]. Measuring about 40 cm long, it extends from the second lumbar vertebra to the root of the neck. Identification of the TD presents significant challenges during surgery. Although several techniques are present for localization and identification of thoracic duct during thoracic surgeries, NIR fluorescence imaging with ICG is a novel emerging promising, simple, easy, and reproducible technology. This review updates the benefits, current usage, and future developments of NIR fluorescence imaging with ICG to identify TD in thoracic surgeries.

Consequences of Chyle Leak

The consequence of chyle leak includes fluid loss with hypovolaemia, loss of proteins, cholesterol, lipids, triglycerides, fat-soluble vitamins, and electrolytes, resulting in malnutrition immunosuppression increasing the risk of respiratory failure and infectious complications and sepsis [2, 5]. It delays oral intake, causes hypovolemia, increases hospital stay, and negatively affects overall survival, and causes loss and depletion of immunoglobulins and T lymphocytes, leading to impairment of cell-mediated immunity and humoral responses [3, 6]. An early surgery with ligation of the thoracic duct shortens recovery time.

Conservative Management

Non-operative measures, such as the complete cessation of oral intake and pleurodesis, are effective treatment methods for low output chylothorax [3, 7]. Nevertheless, for high-output chylous leaks, conservative treatment has met with a high failure rate, thereby necessitating an early surgical intervention. Also, there is a wide disparity in the success rate of conservative treatment varying from 3 to 90%, depending on the underlying cause of the disease [8].

Mass Ligation of the Thoracic Duct

Surgical intervention, mostly mass ligation of the TD through a video-assisted thoracoscopic surgery (VATS) approach, remains an essential curative procedure for postoperative chylothorax. However, prophylactic thoracic duct mass approach though a safe procedure [9] is not universally accepted and required in all cases, and the long-term consequences of thoracic duct blockage remain unknown [10]. Besides, the procedure is inherently traumatic and could potentially cause chyle leakage.

Detection and Identification of Thoracic Duct

Several methods to visualize chylous leakage have been reported. Lymphoscintigraphy using technetium-99 filtered sulfur colloid combined with single-photon emission computed tomography (SPECT-CT) was described as a very effective imaging approach for identifying the site of a leak in postoperative chylothorax [11, 12]. Magnetic resonance-thoracic ductography provided a three-dimensional reconstruction with a good view of the TD in 88% of the cases in a cohort of 78 patients evaluated [13]. However, all these methods do not provide real-time imaging and therefore are not available for the surgeon in operative theatre and lack acute precision in localizing the chylous leak site. Preoperative oral administration of milk heavy cream or olive oil was found to facilitate the thoracic duct identification and decrease the risk of iatrogenic injury to the thoracic duct during thoracoscopic esophagectomy [14–16]. However, the contrast provided here is low with poor reproducibility [16].

NIR-ICG technique may be a great clinical tool for intraoperative assessment of unidentified thoracic duct injury providing a precise kit for identification of a chylous leakage site with great sensitivity and specificity.

Introduction of ICG

ICG is a small hydrophilic tricarbocyanine dye exhibiting fluorescence when activated by NIR light of wavelength of 760 to 780 nm delivered by a dedicated near-infrared optical system. It generates fluorescence emission peak at 800 to 850-nm wavelength [17]. The inherent emission of light in the NIR spectral range provides ICG, virtually no interfering background autofluorescence originating from the main blood components (hemoglobin and water). The resultant depth of penetration in tissue that can be utilized to identify NIR fluorescence varies from 0.5 to 1 cm. Post intravenous injection, ICG hitches to plasma proteins making the agent confined within the intravascular compartment.

This hydrodynamic molecule possesses a tiny diameter, which allows it to negotiate quickly through the lymphatics, lymph nodes, and blood vessels. Post submucosal injection, ICG disperses in lymph, where it binds to lipoproteins and is drained via lymphatic pathways and nodes. Given these characteristics, ICG can be used as a perfect marker for sentinel lymph node mapping. The liver excretes the ICG protein complexes in bile. The ICG fluorescence of the bile can be utilized for real-time visualization of the extrahepatic bile ducts during NIR fluorescence cholangiography.

The safety spectrum is well established, with a low risk of adverse effects. The dye incorporates sodium iodide in a small fraction and should be used with caution in patients who are allergic to iodides and is contraindicated in patients with hepatic insufficiency. The availability of NIR equipment allows fluorescent images to be superimposed onto video images in real time, allowing ICG to be used in many surgical applications, including assessment of flap vascularity, evaluation of anastomotic perfusion, recognition of anatomical structures (such as blood vessels, biliary vessels, and lymphatic vessels), and detection of lymphatic drainage in oncologic surgery. In thoracic surgery, NIR-ICG fluorescence imaging can be utilized to identify lung nodules, intersegmental plane, and conduit vascular evaluation during esophagectomy. Ogata et al. performed lymphography successfully using near-infrared indocyanine green fluorescence labeling in lymphaticovenular anastomoses in patients with lymphedema [18].

ICG in Animal Models

Ashitate et al. reported that NIR fluorescence imaging with ICG could provide real-time imaging of thoracic duct anatomy in animal models [19]. Five minutes after injection of ICG into the lower limbs of pigs, real-time thoracic duct fluorescent imaging was obtained, sustaining for at least 1 h post-injection. Besides, an injury model demonstrated that it was possible to identify chyle leaks without loss of accuracy.

Steffers et al. successfully achieved thoracoscopic thoracic duct (TD) ligation in 15 dogs by identifying thoracic duct using intraoperative near-infrared fluorescence lymphography by indocyanine green (ICG) via popliteal lymph nodal injection of ICG. In contrast, preoperative CT lymphography identified TD in only 13 dogs [20].

Kamijo et al. compared CT lymphography and near-infrared fluorescent thoracoscopy to identify thoracic duct in cats [21]. Two clinically healthy cats were utilized for the near-infrared fluorescent thoracoscopy and three for the CT lymphography. Dye was injected in subcutaneous tissue perianally and massaged for 5 min in both the techniques. Four minutes after the subcutaneous injection of indocyanine green (1.8 ml/kg) by utilizing a video endoscopic system (Karl Storz Endoskope Japan, Tokyo, Japan), thoracic duct was identified at thoracoscopy running alongside the aorta.

ICG Identification of Thoracic Duct/ Chyle Leak in Adults

Kamiya et al. first described the utility of indocyanine green (ICG) lymphography in a 62-year gentleman diagnosed with chylothorax after esophageal resection for esophageal cancer. By injecting 1.5 ml of ICG subcutaneously at the bilateral inguinal region, fluorescence images of the lymph flow in the thoracic cavity were obtained using a near-infrared camera system [22].

Kaburagi et al. reported a chylothorax in a 65-year-old man who underwent radical esophagectomy for adenocarcinoma of the esophagogastric junction. Ligation and occlusion of the remnant thoracic duct were confirmed with the aid of intraoperative indocyanine green (ICG) fluorescence lymphography [23].

Matsutani et al. reported a case report of refractory chylothorax in a 70-year-old man who, after radical esophagectomy for advanced esophageal cancer, received conservative therapy and a session of unsuccessful thoracoscopy-assisted ligation of the TD. Then, the authors performed successful transabdominal ligation of the thoracic duct at the level of the right crus of the diaphragm under the guidance of fluorescence navigation with indocyanine green (ICG) [24].

Bassi et al. described the usage of intraoperative use of indocyanine green to visualize and ligate the thoracic duct (TD) in a female patient of 70 years with a history of recurrent idiopathic chylothorax where the TD course was elusive, and the leak was unspotted despite fatty meal administration [25]. Chronic inflammation and previous surgery produced tenacious adhesions that made the identification of the TD challenging. Bilateral inguinal injection of 0.2 mg/kg indocyanine green, combined with albumin, provides an effectual and long-lasting visualization of the TD course and to detect the leak.

Carlo Alberto et al. reported a case of high output chylous fistula following McKeown esophagectomy for a locally advanced esophageal carcinoma not responding to conservative treatment. Successful identification and selective ligation of TD were performed under ICG fluorescence guidance 30 min after injecting 1 ml of ICG in bilateral inguinal nodes [26].

Vecchiato et al. recently reported successful identification of thoracic duct (TD) in real time by using NIR-ICG fluorescence in a series of 19 patients undergoing minimally invasive esophagectomy in the prone position. Before thoracoscopy, a 0.5 mg/kg solution of indocyanine green (ICG) was injected percutaneously in the inguinal nodes.TD anatomy was identified and delineated after a mean of 52.7 min from the time of injection. The TD was cut for oncological radicality in two patients, and in rest, it was successfully ligated under the ICG guidance [27].

Thoracic Duct Identification in Neck

The thoracic duct recognition and preservation during the lateral neck dissection are often clinically challenging, as the duct is thin-walled, 3- to 5-mm size, and often associated with a variant course. There have been no intraoperative diagnostic tests that can help to identify or repair thoracic duct injury and prevent the morbidity of a chylous fistula.

Chakedis et al. described the successful identification of thoracic duct in five of six patients (83.3%) undergoing lateral modified radical neck dissection for thyroid cancer and melanoma [28]. During the dissection, the left foot was injected with 1–2 ml of ICG, and a handheld NIR probe was held at the angle of the mandible to perform imaging of the space below the clavicle. No injury to the thoracic duct was identified, and there were no chylous fistulas on follow-up. It was a simple technique and added 5–10 min to the operation. The authors hypothesized that one patient in whom the TD was not visualized was due to duct obliteration from the previous dissection or might be related to the injection timing.

Bibas et al. reported a case of chyle leak in a 55-year male patient following radical neck dissection for a recurrent oropharyngeal carcinoma treated by definitive chemoradiation. Conservative management failed, and operative management was sought [29]. Under sonographic guidance, 2 ml of 0.5% ICG solution was injected in bilaterally inguinal lymph nodes. Approximately 5 min after the local massage, the thoracic duct was visualized in green fluorescence in thorax by thoracoscopic surgery and was successfully clipped. The patient had a good recovery with no recurrence of chylous fistula in the follow-up period.

Thoracic Duct Identification After Lung Surgery

Yang et al. described the utility of ICG in 4 patients diagnosed with chylothorax after pulmonary resection and mediastinal nodal dissection [30]. ICG dye at a dosage of 0.2 mg/kg of ICG was injected subcutaneously into the bilateral inguinal region approximately 30 min before surgery to detect the site of the leak. Intraoperative fluorescence imaging using D-light near-infrared thoracoscope was used for providing real-time fluorescence lymphography. The chylous fistulas and the thoracic duct were successfully identified (At the site of 4R lymph node behind the azygos vein in 3 cases and prophylactic ligation of the thoracic duct in one) and ligated, resulting in resolution of chylothorax in all.

Steps to Perform ICG Fluorescence TD Lymphography

In chest: Below are the details of ICG TD lymphography as described by Vecchiato et al. [27]. Indocyanine green is reconstituted with 10 ml of sterile saline in a commercial vial containing 25 mg of powder to make a final concentration of 2.5 mg/ml; 0.5 mg/kg of ICG is injected percutaneously bilaterally in the superficial inguinal nodes under sonographic guidance. Then, patient is turned to prone position for thoracoscopic mobilization of esophagus, pneumothorax is established, ports are placed. The inferior pulmonary ligament and the mediastinal pleura over esophagus are divided. The azygous vein is dissected, and its arch is divided by a vascular stapler or ligaclips and thoracic duct is exposed in its entire length. NIR-ICG camera is switched on, and thoracic duct is demonstrated in ICG fluorescence.

In neck: Below are the details of ICG TD lymphography as described by Chakedis et al. [28]. Indocyanine green is reconstituted with 10 ml of sterile saline in a commercial vial containing 25 mg of powder to make a final concentration of 2.5 mg/ml. A 25-gauge insulin type needle mounted on a 5-ml syringe is employed for injecting 1–2 ml (2.5–5 mg) ICG. A left lateral dissection (LND) is performed, including levels 2, 3, and 4 routinely, with dissection of levels 5 and 6 when clinically indicated. Approximately 15 min prior to dissection of level 4, ICG is injected subcutaneously in the dorsum of the left foot just below the ankle in an area of normal skin. Imaging is performed periodically throughout dissection of level 4 as dissection of the subclavian vein and junction with the internal jugular vein are continued. The time from ICG injection to imaging of the TD as well as the total imaging time is recorded. After the dissection is completed, specimen is removed, and the TD is identified, final imaging is performed. If the TD is not identified within 30 min after injection, the ICG is re-dosed with another 1–2 ml.

Dosage and site of administration and system used (Tables 1 and 2)

Table 1.

Showing various studies and details of ICG thoracic lymphography

Authors	Year	n	Age/sex	Condition	Prophylactic/therapeutic	Dose	Site of injection	Appearance time
Kamiya et al. [22]	2009	1	62/M	Esophageal cancer, post-CTRT	Postoperative chylothorax	1.5 mg	B/L groin (s/c)	14 min
Kaburgi et al. [23]	2013	1	65/M	GEJ cancer upfront	Postoperative chylothorax	1 mg	Small bowel mesentery	NA
Matsutani et al. [24]	2014	1	70/M	Esophageal cancer surgery post NACT	Refractory postoperative chylothorax	0.75 mg	B/L groin (s/c)	10 min
Yang et al. [30]	2017	4	61–76 (2 F, 2 M)	Lung cancer surgery, MLND (upfront)	Postoperative chylothorax	0.2 mg/kg	B/L groin (s/c)	30 min
Chakedis [28]	2018	6	27–76 (4 M, 2 F)	Neck dissection	Prophylactic/real-time identification	2.5 to 5 mg	Dorsum of foot	15–90 min
Bibas et al. [29]	2019	1	55/M	Recurrent oro-pharyngeal cancer, post-ND	Postoperative chylothorax	1 mg	Groin nodes bilaterally	5 min
Carlo Alberto et al. [26]	2019	1	66 M	Esophageal cancer post CTRT	Postoperative chylothorax	1 ml	Groin nodes bilaterally	30 min
Bassi et al. [25]	2020	1	70 F	Recurrent episodes of chylothorax	Recurrent idiopathic chylothorax	0.2 mg/kg combined with albumin	Groin bilaterally	30 min
Vecchiato et al. [27]	2020	19	51–81 (4 F, 15 M)	Esophageal cancer post CTRT	Prophylactic/real-time identification	0.5 mg/kg	Groin nodes	52.7 min

n number, M male, F female, CTRT chemoradiation, GEJ gastro-esophageal junction, TEF tracheo-esophageal fistula, NACT neoadjuvant chemotherapy, MLND mediastinal lymph nodal dissection, ND nodal dissection, s/c subcutaneously

Table 2.

Shows different studies, dose of ICG used, and system employed

Author	Year	Study design	System	Company
Kamiya et al. [22]	2009	Case report	Near-infrared PDE camera system	Hamamatsu Photonics, Japan
Kaburagi et al. [23]	2011	Case report	Near-infrared PDE camera system	Hamamatsu Photonics, Japan
Matsutani et al. [24]	2014	Case report	Near-infrared PDE camera system	Hamamatsu Photonics, Japan
Yang et al. [30]	2017	Case report	D-light P NIR thoracoscope	KARL STORZ
Chakedis et al. [28]	2018	Case series	PDE-neo 2 imager	Hamamatsu Photonics, Japan
Bibas et al. [29]	2019	Case report	PINPOINT endoscopic fluorescence camera system	Strykers
Vecchiato et al. [27]	2020	Case series	OPAL1 camera system	KARL STORZ
Bassi et al. [25]	2020	Case report	D-light P NIR thoracoscope	KARL STORZ

Site: Groin nodes were utilized by Carlo Alberto et al., Vecchiato et al., Bibas et al. [26, 27, 29]. All have utilized sonographic guidance for visualizing and injecting dye into groin nodes. This has produced the most consistent results with TD successfully identified and seen in all cases, even after repeated failed surgeries. Vecchiato et al. identified and delineated TD anatomy clearly after a mean of 52.7 min from the time of injection [27], Bibas et al. after 5 min [29], and Carlo Alberto after 30 min [26]. Bilateral groin subcutaneous injection was employed by Kamiya, Matsutani, and Yang et al. [22, 24, 30]. In contrast the dorsum of foot injection were employed by Chakedis et al. [28], whereas Kaburgi et al. [23] successfully injected into the mesentery of the small bowel (Table 1).

The dose has been variedly used with no standardization. In adults, the dose ranged from 0.2 mg/kg body weight to 5 mg. Some have used an extra dose if the TD was not visualized clearly after the initial dose. After a few minutes, a new measurement is also possible. Table 2 shows the different NIR systems used.

Future Studies

FLOTOR study is an ongoing non-randomized study assessing the technique of using indocyanine green as a fluorescent dye to highlight the thoracic duct during esophagectomy with the eventual aim of developing its routine use to prevent thoracic duct injuries (NCT03292757) [31]. Another study is studying indocyanine green lymphangiography usage in identifying thoracic duct during neck surgery (NCT03532581) [32].

Conclusions

ICG TD lymphography is a novel technique that can be successfully used to identify chyle leaks following thoracic surgery and esophagectomy. The procedure provides good localization and identification of the site of the leak and enables its ligation and also confirms that repair is complete. NIR- ICG fluorescence imaging is an easy-to-use tool for real-time identification of thoracic duct during thoracic surgeries thereby decreasing thoracic duct injury. ICG thoracic duct lymphography is a convenient tool for the treatment of symptomatic chyle leak and should be considered in the diagnostic and treatment algorithm, especially when dissection is difficult, as in re-operative and post radiated cases.

The technique allows a safe dissection, giving constant anatomic feedback to the surgeon, and can be easily reproduced. Furthermore, it allows the preservation of TD without injury during surgery by visualizing thoracic duct in real time. Further work is required to optimize the procedure so it can be incorporated easily into routine practice.

Declarations

Conflict of Interest

The authors declare no competing interests.