Indocyanine green

Structural formula
ICG sodium salt
General
Non-proprietary name	Indocyanine green
other names	Sodium 4 - [(2 E ) -2 - {(2 E , 4 E , 6 E ) -7- [1,1-dimethyl-3- (4-sulfonatobutyl) -1 H -benzo [ e ] indolium- 2-yl] -2,4,6-heptatrien-1-ylidene} -1,1-dimethyl-1,2-dihydro-3 H -benzo [ e ] indol-3-yl] -1-butanesulfonate ( IUPAC ) 1,7-bis [1,1-dimethyl-3- (4-sulfobutyl) -1 H -benz [ e ] indol-2-yl] heptamethinium betaine sodium salt INDOCYANINE GREEN ( INCI )
Molecular formula	C 43 H 47 N 2 NaO 6 S 2
External identifiers / databases
CAS number 3599-32-4 ( sodium salt ) 28782-33-4 (inner salt) EC number 222-751-5 ECHA InfoCard 100.020.683 PubChem 11967809 ChemSpider 18108 Wikidata Q905662
Drug information
ATC code	V04 CX
Drug class	Diagnosticum
properties
Molar mass	774.99 g mol −1
solubility	good in water, methanol and ethanol
safety instructions
Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed GHS labeling of hazardous substances Caution H and P phrases H: 315-319-335 P: 302 + 352-305 + 351 + 338
Toxicological data	60 mg kg −1 ( LD 50 ,  mouse ,  iv ) 87 mg kg −1 ( LD 50 ,  rat ,  iv )
As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Indocyanine green (ICG from indocyanine green ) is a fluorescent dye that is used in medicine as an indicator substance (e.g. for photometric liver function diagnostics and fluorescence angiography ) for cardiovascular, liver and eye diseases. It is administered intravenously and, depending on liver performance, eliminated from the body with a half-life of approx. 3-4 minutes. ICG sodium salt is usually in powder form and can be dissolved in various solvents ; usually 5% (<5% depending on the batch ) sodium iodide is added for better solubility . The sterile lyophilisate of a water-ICG solution is approved in Germany and the Netherlands under the name Verdye (manufacturer: Diagnostic Green ) as a diagnostic agent for intravenous use.

history

ICG was developed as a dye for photography during World War II and tested for use in human medicine at the Mayo Clinic in 1957 . After FDA approval in 1959, ICG was initially used primarily in liver function diagnostics and later in cardiology . In 1964 the renal blood flow could be determined with the help of indocyanine green from S. Schilling . From 1969 ICG was also used for research and diagnostics on subretinal processes in the eye (in the choroid ). In the years since 1980, the development of new cameras and better film material and new photometric measuring devices have eliminated many technical difficulties. In the meantime, the use of ICG in medicine (and in particular in fluorescence angiography in ophthalmology ) has established itself as the standard. Therefore, when designating fluorescence angiography, a distinction is also made between NA fluorescence angiography and ICGA / ICG fluorescence angiography. Around 3000 scientific publications on ICG have now been published worldwide.

Optical properties

The absorption and fluorescence spectrum of ICG is in the near infrared range. Both are highly dependent on the solvent used and the concentration. ICG mainly absorbs between 600 nm and 900 nm and emits fluorescence between 750 nm and 950 nm. The large overlap of the absorption and fluorescence spectra leads to a strong reabsorption of the fluorescence by ICG itself.

The fluorescence spectrum is quite broad. Its maxima are around 810 nm in water and around 830 nm in blood. For medical applications based on absorption, the absorption maximum at around 800 nm (in blood plasma at low concentrations) is important. In combination with fluorescence detection, lasers with a wavelength of around 780 nm are often used. At this wavelength, ICG still absorbs very well, and it is still technically possible to suppress the excitation light in order to detect the fluorescence.

Toxicity and side effects

Indocyanine green is metabolized microsomally in the liver and only excreted via the liver and biliary tract ; Since it is not absorbed by the intestinal mucosa , the toxicity can be classified as low. A dose during pregnancy is not without risk. It has been known since September 2007 that exposure to UV light causes ICG to break down into toxic waste. This creates several, as yet unknown substances. However, a study published in February 2008 shows that ICG (the substance without UV exposure) is generally only slightly toxic as such. The intravenous LD ₅₀ values measured in animals are 60 mg / kg in mice and 87 mg / kg in rats.

Rarely - in one in 42,000 cases - people experience mild side effects such as sore throats and hot flashes. Effects such as anaphylactic shock , hypotension , tachycardia , dyspnoea and urticaria have only been found in individual cases; the risk of serious side effects increases in patients with chronic kidney failure . The frequencies of mild, moderate and severe side effects are only 0.15%, 0.2% and 0.05%; the death rate is 1: 333,333. With the competing substance fluorescein , the proportion of people with side effects is 4.8% and the death rate is 1: 222,222.

Because the preparation contains sodium iodide, iodine intolerance must be tested. Since about 5% iodide is added, the iodine content of a 25 mg ampoule is 0.93 mg. In comparison, in preparations for KM - CT (140 ml) 300 mg / ml or for a Corona include angiography (200 ml) 350 mg / ml iodine.

use

ICG angiography in ophthalmology / ophthalmology

Indocyanine green has the ability  to bind 98% to plasma proteins - 80% to globulins and 20% to alpha lipoprotein and albumin - and thus shows less leakage compared to fluorescein as a marker (slower color leakage from the vessels, extravascularly ). Due to the plasma protein binding, ICG remains in the vessels for up to 20–30 minutes ( intravascularly ); When examining the eye, it therefore remains for a long time in tissues with more blood flow, such as the choroid and the blood vessels of the retina .

ICG angiography is used in ophthalmology for angiography of the fundus in the following cases:

• If there is suspicion of damage to the retina with poorly demarcated borders and if there is bleeding
• In the basic diagnosis if a certain form of AMD is suspected
• If chorodial neovascularization (CNV) is suspected
• If polypoidal chorodial vasculopathy (PCV) is suspected
• If retinal angiomatous proliferation (RAP) is suspected
• If a choroidal melanoma is suspected
• If a choroidal hemangioma is suspected
• If choroidal metastases are suspected
• In individual cases for extended diagnostics or documentation ( differential diagnostics )

ICG angiography is currently used to monitor therapy and assess the course of the new VEGF inhibitors ( Macugen , Lucentis , Avastin ).

ICG diagnostics for non-invasive monitoring of liver or splanchnic perfusion

Due to the high rate of binding of indocyanine green to the plasma proteins, the substance allows the liver or splanchnic perfusion to be measured by monitoring changes in the ICG-PDR ( ICG plasma disappearance rate ). This method is therefore suitable as a prognostic parameter for the probability of survival in surgical intensive care patients. Since reduced PDR values ​​can be measured in about two thirds of surgical intensive care patients for whom extended hemodynamic monitoring is indicated, one can speak of a significantly increased mortality. Regular monitoring of the ICG-PDR (usually twice a day) helps to identify restrictions in liver or splanchnic perfusion at an early stage. After intravenous ICG administration, the plasma disappearance rate is measured by an external monitoring device.

Perfusion diagnostics of tissues and organs with ICG

ICG is used as a marker in assessing the perfusion of tissues and organs in many medical fields. The light required to excite the fluorescence is generated by a near-infrared light source that is attached directly to a camera. A digital video camera allows the recording of the ICG fluorescence in real time, whereby a perfusion can be assessed and documented.

It is used at:

• Plastic Surgery: Skin and Muscle Grafts; Determination of the amputation level
• Abdominal surgery: gastrointestinal anastomoses
• General surgery: wound healing and ulcers
• Internal medicine: diabetic extremities
• Cardiac surgery: aortocoronary bypasses

ICG can also be used as a tracer in brain perfusion diagnostics. In the case of stroke patients, monitoring in the recovery phase appears to be feasible by measuring both the ICG absorption and the fluorescence in everyday clinical practice.

ICG-based navigation to sentinel lymph node biopsy in tumors

The sentinel node - biopsy , also called "sentinel node biopsy" ( SLB or SLN biopsy ) called, allows a selective, minimally invasive approach for the assessment of regional lymph node status in malignant tumors. The first draining lymph node, the "guardian", represents an existing or non-existent tumor in an entire lymph node region. The method has been validated using radionuclides and / or blue dye for breast cancer , malignant melanoma, but also gastrointestinal tumors and enables a good detection rate and sensitivity. A reduced mortality was demonstrated for SLB compared to complete lymph node dissection, but disadvantages remain for the methods with regard to the availability, use and disposal of the radionuclide and the risk of anaphylaxis (up to 1%) for the blue dye. Due to its near-infrared fluorescence and previous toxicity studies, indocyanine green (ICG) was evaluated in this study as a new, alternative method for SLB with regard to the clinical application of transcutaneous navigation and lymph vessel visualization as well as SLN detection. With ICG fluorescence navigation, a high detection rate and sensitivity rate can be achieved compared to conventional methods. Taking into account a learning curve, the new, alternative method offers the combination of lymphography and SLB as well as the possibility of SLB without radioactive substances in solitary tumors.

Rheumatism diagnostics

The Physikalisch-Technische Bundesanstalt and mivenion GmbH developed an imaging process called "Rheumascan" for diagnosing microcirculation disorders in the hands. This imaging procedure can be used for arthritic and rheumatoid diseases. ICG is used as a marker for the microcirculatory disorder. Rheumascan was first presented at the European Congress of Radiology 2009.

Current research

From today's perspective, research in the field of ICG is far from over. In particular, it seems that under certain circumstances - such as the appropriate laser strength and certain wavelengths - ICG has the property of triggering a photodynamic reaction. This means that ICG could also be used as a PDT therapeutic in the medium term . In a further investigation it was shown that indocyanine green is destroyed by laser light. The resulting products had a negative effect on cells from the porcine retina in vitro.

On the other hand, ICG is very universally applicable in the field of (perfusion) diagnostics, which is why further research is taking place here as well.

Web links

• PE Stanga, JI Lim, P. Hamilton: Indocyanine green angiography in chorioretinal diseases: indications and interpretation: an evidence-based update. In: Ophthalmology. Vol. 110, 2003, pp. 15-21. PMID 12511340 - Evidence level I study of 350 publications
• Optical Absorption of Indocyanine Green (ICG )
• ICG at the manufacturer Diagnostic Green (English)

Individual evidence

1. ↑ Entry on INDOCYANINE GREEN in the CosIng database of the EU Commission, accessed on February 24, 2020.
2. ↑ External identifiers or database links for indocyanine green, acid : CAS number: 28782-33-4, PubChem : 71587099 , ChemSpider : 19800615 , DrugBank : DB09374 , Wikidata : Q27275190 .
3. ↑ ^{a b c d e f} S. H. Wipper: Validation of fluorescence angiography for intraoperative assessment and quantification of myocardial perfusion. (PDF; 1.6 MB) Dissertation, 2006, pp. 18–23.
4. ↑ ^{a b} Data sheet Cardiogreen from Sigma-Aldrich , accessed on February 24, 2020 ( PDF ).
5. ↑ ^{a b c d} Entry on indocyanine green in the ChemIDplus database of the United States National Library of Medicine (NLM) .
6. ↑ ^{a b} Toxicology and Applied Pharmacology . Volume 44, 1978, p. 225.
7. ↑ ^{a b} Drugs in Japan , 1995, p. 189.
8. ↑ ^{a b c} A. J. Augustin, GK Krieglstein in: Augenheilkunde , 2001 , Springer-Verlag, ISBN 3-540-65947-1 .
9. ↑ ABDA database (as of December 5, 2009).
10. ^ Optical Optical Properties of ICG (English) .
11. ^ ^{A b} Manfred J. Müller: Nutritional Medicine Practice: Methods - Prevention - Treatment. 2nd edition, Springer, Kiel 2007, ISBN 978-3-540-38230-0 , p. 76.
12. ↑ J. Hillenkamp: Investigation of Indocyanine Green Toxicity in vitro. DOG , Volume 09, 2007, University of Regensburg .
13. ^ R. Benya, J. Quintana, B. Brundage: Adverse reactions to indocyanine green: A case report and a review of the literature. In: Cathet and Cardiov Diagnosis Volume 17, 1989, pp. 231-233.
14. ^ Schmidt-Erfurt, DOG Congress Berlin 2007.
15. ↑ S. Sakka, Konrad Reinhart, Andreas Meier-Hellmann in: Chest Volume 122, No. 5, 2002, pp. 1715-1720.
16. ↑ A. Liebert, H. Wabnitz, J. Steinbrink, M. Möller, R. Macdonald, H. Rinneberg, A. Villringer, H. Obrig: Bed-side assessment of cerebral perfusion in stroke patients based on optical monitoring of a dye bolus by time-resolved diffuse reflectance. In: Neuroimage , Volume 24, 2005, pp. 426-435.
17. ^ A. Liebert, H. Wabnitz, H. Obrig, R. Erdmann, M. Möller, R. Macdonald, H. Rinneberg, A. Villringer, J. Steinbrink: Non-invasive detection of fluorescence from exogenous chromophores in the adult human brain. In: Neuroimage , Volume 31, 2006, pp. 600-608.
18. ^ Berufsgenossenschaftliche Unfallklinik Ludwigshafen (BG Klinik): Research group "Fluorescent dye-supported navigation for sentinel lymph node biopsy and real-time lymphography in solitary tumors". ( Memento from December 5, 2013 in the Internet Archive )
19. ↑ C. Hirche, D. Murawa, Z. Mohr, S. Kneif, M. Hünerbein: ICG fluorescence-guided sentinel node biopsy for axillary nodal staging in breast cancer. In: Breast Cancer Res Treat . Volume 121, No. 2, June 2010, pp. 373-378.
20. ↑ C. Hirche, S. Dresel, R. Krempien, M. Hünerbein: Sentinel node biopsy by indocyanine green retention fluorescence detection for inguinal lymph node staging of anal cancer: preliminary experience. In: Ann Surg Oncol . Volume 17, No. 9, September 2010, pp. 2357-2362.
21. ↑ "Rheuma-Video" reveals sources of inflammation early on. Report to TSBmedici from August 20, 2009.
22. ↑ C. Bremer, S. Werner, H.-E. Langer: Assessing activity of rheumatoid arthritis with fluorescence optical imaging. In: European Musculoskeletal Review. Volume 4, No. 2, 2009.
23. ↑ Rheumatism video reveals foci of inflammation early on. ( Memento from December 3, 2013 in the Internet Archive ) In: Ärzte Zeitung , August 21, 2009.
24. ↑ Christoph Abels, Sonja Fickweiler, Petra Weiderer, Wolfgang Bäumler, Ferdinand Hofstädter, Michael Landthaler and R.-M. Szeimies: Indocyanine green (ICG) and laser irradiation induce photooxidation. In: Archives of Dermatological Research . Springer Berlin / Heidelberg, Volume 292, No. 8, August 2000. doi : 10.1007 / s004030000147 .
25. ↑ R.-M. Szeimies, T. Lorenzen, S. Karrer, C. Abels and A. Plettenberg: Photochemotherapy of cutaneous AIDS-associated Kaposi sarcomas with indocyanine green and laser light. In: Der Hautarzt , Springer, Berlin / Heidelberg, Volume 52, No. 4, March 2001, pp. 322–326. doi : 10.1007 / s001050051315 .
26. ↑ Eva Engel, Rüdiger Schraml, Tim Maisch, Karin Kobuch, Burkhard König, Rolf-Markus Szeimies, Jost Hillenkamp, ​​Wolfgang Bäumler, Rudolf Vasold: Light-induced decomposition of indocyanine green In: Invest. Ophthalmol. Vis. Sci. Volume 49, No. 5, May 2008. doi : 10.1167 / iovs.07-0911 .

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