How Indocyanine Green Is Used in Surgery and Imaging

Indocyanine green, usually called ICG, is a fluorescent dye that glows under near-infrared light and has become one of the most versatile tools in modern surgery and medical imaging. Approved by the U.S. Food and Drug Administration for more than 60 years, it was originally developed for cardiac output testing and liver function assessment, but its uses have expanded dramatically since then.¹ Today, surgeons inject it to light up bile ducts during gallbladder removal, map lymph nodes during cancer operations, verify blood supply to freshly joined intestines, and guide tumor removal in the brain and lungs. What makes ICG unusual is the combination of a strong safety record, rapid clearance from the body, and the ability to fluoresce at wavelengths that penetrate tissue far better than visible light.

What ICG Is and How It Works

ICG is a water-soluble dye that absorbs light at near-infrared wavelengths, peaking around 780 nanometers in water, and emits fluorescence with a peak around 820 nanometers. Once injected into the bloodstream, it binds to proteins in the blood, especially albumin, and this binding shifts its absorption peak to about 815 nanometers.² That near-infrared range matters because tissues like skin, fat, and muscle are relatively transparent to it. Visible-light dyes get absorbed or scattered within millimeters of the surface, but near-infrared fluorescence can be detected through several millimeters of overlying tissue, which is why a surgeon can see a glowing bile duct or lymph node even before cutting down to it.

When a near-infrared camera system is pointed at tissue that has taken up ICG, the dye lights up on a screen in real time. Most modern surgical platforms, including robotic systems, come equipped with this capability. The surgeon toggles between normal white-light views and the fluorescence view, essentially giving them a live map of where the dye has traveled. Because ICG binds to plasma proteins and stays in the bloodstream until the liver clears it, structures with good blood flow glow brightly, and structures without it stay dark. That contrast is the basis for almost every clinical application.

How the Body Handles ICG

One of ICG’s most useful properties is also one of its simplest: the liver takes it up almost exclusively, and it gets excreted into bile without being metabolized. This means the dye does not linger in the body. In healthy individuals, the plasma half-life is only a few minutes. The liver’s uptake cells grab ICG from the bloodstream, and the dye passes into bile and eventually out through the gastrointestinal tract.

Research in pharmacokinetic modeling has shown that ICG clearance depends primarily on the liver cells’ capacity to absorb the dye and on biliary excretion, not on how much blood is flowing through the liver at any given moment.³ In patients with cirrhosis, blood clearance of ICG drops substantially. Studies have shown that this reduction is mainly caused by a decrease in the liver cells’ intrinsic ability to take up the dye, along with some leakage of the dye back into the plasma, rather than by changes in hepatic blood flow.⁴ This tight relationship between liver function and ICG clearance is exactly why the dye became a bedside test for liver health decades ago, and why it remains one today.

Testing Liver Function Before Major Surgery

Before removing a large portion of someone’s liver, surgeons need to know whether the remaining liver can handle the workload. Standard blood tests like bilirubin and albumin levels give a rough picture, but ICG clearance offers something more dynamic: a real-time measurement of how quickly the liver can process and excrete a known substance. Two metrics are commonly used. The plasma disappearance rate (PDR) measures how fast ICG leaves the bloodstream per minute. The retention rate at 15 minutes (R15) measures how much of the injected dose is still circulating after a quarter of an hour. A healthy liver clears ICG quickly, producing a high PDR and a low R15.

A large study analyzing preoperative ICG clearance in patients undergoing liver resection found that both PDR and R15 were significantly associated with postoperative liver dysfunction, even after accounting for other risk factors. The study identified cutoffs: a PDR below about 19.5 percent per minute or an R15 above about 5.6 percent flagged patients at higher risk of their remaining liver failing after surgery.⁵ ICG kinetics have also been reviewed extensively for their role in liver transplantation, where the stakes are even higher and knowing the graft’s real-time function can guide postoperative management.⁶

Lighting Up the Bile Ducts During Gallbladder Removal

Laparoscopic cholecystectomy, the keyhole surgery used to remove the gallbladder, is one of the most common operations worldwide. The most feared complication is accidentally cutting or clipping the common bile duct, which connects the liver to the intestine. Identifying the correct anatomy can be tricky, especially when inflammation from gallstones has distorted the tissue planes. This is where ICG fluorescence cholangiography has carved out a significant role.

A small dose of ICG is injected intravenously before or during surgery. Because the liver excretes it into bile, the bile ducts themselves start to glow under near-infrared imaging within minutes. The surgeon can then see the cystic duct (the one that needs to be cut), the common bile duct (the one that absolutely should not be cut), and the junction between them, all highlighted in fluorescent green on the screen. Multiple studies have confirmed that this technique improves visualization and identification of the biliary tree.⁷ Even in difficult cases with severe inflammation from acute cholecystitis, fluorescence cholangiography has been shown to help surgeons identify anatomical landmarks reliably and reduce operating time compared to traditional X-ray-based cholangiography.⁸ The confidence boost this provides is particularly valuable for surgeons in training and in emergency settings where the anatomy is obscured.⁹

Finding Sentinel Lymph Nodes in Cancer Surgery

In cancers like breast cancer and melanoma, the first lymph node that drains a tumor, called the sentinel node, is the one most likely to contain cancer cells if the disease has started to spread. Identifying and removing it for biopsy is a critical step in staging. Traditionally, this has involved radioactive tracers, blue dyes, or both. ICG fluorescence has emerged as a compelling alternative and supplement.

In breast cancer, a prospective study comparing ICG to the standard radiotracer scintigraphy found ICG achieved a detection rate just under 89 percent compared to scintigraphy’s 96 percent, with no systemic or local side effects from the dye. The fluorescence method was also significantly less expensive. The main limitation was in patients with very high body mass index, where the near-infrared signal struggled to penetrate the overlying tissue.¹⁰ When compared head-to-head with methylene blue dye, ICG found more sentinel nodes per patient, with an average of about 3.5 nodes versus 2.4 for blue dye, and achieved a perfect 100 percent detection rate versus 93 percent for methylene blue.¹¹ Combining ICG with a conventional blue dye pushes detection rates even higher, approaching 99.5 percent, and catches involved lymph nodes that either method alone might miss.¹²

In melanoma, near-infrared fluorescence imaging with ICG bound to human serum albumin showed 98 percent accuracy compared to the radioactive colloid standard. As doses were escalated, the signal-to-background ratio improved substantially, helping the surgeon distinguish the glowing node from surrounding tissue.¹³ The visual, real-time nature of ICG fluorescence is a practical advantage over radioactive methods, which require a handheld gamma probe and preoperative scheduling with a nuclear medicine department.¹⁴

Checking Blood Supply to Prevent Anastomotic Leaks

When surgeons reconnect two ends of the colon or rectum after removing a segment for cancer, the join (anastomosis) can sometimes leak. Anastomotic leaks are among the most dreaded complications in colorectal surgery because they lead to infection, additional operations, and sometimes death. One of the main causes is insufficient blood flow to the tissue at the join. ICG fluorescence lets the surgeon check perfusion in real time: inject the dye, switch to near-infrared view, and watch whether the tissue at the planned anastomosis lights up brightly.

An early study of robotic rectal surgery found that in about one in five patients, the ICG perfusion check prompted the surgeon to move the point where they transected the colon, choosing a better-perfused location. The leak rate in the ICG group was 6 percent compared to 18 percent in a control group that relied on the surgeon’s naked-eye judgment alone.¹⁵ These findings have since been confirmed at a larger scale. A systematic review and meta-analysis of randomized controlled trials found that ICG-guided perfusion assessment reduced clinical anastomotic leaks by about 31 percent compared to standard assessment, translating to roughly 29 fewer leaks per 1,000 procedures.¹⁶ For a complication that can mean weeks in the hospital and a temporary stoma, that is a meaningful reduction.

Applications in Brain Surgery

Cerebrovascular surgery, particularly the clipping of brain aneurysms, demands precision at a level measured in fractions of a millimeter. A misplaced clip can occlude a normal artery feeding healthy brain tissue, or it can leave a neck of the aneurysm patent so it continues to bleed. Microscope-integrated ICG video angiography lets the neurosurgeon see, in real time, whether the clip has fully excluded the aneurysm and whether the parent and branching arteries remain open.¹⁷

A retrospective study comparing outcomes with and without ICG angiography during ruptured aneurysm clipping found that the ICG group had a significantly lower rate of vascular complications: roughly 3 percent versus nearly 10 percent in the group that did not use fluorescence imaging.¹⁸ The technique has also proven useful in arteriovenous malformation surgery and bypass procedures, though it does have a limitation: because ICG shows only the surface of the surgical field, structures hidden beneath brain tissue or thick clot cannot be visualized. For those situations, conventional catheter-based angiography remains the gold standard.

Imaging the Choroid in Ophthalmology

Before ICG became a surgical staple, ophthalmologists were already using it to photograph the blood vessels behind the retina. The choroid, the vascular layer that nourishes the outer retina, is difficult to image with standard fluorescein angiography because fluorescein does not penetrate the retinal pigment epithelium well. ICG, with its near-infrared fluorescence and strong protein binding, passes through that pigment layer more easily, revealing the deeper choroidal vasculature in sharp detail.

In age-related macular degeneration, ICG angiography plays a specific role that standard fluorescein cannot fill. It differentiates types of abnormal blood vessel growth beneath the retina and identifies particular entities like polypoidal choroidal vasculopathy that look ambiguous on other imaging.¹⁹ While the advent of anti-VEGF treatments has somewhat reduced the need to pinpoint the exact location of abnormal vessels before treatment, many clinicians still use ICG angiography alongside other retinal imaging to classify the subtype and guide management decisions.²⁰ Recent research using ICG angiography has also characterized the distribution patterns of choroidal arteries and veins in AMD eyes, revealing atrophy of small blood vessels and reduced perfusion pressure, which may eventually inform how aggressively certain subtypes are treated.²¹

Locating Liver Cancer Metastases in the Lungs

One of ICG’s more surprising applications exploits the same hepatic uptake mechanism that makes it useful for liver function testing, but in reverse. Hepatocellular carcinoma cells, even when they have spread to distant sites like the lungs, retain some of the liver cell machinery that takes up ICG. When a patient receives ICG intravenously before surgery, the cancer cells absorb it but cannot excrete it normally, so the dye accumulates and fluoresces under near-infrared light. This has proven useful for finding small pulmonary metastases during thoracoscopic surgery.

In one series, ICG fluorescence was confirmed through the surface of the lung in six of seven lesions removed by wedge resection, and all tumors fluoresced when cut open. Every lesion was confirmed as metastatic hepatocellular carcinoma on pathology.²² In another study examining 28 lesions intraoperatively, 24 showed ICG fluorescence and were pathologically confirmed as metastases, with five of those 28 being newly discovered only because of the fluorescence, meaning they were not visible or palpable by conventional means.²³ Thoracoscopic approaches have also used the fluorescence signal to confirm adequate surgical margins during minimally invasive resection.²⁴ This technique does not work for all cancers, since the mechanism relies on the tumor cells’ retained liver-specific uptake pathways, but for hepatocellular carcinoma it has become a genuinely useful intraoperative tool.

Safety and Side Effects

ICG has an excellent safety profile, which is a large part of why it has spread into so many surgical specialties so quickly. In one prospective evaluation of more than 1,900 intravenous ICG administrations for ophthalmic angiography, the incidence of mild adverse reactions was about 0.15 percent, moderate reactions about 0.2 percent, and severe reactions about 0.05 percent. A similarly large series of nearly 3,800 ICG administrations reported an adverse reaction rate of just 0.34 percent, with most reactions being mild.²⁵

That said, severe reactions do happen, including rare cases of anaphylactic shock and death. Early assumptions blamed the iodide component in some ICG preparations, but adverse events have been documented with iodide-free formulations as well, and ICG has been used safely in patients with known iodine allergies. There is no established dose threshold below which reactions cannot occur: anaphylaxis has been reported after as little as 5 milligrams intravenously. Skin testing and low-dose intravenous challenges have not proven useful for predicting who will react. The practical takeaway is that while the risk is very low, any facility using ICG should have anaphylaxis protocols in place.²⁶

Pediatric Uses

The same properties that make ICG useful in adults translate well to pediatric surgery, where the smaller anatomy and limited margin for error make real-time visualization even more valuable. In children, ICG fluorescence has been applied to assess perfusion during complex pelvic reconstructions, check the blood supply at anastomoses after esophageal atresia repair, and delineate the dissection plane in the Kasai procedure, which is the operation for biliary atresia where the surgeon creates a new connection between the liver and the intestine. Because ICG accumulates in liver tumors much as it does in adult hepatocellular carcinoma, it has been used to identify primary and metastatic hepatoblastoma lesions, the most common liver cancer in young children. Subcutaneous injection of ICG can also map lymphatic flow, helping locate chylous leaks and improve sentinel lymph node biopsy results in pediatric oncology cases.²⁷

Research Into Phototherapy and Nanoparticle Delivery

Beyond imaging, ICG has attracted attention as a potential therapeutic agent because it converts absorbed near-infrared light into heat and also generates reactive oxygen species, two mechanisms that can damage cancer cells directly. The challenge is that free ICG in solution degrades quickly: it aggregates, loses its fluorescence, and gets cleared from the blood before enough of it can accumulate in a tumor. Researchers have been working to solve this by packaging ICG inside nanoparticles.

Gold nanoparticles conjugated with ICG have been shown to combine photothermal and photodynamic effects, killing cancer cells more effectively than either approach alone while also improving ICG’s stability under laser irradiation.²⁸ Tumor-targeting liposomes loaded with ICG and modified with peptides that help them penetrate tumors have shown accurate detection of breast tumors in imaging studies and enhanced therapeutic effect.²⁹ A persistent problem has been that even encapsulated ICG tends to degrade during storage. Hybrid nanoparticles made from the plant protein zein and phosphatidylcholine nearly completely prevented ICG aggregation during storage and doubled the phototoxicity against cancer cells compared to standard phospholipid nanoparticles alone.³⁰ Other groups have stabilized ICG aggregates inside liposomes, finding that optimizing the lipid composition, particularly using high-melting-point lipids and cholesterol, preserved the dye’s properties in biological fluids like blood and serum.³¹

These engineered formulations also open doors to newer imaging techniques. ICG-loaded perfluorocarbon nanodroplets have been demonstrated as dual-contrast agents for both photoacoustic and ultrasound imaging, where a laser pulse triggers the droplet to vaporize into a bubble that enhances ultrasound signal while the ICG simultaneously provides photoacoustic contrast.³² PEGylated ICG liposomes have been imaged with multispectral optoacoustic tomography, showing strong signal generation and allowing researchers to track tumor accumulation over time with high resolution.³³ Photoacoustic tomography with ICG has even been used to reproduce the fluorescence patterns of human liver tumors in resected specimens, suggesting it could eventually improve cancer detection during ultrasonographic exams.³⁴ None of these nanoparticle-based approaches have reached routine clinical use yet, but they illustrate how a 60-year-old dye continues to find new life in modern medicine.

Veterinary Surgery

ICG fluorescence has begun crossing over into veterinary medicine, where many of the same surgical challenges exist. In dogs undergoing surgery for liver masses, ICG fluorescence imaging proved useful for identifying tumor margins and assessing whether resection was complete. Although the fluorescence pattern alone could not reliably distinguish between different types of liver tumors, confirming complete removal of hepatocellular carcinoma with fluorescence guidance appeared to offer a survival benefit.³⁵ The technique has also been used successfully to visualize adrenal tumor margins during removal of a pheochromocytoma in a dog, helping the surgeon achieve complete resection while minimizing the risks of a lengthy procedure under anesthesia.³⁶ In endocrine surgery, ICG has been tested as a way to locate parathyroid glands during thyroidectomy in dogs, where accidentally removing these tiny glands can cause dangerous drops in calcium levels. The near-infrared fluorescence allowed reliable detection of the glands, offering a potential safeguard for veterinary surgeons performing thyroid procedures.³⁷