What is the dose of indocyanine green for pediatric patients for visualization during gallbladder surgery?

What is the dose of indocyanine green for pediatric patients for visualization during gallbladder surgery?

Comment by InpharmD Researcher

For pediatric patients requiring visualization during gallbladder surgery, dosages of indocyanine green (ICG) have ranged between 0.1 mg/kg and 2.5 mg total, and have been given from up to 24 hours preoperatively to just prior to incision (see Table 1). There is a paucity of data to determine the most optimal strategy out of previously published doses.

Background

A 2021 review article briefly discusses the use of indocyanine green (ICG) in pediatric imaging cases. ICG has a wide safe dose range with a recommended bolus of 0.1 to 2 mg/kg (max 2 mg/kg/24h). The most common dose is 0.2 to 0.4 mg/kg repeated as needed. Once the drug is diluted in sterile water for injection, the reconstituted product must be used within 6 hours. [1]

A 2021 systematic review and narrative analysis was conducted of relevant articles for ICG used in pediatric surgical patients. A total of 64 articles (N= 664 pediatric patients) were included for analysis with over half being case reports and case series. Only 29 studies mentioned the dose of ICG which varied greatly between articles and indications. One Japanese study for hepatoblastoma with biliary atresia administered 0.5 mg/kg intravenous (IV), 23 hours pre-operatively. Other doses were largely weight-based and could range from 0.2 to 0.5 mg/kg for general surgery. In their discussion, the authors note the recommended dose for hepatobiliary anatomy visualization in patients aged 12 to 17 years old is 2.5 mg, which is based off a specific monograph (Spy Agent™ Green). [2]

A recently published review article discussed the role of ICG fluorescence-enhanced applications in pediatric surgery. In various surgical scenarios, pediatric patients receive doses tailored to specific tissue targets. Literature indicates successful and safe utilization of doses ranging from 0.01 to 0.5 mg/kg, with a maximum daily recommended dosage of 2 mg/kg. For a summary on different dosages used for cholelithiasis, biliary atresia, and choledochal cysts, please refer to Table 1. [3]

Literature Review

A search of the published medical literature revealed 3 studies investigating the researchable question:

What is the dose of indocyanine green for pediatric patients for visualization during gallbladder surgery?

Level of evidence

C - Multiple studies with limitations or conflicting results Read more→

Please see Tables 1-3 for your response.

Non-oncologic pediatric experience with ICG-guided cholangiography
Condition	Fluorescence target	Dose	Dose timing	N	Impact	Reference (s)
Cholelithiasis	Biliary anatomy	0.4 mg/kg	15.5 - 18 hrs preop	36	Reduced operative time, reduced complications	Esposito 2019,2022
Cholelithiasis	Biliary anatomy	2.5 mg total	just prior to incision	29	Reduced operative time	Calabro 2019
Biliary atresia	Biliary anatomy	0.1 mg/kg	24 hrs preop	5	Delineated dissection plane, Fecal bile confirmation postop	Hirayama 2015
Biliary atresia	Biliary anatomy	0.5 mg/kg	24 hrs preop	10	Reduced postoperative hyperbilirubinemia	Yanagi 2019
Choledochal Cysts	Biliary anatomy	0.5 mg/kg	8 hrs preop	1	Biliary duct delineation, leak assessment	Delgado-Miguel 2023
Choledochal Cysts	Biliary anatomy	0.1 mg/kg	4 hrs preop	1	Biliary duct delineation, leak assessment	Garcia Hernandez 2022

References:

Adapted from:
Sincavage J, Gulack BC, Zamora IJ. Indocyanine green (ICG) fluorescence-enhanced applications in pediatric surgery. Semin Pediatr Surg. 2024;33(1):151384. doi:10.1016/j.sempedsurg.2024.151384

Twenty-Five Year Experience with Laparoscopic Cholecystectomy in the Pediatric Population-From 10 mm Clips to Indocyanine Green Fluorescence Technology: Long-Term Results and Technical Considerations
Design	Retrospective chart review N= 215
Objective	To review our 25-year experience with pediatric laparoscopic cholecystectomy (LC) to assess its long-term outcome
Study Groups	Study cohort (N= 215)
Inclusion Criteria	Patients in the institution's pediatric surgical unit, underwent LC
Exclusion Criteria	Not described
Methods	Data were collected from an electronic health record of patients meeting inclusion criteria. All patients underwent LC using the traditional four-port technique. Overweight and obese patients underwent preoperatively a bowel preparation with simethicone 80 mg tablets TID for at least 5 days before surgery and enemas the day prior to surgery. In the last 15 cases, indocyanine green (ICG) fluorescence technology was utilized to identify gallbladder and biliary tree anatomy. The ICG dye was injected into a peripheral vein 18 hours before the procedure at a dose of 0.4 mg/kg, using vials of 25 mg/5 mL.
Duration	March 1993 to December 2018
Outcome Measures	Incidence and management of complications
Baseline Characteristics		Study cohort (N= 215)
	Age, years	10.2
	Male	88 (40.9%)
	Weight, kg	46.5
	Body mass index >30	24.6%
	Idiopathic cholelithiasis	86%
	Secondary cholelithiasis Sickle cell disease Hereditary spherocytosis Thalassemia Cystic fibrosis	14% 6.5% 4.2% 1.4% 1.9%
Results	Endpoint	Study cohort (N= 215)
	Intraoperative diagnosis of anatomic anomalies Bile duct anomalies Cystic artery anomalies	6.9% 2.3% 4.6%
	Average analgesic requirement, h	20
	Average hospitalization, h	49.5
	Intraoperative complications Instrument failure Gallbladder perforation	2.8% 0.5% 2.3%
	Average operative time pre-ICG fluorescence, min	69
	Average operative time with ICG fluorescence, min	52
Adverse Events	See Results
Study Author Conclusions	LC is a standardized and effective procedure to perform in children. Our 25-year experience showed that major complications (Clavien IIIb) can occur even in experienced surgeons' hands. Age, weight, and preoperative cholecystitis were significantly associated with the risk of bile duct injury in our series. Considering its versatility and safety, we believe that ICG fluorescence technology may be adopted in every LC to ease the dissection and reduce the likelihood of complications.
InpharmD Researcher Critique	Due to the retrospective nature of the study, data may be missing or misclassified, which has the potential to bias the findings. ICG fluorescence was additionally only used in 15 cases total out of the 215-patient cohort, further limiting applicability to a larger pediatric population.

References:

Esposito C, Corcione F, Settimi A, et al. Twenty-Five Year Experience with Laparoscopic Cholecystectomy in the Pediatric Population-From 10 mm Clips to Indocyanine Green Fluorescence Technology: Long-Term Results and Technical Considerations. J Laparoendosc Adv Surg Tech A. 2019;29(9):1185-1191. doi:10.1089/lap.2019.0254

Efficacy of indocyanine green (ICG) fluorescent cholangiography to improve intra-operative visualization during laparoscopic cholecystectomy in pediatric patients: a comparative study between ICG-guided fluorescence and standard technique
Design	Retrospective, observational chart review N= 43
Objective	To compare the results of laparoscopic cholecystectomy (LC) with and without use of indocyanine green fluorescent cholangiography (ICG-FC) and to assess if ICG fluorescence is a useful tool to improve intra-operative visualization of biliary structures and to reduce bile duct injuries in children undergoing laparoscopic cholecystectomy
Study Groups	Standard LC (n= 22) ICG-FC LC (n= 21)
Inclusion Criteria	LC pediatric patients at the institutional surgical unit
Exclusion Criteria	Presence of hepatic failure, a history of bile duct surgery, and allergy to iodides or shellfish
Methods	In cases operated using ICG-FC, patients were admitted the day prior to surgery for ICG administration. A vial of ICG (5 mg/mL) was diluted with 10 mL of sterile water, then 0.35 mg/kg of the ICG solution was injected intravenously. Timing of administration prior to surgery varied (median 15.5 h). All patients were operated in general anesthesia with orotracheal intubation, with a 4-trocars technique utilized.
Duration	June 2017 to June 2021
Outcome Measures	Intra-operative ICG-FC visualization rate and complications
Baseline Characteristics		Standard LC (n= 22)	ICG-FC LC (n= 21)
	Age, years	10.8	12.2
	Female	7 (31.8%)	9 (42.9%)
	Weight, kg	37.8	56.2
	Body mass index, kg/m2	22.5	27.5
	Comorbidity Concomitant medical therapy	9.0% 0	14.3% 4.7%
	Patients in the ICG-FC LC group had a higher body mass index and weight versus standard LC (p= 0.01 for both).
Results	Endpoint	Standard LC (n= 22)	ICG-FC LC (n= 21)	p-value
	Intra-operative complications	13.6%	0	0.001
	Intra-operative ICG-FC visualization rate	--	95.2%	--
	Intra-operative identification of biliary anatomical anomalies	4.5%	19.0%	0.001
	Median LOS, hours	63	57	0.55
	Post-operative complications	0	0	--
	Re-operations	0	0	--
	Abbreviations: LOS, length of stay
Adverse Events	N/A
Study Author Conclusions	Based upon our experience, we strongly recommend the use of ICG-FC in all pediatric patients undergoing LC. ICG-guided fluorescence provided an excellent real-time visualization of the extrahepatic biliary tree and allowed faster and safer dissection, minimizing the risk of bile duct injuries. Furthermore, ICG use was clinically safe, with no adverse reactions to the product.
InpharmD Researcher Critique	The small sample size and retrospective nature of the study preclude definitive conclusions regarding clinical outcomes. The dose utilized by the institution appears to be preoperatively provided at a timepoint based on provider discretion, and no discussion on the rationale behind 0.35 mg/kg dosage was provided. Patients in the cohort utilizing ICG-FC were also larger than their peers who were not administered ICG.

References:

Esposito C, Settimi A, Cerulo M, Escolino M. Efficacy of indocyanine green (ICG) fluorescent cholangiography to improve intra-operative visualization during laparoscopic cholecystectomy in pediatric patients: a comparative study between ICG-guided fluorescence and standard technique. Surg Endosc. 2022;36(6):4369-4375. doi:10.1007/s00464-021-08784-5