Visualization is one of the fundamental pillars (including CO2 insufflation and instrumentation) critical to performing MIS. Initially evolved from direct view through the laparoscope to indirect view on the monitor projected from a camera system. Early advances were geared towards improving the image quality and reproduction of stereoscopic vision. Current advancements involve in part or in combination, the application of optical filters to manipulate specific light spectrums (narrow-band imaging) and the use of fluorescent dye (indocyanine green-fluorescent imaging) to see beyond what can be viewed with the naked eye, coupled with the advantage of real-time application. Narrow-band imaging is primarily used in gastrointestinal endoscopy to detect mucosal pathologies, while ICG aid in revealing specific structures beneath tissues and assess tissue perfusion; it is finding interest for application in various MIS procedures.

Indocyanine Green-Enhanced Imaging

History of Indocyanine Green (ICG). ICG-enhanced imaging is based on the properties of the cyanine dye. The Kodak research laboratories developed the ICG dye in 1955 for near-infrared photography [1, 2]. Its FDA-approved medical application began in 1956, initially used for quantitative measurement of hepatic and cardiac function; subsequently extended to use in ophthalmology with the investigation into its fluorescent properties in the 1970s [1]. Its use was hindered by technological limitations until recently with the development of improved digital imaging, allowing the broad application of ICG imaging.

Rationale for Using ICG. Use of ICG has several advantages: good signal-to-noise ratio where the target can be seen clearly due to the absence of background tissue auto fluorescence, rapid clearance of the dye allows repeated applications, the near-infrared light used to excite and fluorescence being viewed functions within the tissue optical window allowing visualization to about 5–10 mm deep, and the system itself merely requires simple affordable imaging devices [3]. The wavelengths below 700 nm are absorbed by hemoglobin and myoglobin, while that above 900 nm are limited by lipid and water absorption [4] (Fig. 1).

Fig. 1
A diagram begins with a light source, then four arrows representing infrared, red, blue, and green light penetrate optical fibre and infrared, blue, and green light only pass to move downward to fluorescent dye, then goes up to penetrate optical fibre to connect to two photographs labelled I R colour mode 1 and 2.

How ICG-enhanced imaging works. (Source: Olympus)

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Properties of ICG. ICG is an amphiphilic, tricarbocyanine iodide dye with a molecular mass of 751.4 Da [1]. It is distributed as a powder and reconstituted with distilled water with good solubility, attaining an aqueous solution of 6.5 pH for intravenous injection. The solution has limited stability to light and must be used within 6–10 h on dilution; once injected, it attains spectral stabilization within seconds. The dye is excited with either filtered (near-infrared) light or laser between 750–800 nm [2]. The fluorescence is detected or viewed around the maximum peak of 832 nm with specifically designated scopes and cameras [1, 2]. It produces a nonlinear fluorescence quantum yield in relation to the concentration.

Injected intravascularly, around 98% binds to plasma proteins (serum albumin, α-, and β-lipoproteins) without altering the protein structure at the same time preventing dye extravasation and decreasing its tendency to aggregate. The concentration of the dye within the body should be kept below 15 mg/L, as it starts to aggregate at higher concentrations, which will result in “quenching” or a decrease in the fluorescence yield. The other 2% is free in the serum; eventually, both are taken up by the liver and excreted unchanged into the bile. Hepatic clearance is at the rate of 18–24% per minute, with exponential clearance observed in the first 10–20 min. After the initial period, the clearance rate slows down, allowing trace amounts to remain for more than an hour; the half-life is around 3–4 min [5]. Multiple or repeated application is possible due to the rapid clearance of the dye [4, 6].

Injected interstitially, the dye similarly binds to proteins and is usually detected in the closest draining lymph nodes within 15 min and to the regional lymph nodes after 1–2 h [2].

The lethal dose (LD50) is 50–80 mg/Kg in animal studies and is practically nontoxic at the standard dosage of <2 mg/Kg (0.1–0.5 mg/ml/Kg) provided the patient has no iodide allergy [1, 2, 6].

Some Applications of ICG Imaging in MIS

Cholecystectomy. Bile duct injury (BDI) is the most dreaded complication of cholecystectomy; the incidence ranges from 0.3% to 1.5% for the laparoscopic technique. Even with the introduction of the Critical View of Safety (CVS) concept by Strasberg, the incidence of bile duct injury remains around 0.42% [7]. Often cited reasons were aberrant anatomy and the distortion or misinterpretation of the biliary tract anatomy due to inflammatory changes. While intraoperative cholangiography (IOC) is accepted to provide a roadmap during surgery, it has several shortcomings such as increased operative time, the need for dedicated radiologic instrumentation and trained staff, requiring partial dissection of the Calot’s triangle and the cannulation of the cystic duct before IOC can be employed, and additional patient exposure to contrast and radiation. ICG allows real-time visualization of the biliary ducts and vessels before and during the dissection of the Calot’s triangle [7] (Fig. 2).

Fig. 2
An image of the gallbladder and extrahepatic biliary ducts in white visible light is displayed on the left. The image depicts a close-up view of the veins and gallbladder. Right, the same photo was taken with near-infrared light and I C G demonstrates unclear details of the gallbladder.

Gallbladder and extrahepatic biliary ducts under white light (left) and the same area under ICG-enhanced imaging (right) show target outline beneath overlying tissues. (Source: Pfiedler Education, Fluorescence Guided Surgery: A Nurse’s Guide to ICG. 2020)

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There is a wide variation in the dosage and timing of the ICG solution infusion for cholecystectomy. The dosage ranges from a single fixed bolus of 2.5 mg to weight-based dosing (0.05–0.5 mg/Kg). The timing varies widely, from just after induction of anesthesia to as long as 48 h before surgery. Tsutsui et al. [3] suggested the optimal timing of infusion to be around 15 h before surgery to attain optimum contrast between the biliary tract against the background liver and surrounding soft tissue. Report by Graves et al. [8] of successful visualization of the cystic duct and common bile duct with direct injection of 0.025 mg/mL ICG-bile solution into the gallbladder of 11 patients for cholecystectomy; the drawback to this technique is obstruction of the cystic duct or gallbladder neck by impacted stone, remedied by milking the stone into the gallbladder and allowing the gallbladder content to flow into the biliary duct. Intraoperative intravenous ICG injection (2–3 mL, 0.4 mg/Kg) may be done to clarify the cystic artery anatomy; it is usually visualized after 60 s and lasting about 32 s, repeat dosing may be done after 15 min to avoid quenching. In a comparative study against IOC by Osayi et al. [9], the biliary anatomy was visualized with ICG in 80% of cases where IOC could not. Similarly, Daskalaki et al. [10] noted a high visualization rate ranging 95.1–99% visualization of the biliary anatomy with ICG.

Bowel Anastomoses. Reconstruction after bowel resection in a gastrointestinal surgery has a wide rate for dehiscence (1–30%), with experienced hands, it is around 3–6%. One of the recognized risk factors for an anastomotic leak is the presence of poor local tissue oxygenation secondary to inadequate anastomotic vascular perfusion. Traditional blood flow assessment is subjective and based on surgical evaluation of bowel color, bowel peristalsis, pulsation of vessels, temperature, and bleeding from the marginal arteries [11]. Usually, more than 10 min are necessary for ischemia demarcation to become visible after vessel division [2]. More objective means have been suggested, such as Doppler measurement; however, this is cumbersome and requires additional training. The injection of ICG would allow real-time evaluation of bowel perfusion before resection and completion of the anastomosis. To evaluate the perfusion of the bowel, intravenous ICG injection is given using two boluses of 5 ml each at a concentration of 0.4 mg/Kg; the first, after the division of the vascular pedicle to help choose the best-perfused site for resection and the second, just before performing the anastomosis to ensure adequate vascularization (Fig. 3). A systematic review on the use of ICG to assess perfusion in colorectal anastomosis concluded that the surgical plan was changed in 10.8% of cases after application of ICG, and the leak rate was reduced from 7.4% to 3.4% [11]. A meta-analysis reported by Shen et al. [12] also suggested that ICG was associated with a lower leak rate OR 0.27 (95% CI 0.13–0.53). The RCT looking into the use of ICG in colorectal anastomoses by Alekseev et al. [11] noted a decrease in the leak rate among low rectal anastomoses (14.4% from 25.7%, p = 0.04).

Fig. 3
A photo indicates the evaluation of bowel perfusion for anastomosis. Two sections of the image are indicated by arrows.

Assessment of bowel perfusion for anastomosis: ICG lighting-up perfused bowel segment (blue arrow) distant from the planned bowel resection site (yellow arrow). (Source: Olympus)

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Summary

Currently, ICG imaging application in cholecystectomy for extrahepatic biliary tract visualization and the assessment of bowel perfusion for anastomoses have shown promising outcomes. Studies on its usage in other fields (gynecology, hepatobiliary surgery, neurosurgery, pediatric surgery, transplant, urology, etc.) are ongoing. In gynecology, oncology and endometrioses are the focus; detection of sentinel lymph nodes (SLN) with ICG may reduce the operative time and improve SLN detection, while endometrioses encounter a lack of robust evidence to conclude. In hepatobiliary surgery, investigations are directed towards liver mapping, cholangiography, tumor visualization, and liver graft evaluation; preliminary concerns exist regarding limited tissue penetration and instances of false positive or negative results. In general, there is a broad interest in applying ICG imaging to currently available diagnostic and therapeutic interventions, and there is a need for more robust studies to provide clear-cut conclusions and recommendations.