Comprehensive Monograph on Indocyanine Green (DB09374)

Executive Summary

Indocyanine Green (ICG) is a tricarbocyanine dye with a remarkable history, evolving from a mid-20th-century diagnostic tool into a cornerstone of modern near-infrared (NIR) fluorescence-guided surgery. First approved by the U.S. Food and Drug Administration (FDA) in 1959, its initial applications were centered on measuring cardiac output and hepatic function, leveraging its unique pharmacokinetic profile. This profile is characterized by rapid and strong binding to plasma proteins, which confines the molecule to the intravascular space, and an exclusive, rapid elimination pathway through the liver into the bile without undergoing metabolic alteration.

The advent of sophisticated NIR imaging technologies has catalyzed a renaissance for ICG, transforming it into a versatile intraoperative navigation aid. Its spectral properties, with absorption and emission peaks in the NIR window, allow for deep tissue penetration with a high signal-to-noise ratio, enabling real-time visualization of anatomical structures and physiological processes. Key contemporary applications include ophthalmic angiography for diagnosing choroidal diseases, intraoperative cholangiography to prevent bile duct injury during cholecystectomy, comprehensive perfusion assessment to reduce anastomotic leaks in colorectal surgery and flap necrosis in reconstructive surgery, and high-precision sentinel lymph node mapping in oncologic surgery.

Despite its broad utility and excellent safety profile—with the primary risk being rare but serious iodide-related hypersensitivity reactions—free ICG possesses intrinsic limitations, including poor photostability, a short circulatory half-life, and a lack of target-cell specificity. Current research is intensely focused on overcoming these challenges through nanotechnology. The development of novel nano-formulations, such as liposomal ICG and targeted nanoparticle conjugates, aims to enhance stability, prolong circulation time, and introduce cancer-cell specificity. These advancements signal a transformative future for ICG, moving it beyond a passive dye and toward a new generation of targeted molecular imaging agents with potential theranostic applications. This report provides an exhaustive analysis of ICG, covering its fundamental chemistry, pharmacology, diverse clinical applications, safety, regulatory status, and the future directions of its research.

I. Identification and Physicochemical Profile

This section establishes the fundamental identity of Indocyanine Green, meticulously clarifying its nomenclature and reconciling data from various sources to provide a definitive chemical and physical characterization. The distinction between the active moiety (acid form/zwitterion) and the clinically utilized sodium salt is critical for a precise understanding of the substance.

1.1. Nomenclature, Synonyms, and Identifiers

Indocyanine Green is known by a variety of chemical names, commercial brand names, and research identifiers, reflecting its long history and diverse applications. The substance queried, "Indocyanine green acid form," corresponds to the active moiety, which exists as a zwitterion or inner salt.[1]

• Primary Identification (Acid Form/Zwitterion):
• DrugBank ID: DB09374 [1]
• CAS Number: 28782-33-4 [3]
• PubChem CID: 135564886 [6]
• Sodium Salt (Common Clinical Form): The form most widely used in pharmaceutical preparations is the sodium salt.
• DrugBank Salt ID: DBSALT001946 [7]
• CAS Number: 3599-32-4 [3]
• UNII (Unique Ingredient Identifier): IX6J1063HV [7]
• PubChem CID: 11967809 (as Cardio-Green), 5282412 (as Indocyanine Green) [2]
• Synonyms and Commercial Names: Over the decades, ICG has been marketed under numerous names, including:
• Common Synonyms: Ic-green, ICG, Foxgreen, Ujoveridin, Vofaverdin, Wofaverdin [1]
• Brand Names: IC-Green®, Cardio-Green, Verdye, Spy Agent Green [2]
• Research/External IDs: IR 125, NK 1611, Crysta-lyn 551522, NK 5078 [1]
• Formal Chemical (IUPAC) Names:
• Sodium Salt: sodium;4-[(2E)-2-[(2E,4E,6E)-7-[1,1-dimethyl-3-(4-sulfonatobutyl)benzo[e]indol-3-ium-2-yl]hepta-2,4,6-trienylidene]-1,1-dimethylbenzo[e]indol-3-yl]butane-1-sulfonate.[2] An alternative name is 1H-Benz[e]indolium, 2-[1,3-dihydro-1,1-dimethyl-3-(4-sulfobutyl)-2H-benz[e]indol-2-ylidene]-1,3,5-heptatrienyl]-1,1-dimethyl-3-(4-sulfobutyl)-,hydroxide, inner salt, sodium salt.[1]

1.2. Chemical Structure, Formula, and Molecular Weight

Indocyanine Green is a water-soluble, tricarbocyanine dye. Its structure is characterized by two substituted benz[e]indole heterocyclic rings linked by a polymethine (heptamethine) bridge.[1] Attached to each nitrogen atom of the indole rings is a sulfobutyl group, which confers the molecule's water solubility.[7]

The slight variations in reported molecular formulas and weights across chemical databases and supplier specifications are not data conflicts but rather reflect the molecule's different chemical states. This highlights the necessity of using precise identifiers like CAS numbers to distinguish between the active moiety and its various forms, a critical detail for analytical chemistry, regulatory submissions, and formulation science.

• Indocyanine Green Acid Form (Zwitterion, DB09374): This is the active moiety without a counter-ion.
• Molecular Formula: C43​H48​N2​O6​S2​ [4]
• Molecular Weight: 752.98 g/mol [4]
• Indocyanine Green Sodium Salt (CAS 3599-32-4): This is the typical form in pharmaceutical products, where one of the acidic protons of the sulfonate groups is replaced by a sodium ion.
• Molecular Formula: C43​H47​N2​NaO6​S2​ [7]
• Molecular Weight (Average): 774.97 g/mol to 775.0 g/mol [2]
• Monoisotopic Mass: 774.27732387 Da [7]
• Indocyanine Green N-Oxide: This is a known impurity and is used as a reference standard in quality control during manufacturing.
• Molecular Formula: C43​H49​N2​O7​S2​ (Note the extra oxygen atom) [3]
• Molecular Weight: 770.0 g/mol [3]

1.3. Physical and Chemical Properties

The physical characteristics of ICG are central to its formulation as a sterile powder for injection and its behavior in solution.

• Appearance: In its solid state, ICG is a dark green, blue-green, olive-brown, or black, odorless or slightly odorous crystalline powder.[8] When reconstituted in an aqueous solution, it forms a deep emerald-green liquid.[8]
• Solubility: ICG is soluble in water and methanol but is practically insoluble in most other organic solvents.[8] Commercial formulations for injection include no more than 5% sodium iodide, which is added to improve solubility and stability in the lyophilized powder form.[1]
• Stability: The molecule is notably unstable in aqueous solutions, which must be prepared under sterile conditions and used within a few hours (typically 6 hours) of reconstitution.[8] Any solution containing a precipitate should be discarded.[18] In contrast, the dye is stable once bound to proteins in plasma and whole blood, allowing samples from discontinuous measurements to be analyzed hours later.[19] It is also sensitive to light and should be protected from it after reconstitution.[17]
• Thermal Decomposition: It decomposes gradually at temperatures above 200°C.[8] Reported melting points vary, with ranges of 190-198°C and a point of 235°C cited, likely reflecting differences in purity and the specific form being tested.[4]
• pH: When reconstituted as directed for injection, the resulting solution has a pH of approximately 6.0 to 6.5.[1]

1.4. Spectral Characteristics

The unique spectral properties of ICG are the absolute foundation of its clinical utility in fluorescence imaging.

• Absorption and Emission: ICG exhibits strong absorption and fluorescence in the near-infrared (NIR) region of the electromagnetic spectrum. Its peak spectral absorption (λmax​) in blood plasma at low concentrations is approximately 800-805 nm.[1] Its fluorescence emission peak occurs at a longer wavelength, typically around 830-840 nm.[17]
• Environmental Dependence: The precise wavelengths for peak absorption and emission are highly dependent on the solvent, the dye's concentration, and its binding state.[17] For example, the emission maximum is ~810 nm in water but shifts to ~830 nm in blood due to protein binding.[17] This dependency is a critical consideration in the design and calibration of the specialized imaging systems used to detect it.
• Significance of the Near-Infrared Window: The absorption and emission spectra of ICG fall squarely within the so-called "optical window" of biological tissue (roughly 700-900 nm). In this range, the absorption of light by endogenous chromophores like hemoglobin and water is at a minimum, and tissue autofluorescence is significantly reduced.[21] This unique property allows the excitation light to penetrate deeper into tissues and the emitted fluorescence to be detected with a high signal-to-noise ratio, enabling clear visualization of structures several centimeters below the surface.[21]

Table 1: Consolidated Physicochemical Properties of Indocyanine Green
Characteristic	Indocyanine Green Acid Form (Zwitterion)	Indocyanine Green Sodium Salt (Clinical Form)
DrugBank ID	DB09374 1	DBSALT001946 7
CAS Number	28782-33-4 3	3599-32-4 3
Molecular Formula	C43​H48​N2​O6​S2​ 4	C43​H47​N2​NaO6​S2​ 7
Molecular Weight	752.98 g/mol 4	774.97 g/mol 7
Appearance	Dark green to black powder 4	Dark green, blue-green, or black powder 8
Solubility	Soluble in water and methanol 8	Soluble in water and methanol 8
Stability	Unstable in aqueous solution; light-sensitive 8	Unstable in aqueous solution (use within 6 hrs); light-sensitive 8
pH (Reconstituted)	Not applicable (not formulated for injection)	~6.5 1
λmax (Absorption)	~800 nm (in blood plasma) 1	~800 nm (in blood plasma) 1
λmax (Emission)	~830 nm (in blood) 21	~830 nm (in blood) 21

II. Pharmacology and Pharmacokinetics

This section details the biological behavior of ICG, explaining the mechanisms that make it a uniquely effective diagnostic and imaging agent. Its action is not pharmacological but rather biophysical, relying entirely on its distribution and optical properties.

2.1. Pharmacodynamics (Mechanism of Action)

Indocyanine Green does not exert a direct pharmacological effect on biological tissues or receptors. Instead, its mechanism of action is that of a diagnostic dye whose utility is derived from its unique fluorescence properties and pharmacokinetic behavior.[8]

The core of its function begins immediately upon intravenous injection, where it rapidly and tightly binds to plasma proteins, with approximately 98% of the injected dose becoming protein-bound.[1] The primary carriers are albumin and various lipoproteins.[17] This high degree of protein binding is a crucial pharmacodynamic characteristic, as it effectively confines the dye to the intravascular space and prevents significant extravasation or diffusion into the surrounding interstitial tissues under normal physiological conditions.[1]

This vascular confinement is fundamental to its applications in angiography and perfusion assessment. When the tissue of interest is illuminated with an external light source in the near-infrared (NIR) spectrum (typically with a laser or LED emitting at ~780-800 nm), the protein-bound ICG molecules are excited. They then release this energy by emitting fluorescent light at a slightly longer wavelength, with a peak around 830 nm.[21] This emitted fluorescence is captured by specialized camera systems, allowing for the real-time visualization of vascular structures, the dynamic assessment of blood flow, and the mapping of lymphatic drainage pathways.[21]

2.2. Pharmacokinetics (ADME Profile)

The absorption, distribution, metabolism, and excretion (ADME) profile of ICG is central to its clinical utility, particularly for intraoperative imaging. The combination of its rapid distribution and clearance creates a profile that is almost perfectly suited for dynamic, real-time surgical guidance.

• Absorption: As a diagnostic agent administered directly into the target compartment, traditional absorption metrics are not applicable. For systemic applications, it is given intravenously. For lymphatic mapping, it is injected interstitially, where it is absorbed into the lymphatic capillaries.[32]
• Distribution: Following intravenous injection, distribution is rapid and almost exclusively confined to the vascular system due to its high affinity for plasma proteins.[1] This results in a small volume of distribution. The circulatory half-life is remarkably short, consistently reported to be between 150 and 180 seconds (2.5 to 3.0 minutes).[1] There is negligible uptake or distribution into extravascular tissues such as the kidneys, lungs, periphery, or cerebrospinal fluid.[1]
• Metabolism: ICG is not metabolized. It undergoes no significant biotransformation, conjugation, or degradation within the body.[1] The dye that is cleared from the body is in the same unconjugated form as it was when administered. This lack of metabolism ensures that its pharmacokinetic profile is consistent and predictable, and that its clearance rate is a pure reflection of organ function rather than enzymatic activity.
• Excretion: The clearance of ICG from the body is highly specific. It is taken up from the plasma almost exclusively by the parenchymal cells of the liver (hepatocytes).[1] From the hepatocytes, it is secreted entirely and unchanged into the bile.[1] There is no significant extrahepatic or enterohepatic circulation, meaning once it enters the bile, it is committed to excretion via the gastrointestinal tract.[1] This exclusive and rapid hepatic clearance pathway is the principle behind its long-standing use as a test for liver function and hepatic blood flow.[1] In cases of biliary obstruction, the dye may appear in the hepatic lymph, suggesting a minor, alternative clearance route under pathological conditions, but this is not a significant pathway in normal physiology.[1]

The unique combination of these pharmacokinetic parameters—a very short half-life, strict vascular confinement, and rapid, exclusive, non-metabolic hepatic clearance—is not merely a collection of properties but a synergistic profile that makes ICG exceptionally well-suited for intraoperative imaging. A long-acting agent would be impractical for dynamic surgical assessment, as a persistent background signal would obscure subsequent measurements. ICG's ~3-minute half-life provides a bright, clear signal for a brief period, after which it is rapidly cleared from the bloodstream. This rapid clearance is a distinct advantage, as it enables surgeons to administer multiple, small, sequential boluses of the dye during a single procedure. This allows for repeated assessments of perfusion at different critical stages, such as before and after the creation of a vascular or intestinal anastomosis, without the problem of cumulative signal interference that would confound the interpretation of later images.[21] This ability to provide immediate, actionable, and repeatable feedback to the surgeon is a key reason for its modern resurgence.

III. Clinical Applications and Efficacy

This section provides an exhaustive review of Indocyanine Green's clinical journey, detailing its evolution from a classic diagnostic agent for internal medicine to an indispensable, high-tech tool for modern surgical navigation.

3.1. Established Diagnostic Indications

Long before its use in fluorescence-guided surgery, ICG was a well-established diagnostic agent, with its primary uses approved by the FDA in 1959.[29] These applications leverage its unique pharmacokinetic properties.

• Hepatic Function and Blood Flow: The exclusive and rapid clearance of ICG by the liver makes it an excellent indicator of hepatic function. Following an intravenous bolus, the rate at which the dye disappears from the plasma is a direct measure of liver blood flow and the functional capacity of hepatocytes.[1] Clinicians can calculate metrics such as the ICG plasma disappearance rate (PDR) and the percentage retention at a specific time point (e.g., 15 minutes) to quantitatively assess liver health, which is particularly valuable in pre-operative planning for liver resections.[21]
• Cardiac Output Determination: In cardiology, ICG is used in indicator-dilution studies. A known quantity of the dye is injected as a rapid bolus into the central circulation (e.g., via a cardiac catheter). The concentration of the dye is then measured over time at a downstream arterial site. The resulting time-concentration curve allows for the calculation of cardiac output, a fundamental measure of heart performance.[1]
• Ophthalmic Angiography: ICG angiography (ICGA) is a cornerstone of diagnostic imaging in ophthalmology. Its near-infrared spectral properties are a key advantage over traditional fluorescein angiography. Because NIR light penetrates pigmented tissues more effectively, ICGA allows for superior visualization of the deeper choroidal vascular network, which lies beneath the retinal pigment epithelium.[21] This makes it an invaluable tool for diagnosing, evaluating, and managing a range of posterior segment eye diseases, including wet age-related macular degeneration (AMD), choroidal neovascularization, central serous retinopathy, and various forms of choroiditis.[1]

3.2. Fluorescence-Guided Surgery (FGS): Anatomical Mapping

The development of sensitive NIR cameras has unlocked the potential of ICG for real-time intraoperative anatomical navigation. In these applications, ICG is not just staining tissue; it is revealing physiological function or dysfunction, making it a functional contrast agent. In cholangiography, it visualizes the function of biliary excretion; in liver tumor detection, it highlights the dysfunction of that excretion; and in lymph node mapping, it traces the function of lymphatic drainage. This provides surgeons with a level of information beyond static anatomy.

• Intraoperative Cholangiography: During laparoscopic cholecystectomy (gallbladder removal), the intravenous administration of ICG leads to its excretion into the bile. Using an NIR-enabled laparoscope, the surgeon can visualize the entire extrahepatic biliary tree—including the cystic duct, common hepatic duct, and common bile duct—as it fluoresces.[29] This "fluorescence cholangiography" provides a real-time roadmap of the critical biliary anatomy, which is especially useful in cases of severe inflammation or anatomical variations where visual identification is difficult. It has been shown to be a faster and less invasive alternative to conventional X-ray cholangiography, which requires catheterization of the bile duct and radiation exposure, and may help reduce the incidence of devastating bile duct injuries.[29]
• Hepatic Surgery: In liver surgery, ICG has dual utility. First, it can be used to demarcate hepatic segments for precise anatomical resections. Different portal vein branches can be selectively injected with ICG to illuminate the corresponding liver segment.[29] Second, it aids in the detection of liver tumors. Hepatocellular carcinoma (HCC) and the non-cancerous liver tissue surrounding metastatic adenocarcinoma foci often have impaired biliary excretion. When ICG is administered pre-operatively, these areas retain the dye longer than healthy liver tissue. Intraoperatively, these retained-ICG areas fluoresce brightly, helping the surgeon identify subcapsular tumors and delineate resection margins, which is particularly valuable in minimally invasive surgery where tactile feedback is limited.[29]
• Sentinel Lymph Node (SLN) Biopsy: This has become a major application in surgical oncology. The technique involves injecting ICG interstitially near a primary tumor (e.g., in the skin around a melanoma, the breast areola for breast cancer, or the uterine cervix for gynecologic cancers).[21] The small ICG molecules are readily absorbed by lymphatic vessels and travel with the flow of lymph to the first draining lymph node(s) in the regional basin—the sentinel nodes. An NIR camera system is then used to visualize the fluorescent lymphatic channels as a "roadmap" leading directly to the glowing sentinel nodes.[29] This allows for highly targeted dissection of the SLNs, minimizing the extent of surgery and the associated morbidity of a full lymph node dissection. This technique has been extensively validated and is widely used in the surgical management of breast cancer, melanoma, and is increasingly adopted for cervical and uterine cancers.[33]

3.3. Fluorescence-Guided Surgery (FGS): Perfusion Assessment

Perhaps the most impactful modern application of ICG is the real-time assessment of tissue and organ blood flow (perfusion) during surgery.

• Anastomotic Perfusion: In gastrointestinal surgery, particularly colorectal surgery, ensuring adequate blood supply to a newly created anastomosis (a surgical connection between two parts of the intestine) is critical. Poor perfusion is a primary cause of anastomotic leakage, a severe and life-threatening complication. After the anastomosis is constructed, the surgeon can request an intravenous bolus of ICG. Within seconds, the arterial blood flow will deliver the fluorescent dye to the intestinal tissue, and the NIR camera will show the tissue "light up." The surgeon can visually confirm robust, uniform fluorescence on both sides of the anastomosis. If an area appears dark, indicating poor perfusion, the surgeon can revise the anastomosis immediately. Multiple large-scale studies and meta-analyses have shown that the routine use of ICG for perfusion assessment in colorectal surgery leads to a change in the planned resection line in a significant number of cases and is correlated with a substantial reduction in the rate of anastomotic leaks.[36]
• Plastic and Reconstructive Surgery: ICG is used to assess the viability of tissue flaps and grafts. Whether it is a free flap transferred with its own microvascular supply or a pedicled flap, surgeons can use ICG fluorescence to visualize the blood flow throughout the flap after it has been inset. This allows for an immediate assessment of whether the entire flap is well-perfused. This can help predict and prevent post-operative flap necrosis, reducing the need for re-operations and improving patient outcomes.[36]
• Cardiovascular Surgery: During coronary artery bypass grafting (CABG), surgeons can use ICG to confirm the patency of the newly placed bypass grafts. An injection of ICG will show the dye flowing through the graft and perfusing the heart muscle distal to the blockage, providing immediate confirmation of a successful bypass.[21]
• Emergency and Other Surgeries: The application of perfusion assessment extends to many other areas. In emergency surgery for acute mesenteric ischemia (lack of blood flow to the intestines), ICG can help the surgeon determine which segments of the bowel are viable and which must be resected.[36] It is also used to assess perfusion in strangulated hernias, in organ transplantation, and in cases of testicular or ovarian torsion to help decide between organ preservation and removal.[36]

3.4. Investigational and Emerging Applications

Research continues to expand the utility of ICG into new clinical domains.

• Pediatric Oncology: Clinical trials are actively investigating the use of ICG for intraoperative tumor visualization in children. The goal is to use NIR imaging to better define tumor margins and detect small metastatic deposits during surgery for solid tumors such as osteosarcoma, neuroblastoma, and Wilms tumor, with the aim of improving the completeness of resection and reducing recurrence.[40]
• Lymphatic Disorders: Beyond oncologic mapping, ICG lymphography is being used as a diagnostic tool to visualize lymphatic architecture and function in patients with disorders like lymphedema and lipoedema. This can help characterize the extent of lymphatic impairment and guide therapeutic interventions.[48]
• Neurosurgery: ICG is used in cerebrovascular neurosurgery to visualize blood flow in real-time. During aneurysm clipping, for example, it can confirm the successful occlusion of the aneurysm while ensuring the patency of the parent and adjacent vessels.[17]

IV. Formulations, Dosage, and Administration

This section provides practical, clinically relevant information on how Indocyanine Green is prepared, formulated, and administered for its various clinical indications.

4.1. Commercial Formulations and Reconstitution

Indocyanine Green is commercially supplied as a sterile, lyophilized (freeze-dried) powder in single-patient-use glass vials, most commonly containing 25 mg of the active substance.[1] The powder has a characteristic green to black appearance.[8] The formulation typically includes a small amount of sodium iodide (not exceeding 5% by weight) which is added during manufacturing to enhance the solubility and stability of the final lyophilized product.[1]

Reconstitution must be performed under sterile conditions immediately prior to use. The powder is dissolved using the diluent provided in the kit, which is Sterile Water for Injection, USP.[18] The concentration of the final solution depends on the intended clinical application. For many surgical imaging applications, a 2.5 mg/mL solution is prepared by adding 10 mL of sterile water to a 25 mg vial.[33] For other specific uses, such as lymphatic mapping in gynecologic oncology, a different concentration of 1.25 mg/mL is required.[33]

A critical handling instruction is that the reconstituted aqueous solution is unstable and must be used within 6 hours of preparation.[18] Before administration, the solution must be visually inspected for any particulate matter or precipitate; if any is present, the solution must be discarded.[18]

4.2. Administration Routes and Indication-Specific Dosing

The route of administration and the dosage of ICG are highly dependent on the clinical objective. The primary routes are intravenous (IV) for applications requiring systemic circulation and interstitial for local tissue and lymphatic mapping.[32] The total cumulative dose administered during a single procedure should not exceed 2 mg/kg of body weight.[18]

The following table provides a consolidated guide to the recommended dosing and administration for the major clinical indications of ICG, compiled from FDA-approved product labeling and clinical guidelines. This table serves as a practical reference for clinicians to ensure appropriate and safe use of the agent.

Table 2: Summary of Clinical Indications, Administration Routes, and Recommended Dosages
Clinical Indication	Target Population	Route of Administration	Recommended Dose & Concentration	Key Administration Notes
Vessel / Tissue Perfusion Imaging	Adults & Pediatric Patients (≥1 month)	Intravenous (IV)	1.25 mg to 5 mg (as 0.5 mL to 2 mL of a 2.5 mg/mL solution). For extremity perfusion, 3.75 mg to 10 mg. 32	Administer as a rapid bolus via central or peripheral line. Immediately follow with a 10 mL saline flush (adjust flush for pediatrics). Multiple doses can be given, not to exceed 2 mg/kg total. 33
Extrahepatic Biliary Duct Visualization	Adults & Pediatric Patients (≥12 years)	Intravenous (IV)	2.5 mg (as 1 mL of a 2.5 mg/mL solution). 32	Administer at least 45 minutes prior to surgery to allow for hepatic uptake and biliary excretion. 32
Lymphatic Mapping (Cervical & Uterine Cancer)	Adults	Interstitial	5 mg total dose, administered as four 1 mL injections of a 1.25 mg/mL solution. 32	Injections are made into the cervical stroma at the 3 and 9 o'clock positions, with both a superficial (1-3 mm) and a deep (1-3 cm) injection at each site. 33
Lymphatic Mapping (Breast Cancer)	Adults	Intradermal	0.25 mg per breast (as two 0.05 mL peri-areolar injections). A subsequent 0.375 mg peri-tumoral dose may be given. 50	Injected into the areola closest to the tumor or around the tumor itself. Fluorescence appears within minutes. 34
Ophthalmic Angiography	Adults & Pediatric Patients	Intravenous (IV)	Up to 40 mg in 2 mL of sterile water. 18	Administered as a rapid bolus into the antecubital vein, immediately followed by a 5 mL bolus of normal saline. 18
Hepatic Function Studies	Adults & Pediatric Patients	Intravenous (IV)	0.5 mg/kg of body weight. 18	Patient should be in a fasting state. Dose is calculated based on weight and injected as a rapid bolus. Blood samples are drawn at timed intervals. 18
Cardiac Output Determination	Adults, Children, Infants	Intravenous (IV)	Adults: 5.0 mg; Children: 2.5 mg; Infants: 1.25 mg. 18	Administered as a rapid bolus, typically in a 1 mL volume, via a cardiac catheter. An average of five dilution curves may be performed. 18

V. Safety, Tolerability, and Risk Management

This section provides a critical evaluation of Indocyanine Green's safety profile, drawing from over six decades of clinical use and regulatory oversight. While generally well-tolerated, there are specific risks, primarily related to hypersensitivity, that require careful management.

5.1. Adverse Reactions and Hypersensitivity

The overall incidence of adverse reactions to ICG is low, but the potential for serious reactions exists.

• Primary Concern - Hypersensitivity: The most significant and frequently reported adverse events are hypersensitivity reactions. These can range in severity from mild urticaria (hives) and pruritus (itching) to severe, life-threatening anaphylaxis.[19] Deaths due to anaphylaxis have been reported, particularly in the context of cardiac catheterization procedures.[19]
• Link to Iodide Content: These hypersensitivity reactions are strongly associated with the sodium iodide present in the formulation. As such, a history of allergy to iodides is a primary contraindication for the use of ICG.[28] Caution is also advised for patients with a known allergy to shellfish, due to the potential for cross-reactivity.[52]
• Risk Mitigation: Due to the risk of severe anaphylactic reactions, it is a mandatory precaution that full cardiopulmonary resuscitation personnel and equipment be readily available whenever ICG is administered. All patients must be closely monitored for signs and symptoms of a hypersensitivity reaction during and after the injection.[19]
• Other Reported Effects: In very rare instances (<1/10,000), patients may experience nausea, a feeling of warmth, or unrest. Coronary artery spasm has also been described in very rare cases.[28] It has been observed that patients with terminal renal insufficiency may have a higher risk of experiencing an anaphylactic reaction.[28]

5.2. Contraindications, Warnings, and Precautions

The safe use of ICG is predicated on adherence to specific contraindications and warnings.

• Contraindications:
• Known Hypersensitivity: ICG is strictly contraindicated in patients with a known history of hypersensitivity to indocyanine green itself or to iodides.[28]
• Thyroid Conditions: It is contraindicated in patients with hyperthyroidism or autonomic thyroid adenomas.[28]
• Pregnancy: Pregnancy is a relative contraindication. Animal reproduction studies have not been conducted, and it is not known if ICG can cause fetal harm. It should be given to a pregnant woman only if the potential benefit justifies the potential risk to the fetus.[19]
• Warnings:
• Anaphylaxis: The product labeling carries a prominent warning regarding the risk of fatal anaphylaxis.[19]
• Interference with Thyroid Function Tests: Due to its iodide content, ICG can interfere with the iodine-binding capacity of the thyroid gland. Therefore, radioactive iodine uptake (RAIU) studies should not be performed for at least one week following the administration of ICG.[19]
• Precautions:
• Drug Interactions: Certain preparations, notably those containing sodium bisulfite (which can be found in some heparin formulations), can alter the absorption peak of ICG in blood samples. These should not be used as an anticoagulant for blood collected for ICG analysis.[19] Probenecid may depress the biliary secretion of ICG, potentially interfering with liver function test results.[28]
• Lactation: It is not known whether ICG is excreted in human milk. Because many drugs are, caution should be exercised when administering ICG to a nursing mother.[19]

5.3. Toxicology Summary

Toxicological data for ICG is primarily derived from acute studies and occupational safety assessments.

• Acute Toxicity (LD50): Non-clinical safety data indicate a low level of acute toxicity via oral and dermal routes. The oral LD50 in rats is reported as 1700 mg/kg, and in mice as 1940 mg/kg. The dermal LD50 in rabbits is greater than 10,000 mg/kg, demonstrating a very wide safety margin for these routes of exposure.[53] Poisoning has been reported via the intravenous route.[15]
• Occupational Hazards: In its lyophilized powder form, ICG is classified as a hazardous chemical under OSHA and GHS standards. It is considered an irritant that can cause skin irritation (H315), serious eye irritation (H319), and potential respiratory irritation (H335) upon exposure.[14] Therefore, handling of the powder requires appropriate personal protective equipment (PPE), including gloves, safety goggles, and use in a well-ventilated area to avoid dust formation.[14]
• Carcinogenicity and Mutagenicity: Long-term studies to evaluate the carcinogenic potential, mutagenic potential, or effects on fertility have not been performed for ICG.[19]
• Concentration-Dependent Toxicity: While ICG is very safe at the low concentrations used clinically, some in vitro research has suggested potential for neurotoxicity at much higher concentrations (e.g., 75-125 μM), which may be related to the formation of ICG aggregates or oligomers.[56] This is a consideration in the research and development of new high-concentration formulations but is not a risk associated with current clinical use.[23]

VI. Regulatory and Commercial Landscape

This section contextualizes Indocyanine Green within the global pharmaceutical and medical device markets, examining its regulatory approvals and the integrated commercial ecosystem that has developed around its use in fluorescence-guided surgery.

6.1. Global Regulatory Status

Indocyanine Green has a long-standing history of approval from major regulatory bodies worldwide, which has facilitated its widespread clinical adoption.

• U.S. Food and Drug Administration (FDA): ICG was first approved by the FDA on February 9, 1959, under the brand name IC-GREEN (NDA 11525).[57] Its original indications were for determining cardiac output, hepatic function, and liver blood flow.[57] Over the years, its indications have expanded to include ophthalmic angiography and, more recently, various fluorescence imaging applications.[32] The original IC-GREEN product is currently listed in the FDA's "Discontinued Drug Product List" section of the Orange Book. However, in a notice published in November 2024, the FDA formally determined that the product was not withdrawn from the market for reasons of safety or effectiveness. This crucial determination clears the regulatory pathway for the FDA to approve Abbreviated New Drug Applications (ANDAs) for generic versions of ICG, ensuring continued availability and potential for market competition.[57]
• European Medicines Agency (EMA) and European Member States: ICG is approved for clinical use across Europe.[23] While a centralized European Public Assessment Report (EPAR) was not identified, its approval is referenced in numerous documents, and it is the only NIR contrast agent, along with methylene blue, approved by both the FDA and EMA for certain surgical indications.[25] Clinical trials involving ICG are registered in the EudraCT database.[52] Marketing authorizations are held in individual member states, such as in Austria and Belgium for products like Verdye and Indocyanine Green Pulsion.[52]
• Other Major Regulatory Bodies:
• Swissmedic (Switzerland): Approved under the brand name Verdye, with Mediconsult AG as the marketing authorization holder. The approval was granted on April 24, 2023, based on a simplified procedure referencing the product's long-standing authorization in Austria.[60]
• TGA (Australia): Approved under the brand name Spy Agent Green on February 19, 2024, for visualization of vessels, biliary ducts, and lymphatic mapping.[30]
• Health Canada: Marketed in Canada under brand names like Spy Agent Green and Indocyanine Green for Injection USP.[12]

6.2. Brand Names, Manufacturers, and Integrated Imaging Systems

The modern commercial landscape for ICG is characterized by a symbiotic relationship between the drug and the specialized medical devices required to use it. ICG is not merely sold as a standalone pharmaceutical; it is often marketed as a key component of an integrated imaging system. This drug-device ecosystem has significant commercial and clinical implications, driving innovation in both the imaging hardware and the dye formulations. For healthcare institutions, the decision to adopt ICG-guided surgery is not just about adding a drug to the formulary but involves a capital investment in a new technology platform. This integrated approach creates a powerful commercial model where the initial sale of the imaging system leads to recurring revenue from the sale of the consumable dye kits validated for that system.

• Key Manufacturers and Distributors:
• Diagnostic Green: A leading global specialist in fluorescence products. The company markets ICG under three main brand names for different territories: IC-Green® in the USA, Indocyanine Green for Injection USP in Canada, and Verdye across Europe and other international markets. Diagnostic Green also manufactures and markets its own CE-approved handheld NIR imaging system, the IC-Flow™, creating a complete product ecosystem.[12]
• Stryker: A major global medical technology company that became a key player in the ICG space through its acquisition of Novadaq Technologies. Stryker markets ICG under the brand name Spy Agent Green. This dye is specifically intended for use with Stryker's extensive portfolio of advanced fluorescence imaging systems, including the SPY Elite (for open surgery), the SPY-PHI (a portable handheld imager), and the PINPOINT and Firefly systems (for minimally invasive/robotic surgery). These systems often include proprietary software, such as SPY-QP, for quantitative perfusion analysis.[45]
• Other Companies: Other pharmaceutical companies like Akorn and Pulsion Medical Systems have historically manufactured or distributed ICG products.[49] Additionally, numerous chemical supply companies such as Cayman Chemical and Adipogen Life Sciences provide ICG for research and laboratory use.[71]

The following table summarizes this integrated commercial landscape, providing a clear overview for analysts, procurement departments, and clinicians evaluating different systems.

Table 3: Global Commercial Landscape: Brand Names, Manufacturers, and Associated Imaging Systems
Brand Name	Manufacturer / Distributor	Associated Imaging System(s)	Key Market Regions
IC-Green®	Diagnostic Green LLC	IC-Flow™ Imaging System; Compatible with other open-platform systems	USA 12
Verdye	Diagnostic Green GmbH	IC-Flow™ Imaging System; Compatible with other open-platform systems	Europe, UK, other international territories 12
Indocyanine Green for Injection, USP	Diagnostic Green	Compatible with open-platform systems	Canada 12
Spy Agent Green	Stryker (formerly Novadaq)	SPY Elite, SPY-PHI, PINPOINT, Firefly (da Vinci)	USA, Canada, Australia, Europe 30
Cardio Green Kit	Multiple historical manufacturers (e.g., Akorn)	Not system-specific	USA 10
Indocyanine Green Pulsion	Pulsion Medical Systems SE	Not system-specific	Europe (e.g., Belgium) 52

VII. Recent Advancements and Future Directions

This final section examines the ongoing evolution of Indocyanine Green, focusing on current research that aims to address its intrinsic limitations and expand its potential, pushing it from a simple dye toward a sophisticated molecular agent.

7.1. Current Clinical Trials

The clinical research landscape for ICG is active and expanding, with numerous trials seeking to refine existing techniques and validate new applications.

• Expanding Oncologic Indications: NCI-supported and other clinical trials are actively investigating the use of ICG in cancers beyond its more established roles. This includes studies on sentinel lymph node mapping in vulvar cancer and endometrial cancer, aiming to provide a less morbid alternative to full lymphadenectomy.[41]
• Pediatric Solid Tumors: A significant area of investigation is the application of ICG in pediatric oncology. Trials like NCT04084067 are designed to assess the feasibility of ICG-guided surgery for identifying neoplastic disease and achieving complete resection in children with solid tumors like osteosarcoma and neuroblastoma.[40]
• Refining "TumorGlow" Techniques: Several trials are built upon the "TumorGlow" concept, which leverages the enhanced permeability and retention (EPR) effect, where ICG passively accumulates in tumors due to their leaky vasculature. Studies like NCT02280954 aim to optimize the dosing and timing of ICG administration and the sensitivity of imaging systems to reliably detect primary tumors, define margins, and identify residual disease after resection across a range of solid tumors.[75]

Table 4: Overview of Key Ongoing and Recent Clinical Trials
ClinicalTrials.gov ID	Trial Title / Objective	Condition(s) Studied	Phase	Status
NCT04084067	The Use of Indocyanine Green as a Diagnostic Adjunct for Pediatric Solid Malignancies 47	Osteosarcoma, Neuroblastoma, various pediatric solid tumors	Early Phase 1	Recruiting
NCT02280954	A Pilot and Feasibility Study of Intraoperative Imagery of Solid Tumors With Indocyanine Green 76	Solid Tumors, Neoplasms	Phase 1	Completed
NCT04854018	Indo-cyanine Green (ICG) in Paediatric Oncology MIS 40	Metastatic Sarcomas, Pediatric Renal Tumor, Rhabdomyosarcoma	Phase 4	Completed
NCT00833599	Imaging Lymphatic Function in Normal Subjects and in Persons With Lymphatic Disorders 48	Lymphedema, Lipoedema, Dercum's Disease, Vascular Malformations	Not Applicable	Unknown
NCT02621268	Imaging Potential of Indocyanine Green in Subjects Undergoing Minimally Invasive Thoracic Surgery 75	Thoracic Neoplasms	Pilot	Recruiting

7.2. Overcoming Intrinsic Limitations: The Rise of Nanotechnology

The most advanced research is focused not just on finding new uses for ICG, but on fundamentally re-engineering the molecule to overcome its inherent weaknesses. While highly useful, free ICG suffers from several limitations: poor photostability (it photobleaches under illumination), instability in aqueous solutions, concentration-dependent aggregation that quenches its fluorescence, a very short circulatory half-life that limits imaging time windows, and a complete lack of cancer-cell specificity.[23]

The solution to these challenges lies in nanotechnology. By encapsulating or conjugating ICG with engineered nanoparticles, researchers can protect it from degradation and add new functionality. This represents a potential leap from a simple perfusion dye to a true molecular imaging agent, transforming ICG from a tool that shows "where blood flows" to one that can show "where cancer is" with high specificity.

• Liposomal ICG: Encapsulating ICG within the aqueous core or lipid bilayer of liposomes (spherical vesicles made of phospholipids) has been shown to significantly enhance its stability, protect it from oxidation, and improve its fluorescence yield. Lipid-bound ICG allows for deeper tissue visualization and enhanced resolution of lymphatic structures compared to free ICG.[25]
• Targeted Nanoparticles (ICG-Glow NPs): A more advanced approach involves creating nanoconstructs designed for active targeting. One such example is the "ICG-Glow NP," a nanoparticle composed of poly(vinyl pyrrolidone) (PVP)-ICG that is cloaked with tannic acid.[23] This formulation was shown to be more photostable and have superior biocompatibility. Crucially, the tannic acid surface is hypothesized to bind to various oncogenic proteins that are overexpressed on the surface of cancer cells. This confers a level of tumor-cell specificity that free ICG lacks, leading to enhanced accumulation and retention in tumors in preclinical models.[23] This line of research could bridge the gap to theranostics, where a single nanoparticle could carry both ICG for imaging and a therapeutic drug for targeted treatment.

7.3. Future Perspectives

The future of ICG in clinical practice will be shaped by technological advancements and the growing body of evidence supporting its use.

• Quantitative Fluorescence Imaging (QFI): A major limitation of current FGS is the subjective interpretation of the fluorescent signal by the surgeon. The future lies in moving toward objective, software-driven quantitative analysis. Imaging systems like Stryker's SPY-QP, which provide color-coded maps and relative perfusion values, are the first step in this direction. QFI will allow for more standardized, reproducible, and data-driven surgical decisions.[43]
• Augmented Reality (AR) in Surgery: The next frontier in surgical visualization is the integration of the fluorescence signal into an augmented reality display. This would involve superimposing the real-time NIR fluorescence image directly onto the surgeon's view of the operative field, either through the surgical microscope, laparoscope, or a head-mounted display. This would create a seamless, intuitive fusion of anatomical and functional information, further enhancing surgical precision.[37]
• Establishment as Standard of Care: As high-quality evidence continues to accumulate, particularly from randomized controlled trials showing improved patient outcomes (e.g., reduced anastomotic leak rates in colorectal surgery), the use of ICG-guided surgery is poised to transition from a novel technique to the standard of care in an increasing number of surgical disciplines.[36]

VIII. Conclusion and Expert Recommendations

Indocyanine Green, a molecule with over six decades of clinical history, is experiencing a profound and impactful renaissance. Its unique combination of near-infrared optical properties and highly specific pharmacokinetic behavior—rapid protein binding, strict intravascular confinement, and exclusive, non-metabolic hepatic excretion—has allowed it to transcend its original diagnostic roles and become an indispensable tool in the modern era of fluorescence-guided surgery.

The analysis confirms that ICG has successfully transitioned from a static diagnostic agent to a dynamic, real-time intraoperative navigation aid. Its application in anatomical mapping and perfusion assessment has been shown to enhance surgical precision, improve safety, and, in several key areas, reduce significant patient morbidity and associated healthcare costs. The primary safety consideration, rare but serious hypersensitivity reactions related to its iodide content, is a well-defined and manageable risk.

The future trajectory for ICG is clear and promising. It will be driven by parallel innovations in two key areas. First, advancements in imaging technology, including the move toward quantitative fluorescence analysis and augmented reality, will make its use more objective, standardized, and intuitive. Second, and more transformatively, progress in nanotechnology is poised to overcome the molecule's intrinsic limitations. The development of targeted ICG-loaded nanocarriers will evolve it from a non-specific dye into a platform for highly specific molecular imaging and, potentially, targeted therapy (theranostics).

It is recommended that healthcare institutions continue to adopt and integrate ICG-based fluorescence imaging into relevant surgical specialties. The growing body of high-quality evidence supports its use as a key technology for improving patient outcomes and represents a critical step toward a higher standard of care in surgery. Continued research into next-generation ICG formulations should be a priority, as it holds the potential to unlock new diagnostic and therapeutic paradigms.

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