Home About us Editorial board Ahead of print Current issue Search Archives Submit article Instructions Subscribe Contacts Login 

 Table of Contents  
REVIEW ARTICLE
Year : 2021  |  Volume : 19  |  Issue : 1  |  Page : 42-45

Indocyanine green beyond quantitative liver function tests – An adjuvant in pediatric imaging: A review of its uses and a protocol for administration in pediatric surgical practice


Department of Surgery, The Children's Hospital at Westmead, Westmead, Sydney, Australia

Date of Submission09-Oct-2020
Date of Decision24-Oct-2020
Date of Acceptance06-Nov-2020
Date of Web Publication13-Jan-2021

Correspondence Address:
Dr. Tarun John K. Jacob
Department of Surgery, The Children's Hospital at Westmead, Westmead, Sydney 2145, NSW
Australia
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/cmi.cmi_133_20

Rights and Permissions
  Abstract 


Indocyanine green (ICG) is a nontoxic, inert, anionic water-soluble tricarbocyanine dye with ability to fluorescence when light of the near infrared spectrum is focused onto it with a customized camera. ICG has been known as a diagnostic agent for decades. As with many diagnostic modalities in the medicine, the use of ICG has slowly expanded to find varied and novel applications in the clinical practice. Its use as an imaging modality in pediatric surgery is only increasingly being recognized. The uses of ICG range from bile duct identification, biliary atresia surgery, bowel ischemia delineation, tumor detection, parathyroid identification, and lymph leak detection to name a few. Its safety profile, property to bind to plasma proteins, and be excreted exclusively in the bile make it ideal for intraoperative pediatric surgical imaging. Data on ICG use in children are limited to a handful of case reports and few case cohorts globally. A broad literature search on the history of ICG use, pharmacology, licensing applications, and clinical reports specifically for pediatric populations was carried out. This review was done with intent to analyze the safety profile and compile the various indications of ICG use in children. The dye finds ever expanding clinical uses in our large tertiary referral unit for children in NSW, Australia, and it was our intent to create a protocol that allows for its safe use in routine clinical practice. This protocol created will benefit not only our patients, but is one that can be adopted for other pediatric surgical services worldwide.

Keywords: Indocyanine green, indocyanine green in children, near infrared spectrum spectography


How to cite this article:
Jacob TJ, Thomas G. Indocyanine green beyond quantitative liver function tests – An adjuvant in pediatric imaging: A review of its uses and a protocol for administration in pediatric surgical practice. Curr Med Issues 2021;19:42-5

How to cite this URL:
Jacob TJ, Thomas G. Indocyanine green beyond quantitative liver function tests – An adjuvant in pediatric imaging: A review of its uses and a protocol for administration in pediatric surgical practice. Curr Med Issues [serial online] 2021 [cited 2021 Apr 20];19:42-5. Available from: https://www.cmijournal.org/text.asp?2021/19/1/42/306935




  Introduction Top


Indocyanine green (ICG) has been known as an imaging and diagnostic agent for decades. As with many modalities in the medicine, the use of ICG has slowly expanded to find the varied and novel applications for the clinical practice.

ICG was initially developed by researchers at Kodak in 1955 as a fluorescent pigment for near infrared photography and was approved in 1956 for clinical use. Over the late sixties and early seventies, its use was limited to cardiac and retinal angiography. It is over the last two decades; however, that the dye has found numerous clinical applications. We discuss its role as a pediatric surgical imaging adjunct and present a protocol for its use in children.


  Methods Top


A literature review revealed 84 publications on ICG. The secondary searches from the bibliography of appropriate articles were performed to look for unlisted publications. The literature search looked at the origins of ICG, pharmacology, and approvals for licensing. Case reports and cohorts of pediatric populations where ICG has been used were searched for and tabulated. Animal trials that provided data on safety and toxic doses were included for the qualitative values of safe dosage recommendations. This review continues to consolidate and ratify our experience with ICG for a wide range of clinical situations in our tertiary care pediatric surgical and transplant hospital in New South Wales, Australia.


  Pharmacology and Safety Profile Top


ICG demonstrates fluorescence when the light of wavelength with peak absorption and emission at 800–830 nm. It is this property for fluorescence is what makes it an easily identifiable diagnostic agent in tissue. The pigment is available as a negatively charged, dry powder that is water soluble in the dye's tricarbocyanine form. It is diluted to the required concentration with sterile water to preserve its spectral properties.[1]

The dye is most commonly administered intravenously. It binds to proteins (alpha 1 lipoprotein) in plasma or lymphatic fluid. The half-life in the vascular compartment is about 3–5 min (normal subjects clear it at an average of 20% a minute).[2] ICG is cleared exclusively through liver metabolism by the first pass effect – and is excreted in bile after being transported through glutathione S-transferase.[3],[4] The fluorescent imaging principle works by the illumination of the tissue in the region of interest with wavelength that will cause excitation and emission of a longer wavelength. There are no toxic metabolites of ICG recorded and the wavelengths that excite the pigment make tissue more translucent and hence provide a better penetration to display underlying vessels. A special camera serves both as an emission device and a capturing-recording device. Various companies make this instrument and the two most commonly available probes are the open surgical the minimally invasive one for thoracoscopy and laparoscopy.

The morbidity of ICG use is those associated with iodine allergy. ICG is constituted of 5% sodium iodine to allow solubility. The quoted risk of anaphylaxis and urticaria is at 4/240,000 cases.[5] The drug maintains solubility and stability in the aqueous solution for about 6 h. It is, however, stable in the plasma and blood, and hence, samples can be read for the levels for longer time durations when used to assess qualitative liver function. ICG concentrations peak in bile by 120 min of administration, however its presence can be imaged bile within a few minutes of administration. Soft-tissue imaging of ICG occurs seconds after administration, and it is this property that makes it useful for acute demarcation of vascular and nonvascularized tissue.

Toxic doses of ICG are based on animal studies. The LD50 values in mice, rats, and rabbits are over twenty times the maximum dose recommended for children indicating a good safety profile.


  Clinical Applications in Pediatric Imaging Top


The application of ICG in clinical pediatric imaging can be divided into three broad categories: Viable vascularized tissue imaging, imaging of biliary tracts, and thirdly imaging of lymphatic drainage.

  • Vascularized tissue imaging remains the broadest application for ICG in the clinical practice. The fluorescence demonstrated seconds after administration in vessels are made use of in the recognition of viable vascularized tissue. A few examples are detailed below:


    • The demarcation of bowel vascularity can be demonstrated with ICG administration. This is particularly important in the diagnosis of resection margins in necrotizing enterocolitis in infants and viable bowel after a bowel ischemia from incarcerated hernia and more commonly volvulus. Studies have shown that the addition of ICG imaging at laparotomy improves the clinical outcomes in 11% of patients by improved decision making accuracy on gut ischemia. ICG can potentially improve the length of viable gut retained and more importantly avoid the surgeon from leaving ischemic gut in vulnerable neonates
    • Tumor fluorescence is another important property of ICG. Nonpalpable metastatic lesions of the liver have been demonstrated with the use of ICG.[6],[7] Selective arterial blockade and perfusion studies with ICG mapping of solid organs can be used to identify safe tumor resection margins for appropriate oncological clearance
    • ICG has a role to play in the reduction of post thyroidectomy morbidity caused by parathyroid gland ischemia. Existing methods to confirm the vascularity of the parathyroid glands are unreliable. When administered after removal of the thyroid gland, ICG fluorescence is visualized in viable parathyroid glands. Nonviable glands can be then appropriately implanted into a muscle pocket. A recent systematic review has examined 18 articles that employ ICG for safer parathyroid preservation[8]
    • ICG can be used to image viability in gonadal torsion,[9] and this use can be potentially extrapolated to the prognostication of gonad loss in staged orchidopexies


  • As ICG is metabolized and excreted by the liver into bile, this is useful to identify biliary anatomy, bile duct leaks, and for biliary atresia. Multiple authors have utilized ICG in infants for the identification and prognostication of the Kasai biliary enteric reconstruction. ICG is given 24 h before a porto-enterostomy and the dye constipates in the terminal biliary tracts allowing for identification at surgery. There is the added benefit of being able to identify ICG in the postoperative stool samples to confirm a successful biliary drainage.[10],[11] These case series were the earliest to demonstrate safe ICG use in infants


  • The demonstration of safe biliary anatomy in cholecystectomies is a common use of the dye in adults and older children. This is particularly useful in difficult laparoscopic cholecystectomies performed during acute cholecystitis[12],[13]

    ICG finds the important use in a hepatobiliary and transplant unit to identify bile leaks. If a biliary leak is suspected, the identification of the exact site is greatly helped by imaging the biliary ICG excretion. Leaks from small surface bile ducts or from the corners of biliary-enteric anastomosis can be repaired with confidence when demonstrated and documented by the fluorescence camera.

  • The third broad use of ICG concerns the lymphatic system. Thoracic duct lymph leaks are common after cardiac and esophageal surgery. Unlike biliary and vascular diagnostic imaging, the ICG is injected into the web spaces or the dorsum of the foot to allow the lymphatic channels to drain the dye and demonstrate its course. Case reports of its use by intratesticular injection for safe lymphatic preservation in varicocele surgery demonstrate its versatility and safety in soft-tissue injection sites.[14],[15],[16]



  Dose and Administration Protocol Top


ICG as an imaging modality is either administered at the time of the procedure or in special indications before the procedure. Administration is done by suitably trained medical personal vigilant of the rare anaphylaxis.

The safe dose range for ICG is wide from 0.1 to 2 mg/kg as a bolus is recommended (maximum 2 mg/kg/24 h). The most common dose used for clinical pediatric imaging is a dose of 0.2–0.4 mg/kg repeated as needed. The drug is diluted with sterile water for injection and must be used within 6 h of reconstitution. The drug is rapidly metabolized in the liver and excreted through the bile within minutes.

A desaturation with the administration has been reported as ICG in the plasma can interfere with pulse oximetry readings. This is transient and can be confirmed by a concomitant blood gas confirming normal oxygenation.

Although ICG is often used in as an acute imaging modality, there exist special situations where ICG imaging is performed after a period of time – the doses and times for these special situations are listed below:

  • Biliary atresia – intravenous administration of 0.5 mg/kg 24 h before the laparotomy
  • Lymphatic leaks – ICG is injected into the web space or dorsum of the foot at 0.5 mg/kg and imaging can commence from 15 to 60 min
  • Delineation of liver tumors – the recommended time is to give the ICG is either 1 week before the surgery at 0.5 mg/kg or a dose of 0.2 mg 72 h before the surgery.


In Australia – ICG requires a Therapeutic Goods Administration (TGA) SAS Form Category A as it is not yet approved for use by the TGA.


  Conclusions Top


ICG offers an ever widening range of clinical applications of imaging in a pediatric surgical practice. Its role in objective judgment of tissue vascularity, identification of bile and lymph leaks, biliary anatomy, and safer oncological surgery makes it an invaluable tool in a pediatric surgical practice. The relatively safe profile of the dye makes it a valuable adjunct to the imaging armamentarium for children.

Financial support and sponsorship

This study was financially supported by Sydney Children's Hospital Network.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Shafy SZ, Hakim M, Lynch S, Chen L, Tobias JD. Fluorescence imaging using indocyanine green dye in the pediatric population. J Pediatr Pharmacol Ther 2020;25:309-13.  Back to cited text no. 1
    
2.
FDA Data Sheet and Pharmacokinetics. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2?006/011525s017lbl.pdf. [Last accessed on 2020 Sep 20].  Back to cited text no. 2
    
3.
Yoneya S, Saito T, Komatsu Y, Koyama I, Takahashi K, Duvoll-Young J. Binding properties of indocyanine green in human blood. Invest Ophthalmol Vis Sci 1998;39:1286-90.  Back to cited text no. 3
    
4.
Engel E, Schraml R, Maisch T, Kobuch K, König B, Szeimies RM, et al. Light-induced decomposition of indocyanine green. Invest Ophthalmol Vis Sci 2008;49:1777-83.  Back to cited text no. 4
    
5.
Perry D, Bharara M, Armstrong DG, Mills J. Intraoperative fluorescence vascular angiography: During tibial bypass. J Diabetes Sci Technol 2012;6:204-8.  Back to cited text no. 5
    
6.
Liu Y, Akers WJ, Bauer AQ, Mondal S, Gullicksrud K, Sudlow GP, et al. Intraoperative detection of liver tumors aided by a fluorescence goggle system and multimodal imaging. Analyst 2013;138:2254-7.  Back to cited text no. 6
    
7.
Boogerd LS, Handgraaf HJ, Lam HD, Huurman VA, Farina-Sarasqueta A, Frangioni JV, et al. Laparoscopic detection and resection of occult liver tumors of multiple cancer types using real-time near-infrared fluorescence guidance. Surg Endosc 2017;31:952-61.  Back to cited text no. 7
    
8.
Spartalis E, Ntokos G, Georgiou K, Zografos G, Tsourouflis G, Dimitroulis D, et al. Intraoperative indocyanine green (ICG) angiography for the identification of the parathyroid glands: current evidence and future perspectives. In Vivo 2020;34:23-32.  Back to cited text no. 8
    
9.
Kohler R, Hamdani A, Grämiger M. Use of intraoperative Indocyanine green fluorescence to assess testicular perfusion and viability when managing testicular torsion in a 26-year old man. Urol Case Rep. 2019 Oct 31;28:101063. doi: 10.1016/j.eucr.2019.101063.  Back to cited text no. 9
    
10.
Yanagi Y, Yoshimaru K, Matsuura T, Shibui Y, Kohashi K, Takahashi Y, et al. The outcome of real-time evaluation of biliary flow using near-infrared fluorescence cholangiography with Indocyanine green in biliary atresia surgery. J Pediatr Surg 2019;54:2574-8.  Back to cited text no. 10
    
11.
Kubota A, Okada A, Fukui Y, Kawahara H, Imura K, Kamata S. Indocyanine green test is a reliable indicator of postoperative liver function in biliary atresia. J Pediatr Gastroenterol Nutr 1993;16:61-5.  Back to cited text no. 11
    
12.
Esposito C, Corcione F, Settimi A, Farina A, Centonze A, Esposito G, et al. Twenty-five year experience with laparoscopic cholecystectomy in the pediatric population-from 10mm clips to indocyanine green fluorescence technology: Long-term results and technical considerations. J Laparoendosc Adv Surg Tech A 2019;29:1185-91.  Back to cited text no. 12
    
13.
Graves C, Ely S, Idowu O, Newton C, Kim S. Direct gallbladder indocyanine green injection fluorescence cholangiography during laparoscopic cholecystectomy. J Laparoendosc Adv Surg Tech A 2017;27:1069-73.  Back to cited text no. 13
    
14.
Esposito C, Turrà F, Del Conte F, Izzo S, Gargiulo F, Farina A, et al. Indocyanine green fluorescence lymphography: A new technique to perform lymphatic sparing laparoscopic palomo varicocelectomy in children. J Laparoendosc Adv Surg Tech A 2019;29:564-7.  Back to cited text no. 14
    
15.
Bibas BJ, Costa-de-Carvalho RL, Pola-Dos-Reis F, Lauricella LL, Pêgo-Fernandes PM, Terra RM. Video-assisted thoracoscopic thoracic duct ligation with near-infrared fluorescence imaging with indocyanine green. J Bras Pneumol 2019;45:e20180401.  Back to cited text no. 15
    
16.
Shirotsuki R, Uchida H, Tanaka Y, Shirota C, Yokota K, Murase N, et al. Novel thoracoscopic navigation surgery for neonatal chylothorax using indocyanine-green fluorescent lymphography. J Pediatr Surg 2018;53:1246-9.  Back to cited text no. 16
    




 

Top
 
 
  Search
 
Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
Access Statistics
Email Alert *
Add to My List *
* Registration required (free)

 
  In this article
Abstract
Introduction
Methods
Pharmacology and...
Clinical Applica...
Dose and Adminis...
Conclusions
References

 Article Access Statistics
    Viewed226    
    Printed8    
    Emailed0    
    PDF Downloaded33    
    Comments [Add]    

Recommend this journal


[TAG2]
[TAG3]
[TAG4]