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Image-Guided Pediatric Surgery Using Indocyanine Green (ICG) Fluorescence in Laparoscopic and Robotic Surgery

Image-Guided Pediatric Surgery Using Indocyanine Green (ICG) Fluorescence in Laparoscopic and... ORIGINAL RESEARCH published: 17 June 2020 doi: 10.3389/fped.2020.00314 Image-Guided Pediatric Surgery Using Indocyanine Green (ICG) Fluorescence in Laparoscopic and Robotic Surgery 1 1 1 1 Ciro Esposito *, Alessandro Settimi , Fulvia Del Conte , Mariapina Cerulo , 1 1 2 3 Vincenzo Coppola , Alessandra Farina , Felice Crocetto , Elisabetta Ricciardi , 1 1 Giovanni Esposito and Maria Escolino 1 2 Pediatric Surgery Unit, Federico II University of Naples, Naples, Italy, Urology Unit, Federico II University of Naples, Naples, Italy, Pharmacy Unit, Federico II University of Naples, Naples, Italy Background: Indocyanine green (ICG)-guided near-infrared fluorescence (NIRF) has been recently adopted in pediatric minimally invasive surgery (MIS). This study aimed to Edited by: report our experience with ICG-guided NIRF in pediatric laparoscopy and robotics and Henri Steyaert, evaluate its usefulness and technique of application in different pediatric pathologies. Queen Fabiola Children’s University Hospital, Belgium Methods: ICG technology was adopted in 76 laparoscopic and/or robotic procedures Reviewed by: accomplished in a single division of pediatric surgery over a 24-month period Thierry Roumeguère, (January 2018–2020): 40 (37 laparoscopic, three robotic) left varicocelectomies with Free University of Brussels, Belgium Thierry Merrot, intra-operative lymphography; 13 (10 laparoscopic, three robotic) renal procedures: Aix Marseille Université, France seven partial nephrectomies, three nephrectomies, and three renal cyst deroofings; *Correspondence: 12 laparoscopic cholecystectomies; five robotic tumor excisions; three laparoscopic Ciro Esposito ciroespo@unina.it abdominal lymphoma excisions; three thoracoscopic procedures: two lobectomies and one lymph node biopsy for suspected lymphoma. The ICG solution was administered Specialty section: into a peripheral vein in all indications except for varicocele and lymphoma in which This article was submitted to it was, respectively, injected into the testis body or the target organ. Regarding the Pediatric Surgery, a section of the journal timing of the administration, the ICG solution was administered intra-operatively in all Frontiers in Pediatrics indications except for cholecystectomy in which the ICG injection was performed 15–18 h Received: 29 March 2020 before surgery. Accepted: 15 May 2020 Published: 17 June 2020 Results: No conversions to open or laparoscopy occurred. No adverse and allergic Citation: reactions to ICG or other postoperative complications were reported. Esposito C, Settimi A, Del Conte F, Cerulo M, Coppola V, Farina A, Conclusions: Based upon our 2 year experience, we believe that ICG-guided NIRF is Crocetto F, Ricciardi E, Esposito G a very useful tool in pediatric MIS to perform a true imaged-guided surgery, allowing an and Escolino M (2020) Image-Guided easier identification of anatomic structures and an easier surgical performance in difficult Pediatric Surgery Using Indocyanine Green (ICG) Fluorescence in cases. The most common applications in pediatric surgery include varicocele repair, Laparoscopic and Robotic Surgery. difficult cholecystectomy, partial nephrectomy, lymphoma, and tumors excision but Front. Pediatr. 8:314. doi: 10.3389/fped.2020.00314 further indications will be soon discovered. ICG-enhanced fluorescence was technically Frontiers in Pediatrics | www.frontiersin.org 1 June 2020 | Volume 8 | Article 314 Esposito et al. ICG-Guided NIRF in Pediatric MIS easy to apply and safe for the patient reporting no adverse reactions to the product. The main limitation is represented by the specific equipment needed to apply ICG-guided NIRF in laparoscopic procedures, that is not available in all centers whereas the ICG system Firefly is already integrated into the robotic platform. Keywords: indocyanine green, fluorescence, technology, children, laparoscopy, robotics INTRODUCTION MATERIALS AND METHODS Near-infrared fluorescence (NIRF) is a common application of ICG technology was adopted in 76 laparoscopic and/or robotic fluorescence image-guided surgery (FIGS) (1–3). Use of NIRF procedures accomplished in a single division of pediatric requires the injection of a specific dye, indocyanine green surgery over a 24-month period (January 2018–2020): 40 (ICG), that first received Food and Drug Administration (FDA) (37 laparoscopic, three robotic) left varicocelectomies with approval to study hepatic and cardiac function in humans, intra-operative lymphography; 13 (10 laparoscopic, three and therefore it was adopted off-label for lymphatic targeting robotic) renal procedures: seven partial nephrectomies, (4–6). Recently, ICG-enhanced fluorescence was proved to three nephrectomies, and three renal cyst deroofings; 12 be very useful to improve intra-operative anatomic view laparoscopic cholecystectomies; five robotic tumor excisions; during laparoscopy or robotics and thus increase patients’ three laparoscopic abdominal lymphoma excisions; three safety during difficult surgical procedures (7–9). Regarding thoracoscopic procedures: two lobectomies and one lymph node the mechanism of action, fluorescence is produced when biopsy for suspected lymphoma. the water-soluble dye, ICG, is excited using a light of a Regarding the equipment, a specific camera system and a specific wavelength in the NIR spectrum (∼820 nm) and is specific 0- or 30-degree laparoscope equipped with a special visualized using specific optics and camera systems (7, 10). filter for detection of both NIR light and standard white light The last generation of robot, such as da Vinci Xi (Intuitive (KARL STORZ SE & Co. KG, Tuttlingen, Germany) were used Surgical, Sunnyvale, CA), is equipped with a software for NIRF in all laparoscopic and thoracoscopic procedures (21). There is detection, named Firefly (Novadaq Technologies, Mississauga, a specific software that reproduces the NIR image in different ON), and its utilization is directly controlled by the console colors through selection of different view modes: green or blue surgeon (11). ICG is almost entirely metabolized by the (CLARA+ CHROMA mode) or white (SPECTRA A mode). The liver and excreted into the bile, so the biliary indications specific view mode can be selected by the surgeon through the are the most obvious (12, 13). Other common applications buttons on the camera head during the initial setting. Switching of ICG fluorescence in adults included sentinel lymph node from white light mode to NIRF is directly activated by the mapping, angiographic study, and perfusion assessment of surgeon through foot-pedal pushing. The visualization of both various organs or tumors in abdominal, thoracic, or urological white and NIR light is enhanced by a professional system of surgery (14–17). image visualization (IMAGE1 S system, KARL STORZ SE & The use of ICG fluorescence imaging in pediatric patients Co. KG, Tuttlingen, Germany). In robotics, the console surgeon is just at embryonal stage. In pediatric patients, use of ICG can switch from standard white light to NIRF by pressing a lymphography has been described for treatment of varicocele button on the robotic joystick. Finally, the ICG dye (Verdye, and neonatal chylothorax or other lymphatic malformations Pulsion Medical Systems, Munich, Germany), available in vials (18–20). Different useful applications of this technology (25 mg/ml), was adopted in all the procedures. As indicated by have been identified in children such as visualization of the FDA recommendations, the routine dose for ICG should be biliary tract anatomy and assessment of vascular territory, 2.5 mg and 1.25 mg in children and infants, respectively (11). tissue perfusion, and tumor localization in various organs. For all indications, ICG vial was diluted with sterile water to However, analyzing the international literature, there is still create a 2.5 mg/ml solution. The ICG solution was administered limited evidence about the usefulness of ICG-guided NIRF into a peripheral vein in all indications except for varicocele imaging in such indications (21–23). Furthermore, as most and lymphoma in which it was, respectively, injected into knowledge and data were generated from adult experience, the the testis body or the target organ. Regarding the timing of dosage, and timing of injection were difficult to standardize the administration, the ICG solution was administered intra- in children. operatively in all indications except for cholecystectomy in which This study aimed to report the results of our experience the ICG injection was performed 15–18 h before surgery. with ICG-enhanced fluorescence imaging in pediatric The study was reviewed and approved by ethics committee of minimally invasive surgery (MIS)—laparoscopy and Federico II University of Naples, in Naples, Italy (216/2018). The thoracoscopy—and in robotics. ItIt also aimed to define patients’ legal guardians provided written informed consent to the indications and to standardize dosage, timing, and participate in this study. modality of application of ICG-guided NIRF in different Details of dosage, timing, and modality of administration of pediatric pathologies. ICG are reported for each surgical procedure (Table 1). Frontiers in Pediatrics | www.frontiersin.org 2 June 2020 | Volume 8 | Article 314 Esposito et al. ICG-Guided NIRF in Pediatric MIS FIGURE 1 | Lymphatics sparing at standard white light (A) and ICG-guided NIRF (B). Clipping and division of the spermatic bundle at standard white light (C) and ICG-guided NIRF (D). Urology Varicocele Repair After pneumoperitoneum induction, a bottle of ICG with a concentration of 25 mg was reconstituted with 8 ml of sterile water, and 2 ml (6.25 mg) of this solution were directly injected into the body of the left testicle using a 23G needle. Under NIR light, the lymphatics appeared fluorescent (blue or green with CLARA + CHROMA mode, white with SPECTRA A mode and green with FIREFLY ) and were easily isolated and spared (Figure 1). Thereafter, both spermatic vein and artery were ligated using 5-mm titanium clips and sectioned following the Palomo’s principle (Figure 1). Furthermore, the lymphatics were also clearly identifiable under standard white light as they appeared green or blue colored. All operative steps are reported in Video 1. FIGURE 2 | ICG-guided NIRF aided to identify the dissection plane between Nephrectomy/Partial Nephrectomy upper and lower moiety during upper pole partial nephrectomy. The ICG solution (dosage 0.3 mg/ml/kg) was injected intravenously, just after the division of the Gerota’s fascia and ICG-guided NIRF allowed to visualize the vascularization of the kidney within 5 min. During nephrectomy, ICG-guided NIRF Renal Cyst Deroofing was adopted to visualize the vascular anatomy before hilar vessel The ICG solution (dosage 0.3 mg/ml/kg) was injected control, especially in patients who had dense adhesions of the intravenously, just after the division of the Gerota’s fascia. perirenal tissues. In case of partial nephrectomy, ICG-enhanced In a matter of about 60 s following the injection, ICG-enhanced fluorescence was very useful to identify the main hilar vessels fluorescence allowed to clearly distinguish the non-vascularized and the vessels supplying the upper/lower moiety. After division cyst dome from the vascularized renal parenchyma. Once of vessels supplying the upper/lower moiety, ICG-guided NIRF identified and exposed, the cyst was punctured with a needle, aided to define the dissection plane between the two moieties that was introduced transabdominally and the liquid content was (Figure 2) and finally check the vascularization of the normal aspirated. The cyst’s roof was resected and the cyst’s concavity moiety following the resection of the non-functioning pole. was finally wadded using a pedicled flap of perirenal fat tissue. Frontiers in Pediatrics | www.frontiersin.org 3 June 2020 | Volume 8 | Article 314 Esposito et al. ICG-Guided NIRF in Pediatric MIS Hepatobiliary Surgery plenty adipose tissue, inflammation and dense tissue adhesions (Figure 3). ICG technology was very helpful to achieve the Cholecystectomy The ICG solution (dosage 0.4 mg/ml/kg) was administered Critical View of Safety (CVS) and avoid the risk of iatrogenic biliary or vascular injuries. The CVS was defined by three criteria: intravenously 15–18 h pre-operatively. This interval time between ICG administration and surgery assured that most of (1) the hepatocystic triangle was freed of adipose and fibrotic tissue; (2) the lower portion of the gallbladder was separated the dye was exclusively concentrated into the extrahepatic biliary from the liver in order to expose the cystic plate; and (3) only the structures and absent in the liver parenchyma. ICG-guided NIRF CD and the cystic artery entered the gallbladder (Figure 4) (24). aided to clearly visualize the gallbladder and the biliary structures ICG-enhanced fluorescence was also useful to identify the thin including the cystic duct (CD), the common bile duct (CBD), dissection plane between the gallbladder and the liver during its and especially the CD-CBD junction, despite the presence of final detachment from the liver bed. Oncology Lymphoma and Abdominal Tumors Removal For this indication, the ICG solution (dosage 0.5 mg/ml/kg) was intra-operatively injected into a peripheral vein and allowed a “real-time” assessment of bowel perfusion. Additionally, ICG- guided NIRF aided to visualize the vascularization of the neoplastic mass, to define the optimal level of resection in case of mesenteric division, and to detect the nodes to biopsy or to resect. Ovarian Tumors Removal Intra-operatively, the ICG solution (dosage 0.5 mg/ml/kg) was injected intravenously and in a matter of about 20–30 s following the injection, ICG-enhanced fluorescence allowed to clearly identify the tumor mass that appeared hypo-fluorescent compared with the normal salpinx and ovarian parenchyma (Figure 5A). ICG-guided NIRF aided the surgeon to identify and FIGURE 3 | ICG-guided NIRF aided to identify the biliary anatomy (Cystic respect the resection edges during the removal of the tumor mass Duct, CD; Common Bile Duct, CBD; CD-CBD junction) during laparoscopic (Figure 5B) and to check the vascularization of the salpinx and cholecystectomy. the uterus following the mass resection (Figure 5C). FIGURE 4 | ICG-guided NIRF was helpful to identify the different structures (cystic duct; cystic artery) in presence of adhesions or inflammation. Frontiers in Pediatrics | www.frontiersin.org 4 June 2020 | Volume 8 | Article 314 Esposito et al. ICG-Guided NIRF in Pediatric MIS FIGURE 5 | ICG-guided NIRF was useful to identify the tumor mass that appeared hypo-fluorescent (A), to respect the resection edges during removal (B), and to check the vascularization of the uterus following the resection (C). FIGURE 6 | Thoracoscopic biopsy of a 2-cm hilar lymph node: pre-operative CT imaging (A), intra-operative view (B), ICG-guided NIRF imaging (C). Thoracic Surgery and with symptoms (testicular pain and/or discomfort) in 26/40 patients (65%). The average length of surgery was 16 ± 9 min. Thoracoscopic Lobectomy At the longest follow-up of 24 months, no persistence and/or Intra-operatively, the ICG solution (dosage 0.25 mg/ml/kg) was recurrence of disease or testicular atrophy or hydrocele were injected into a peripheral vein, with the aim to identify the inter- observed. Furthermore, no adverse reactions of the left testicle segmental plane between the cystic malformation and the normal such as postoperative edema, hematoma, orchitis, and/or pain, lung parenchyma and better define the resection margins. were reported. Lymph Node Thoracoscopic Biopsy Intra-operatively, the ICG solution (dosage 0.5 mg/ml/kg) was Nephrectomy/Partial Nephrectomy injected into the lung parenchyma with a metallic needle, that ICG-enhanced fluorescence was adopted during laparoscopic was introduced through a 5-mm trocar. ICG-guided NIRF was partial nephrectomy (n = 7) and laparoscopic nephrectomy helpful to localize the pathological node to biopsy (Figure 6). (n = 3). There were four girls and six boys and the mean patient age at surgery was 5.7 years (range 1–17). The indications RESULTS for nephrectomy included non-functioning hydronephrotic kidney (n = 2) and non-functioning kidney due to vesico- All the surgical procedures were performed under ureteral reflux (VUR) nephropathy (n = 1). The indications general anesthesia and were completed laparoscopically, for partial nephrectomy included non-functioning symptomatic thoracoscopically, or robotically without conversions. No obstructive upper pole moiety (n = 4) and non-functioning patients had a previous history of allergy to iodide. No adverse symptomatic lower pole moiety associated with VUR (n = 3). and allergic reactions to ICG were reported. The average operative time was 78.5 ± 8 min. No intra- and Other results are reported separately for each post-operative complications occurred in all patients. surgical procedure. Urology Renal Cyst Deroofing Varicocele Repair Robotic deroofing of simple renal cyst (SRC) was performed Left varicocelectomy with intra-operative lymphography was in three boys. The mean patient age at surgery was 10.3 years accomplished via laparoscopic (n = 37) and robot-assisted (n (range 6–15). The median pre-operative cyst size was 70 mm = 3) approach. The mean patient age at surgery was 16.8 (range 42–90) and all cysts were identified as II grade according years (range 8–18). The indications for surgery were high grade to Bosniak classification. All patients were symptomatic with varicocele associated with left testicular hypotrophy in all cases recurrent flank pain. The average operative time was 75 ± Frontiers in Pediatrics | www.frontiersin.org 5 June 2020 | Volume 8 | Article 314 Esposito et al. ICG-Guided NIRF in Pediatric MIS 11 min including surgical and docking time. No intra- and post- DISCUSSION operative complications occurred in all patients, who remained The use of intra-operative NIRF imaging using ICG has been asymptomatic throughout the follow-up period. recently described as a very useful tool in decision-making strategy during challenging surgical procedures with a growing Hepatobiliary Surgery evidence in the adult literature (7–9). The applications of ICG- Cholecystectomy enhanced fluorescence in adults are wide and include oncologic An elective laparoscopic 4-trocars cholecystectomy was and non-oncologic indications in different specialties such accomplished in twelve obese adolescents (four boys and eight as colorectal, vascular, hepatobiliary, urological, and thoracic girls) with a mean age at surgery of 16.8 years (range 12–17) surgery with very promising results (11–16). ICG-enhanced and a mean BMI of 33.1 ± 2.0 kg/m . The average length of fluorescence has also been employed in pediatric MIS with the surgery was 62 ± 15 min. No complications occurred intra- aim to provide a more precise visualization of intra-operative or post-operatively. In one patient affected by Crigler–Najjar anatomy (21). However, there is still very limited evidence in syndrome type II, who was under phenobarbital treatment, we the pediatric literature and the indications of ICG-guided NIRF noticed intra-operatively a weak fluorescence of the extrahepatic are not yet so clear in pediatric patients (21–24). Based upon biliary structures due to the increased hepatic metabolism of our preliminary experience with application of ICG-enhanced ICG induced by phenobarbital. In this patient, an additional fluorescence in pediatric surgery and pediatric urology, we would administration of ICG (dosage 0.4 mg/ml/kg) was needed make some general considerations about its use in children. intra-operatively in order to visualize the cystic artery. As ICG is entirely excreted into the bile, the identification of the anatomic structures of the Calot’s triangle during hepatobiliary surgery represented one of the most frequent Oncology and worthwhile applications of ICG-guided NIRF in both Lymphoma and Abdominal Tumors Removal adults and children (13, 24, 25). In fact, iatrogenic biliary ICG-guided NIRF was adopted intra-operatively in three patients damages, commonly due to the scarce intra-operative (one girl and two boys), who underwent laparoscopic excision of visualization of biliary structures, probably represent the most abdominal lymphoma. The mean patient age at surgery was 4.1 feared complications of cholecystectomy (26). Inexperience, years (range 2–8). The average duration of surgery was 138 ± inflammation, and aberrant anatomy are key risk factors (27). 8 min. No complications occurred intra- or post-operatively. It has been reported that the intra-operative real-time virtual cholangiography, provided by ICG-guided NIRF, allowed to Ovarian Tumors Removal perform a precise and safe dissection of the Calot’s triangle ICG-guided NIRF was adopted during robot-assisted removal of and decreased the risk of iatrogenic biliary duct injury (13, 14). five ovarian tumors. The mean patient age at surgery was 13.5 In our experience, ICG-guided NIRF aided to clearly visualize years (range 11–16). The mean pre-operative size of adnexal mass the gallbladder and the biliary structures including the CD, was 8.5 cm (range 7–15). The average length of surgery was 78 the CBD, and especially the CD-CBD junction in all cases, ± 12 min. No complications occurred intra- or post-operatively. despite the presence of plenty adipose tissue, inflammation, and The histological diagnosis included mature teratoma (n = 3) and dense tissue adhesions (Figures 3, 4). ICG technology was very seromucinous cystadenoma (n = 2). helpful to achieve the CVS and further decrease the incidence of iatrogenic biliary or vascular injuries. We recently published our 25-year experience with laparoscopic cholecystectomy using Thoracic Surgery both standard laparoscopic technique and ICG-guided NIRF Thoracoscopic Lobectomy (24). We reported a postoperative complications rate of 1.9%: ICG-enhanced fluorescence was adopted during thoracoscopic one bleeding from the cystic artery, one dislocation of the clips left lower lobectomy in two patients (one girl and one boy), who on the CD, and two iatrogenic injuries to the main bile duct (24). were affected by congenital cystic adenomatoid malformation (n All the complications occurred in patients who were operated = 1) and pulmonary extra-lobar sequestration (n= 1). The mean using standard laparoscopic technique. No postoperative patient age at surgery was 15.5 months (range 11–20). We found complications occurred in patients who were operated using no true benefits of ICG-guided NIRF during these procedures, intra-operative ICG-guided fluorescence imaging (24). because we were not able to identify a clear demarcation line The optimal timing of ICG administration in such indication between the cystic malformation and the normal parenchyma. has also been long debated (13); in our series, the ICG solution (dosage 0.4 mg/ml/kg) was administered intravenously 15–18 h Lymph Node Thoracoscopic Biopsy pre-operatively, allowing a successful visualization of the biliary ICG-enhanced fluorescence was also adopted during anatomy in the totality of patients. This interval time between thoracoscopic biopsy of a 2-cm hilar lymph node with suspicion ICG injection and surgery assured that most of the dye was of lymphoma in a 6 years-old boy. The length of surgery was exclusively concentrated into the extrahepatic biliary structures, 68 min. No complications occurred intra- or post-operatively. so as to avoid the background hyper-fluorescence of the liver that Histology excluded the presence of malignant cells and the was typically observed when the injection was performed just patient is currently being followed-up by pediatric oncologists. before the procedure. We also observed a poor visualization of Frontiers in Pediatrics | www.frontiersin.org 6 June 2020 | Volume 8 | Article 314 Esposito et al. ICG-Guided NIRF in Pediatric MIS TABLE 1 | Technical details of ICG applications in pediatric surgical procedures. Indication Dosage Timing of administration Modality of Advantage* administration Varicocele repair 3.125 Intra-operatively Intra-parenchymal + + ++ mg/ml testicular injection Nephrectomy 0.3 Intra-operatively Intravenous ++ mg/ml/kg injection Partial nephrectomy 0.3 Intra-operatively Intravenous + + ++ mg/ml/kg injection Renal cyst deroofing 0.3 Intra-operatively Intravenous + + + mg/ml/kg injection Cholecystectomy 0.4 16–18 h pre-operatively Intravenous + + ++ mg/ml/kg injection Lymphoma/abdominal tumors removal 0.5 Intra-operatively Intravenous + + ++ mg/ml/kg injection Ovarian tumor removal 0.5 Intra-operatively Intravenous + + + mg/ml/kg injection Lobectomy 0.25 Intra-operatively Intravenous + mg/ml/kg injection Thoracic lymph node biopsy 0.5 Intra-operatively Intra-parenchymal + + + mg/ml/kg lung injection *Advantage scoring: +none; ++low; + + +average; + + ++high. the extra-hepatic biliary structures under NIRF in one patient dissection plane between the two moieties, thus decreasing affected by Crigler–Najjar syndrome type II who was under the risk of injury to the normal moiety or post-operative treatment with phenobarbital. The weak fluorescence of the urinary leakage. Furthermore, it was also useful to check the biliary tree in this patient was due to the pharmacodynamics of vascularization of the normal moiety following the resection of the phenobarbital, that accelerated the liver metabolism and the the affected moiety. biliary excretion of the dye. Based upon this finding, we suggest Another interesting clinical application of ICG-enhanced that the timing of ICG injection should be corrected in patients fluorescence was for oncological indications (30, 31). In our under phenobarbital treatment and should be performed at least series, ICG-guided NIRF was very helpful to detect also smaller 7–9 h prior to the surgery instead of 15–18 h pre-operatively, as tumors and to visualize the vascular anatomy and the resection routinely done. plane of the tumor so as to perform a safe and precise dissection Another very good indication of ICG-enhanced fluorescence and removal of the mass. in pediatric surgery is intra-operative lymphography during Regarding nephrectomy and lobectomy, our preliminary laparoscopic Palomo varicocelectomy (17). In our experience, experience using ICG-guided NIRF in such procedures ICG-enhanced fluorescence allowed to identify lymphatics in demonstrated no clear advantages, and probably a larger case 100% of cases (Figure 1) and to perform a lymphatic sparing series is needed to achieve further evidence about usefulness of procedure avoiding the risk of postoperative hydrocele. Before ICG technology for such indications. Considering the paucity of the advent of ICG-enhanced fluorescence, we already performed the available data that made dosage and timing of administration lymphatic-sparing varicocele repair using intradartoic/ difficult to standardize in children (23), we set up modality, intratesticular injection of isosulfan blue dye. As we already timing, and dosage of administration of ICG for each indication. published, we recorded no postoperative hydrocele also using Regarding the modality of administration, the ICG dye was this last technique (28). Thereafter, we decided to adopt ICG injected intravenously in most indications; in few cases such as to perform lymphography and we standardized the injection lymphatic sparing varicocele repair or oncologic procedures, technique (18). We found two main advantages of using ICG the dye must be directly injected in the target tissue or organ. over isosulfan blue: first, ICG, being metabolized by the liver, did Regarding the timing of administration, the product was injected not modify the urines’ color, and secondly ICG did not cause any during surgery in most indications except for cholecystectomy, color changes of the skin in the injection site (17). Currently, in which the ICG injection was performed at least 16–18 h prior ICG-enhanced fluorescence has become our first choice to to the surgery. Regarding the dosage of ICG, we standardized the perform lymphatic-sparing Palomo procedure. dosage for each procedure (Table 1); in our clinical practice, the ICG technology may be useful during partial nephrectomy dosages ranged between 0.3 and 0.5 mg/ml/kg and were much (29). In this indication, ICG-guided NIRF aided to exactly lower than the reported toxicity levels (3, 7). identify the vascularization of both normal and non-functioning Based upon our preliminary experience, we believe that ICG- moieties (Figure 2). After division of the vessels supplying the enhanced fluorescence provided several advantages in pediatric upper/lower moiety, ICG-guided NIRF aided to define the patients allowing to better identify the surgical anatomy and Frontiers in Pediatrics | www.frontiersin.org 7 June 2020 | Volume 8 | Article 314 Esposito et al. ICG-Guided NIRF in Pediatric MIS fasten the surgical procedure while maintaining the patient’s fluorescence was technically easy to apply and safe for the safety. This technique was no time-consuming since it just patient reporting no adverse reactions to the product. The main required an intravenous or intra-parenchymal injection of ICG limitation is represented by the specific equipment needed to solution and fluorescence of target tissue/organ was visualized apply ICG-guided NIRF in laparoscopic procedures, that is not in real-time intra-operatively (7). Furthermore, ICG use was available in all centers whereas the ICG system Firefly is already clinically safe since no allergy and other adverse systemic integrated into the robotic platform. reactions or any testicular injury related to the intra-testicular DATA AVAILABILITY STATEMENT ICG injection were reported in the early or late postoperative course (17, 21). Use of ICG-guided NIRF was also cost-effective; All datasets presented in this study are included in the in fact, since the operating room was already equipped with the article/Supplementary Material. specific camera system and laparoscopic equipment for NIR light detection and the robotic platform was already integrated with the Firefly software for NIR light detection, use of NIRF in both ETHICS STATEMENT laparoscopy and robotics did not require any adjunctive costs The study was reviewed and approved by ethics committee of except for the ICG vial (cost about 40 eur). Federico II University of Naples, in Naples, Italy. The patients’ However, ICG technology does have its limitations: first, the legal guardians provided written informed consent to participate special equipment required for its use in laparoscopic surgery in this study. may not be available in all centers. This problem is overcome in robotic surgery, since the ICG software Firefly is already integrated into the robotic platform (11). The sensitivity and AUTHOR CONTRIBUTIONS visualization of ICG are significantly affected by the depth and CE contributed conception and design of the study and wrote size of the lesion (23). In fact, very small lesions are difficult to the first draft of the manuscript. AS contributed conception and detect if the intensity of fluorescence is too weak (20, 23). Finally, design of the study and wrote sections of the manuscript. FDC, the use of ICG is not recommended in patients who reported MC, VC, AF, FC, ER, GE, and ME organized the database and allergy to iodides since ICG contains sodium iodide (23). wrote sections of the manuscript. All authors contributed to Based upon our 2 year experience, we believe that ICG- manuscript revision, read, and approved the submitted version. guided NIRF is a very useful tool in pediatric MIS to perform a true imaged-guided surgery, allowing an easier identification of anatomic structures and an easier surgical performance in SUPPLEMENTARY MATERIAL difficult cases. The most common applications in pediatric The Supplementary Material for this article can be found surgery include varicocele repair, difficult cholecystectomy, online at: https://www.frontiersin.org/articles/10.3389/fped. partial nephrectomy, lymphoma, and tumors excision but 2020.00314/full#supplementary-material further indications will be soon discovered. ICG-enhanced REFERENCES fluorescence in laparoscopic surgery. Surg Endosc. (2015) 29:2046–55. doi: 10.1007/s00464-014-3895-x 1. Schaafsma BE, Mieog JS, Hutteman M, van der Vorst JR, Kuppen PJ, Lowik 8. 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ICG-Guided NIRF in Pediatric MIS urologic cancers: a systematic review and meta-analysis. Minerva Urol Nefrol. Laparoendosc Adv Surg Tech A. (2019) 29:1185–91. doi: 10.1089/lap.201 (2018) 70:361–9. doi: 10.23736/S0393-2249.17.02932-0 9.0254 15. Goyal A. New technologies for sentinel lymph node detection. Breast Care 25. Graves C, Ely S, Idowu O, Newton C, Kim S. Direct gallbladder indocyanine (Basel). (2018) 13:349–53. doi: 10.1159/000492436 green injection fluorescence cholangiography during laparoscopic 16. Chand M, Keller DS, Joshi HM, Devoto L, Rodriguez-Justo M, Cohen R. cholecystectomy. J Laparoendosc Adv Surg Tech A. (2017) 27:1069–73. Feasibility of fluorescence lymph node imaging in colon cancer: FLICC. Tech doi: 10.1089/lap.2017.0070 Coloproctol. (2018) 22:271–7. doi: 10.1007/s10151-018-1773-6 26. Cohen JT, Charpentier KP, Beard RE. An update on iatrogenic biliary injuries: 17. 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(2015) 50:833–6. doi: 10.1016/j.jpeds.2013.12.052 doi: 10.1016/j.jpedsurg.2015.01.014 21. Esposito C, Del Conte F, Cerulo M, Gargiulo F, Izzo S, Esposito G, 31. Yamada Y, Ohno M, Fujino A, Kanamori Y, Irie R, Yoshioka T, et al. et al. Clinical application and technical standardization of indocyanine Fluorescence-guided surgery for hepatoblastoma with indocyanine green. green (ICG) fluorescence imaging in pediatric minimally invasive Cancers (Basel). (2019) 11:1215. doi: 10.3390/cancers11081215 surgery. Pediatr Surg Int. (2019) 35:1043–50. doi: 10.1007/s00383-019-0 4519-9 Conflict of Interest: The authors declare that the research was conducted in the 22. Fernández-Bautista B, Mata DP, Parente A, Pérez-Caballero R, De Agustín JC. absence of any commercial or financial relationships that could be construed as a First experience with fluorescence in pediatric laparoscopy. Eur J Pediatr Surg potential conflict of interest. Rep. (2019) 7:e43–e46. doi: 10.1055/s-0039-1692191 23. Lau CT, Au DM, Wong KKY. Application of indocyanine Copyright © 2020 Esposito, Settimi, Del Conte, Cerulo, Coppola, Farina, Crocetto, green in pediatric surgery. Pediatr Surg Int. (2019) 35:1035–41. Ricciardi, Esposito and Escolino. This is an open-access article distributed under the doi: 10.1007/s00383-019-04502-4 terms of the Creative Commons Attribution License (CC BY). The use, distribution 24. Esposito C, Corcione F, Settimi A, Farina A, Centonze A, Esposito or reproduction in other forums is permitted, provided the original author(s) and G, et al. Twenty-five year experience with laparoscopic cholecystectomy the copyright owner(s) are credited and that the original publication in this journal in the pediatric population-from 10 mm clips to indocyanine green is cited, in accordance with accepted academic practice. No use, distribution or fluorescence technology: long-term results and technical considerations. J reproduction is permitted which does not comply with these terms. Frontiers in Pediatrics | www.frontiersin.org 9 June 2020 | Volume 8 | Article 314 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Frontiers in Pediatrics Pubmed Central

Image-Guided Pediatric Surgery Using Indocyanine Green (ICG) Fluorescence in Laparoscopic and Robotic Surgery

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Copyright © 2020 Esposito, Settimi, Del Conte, Cerulo, Coppola, Farina, Crocetto, Ricciardi, Esposito and Escolino.
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10.3389/fped.2020.00314
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ORIGINAL RESEARCH published: 17 June 2020 doi: 10.3389/fped.2020.00314 Image-Guided Pediatric Surgery Using Indocyanine Green (ICG) Fluorescence in Laparoscopic and Robotic Surgery 1 1 1 1 Ciro Esposito *, Alessandro Settimi , Fulvia Del Conte , Mariapina Cerulo , 1 1 2 3 Vincenzo Coppola , Alessandra Farina , Felice Crocetto , Elisabetta Ricciardi , 1 1 Giovanni Esposito and Maria Escolino 1 2 Pediatric Surgery Unit, Federico II University of Naples, Naples, Italy, Urology Unit, Federico II University of Naples, Naples, Italy, Pharmacy Unit, Federico II University of Naples, Naples, Italy Background: Indocyanine green (ICG)-guided near-infrared fluorescence (NIRF) has been recently adopted in pediatric minimally invasive surgery (MIS). This study aimed to Edited by: report our experience with ICG-guided NIRF in pediatric laparoscopy and robotics and Henri Steyaert, evaluate its usefulness and technique of application in different pediatric pathologies. Queen Fabiola Children’s University Hospital, Belgium Methods: ICG technology was adopted in 76 laparoscopic and/or robotic procedures Reviewed by: accomplished in a single division of pediatric surgery over a 24-month period Thierry Roumeguère, (January 2018–2020): 40 (37 laparoscopic, three robotic) left varicocelectomies with Free University of Brussels, Belgium Thierry Merrot, intra-operative lymphography; 13 (10 laparoscopic, three robotic) renal procedures: Aix Marseille Université, France seven partial nephrectomies, three nephrectomies, and three renal cyst deroofings; *Correspondence: 12 laparoscopic cholecystectomies; five robotic tumor excisions; three laparoscopic Ciro Esposito ciroespo@unina.it abdominal lymphoma excisions; three thoracoscopic procedures: two lobectomies and one lymph node biopsy for suspected lymphoma. The ICG solution was administered Specialty section: into a peripheral vein in all indications except for varicocele and lymphoma in which This article was submitted to it was, respectively, injected into the testis body or the target organ. Regarding the Pediatric Surgery, a section of the journal timing of the administration, the ICG solution was administered intra-operatively in all Frontiers in Pediatrics indications except for cholecystectomy in which the ICG injection was performed 15–18 h Received: 29 March 2020 before surgery. Accepted: 15 May 2020 Published: 17 June 2020 Results: No conversions to open or laparoscopy occurred. No adverse and allergic Citation: reactions to ICG or other postoperative complications were reported. Esposito C, Settimi A, Del Conte F, Cerulo M, Coppola V, Farina A, Conclusions: Based upon our 2 year experience, we believe that ICG-guided NIRF is Crocetto F, Ricciardi E, Esposito G a very useful tool in pediatric MIS to perform a true imaged-guided surgery, allowing an and Escolino M (2020) Image-Guided easier identification of anatomic structures and an easier surgical performance in difficult Pediatric Surgery Using Indocyanine Green (ICG) Fluorescence in cases. The most common applications in pediatric surgery include varicocele repair, Laparoscopic and Robotic Surgery. difficult cholecystectomy, partial nephrectomy, lymphoma, and tumors excision but Front. Pediatr. 8:314. doi: 10.3389/fped.2020.00314 further indications will be soon discovered. ICG-enhanced fluorescence was technically Frontiers in Pediatrics | www.frontiersin.org 1 June 2020 | Volume 8 | Article 314 Esposito et al. ICG-Guided NIRF in Pediatric MIS easy to apply and safe for the patient reporting no adverse reactions to the product. The main limitation is represented by the specific equipment needed to apply ICG-guided NIRF in laparoscopic procedures, that is not available in all centers whereas the ICG system Firefly is already integrated into the robotic platform. Keywords: indocyanine green, fluorescence, technology, children, laparoscopy, robotics INTRODUCTION MATERIALS AND METHODS Near-infrared fluorescence (NIRF) is a common application of ICG technology was adopted in 76 laparoscopic and/or robotic fluorescence image-guided surgery (FIGS) (1–3). Use of NIRF procedures accomplished in a single division of pediatric requires the injection of a specific dye, indocyanine green surgery over a 24-month period (January 2018–2020): 40 (ICG), that first received Food and Drug Administration (FDA) (37 laparoscopic, three robotic) left varicocelectomies with approval to study hepatic and cardiac function in humans, intra-operative lymphography; 13 (10 laparoscopic, three and therefore it was adopted off-label for lymphatic targeting robotic) renal procedures: seven partial nephrectomies, (4–6). Recently, ICG-enhanced fluorescence was proved to three nephrectomies, and three renal cyst deroofings; 12 be very useful to improve intra-operative anatomic view laparoscopic cholecystectomies; five robotic tumor excisions; during laparoscopy or robotics and thus increase patients’ three laparoscopic abdominal lymphoma excisions; three safety during difficult surgical procedures (7–9). Regarding thoracoscopic procedures: two lobectomies and one lymph node the mechanism of action, fluorescence is produced when biopsy for suspected lymphoma. the water-soluble dye, ICG, is excited using a light of a Regarding the equipment, a specific camera system and a specific wavelength in the NIR spectrum (∼820 nm) and is specific 0- or 30-degree laparoscope equipped with a special visualized using specific optics and camera systems (7, 10). filter for detection of both NIR light and standard white light The last generation of robot, such as da Vinci Xi (Intuitive (KARL STORZ SE & Co. KG, Tuttlingen, Germany) were used Surgical, Sunnyvale, CA), is equipped with a software for NIRF in all laparoscopic and thoracoscopic procedures (21). There is detection, named Firefly (Novadaq Technologies, Mississauga, a specific software that reproduces the NIR image in different ON), and its utilization is directly controlled by the console colors through selection of different view modes: green or blue surgeon (11). ICG is almost entirely metabolized by the (CLARA+ CHROMA mode) or white (SPECTRA A mode). The liver and excreted into the bile, so the biliary indications specific view mode can be selected by the surgeon through the are the most obvious (12, 13). Other common applications buttons on the camera head during the initial setting. Switching of ICG fluorescence in adults included sentinel lymph node from white light mode to NIRF is directly activated by the mapping, angiographic study, and perfusion assessment of surgeon through foot-pedal pushing. The visualization of both various organs or tumors in abdominal, thoracic, or urological white and NIR light is enhanced by a professional system of surgery (14–17). image visualization (IMAGE1 S system, KARL STORZ SE & The use of ICG fluorescence imaging in pediatric patients Co. KG, Tuttlingen, Germany). In robotics, the console surgeon is just at embryonal stage. In pediatric patients, use of ICG can switch from standard white light to NIRF by pressing a lymphography has been described for treatment of varicocele button on the robotic joystick. Finally, the ICG dye (Verdye, and neonatal chylothorax or other lymphatic malformations Pulsion Medical Systems, Munich, Germany), available in vials (18–20). Different useful applications of this technology (25 mg/ml), was adopted in all the procedures. As indicated by have been identified in children such as visualization of the FDA recommendations, the routine dose for ICG should be biliary tract anatomy and assessment of vascular territory, 2.5 mg and 1.25 mg in children and infants, respectively (11). tissue perfusion, and tumor localization in various organs. For all indications, ICG vial was diluted with sterile water to However, analyzing the international literature, there is still create a 2.5 mg/ml solution. The ICG solution was administered limited evidence about the usefulness of ICG-guided NIRF into a peripheral vein in all indications except for varicocele imaging in such indications (21–23). Furthermore, as most and lymphoma in which it was, respectively, injected into knowledge and data were generated from adult experience, the the testis body or the target organ. Regarding the timing of dosage, and timing of injection were difficult to standardize the administration, the ICG solution was administered intra- in children. operatively in all indications except for cholecystectomy in which This study aimed to report the results of our experience the ICG injection was performed 15–18 h before surgery. with ICG-enhanced fluorescence imaging in pediatric The study was reviewed and approved by ethics committee of minimally invasive surgery (MIS)—laparoscopy and Federico II University of Naples, in Naples, Italy (216/2018). The thoracoscopy—and in robotics. ItIt also aimed to define patients’ legal guardians provided written informed consent to the indications and to standardize dosage, timing, and participate in this study. modality of application of ICG-guided NIRF in different Details of dosage, timing, and modality of administration of pediatric pathologies. ICG are reported for each surgical procedure (Table 1). Frontiers in Pediatrics | www.frontiersin.org 2 June 2020 | Volume 8 | Article 314 Esposito et al. ICG-Guided NIRF in Pediatric MIS FIGURE 1 | Lymphatics sparing at standard white light (A) and ICG-guided NIRF (B). Clipping and division of the spermatic bundle at standard white light (C) and ICG-guided NIRF (D). Urology Varicocele Repair After pneumoperitoneum induction, a bottle of ICG with a concentration of 25 mg was reconstituted with 8 ml of sterile water, and 2 ml (6.25 mg) of this solution were directly injected into the body of the left testicle using a 23G needle. Under NIR light, the lymphatics appeared fluorescent (blue or green with CLARA + CHROMA mode, white with SPECTRA A mode and green with FIREFLY ) and were easily isolated and spared (Figure 1). Thereafter, both spermatic vein and artery were ligated using 5-mm titanium clips and sectioned following the Palomo’s principle (Figure 1). Furthermore, the lymphatics were also clearly identifiable under standard white light as they appeared green or blue colored. All operative steps are reported in Video 1. FIGURE 2 | ICG-guided NIRF aided to identify the dissection plane between Nephrectomy/Partial Nephrectomy upper and lower moiety during upper pole partial nephrectomy. The ICG solution (dosage 0.3 mg/ml/kg) was injected intravenously, just after the division of the Gerota’s fascia and ICG-guided NIRF allowed to visualize the vascularization of the kidney within 5 min. During nephrectomy, ICG-guided NIRF Renal Cyst Deroofing was adopted to visualize the vascular anatomy before hilar vessel The ICG solution (dosage 0.3 mg/ml/kg) was injected control, especially in patients who had dense adhesions of the intravenously, just after the division of the Gerota’s fascia. perirenal tissues. In case of partial nephrectomy, ICG-enhanced In a matter of about 60 s following the injection, ICG-enhanced fluorescence was very useful to identify the main hilar vessels fluorescence allowed to clearly distinguish the non-vascularized and the vessels supplying the upper/lower moiety. After division cyst dome from the vascularized renal parenchyma. Once of vessels supplying the upper/lower moiety, ICG-guided NIRF identified and exposed, the cyst was punctured with a needle, aided to define the dissection plane between the two moieties that was introduced transabdominally and the liquid content was (Figure 2) and finally check the vascularization of the normal aspirated. The cyst’s roof was resected and the cyst’s concavity moiety following the resection of the non-functioning pole. was finally wadded using a pedicled flap of perirenal fat tissue. Frontiers in Pediatrics | www.frontiersin.org 3 June 2020 | Volume 8 | Article 314 Esposito et al. ICG-Guided NIRF in Pediatric MIS Hepatobiliary Surgery plenty adipose tissue, inflammation and dense tissue adhesions (Figure 3). ICG technology was very helpful to achieve the Cholecystectomy The ICG solution (dosage 0.4 mg/ml/kg) was administered Critical View of Safety (CVS) and avoid the risk of iatrogenic biliary or vascular injuries. The CVS was defined by three criteria: intravenously 15–18 h pre-operatively. This interval time between ICG administration and surgery assured that most of (1) the hepatocystic triangle was freed of adipose and fibrotic tissue; (2) the lower portion of the gallbladder was separated the dye was exclusively concentrated into the extrahepatic biliary from the liver in order to expose the cystic plate; and (3) only the structures and absent in the liver parenchyma. ICG-guided NIRF CD and the cystic artery entered the gallbladder (Figure 4) (24). aided to clearly visualize the gallbladder and the biliary structures ICG-enhanced fluorescence was also useful to identify the thin including the cystic duct (CD), the common bile duct (CBD), dissection plane between the gallbladder and the liver during its and especially the CD-CBD junction, despite the presence of final detachment from the liver bed. Oncology Lymphoma and Abdominal Tumors Removal For this indication, the ICG solution (dosage 0.5 mg/ml/kg) was intra-operatively injected into a peripheral vein and allowed a “real-time” assessment of bowel perfusion. Additionally, ICG- guided NIRF aided to visualize the vascularization of the neoplastic mass, to define the optimal level of resection in case of mesenteric division, and to detect the nodes to biopsy or to resect. Ovarian Tumors Removal Intra-operatively, the ICG solution (dosage 0.5 mg/ml/kg) was injected intravenously and in a matter of about 20–30 s following the injection, ICG-enhanced fluorescence allowed to clearly identify the tumor mass that appeared hypo-fluorescent compared with the normal salpinx and ovarian parenchyma (Figure 5A). ICG-guided NIRF aided the surgeon to identify and FIGURE 3 | ICG-guided NIRF aided to identify the biliary anatomy (Cystic respect the resection edges during the removal of the tumor mass Duct, CD; Common Bile Duct, CBD; CD-CBD junction) during laparoscopic (Figure 5B) and to check the vascularization of the salpinx and cholecystectomy. the uterus following the mass resection (Figure 5C). FIGURE 4 | ICG-guided NIRF was helpful to identify the different structures (cystic duct; cystic artery) in presence of adhesions or inflammation. Frontiers in Pediatrics | www.frontiersin.org 4 June 2020 | Volume 8 | Article 314 Esposito et al. ICG-Guided NIRF in Pediatric MIS FIGURE 5 | ICG-guided NIRF was useful to identify the tumor mass that appeared hypo-fluorescent (A), to respect the resection edges during removal (B), and to check the vascularization of the uterus following the resection (C). FIGURE 6 | Thoracoscopic biopsy of a 2-cm hilar lymph node: pre-operative CT imaging (A), intra-operative view (B), ICG-guided NIRF imaging (C). Thoracic Surgery and with symptoms (testicular pain and/or discomfort) in 26/40 patients (65%). The average length of surgery was 16 ± 9 min. Thoracoscopic Lobectomy At the longest follow-up of 24 months, no persistence and/or Intra-operatively, the ICG solution (dosage 0.25 mg/ml/kg) was recurrence of disease or testicular atrophy or hydrocele were injected into a peripheral vein, with the aim to identify the inter- observed. Furthermore, no adverse reactions of the left testicle segmental plane between the cystic malformation and the normal such as postoperative edema, hematoma, orchitis, and/or pain, lung parenchyma and better define the resection margins. were reported. Lymph Node Thoracoscopic Biopsy Intra-operatively, the ICG solution (dosage 0.5 mg/ml/kg) was Nephrectomy/Partial Nephrectomy injected into the lung parenchyma with a metallic needle, that ICG-enhanced fluorescence was adopted during laparoscopic was introduced through a 5-mm trocar. ICG-guided NIRF was partial nephrectomy (n = 7) and laparoscopic nephrectomy helpful to localize the pathological node to biopsy (Figure 6). (n = 3). There were four girls and six boys and the mean patient age at surgery was 5.7 years (range 1–17). The indications RESULTS for nephrectomy included non-functioning hydronephrotic kidney (n = 2) and non-functioning kidney due to vesico- All the surgical procedures were performed under ureteral reflux (VUR) nephropathy (n = 1). The indications general anesthesia and were completed laparoscopically, for partial nephrectomy included non-functioning symptomatic thoracoscopically, or robotically without conversions. No obstructive upper pole moiety (n = 4) and non-functioning patients had a previous history of allergy to iodide. No adverse symptomatic lower pole moiety associated with VUR (n = 3). and allergic reactions to ICG were reported. The average operative time was 78.5 ± 8 min. No intra- and Other results are reported separately for each post-operative complications occurred in all patients. surgical procedure. Urology Renal Cyst Deroofing Varicocele Repair Robotic deroofing of simple renal cyst (SRC) was performed Left varicocelectomy with intra-operative lymphography was in three boys. The mean patient age at surgery was 10.3 years accomplished via laparoscopic (n = 37) and robot-assisted (n (range 6–15). The median pre-operative cyst size was 70 mm = 3) approach. The mean patient age at surgery was 16.8 (range 42–90) and all cysts were identified as II grade according years (range 8–18). The indications for surgery were high grade to Bosniak classification. All patients were symptomatic with varicocele associated with left testicular hypotrophy in all cases recurrent flank pain. The average operative time was 75 ± Frontiers in Pediatrics | www.frontiersin.org 5 June 2020 | Volume 8 | Article 314 Esposito et al. ICG-Guided NIRF in Pediatric MIS 11 min including surgical and docking time. No intra- and post- DISCUSSION operative complications occurred in all patients, who remained The use of intra-operative NIRF imaging using ICG has been asymptomatic throughout the follow-up period. recently described as a very useful tool in decision-making strategy during challenging surgical procedures with a growing Hepatobiliary Surgery evidence in the adult literature (7–9). The applications of ICG- Cholecystectomy enhanced fluorescence in adults are wide and include oncologic An elective laparoscopic 4-trocars cholecystectomy was and non-oncologic indications in different specialties such accomplished in twelve obese adolescents (four boys and eight as colorectal, vascular, hepatobiliary, urological, and thoracic girls) with a mean age at surgery of 16.8 years (range 12–17) surgery with very promising results (11–16). ICG-enhanced and a mean BMI of 33.1 ± 2.0 kg/m . The average length of fluorescence has also been employed in pediatric MIS with the surgery was 62 ± 15 min. No complications occurred intra- aim to provide a more precise visualization of intra-operative or post-operatively. In one patient affected by Crigler–Najjar anatomy (21). However, there is still very limited evidence in syndrome type II, who was under phenobarbital treatment, we the pediatric literature and the indications of ICG-guided NIRF noticed intra-operatively a weak fluorescence of the extrahepatic are not yet so clear in pediatric patients (21–24). Based upon biliary structures due to the increased hepatic metabolism of our preliminary experience with application of ICG-enhanced ICG induced by phenobarbital. In this patient, an additional fluorescence in pediatric surgery and pediatric urology, we would administration of ICG (dosage 0.4 mg/ml/kg) was needed make some general considerations about its use in children. intra-operatively in order to visualize the cystic artery. As ICG is entirely excreted into the bile, the identification of the anatomic structures of the Calot’s triangle during hepatobiliary surgery represented one of the most frequent Oncology and worthwhile applications of ICG-guided NIRF in both Lymphoma and Abdominal Tumors Removal adults and children (13, 24, 25). In fact, iatrogenic biliary ICG-guided NIRF was adopted intra-operatively in three patients damages, commonly due to the scarce intra-operative (one girl and two boys), who underwent laparoscopic excision of visualization of biliary structures, probably represent the most abdominal lymphoma. The mean patient age at surgery was 4.1 feared complications of cholecystectomy (26). Inexperience, years (range 2–8). The average duration of surgery was 138 ± inflammation, and aberrant anatomy are key risk factors (27). 8 min. No complications occurred intra- or post-operatively. It has been reported that the intra-operative real-time virtual cholangiography, provided by ICG-guided NIRF, allowed to Ovarian Tumors Removal perform a precise and safe dissection of the Calot’s triangle ICG-guided NIRF was adopted during robot-assisted removal of and decreased the risk of iatrogenic biliary duct injury (13, 14). five ovarian tumors. The mean patient age at surgery was 13.5 In our experience, ICG-guided NIRF aided to clearly visualize years (range 11–16). The mean pre-operative size of adnexal mass the gallbladder and the biliary structures including the CD, was 8.5 cm (range 7–15). The average length of surgery was 78 the CBD, and especially the CD-CBD junction in all cases, ± 12 min. No complications occurred intra- or post-operatively. despite the presence of plenty adipose tissue, inflammation, and The histological diagnosis included mature teratoma (n = 3) and dense tissue adhesions (Figures 3, 4). ICG technology was very seromucinous cystadenoma (n = 2). helpful to achieve the CVS and further decrease the incidence of iatrogenic biliary or vascular injuries. We recently published our 25-year experience with laparoscopic cholecystectomy using Thoracic Surgery both standard laparoscopic technique and ICG-guided NIRF Thoracoscopic Lobectomy (24). We reported a postoperative complications rate of 1.9%: ICG-enhanced fluorescence was adopted during thoracoscopic one bleeding from the cystic artery, one dislocation of the clips left lower lobectomy in two patients (one girl and one boy), who on the CD, and two iatrogenic injuries to the main bile duct (24). were affected by congenital cystic adenomatoid malformation (n All the complications occurred in patients who were operated = 1) and pulmonary extra-lobar sequestration (n= 1). The mean using standard laparoscopic technique. No postoperative patient age at surgery was 15.5 months (range 11–20). We found complications occurred in patients who were operated using no true benefits of ICG-guided NIRF during these procedures, intra-operative ICG-guided fluorescence imaging (24). because we were not able to identify a clear demarcation line The optimal timing of ICG administration in such indication between the cystic malformation and the normal parenchyma. has also been long debated (13); in our series, the ICG solution (dosage 0.4 mg/ml/kg) was administered intravenously 15–18 h Lymph Node Thoracoscopic Biopsy pre-operatively, allowing a successful visualization of the biliary ICG-enhanced fluorescence was also adopted during anatomy in the totality of patients. This interval time between thoracoscopic biopsy of a 2-cm hilar lymph node with suspicion ICG injection and surgery assured that most of the dye was of lymphoma in a 6 years-old boy. The length of surgery was exclusively concentrated into the extrahepatic biliary structures, 68 min. No complications occurred intra- or post-operatively. so as to avoid the background hyper-fluorescence of the liver that Histology excluded the presence of malignant cells and the was typically observed when the injection was performed just patient is currently being followed-up by pediatric oncologists. before the procedure. We also observed a poor visualization of Frontiers in Pediatrics | www.frontiersin.org 6 June 2020 | Volume 8 | Article 314 Esposito et al. ICG-Guided NIRF in Pediatric MIS TABLE 1 | Technical details of ICG applications in pediatric surgical procedures. Indication Dosage Timing of administration Modality of Advantage* administration Varicocele repair 3.125 Intra-operatively Intra-parenchymal + + ++ mg/ml testicular injection Nephrectomy 0.3 Intra-operatively Intravenous ++ mg/ml/kg injection Partial nephrectomy 0.3 Intra-operatively Intravenous + + ++ mg/ml/kg injection Renal cyst deroofing 0.3 Intra-operatively Intravenous + + + mg/ml/kg injection Cholecystectomy 0.4 16–18 h pre-operatively Intravenous + + ++ mg/ml/kg injection Lymphoma/abdominal tumors removal 0.5 Intra-operatively Intravenous + + ++ mg/ml/kg injection Ovarian tumor removal 0.5 Intra-operatively Intravenous + + + mg/ml/kg injection Lobectomy 0.25 Intra-operatively Intravenous + mg/ml/kg injection Thoracic lymph node biopsy 0.5 Intra-operatively Intra-parenchymal + + + mg/ml/kg lung injection *Advantage scoring: +none; ++low; + + +average; + + ++high. the extra-hepatic biliary structures under NIRF in one patient dissection plane between the two moieties, thus decreasing affected by Crigler–Najjar syndrome type II who was under the risk of injury to the normal moiety or post-operative treatment with phenobarbital. The weak fluorescence of the urinary leakage. Furthermore, it was also useful to check the biliary tree in this patient was due to the pharmacodynamics of vascularization of the normal moiety following the resection of the phenobarbital, that accelerated the liver metabolism and the the affected moiety. biliary excretion of the dye. Based upon this finding, we suggest Another interesting clinical application of ICG-enhanced that the timing of ICG injection should be corrected in patients fluorescence was for oncological indications (30, 31). In our under phenobarbital treatment and should be performed at least series, ICG-guided NIRF was very helpful to detect also smaller 7–9 h prior to the surgery instead of 15–18 h pre-operatively, as tumors and to visualize the vascular anatomy and the resection routinely done. plane of the tumor so as to perform a safe and precise dissection Another very good indication of ICG-enhanced fluorescence and removal of the mass. in pediatric surgery is intra-operative lymphography during Regarding nephrectomy and lobectomy, our preliminary laparoscopic Palomo varicocelectomy (17). In our experience, experience using ICG-guided NIRF in such procedures ICG-enhanced fluorescence allowed to identify lymphatics in demonstrated no clear advantages, and probably a larger case 100% of cases (Figure 1) and to perform a lymphatic sparing series is needed to achieve further evidence about usefulness of procedure avoiding the risk of postoperative hydrocele. Before ICG technology for such indications. Considering the paucity of the advent of ICG-enhanced fluorescence, we already performed the available data that made dosage and timing of administration lymphatic-sparing varicocele repair using intradartoic/ difficult to standardize in children (23), we set up modality, intratesticular injection of isosulfan blue dye. As we already timing, and dosage of administration of ICG for each indication. published, we recorded no postoperative hydrocele also using Regarding the modality of administration, the ICG dye was this last technique (28). Thereafter, we decided to adopt ICG injected intravenously in most indications; in few cases such as to perform lymphography and we standardized the injection lymphatic sparing varicocele repair or oncologic procedures, technique (18). We found two main advantages of using ICG the dye must be directly injected in the target tissue or organ. over isosulfan blue: first, ICG, being metabolized by the liver, did Regarding the timing of administration, the product was injected not modify the urines’ color, and secondly ICG did not cause any during surgery in most indications except for cholecystectomy, color changes of the skin in the injection site (17). Currently, in which the ICG injection was performed at least 16–18 h prior ICG-enhanced fluorescence has become our first choice to to the surgery. Regarding the dosage of ICG, we standardized the perform lymphatic-sparing Palomo procedure. dosage for each procedure (Table 1); in our clinical practice, the ICG technology may be useful during partial nephrectomy dosages ranged between 0.3 and 0.5 mg/ml/kg and were much (29). In this indication, ICG-guided NIRF aided to exactly lower than the reported toxicity levels (3, 7). identify the vascularization of both normal and non-functioning Based upon our preliminary experience, we believe that ICG- moieties (Figure 2). After division of the vessels supplying the enhanced fluorescence provided several advantages in pediatric upper/lower moiety, ICG-guided NIRF aided to define the patients allowing to better identify the surgical anatomy and Frontiers in Pediatrics | www.frontiersin.org 7 June 2020 | Volume 8 | Article 314 Esposito et al. ICG-Guided NIRF in Pediatric MIS fasten the surgical procedure while maintaining the patient’s fluorescence was technically easy to apply and safe for the safety. This technique was no time-consuming since it just patient reporting no adverse reactions to the product. The main required an intravenous or intra-parenchymal injection of ICG limitation is represented by the specific equipment needed to solution and fluorescence of target tissue/organ was visualized apply ICG-guided NIRF in laparoscopic procedures, that is not in real-time intra-operatively (7). Furthermore, ICG use was available in all centers whereas the ICG system Firefly is already clinically safe since no allergy and other adverse systemic integrated into the robotic platform. reactions or any testicular injury related to the intra-testicular DATA AVAILABILITY STATEMENT ICG injection were reported in the early or late postoperative course (17, 21). Use of ICG-guided NIRF was also cost-effective; All datasets presented in this study are included in the in fact, since the operating room was already equipped with the article/Supplementary Material. specific camera system and laparoscopic equipment for NIR light detection and the robotic platform was already integrated with the Firefly software for NIR light detection, use of NIRF in both ETHICS STATEMENT laparoscopy and robotics did not require any adjunctive costs The study was reviewed and approved by ethics committee of except for the ICG vial (cost about 40 eur). Federico II University of Naples, in Naples, Italy. The patients’ However, ICG technology does have its limitations: first, the legal guardians provided written informed consent to participate special equipment required for its use in laparoscopic surgery in this study. may not be available in all centers. This problem is overcome in robotic surgery, since the ICG software Firefly is already integrated into the robotic platform (11). The sensitivity and AUTHOR CONTRIBUTIONS visualization of ICG are significantly affected by the depth and CE contributed conception and design of the study and wrote size of the lesion (23). In fact, very small lesions are difficult to the first draft of the manuscript. AS contributed conception and detect if the intensity of fluorescence is too weak (20, 23). Finally, design of the study and wrote sections of the manuscript. FDC, the use of ICG is not recommended in patients who reported MC, VC, AF, FC, ER, GE, and ME organized the database and allergy to iodides since ICG contains sodium iodide (23). wrote sections of the manuscript. All authors contributed to Based upon our 2 year experience, we believe that ICG- manuscript revision, read, and approved the submitted version. guided NIRF is a very useful tool in pediatric MIS to perform a true imaged-guided surgery, allowing an easier identification of anatomic structures and an easier surgical performance in SUPPLEMENTARY MATERIAL difficult cases. The most common applications in pediatric The Supplementary Material for this article can be found surgery include varicocele repair, difficult cholecystectomy, online at: https://www.frontiersin.org/articles/10.3389/fped. partial nephrectomy, lymphoma, and tumors excision but 2020.00314/full#supplementary-material further indications will be soon discovered. ICG-enhanced REFERENCES fluorescence in laparoscopic surgery. Surg Endosc. (2015) 29:2046–55. doi: 10.1007/s00464-014-3895-x 1. Schaafsma BE, Mieog JS, Hutteman M, van der Vorst JR, Kuppen PJ, Lowik 8. 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Lau CT, Au DM, Wong KKY. Application of indocyanine Copyright © 2020 Esposito, Settimi, Del Conte, Cerulo, Coppola, Farina, Crocetto, green in pediatric surgery. Pediatr Surg Int. (2019) 35:1035–41. Ricciardi, Esposito and Escolino. This is an open-access article distributed under the doi: 10.1007/s00383-019-04502-4 terms of the Creative Commons Attribution License (CC BY). The use, distribution 24. Esposito C, Corcione F, Settimi A, Farina A, Centonze A, Esposito or reproduction in other forums is permitted, provided the original author(s) and G, et al. Twenty-five year experience with laparoscopic cholecystectomy the copyright owner(s) are credited and that the original publication in this journal in the pediatric population-from 10 mm clips to indocyanine green is cited, in accordance with accepted academic practice. No use, distribution or fluorescence technology: long-term results and technical considerations. J reproduction is permitted which does not comply with these terms. Frontiers in Pediatrics | www.frontiersin.org 9 June 2020 | Volume 8 | Article 314

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Frontiers in PediatricsPubmed Central

Published: Jun 17, 2020

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