Routine Intraoperative Fluorescence Lymphography Using Indocyanine Green During Esophagectomy: A Feasibility Study

Summary

This manuscript describes intraoperative fluorescence lymphography using indocyanine green during esophagectomy to visualize the thoracic duct (collaterals).

Abstract

For resectable esophageal cancer, major oncological centers recommend a transthoracic esophagectomy with an en-bloc mediastinal lymphadenectomy that includes resection of the thoracic duct. However, thoracic duct resection may increase the risk of postoperative chyle leakage because of injury to the main duct, collaterals, or side branches. Intraoperative, real-time fluorescence lymphography using indocyanine green (ICG) has emerged as a promising technique to enhance visualization of the thoracic duct, side branches, and collaterals during esophagectomy. This study aims to investigate the feasibility of routine fluorescence lymphography with ICG during esophagectomy for cancer to accurately visualize the thoracic duct and its collaterals.

For fluorescence lymphography, 2 mL of ICG solution (2.5 mg ICG/mL) is administered bilaterally in the inguinal lymph nodes, before the thoracic phase of esophagectomy, or into the small bowel mesenteric root shortly before abdominal closure. A near-infrared (NIR) camera is used to assess fluorescence lymphography. Under fluorescence visualization, the thoracic duct is double-clipped distally at the level of the arch of the azygos vein and clipped proximally 4-5 cm above the level of the diaphragm and transected en bloc with the esophagectomy specimen. Additional clipping or suture ligation is performed in case of chyle leakage of the main duct or any remaining collateral ducts/side branches.

Fluorescence lymphography was performed in 20 patients undergoing esophagectomy for esophageal cancer. The thoracic duct was successfully visualized in 18 patients (90%). In 67% of patients in whom successful fluorescence lymphography was performed, this led to a change of management, for example, the placement of extra clips. Fluorescence lymphography with ICG helps visualize the thoracic duct and its collaterals and identify chyle leakage intraoperatively, which often results in a change in operative management. Further development of the study is needed to refine the technique and confirm its application in preventing postoperative chyle leakage.

Introduction

Curative treatment for resectable esophageal cancer generally includes neoadjuvant chemotherapy or chemoradiotherapy, followed by esophagectomy¹. A frequently applied neoadjuvant treatment strategy consists of five cycles of carboplatin and paclitaxel with concurrent radiotherapy (41.4 Gy in 23 fractions), followed by esophagectomy after a 6-10 week interval. A radical transthoracic esophagectomy in our center routinely encompasses an en-bloc resection of the thoracic duct for adequate mediastinal lymphadenectomy, justified by the anatomical location of the duct between the azygos vein and descending thoracic aorta, which has been shown to harbor both lymph nodes as well as lymph node metastases^2,3,4.

The function of the thoracic duct includes transporting lymph from the left and right sides of the body below the diaphragm back into the circulation, via the junction of the left subclavian and internal jugular vein, the subclavian vein, or the internal jugular vein^5,6. One of the functions of the lymphatic system is to transport chyle (lymphatic fluid containing chylomicrons from the gastrointestinal tract, which carry proteins, white blood cells (mainly lymphocytes), fat-soluble vitamins, glucose, and digestive products) from the digestive tract to the circulatory system.

Large variation between patients exists in the anatomy of the thoracic duct. The frequency of physiologic variants and the presence of several side branches and collaterals render the duct prone to inadvertent injury during surgery, possibly leading to chyle leakage postoperatively⁷. The thoracic duct is vulnerable to trauma during esophagectomy in general, and thoracic duct resection has historically been associated with a higher risk of postoperative chyle leakage⁸.Chyle leakage is a frequent complication after esophagectomy, with incidences in literature widely ranging from 2% to 21%, due to the use of different definitions as well as the large variety in surgical techniques and extent of lymphadenectomy^9,10,11,12. The occurrence of chyle leakage is associated with unpleasant dietary restrictions, prolonged thoracic drainage, re-interventions, and prolonged hospital admission^11,12. Recently, chyle leakage was also found to be associated with a decreased overall survival, presumably as a result of hyponatremia, hyperproteinemia, impaired nutrition, and decreased immune function¹³.

To achieve maximum oncological safety with adequate mediastinal lymphadenectomy and prevent inadvertent injury leading to postoperative chyle leakage, sufficient vigilance during resection of the thoracic duct and its collateral branches is vital. Intraoperative detection of chyle leakage may be challenging, as patients undergoing esophagectomy are starved, leading to low chyle flow and a smaller thoracic duct diameter. Therefore, chyle leakage is usually detected on day 2 or 3 postoperatively, when enteral feeding is intensified. Indocyanine green (ICG) is a nontoxic dye that binds strongly to proteins that are transported through the lymphatic system and can be made visible with near-infrared light. This provides real-time duct enhancement with fluorescence-guided control of the anatomy and intraoperative detection of any injury, which can be managed directly. Intraoperative improved recognition of the thoracic duct, side branches, and collaterals, as well as detection of possible chyle leakage by real-time intraoperative fluorescence lymphography using ICG, may result in reduced postoperative chyle leakage rates¹⁴.

Thoracic duct identification with ICG has previously been found feasible, effective, and non-time demanding during re-operations for chyle leakage after thoracoscopic lung and esophageal surgery, during cervical lymphadenectomy for thyroid cancer or melanoma, and during minimally invasive esophagectomy without routine thoracic duct resection for squamous cell carcinoma^15,16,17,18. Whether its routine use during esophagectomy with standard resection of the thoracic duct is successful is yet unknown. Therefore, in this pilot study, the primary aim is to investigate the feasibility of routine intraoperative fluorescence lymphography during esophagectomy with the routine resection of the thoracic duct to visualize the thoracic duct, its collaterals, and anatomical variations. Second, it will be investigated whether this visualization leads to a change in operative management (e.g., additional clipping as a subsequent treatment for intraoperative leakage). The ultimate aim is to reduce the incidence of postoperative chyle leakage after esophagectomy and its clinical implications (prolonged chest drainage, extended hospitalization, the need for additional interventions, dietary restrictions, and reduced overall survival).

Protocol

All patients provided written informed consent for the use of their clinical data, in accordance with the institutional Medical Research Human Research Ethics Committee. The protocol is fully written in the context of total minimally invasive esophagectomy. The sequence of protocol steps depends on the procedure: Ivor Lewis (two-stage esophagectomy; abdominal phase first, followed by thoracic phase) versus McKeown esophagectomy (three-stage esophagectomy; thoracic phase first, followed by abdominal phase and cervical phase). Primarily, the protocol is written in the context of Ivor Lewis esophagectomy; in the NOTE following step 11, the sequence and additional steps for McKeown esophagectomy are described. In Ivor Lewis esophagectomy, ICG is either administered at the end of the abdominal phase at the base of the small bowel mesentery, or ultrasound guided bilaterally in inguinal lymph nodes before initiating the thoracic phase. In McKeown esophagectomy, ICG is administered ultrasound guided bilaterally in the inguinal lymph nodes at the beginning of surgery.

1. Patients

1. To be eligible for this study, ensure that a patient meets all the following inclusion criteria: age of 18 years and older; undergoing total minimally invasive or robotic-assisted Ivor Lewis or McKeown esophagectomy; for resectable (cT1-4a, N0-3, M0) esophageal or gastro-esophageal junction carcinoma.
2. Set the following exclusion criteria: allergy to ICG, iodide, or sodium iodide; hyperthyroidism or benign thyroid tumor; thyroid examination using radioactive iodide <1 week; prior history of inguinal lymphadenectomy.

2. Anesthesia protocol

1. Preoperatively, bring the patient under general and regional anesthesia using either a thoracic epidural (steps 2.1.1-2.1.5) or paravertebral catheter (steps 2.1.6-2.1.10).
   1. Perform epidural catheter placement at an intervertebral level between T5 and T8 using the loss-of-resistance technique.
   2. Within the first hour after induction, administer 5-10 mL of bupivacaine 0.25% bolus epidurally.
   3. Thereafter, start continuous epidural analgesia with bupivacaine 0.125% and sufentanil 0.5 µg/mL and titrate to the patient's comfort.
   4. Provide escape medication according to the local institutional protocol.
   5. Remove the epidural catheter on the third postoperative day.
   6. Locate the paravertebral space on both sides of the spinal canal and place the catheter in the right subpleural space at the level of T4-5 under direct thoracoscopic vision with an 18-19 G Tuohy needle.
   7. Administer a bolus of 20 mL of bupivacaine 0.125% at the beginning of thoracoscopy.
   8. Continue paravertebral analgesia on bupivacaine 0.125% 8-12 mL/h depending on weight, and titrate to the patient's comfort.
   9. Provide additionally patient-controlled intravenous analgesia according to the local protocol of the center.
   10. Remove the paravertebral catheter on the third postoperative day.
2. Intubate the patient with a double-lumen endobronchial tube (Ivor Lewis) or a single-lumen tube (Ivor Lewis) or without (McKeown) a bronchial blocker.

3. Antibiotics protocol

1. Administer prophylactic antibiotics 1 h before start of surgery (1,000 mg of cefazolin and 500 mg of metronidazole intravenous; repeat after 6 h of surgery).

4. Abdominal phase of esophagectomy

1. Position the patient in the supine position. Disinfect and sterile expose.
2. Insert a 12 mm trocar and camera supraumbilically.
3. Create pneumoperitoneum with a maximum pressure of 10-12 mmHg CO₂.
4. Insert one 10 mm and two 5 mm trocars and a Nathanson laparoscopic liver retractor.
5. Open the hepatogastric ligament. Mobilize the esophagogastric junction in the hiatus, including the left and right paracardial lymph node stations.
6. Perform lymphadenectomy through the hepatogastric ligament, along the hepatoduodenal ligament, the common hepatic artery, the splenic artery, the left gastric artery, and around the celiac trunk, with ligation of the vena coronaria and left gastric artery.
7. Mobilize the greater curvature and preserve the right gastroepiploic artery and vein.
8. Ligate the left gastroepiploic artery and vein and transect the short gastric arteries. Skeletonize the lesser curvature at the level of the angulus and preserve the right gastric artery.
9. Create a gastric conduit by stapling longitudinally from the angulus towards the fundus, to create a 3-4 cm wide gastric tube. Oversew the staple lines with interrupted absorbable braided 3-0 sutures.
10. Create a feeding jejunostomy 20 cm distal to Treitz. Secure the jejunostomy to the abdominal wall with a pouch suture using absorbable braided 3-0 sutures and to the skin with non-absorbable braided sutures. Place two antirotation sutures.
11. Test the gastric tube to reveal no leakage and good patency.
    NOTE: In case of Ivor Lewis esophagectomy with mesenteric root administration, the protocol is continued with sections 5 and 6; section 7 is skipped. In case of Ivor Lewis esophagectomy with inguinal lymph node ICG administration, section 5 is skipped and the protocol is continued with sections 6 and 7.

5. Mesenteric root administration of ICG

1. Dissolve 25 mg of ICG in 10 mL of sterile water, obtaining a solution of 2.5 mg of ICG per mL.
2. Inject 2 mL (5 mg) into the mesenteric root at the level of the planned jejunostomy site.

6. End of abdominal phase

1. Remove the trocars and liver retractor under direct visualization.
2. In case of Ivor Lewis esophagectomy, close wounds: fascia with absorbable braided 0 sutures and skin with intracutaneously synthetic absorbable monofilament 4-0 sutures.

7. Inguinal administration of ICG

1. Dissolve 25 mg of ICG in 10 mL of sterile water, obtaining a solution of 2.5 mg ICG/mL. Divide this into two 2 mL syringes, obtaining two 2 mL syringes containing 5 mg of ICG each.
2. Use ultrasound as a guide to locate a superficial inguinal lymph node bilaterally. Administer a bolus of 2 mL of ICG solution (2.5 mg ICG/mL, 5 mg in total) percutaneously into a right inguinal lymph node and a left inguinal superficial lymph node under ultrasound guidance.

8. Thoracic phase of esophagectomy

1. Turn the patient to the prone position. Disinfect and sterile expose.
2. Open introduction at the level of the posterior axillary line, that is, at the tip of the scapula, with a 12 mm trocar and camera. Create a right-sided pneumothorax with a maximum CO₂ pressure of 6-8 mmHg.
3. Insert two 12 mm trocars and one 5 mm trocar along the scapula and one more distally (intercostal space 8 or 9).
4. Dissect the right pulmonary ligament. Expose the pericardium, from the right pulmonary vein to the left pulmonary vein.
5. Dissect the hiatus. Perform subcarinal lymph node dissection.
6. Isolate and ligate the arc of the azygos vein using a vascular stapler.
7. Perform a lower paratracheal lymph node dissection on the left and right sides and in the aortopulmonary window.

9. Thoracic duct resection

1. Use the near-infrared (NIR) camera to assess fluorescence lymphography. Evaluate fluorescent enhancement of the thoracic duct through the pleura.
2. Open the mediastinal pleura along the azygos vein. Isolate the thoracic duct circumferentially distally, at the level of the arch of the azygos vein.
3. Under fluorescence visualization, double clip the thoracic duct at the level of the arch of the azygos vein (Ivor Lewis) or at the level of the thoracic inlet (McKeown) with two metal clips. Transect the thoracic duct between the clips.
4. Under fluorescence visualization, dissect the thoracic duct en bloc with the esophagectomy specimen, from the tissue between the azygos vein and the thoracic descending aorta towards proximally, until several centimeters above the level of the diaphragm.
5. Under fluorescence visualization, clip the thoracic duct 4-5 cm above the level of the diaphragm with a metal clip. Transect the thoracic duct between the clips.
   NOTE: The thoracic duct is now dissected en bloc with the esophagectomy specimen, and the descending aorta is completely exposed.
6. Both 10 and 30 min after completing thoracic duct resection, inspect the operating area for chyle leakage. If chyle leakage is identified, clip the leaking duct/collateral vessels as well.

10. Anastomosis

1. Pull the gastric tube up into the chest.
2. Transect the esophagus at the level of the arch of the azygos vein. Luxate the specimen in the wound.
3. Completely dissect the specimen from the gastric conduit with the linear stapler.
4. Insert the anvil (25 or 29 mm) in the esophageal stump with a purse string suture. Measure the length of the gastric conduit.
5. Insert the stapler in the gastric conduit and perforate the gastric conduit wall with the stapler tip. Align the stapler parts and close the stapler. Fire the stapler and check the doughnuts. Close the gastric conduit with the linear stapler.
6. Mark the specimen. Bring the specimen to the pathologist.
7. Oversew the stapler crossings with interrupted resorbable braided suture 3-0.
8. Fixate the tip of the gastric conduit below the pleural flap. Perform omentoplasty.

11. End of thoracoscopy

1. At the end of thoracoscopy, place a single silicone 27 French chest tube in the right pleural cavity for drainage of remaining CO₂ and a Jackson-Pratt tube for postoperative fluid drainage.
2. Remove trocars under direct visualization.
3. Close wounds: fascia with absorbable braided 0 sutures and skin with intracutaneously synthetic absorbable monofilament 4-0 sutures.
   NOTE: In case of McKeown esophagectomy, after section 3, the protocol is continued with sections 7, 8, and 9. During the thoracic phase, additional lymphadenectomy of the higher paratracheal lymph node stations is performed. Thereafter, the protocol is continued with sections 11, 4, and 6. After the abdominal phase, the protocol is continued with section 12, which is only applicable for McKeown esophagectomy, the cervical incision for anastomosis. Sections 5 and 10 of the Ivor Lewis protocol are not applicable to McKeown esophagectomy.

12. Cervical incision for anastomosis (in case of McKeown esophagectomy)

1. Perform left cervical incision. Mobilize the cervical esophagus, considering the location of the recurrent laryngeal nerves on both sides.
2. Divide the esophagus. Perform a small laparotomy. Insert wound protector. Luxate the specimen in the wound.
3. Completely dissect the specimen from the gastric conduit with the linear stapler. Mark the specimen. Bring the specimen to the pathologist.
4. Suture the crossings of the staple line with interrupted PDS 3-0 sutures.
5. Bring the gastric conduit to the cervical region prevertebrally. Create anastomosis using three staplers (modified Collard technique). Place a nasogastric tube in the gastric conduit.
6. Close cervical wounds: musculus platysma with absorbable braided 3-0 sutures and skin with intracutaneously synthetic absorbable monofilament 4-0 sutures.
7. Create a feeding jejunostomy 20 cm distal to Treitz. Secure the jejunostomy to the abdominal wall with a pouch suture using absorbable braided 3-0 sutures and to the skin with non-resorbable braided sutures.
8. Place two antirotation sutures.
9. Test the gastric tube to reveal no leakage and good patency.
10. Close abdominal wounds: fascia with absorbable braided 0 sutures and skin with intracutaneously synthetic absorbable monofilament 4-0 sutures.

13. Postoperative care and monitoring

1. Detubate the patient in the operating room.
2. Postoperatively, transport the patient to the PACU (Post Anesthesia Care Unit) for one night of monitoring.
3. At the PACU, perform a chest X-ray to check for pneumothorax. Hold the chest tube on -10 cmH₂O suction until after the X-ray. If there is no air leakage or no pneumothorax, put the chest drain on H₂O lock.
4. Remove the chest tube on postoperative day 1 if there is no air leakage and no pneumothorax.
5. Remove the JP drain on the ward if production has a clear aspect and is less than 200 mL/24 h.

Results

At our institution, ICG fluorescence lymphography is the standard of clinical care during esophagectomy for esophageal cancer, based on published evidence and established practice in international expert centers. Routinely, all patients undergo esophagectomy with intraoperative fluorescence lymphography and thoracic duct resection according to this protocol. At the time of writing, fluorescence lymphography was performed in 20 patients undergoing esophagectomy for esophageal cancer. Table 1 provides thei...

Discussion

Critical steps in the protocol and modifications and troubleshooting of the technique

One of the most critical steps in the protocol includes the successful injection of ICG. In the first 10 patients, the thoracic duct was not visualized in 20%. Following discussion with experienced surgeons at international conferences and in light of available literature, ICG administration via mesenteric injection was introduced¹⁹. Instead of an inguinal injection, I...

Materials

List of materials used in this article

Name	Company	Catalog Number	Comments
Specific for ICG fluorescence lymphography
Arietta V70 Ultrasound	Hitachi		Ultrasound device with linear probe
da Vinci Surgeon Console	Intuitive Surgical	SS999	Used to control the surgical robot
da Vinci Vision Cart	Intuitive Surgical	VS999	The vision cart houses advanced vision and energy technologies and provides communications across da Vinci system components
da Vinci Xi	Intuitive Surgical	K131861	The surgical robot: 'patient side-cart'
da Vinci Xi Endoscope with Camera, 8 mm, 30°	Intuitive Surgical	470027	The camera of the da Vinci robot
Fluorescence camera system (Stryker PINPOINT, 1688 AIM 4K Platform, optics at 30 degrees with a video camera drape or Spy-PHI with drape	Stryker
Freka Connect ENFit/ProNeo syringe 60 mL	Freka	3044683	To administer enteral cream
Hem-o-lock large clips			To clip thoracic duct
Indocyanine green dye powder 25 mg flacon	Diagnostic Green	PICG0025NL	Indocyanine green powder
Lumbar needles Spinocan 20G x 3 1/2" 0.9 x 88 mm (2x)	BBraun	4509900-01	To puncture the inguinal nodes
Metal clips		ER320	To clip thoracic duct
Nutridrink compact 50 ml	Nutricia	62173	Enteral cream to stimulate chyle flow
Pajunk SonoPlex needle 22G x 50 mm (2x)	Pajunk	001185-74	To puncture the inguinal nodes
Red drawing needle			To make ICG solution
Sterile water for injection 10 mL	Fresenius Kabi		To dissolve ICG powder
Syringe 10 mL	BD	300912	To make ICG solution
Syringes 3 mL (2x)	BD	309658	To administer ICG solution
Supplies esophagectomy in general
1000 mg cefazolin
10 x 10 sterile gauzes
18-19 Gauche Ruohy needle
1x Ethibond 2/0 (fix. jejunostomy)
1x PDS 2/0 SH (fascia)
1x Vicryl 0 MH (fascia)
1x Vicryl 0 UR-6 (fascia)
1x Vicryl 0 UR-6 (fascia)
1x vicryl 3/0 SH (jejunostomy)
1x vicryl 3/0 SH (subcutis)
1x vicryl 3/0 SH-1 14 cm
1x V-loc 23 cm (anastomosis)
2x Monocryl 4/0 (skin)
2x Monocryl 4-0 (skin)
2x vicryl 2/0 SH (fixation 27 drain)
3 x 5 mm trocar
500 mg metronidazole
5 x 12mm trocar
Blue endo hook
Bupivacaine 0,125%
Bupivacaine 0,25%
Camera
Ch27 drain
Crush hechtingen Ethibond 0 EN-3
Diathermy
Disposable laparoscopy scissors
Double lumen endobronchial tube
Endo eye HD optic
Endoloop
Endostitch
Epidural catheter
Gastroscopy system
Gastroscopy tower
Jejunostomy feeding catheter
Laparoscopic mini liver retractor
Ligaclip 10 mm
Ligasure blunt tip
Microbead mattress
Paravertebral catheter
Powered Echelon Circular Stapler 25 and 29 mm
Powered Echelon Flex 60 mm stapler
Reloads 60mm Echelon White/Blue/Green
Suction and smoke evacuation system
Sufentanil 0.5 mcg/mL
Verres needle
Videotower