Despite the widespread use of LC for benign gallbladder pathology, ICG cholangiography has not yet become standard of care as an adjunct to the critical view of safety. Our institution has previously shown the benefits of ICG for LC and adopted this strategy for routine use. [9, 10] There is currently no consensus on the ICG dose or timing of administration that facilitates optimal intraoperative biliary visualization. In this study, we demonstrate that implementation of a low-dose ("microdose") ICG protocol provides non-inferior biliary visualization compared to our historical standard protocol with equivalent operative time and perioperative outcomes. Simplifying the ICG protocol for LC may help to streamline perioperative workflows and increase adoption of the technique.

Reported ICG protocols vary widely in the literature. A randomized trail published in 2020 by Chen et al. asserted that the optimal effect of FC is achieved by performing 10 mg ICG injections 10 to 12 h prior to surgery [17]. Conversely, more recent prospective studies have investigated lower ICG dose protocols. Ladd et al. randomized 55 adult patients to receive either 0.05 mg or 0.25 mg of ICG on induction of anesthesia and found that the lower dose led to a quantitative improvement in biliary visualization by minimizing background liver fluorescence [14]. The study also found the low-dose protocol provided satisfactory qualitative visualization of major extrahepatic biliary anatomy. Another recent randomized trial using a 4 K fluorescent imaging system for FC found that ICG doses ranging from 10 to 25 µg (0.01 to 0.025 mg) given within 30 min preoperatively provided adequate biliary visualization [18]. Other groups have advocated for weight-based ICG dosing and even transhepatic intracholecystic injection of ICG in select patients [19, 20]. While ICG cholangiography is efficacious across a range of strategies, intraoperative administration of low-dose ICG likely provides the most streamlined and cost-effective approach. ICG administration several hours prior to surgery is often not feasible for planned outpatient cholecystectomy. In addition, broad use of lower ICG doses may help to alleviate potential ICG shortages by reducing waste, and intraoperative administration removes an additional step in nursing workflows [21]. The demonstrated efficacy of low-dose ICG at the time of induction also enables redosing intraoperatively for unsatisfactory visualization as needed.

Although the CHD and CBD were identified in all cases for both groups, there were several instances in which we observed sluggish CD filling or no CD filling altogether. One patient in the microdose group who had previously received hepatotoxic chemotherapy for a hematologic malignancy had no CD filling at 18 min after ICG administration; however, we observed complete CD filling in real time over the next several minutes without having to give additional ICG. There were also several patients in both groups with cystic duct obstruction secondary to chronic cholecystitis who did not achieve CD filling during surgery. Pharmacokinetic studies have shown a measurable decrease in ICG hepatic clearance in patients with cirrhosis due to a decrease in intrinsic liver function [22]. ICG intrinsic hepatic clearance is also an independent predictor of survival in cirrhosis [23]. Biliary excretion of ICG is subsequently delayed due to decreased hepatic clearance, leading some studies to recommend intracholecystic ICG injection for patients with cirrhosis and fatty liver disease [20, 24]. In our experience, waiting a number of minutes for complete biliary excretion of ICG was sufficient for visualization in patients with decreased liver function. Therefore, there may be a role for modestly delaying ICG administration in patients with suspected liver impairment to account for reduced hepatic clearance and prevent prolonged operative time. In addition, despite not being able to visualize the CD in some patients with chronic gallbladder inflammation, the CBD and CHD were always visible and facilitated our ability to safely complete each case using these structures as key landmarks.

The rapid growth of fluorescence-guided surgery (FGS) as a field is demonstrated by the release of several flagship fluorescence imaging devices by large medical device companies. A recent systematic review identified 10 devices developed specifically for minimally invasive surgery, each designed to work within the ICG wavelength of 780 to 830 nm [25]. Each system provides 3 to 4 similar imaging modes, such as monochromatic, green fluorescence overlay, fluorescence only, and gradient overlay depending on signal intensity. These devices represent a significant advancement from early investigations into laparoscopic infrared imaging dating back to the inception of laparoscopic surgery [26]. As camera sensor and imaging technology continue to advance, clinical protocols for the use of fluorescent agents will likely need to adapt. There may also be a role for manufacturers of these fluorescent agents to modify the production of injection kits, as propagation of more sensitive imaging systems will likely result in less dye being needed in each kit to achieve the same degree of visualization. Alternatively, efforts could also be made to allow one vial of a fluorescent dye to be used for multiple patients to reduce waste and cost.

There are several limitations to this study, namely its retrospective single-center design and lack of randomization. Older generation camera systems were used for standard dose cases, which could feasibly impact the qualitative assessment performed. Moreover, video reviewers could not be blinded to the ICG dose given, as there was a clear identifiable difference in operative video quality between systems. Further study is necessary to examine the effect of various patient factors on biliary visualization using this protocol, such as inflammation, body mass index, and visceral fat. Validation of low-dose ICG protocols in a larger sample of various patient presentations will also be necessary to support adoption.