Adverse Reactions due toIndocyanine Green

Monique Hope-Ross, FRCS, MRCP,l Lawrence A. Yannuzzi, MD,lEvangelos S. Gragoudas, MD,2David R. Guyer, MD,lJason S. Slakter, MD,1 John A. Sorenson, MD,1 Sara Krupsky, MD,2Dennis A. Orlock, CRA,l Carmen A. Puliafito, MD3

Background: Although adverse reactions to indocyanine green (ICG) are knownto occur, the dye has been used for more than 30 years in tests of cardiac and hepaticfunction, with a high level of safety. Improved digital video technology has renewedinterest in the use of intravenous ICG in ophthalmic imaging. This report describes theauthors' experience regarding the safety of ICG for digital angiography and their rec­ommendations for its use in the ophthalmic setting.

Methods: Digital ICG videoangiography was performed in 1226 consecutive pa­tients, and 1923 ICG videoangiography tests were performed. A registry of adversereactions to ICG was established. Criteria were used to define mild, moderate, andsevere adverse reactions, and these data were recorded for every ICG study performed.

Results: There were three (0.15%) mild adverse reactions, four (0.2%) moderatereactions, and one (0.05%) severe adverse reaction. There were no deaths.

Conclusions: This study documents the safety of intravenous ICG for use inophthalmic videoangiography. Ophthalmology 1994;101:529-533

Indocyanine green (lCG) is a tricarbocyanine dye thatwas first approved for diagnostic use in humans in 1956.It has been used for more than 30 years in measurementsofhepatic function, liver blood flow, and cardiac output. 1,2

The potential application of ICG in ophthalmic an­giography was conceived and first attempted by Kogureand co-workers.' Early attempts were limited by the weakfluorescent efficiency of the dye. Advances in digital videotechnology allowed improved imaging of ICG and haveled to useful clinical applications of digital ICG videoan­giography.v?

Indocyanine green has been used widely in medicalimaging, and it has been proven to be a relatively safedrug." Adverse reactions, however, can occur, and twodeaths have been reported after ICG administration. Thepurpose of this report is to document our experience of

Originally received: June 14, 1993.Manuscript accepted: September 20, 1993.

I LuEsther T. Mertz Retinal Research Laboratory of the Manhattan Eye,Ear and Throat Hospital, New York.

2 Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston.

3 New England Eye Center, Boston.

Reprint requests to Lawrence A. Yannuzzi, MD, Manhattan Eye, Earand Throat Hospital, 210 East 64th St, New York, NY 10021.

adverse reactions to ICG when used in ophthalmic vid­eoangiography.

Materials and Methods

After the introduction of ICG videoangiography to ourpractices between October 1990 and February 1991, aregistry was established to record all adverse reactions toICG. The data from our experience with ICG videoan­giography, from October 1990 to January 1993, were re­viewed.

The data collected on each study included the doseused, the technique ofadministration, and the use of pre­medications. Adverse reactions were documented.

Classification of Adverse Reactions

The classification was based on a previous report by ourgroup on adverse reactions to intravenous fluorescein. 8

Mild Adverse Reaction

A mild reaction was defined as a transient effect that didnot require any treatment. Complete and rapid resolution

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Table 1. Adverse Reactions to Indocyanine Green

other mild ad verse reactions after ICG administration.The frequency rate of mild adverse reactions was I (0.15%)per 641 injections.

In four patients, moderate adverse reactions developed.In a 72-year-old man who had no history of allergies,generalized urticaria developed immediately after ICGadministration. He had no other symptoms, was nor­motensive, and was given 50 mg diphenhydramine. Ur­ticaria resol ved fully within minutes.

A 65- year-old woman underwent routine ICG vid­eoangiography for the second time. No reaction had de­veloped after the first ICG injection. She was allergic topen icillin . Urticaria developed I hour after ICG admin­istration. Oral diphenhydramine (25 mg) was prescribed,and the urticaria resolved. The patient subsequently un­derwent repeat ICG videoangiography 6 months later anddid not have any adverse reaction.

A 72-year-old man with no previous history of allergiesbecame faint after ICG injection and had a vasovagal ep­isode. He was pale and sweaty , and his blood pressurewas 100/70 mmHg. He was placed in the prone positionand recovered spontaneously. He had had a previous va­sovagal reaction after an injection.

A 26-year-old man became faint after ICG injection.He was pale and clammy, did not lose consciousness, andwas placed in the prone position. He recovered sponta­neously. He had no history of allergies.

The frequency rate of moderate ad verse reactions was[ (0.2%) per 480 ICG injections.

There was one severe ad verse reaction. A 68-year-oldwoman was given 5 mg/kg ICG intravenously for ICG­enhanced laser treatment. She had no history of allergiesand had a history ofbenign essential hypertension. Sevenminutes after injection, she became faint, pale , andclammy. She did not lose consciousness. She breathedspontaneously, and her systolic blood pressure was 80mmHg. She was placed in the prone position, an intra­venous infusion of normal saline was commenced withoxygen via a nasal catheter, and a cardiac monitor wasattached. Her systolic blood pressure dropped to 50mmHg, and her heart rate was 50 beats per minute. Shewas transferred to the coronary care unit for assessment.There was no evidence ofcardiac ischemia, and the patientwas discharged the next da y, after fully recovering. Thisadverse reaction was classified as a severe adverse reaction,although the reaction was probably vaso vagal.

The frequency rate for severe adverse reactions was [(0.05%) per 1923 (Table I).

There were no deaths after ICG videoangiography.

occurred without any sequelae. Nausea, vomiting, ex­travasation, sneezing, and pruritus were classified as mildreactions.

Moderate Adverse Reaction

A moderate adverse reaction also was defined as a tran­sient effect. Some form of medical treatment may be re­quired. This type of reaction posed no threat to the pa­tient's safety; there was complete reco very with no se­quelae. Urticaria, syncope, other skin eruptions, pyrexia,local tissue necrosis, and nerve palsy were categorized asmoderate adverse reactions.

Severe Adverse Reaction

A severe adverse reaction was defined as one exhibitingprolonged effects that required intense treatment. It alsoposed a threat to the patient's safety, and it resulted in avariable recovery. A severe adverse reaction involved thecardiac, respiratory, and neurologic systems. Respiratoryadverse reactions included bronchospasm, laryngospasm,and anaphylaxis. Cardiac adverse reactions included cir­culatory shock , myocardial infarction, and arrest. A tonic­clonic seizure was classified as a severe adverse reaction.

Death

Death was attributed to the use of intravenous ICG ifsymptoms were noted within 24 hours and the event oc­curred within 48 hours of the procedure.

Results

Including ICG-enhanced laser photocoagulation, 1923ICG videoangiography tests were performed. On a numberof occasions, ICG videoangiography was repeated in 583patients, and 1226 patients underwent ICG videoangiog­raphy.

In every ICG videoangiography, the medical photog­rapher or technician gave the injection using a 23-gaugebutterfly needle or a hep block. No premedications wereused. The needle was removed after completion.

The dosage oflCG varied. In 199[ , when the dye wasreadily available, 1 to 5 mg/kg was used (the higher dosewas for ICG-enhanced laser photocoagulation). Whenthere was a shortage of the dye, the total dose was reducedto [2 .5 mg. The dosage currently used is between 25 and50 mg.

Contraindications to the use of ICG were establishedas iodine allergy, pregnancy, liver disease , uremia, and aprevious anaphylactic reaction to a dye injection.

In the 1923 ICG videoangiography tests performed,there were a number ofmild, moderate, and severe adversereactions. Three patients had mild adverse reactions afterICG injection. Two patients complained of discomfortafter ICG injection, one patient had nausea and anotherhad nausea and vomiting. Subcutaneous extravasation ofICG resulted in stinging in one patient. There were no

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Type of Reaction

MildModerateSevereDeaths

No.(%)

3 (0.15)4 (0.2)1 (0.05)0(0)

Hope-Ross et al . Adverse Reactions to Indocyanine Green

There was no correlation of adverse reactions to thedose ofICG used, except for one patient who had a severeadverse reaction and had been given 5 mg/kg ICG forICG-enhanced laser treatment. This number is too smallto draw conclusions about the effect of ICG dosage onthe incidence of adverse reactions.

A number of patients had a history of allergies. Fivepatients were allergic to penicillin, two had severe asthma,and three had a history of allergy to shellfish. One of thepatients in whom a moderate adverse reaction developedwas allergic to penicillin.

Discussion

Indocyanine green is a sterile, water-soluble tricarbocy­anine dye. It contains not more than 5.0% sodium iodide.Chemically, it is an N-hydro-3,3,3',3'-tetramethyl-l, l'-di­(4-sulfobutyl)-4,5,4'5'-dibenzoindotricarbocyanine hy­droxide sodium salt with a molecular weight of 775 (Fig1). The empirical formula ofICG is C43H47N2Na06S2.

After injection, ICG is bound rapidly to plasma pro­teins. Albumin was thought to be the major carrier; how­ever, it has been demonstrated that in human serum, 80%of ICG is bound to globulins, probably alpha-I lipopro­teins.9, l o

Indocyanine green is not metabolized after injectionand is excreted exclusively by the liver. It is not resorbedfrom the intestine and does not undergo enterohepaticcirculation. The dye is taken from the plasma by the he­patic parenchymal cells and secreted into the bile.10 Neg­ligible renal, peripheral, lung, or cerebrospinal uptake ofthe dye occurs. Excretion by the kidney does not occur. II

No dye can be detected in the spinal fluid (Rapaport E;unpublished data).

Indocyanine green is not very toxic in animals, andthe LD50after intravenous administration ranges from 60to 80 mg/kg in mice.'? There are no data following over­dosage in humans.

Indocyanine green has been used in medical practicesince 1956 (Fox 11; unpublished data). It is estimated thata million tests have been performed using the dye (per­sonal communication; T. R. Carski, Corporate Medicaldirector, Becton and Dickinson). It has proved to be asafe dye, but side effects have occurred. 13

Indocyanine green can cause adverse reactions by atruly allergic mechanism or a pseudo-allergic mechanism.The exact mechanism is poorly understood. The reactionsmay be due to sodium iodide or the molecule itself.

Mild and moderate adverse reactions appear to bepseudo-allergic in nature. Nonimmunologic release ofhistamine could explain these adverse reactions. The re­lease of other inflammatory mediators is another possi­bility. It has been demonstrated that injection of ra­diocontrast media disrupts the endothelial lining of bloodvessels causing subsequent release of plasminogen acti­vator. This disruption, in turn, can cause activation ofthe complement system." Indocyanine green may havea similar mechanism of action.

Severe adverse reactions and deaths may be caused bya true allergic reaction, an anaphylactic reaction." In­docyanine green may combine with a protein forming ahapten-protein complex. The hapten-protein complex isrecognized by 19E, and there is degranulation of mast cellswith liberation of histamine and other kinins. Clinically,this is manifest as anaphylactic shock, with hypotension,bronchospasm, laryngospasm, edema, and urticaria. Car­diorespiratory arrest may supervene. Anaphylactic reac­tions occur immediately after administration ofICG, andthe reaction is not dose-dependent.

A review of the world literature shows there have been16 severe adverse reactions to ICG. 13,15-21 The dose ofICG administered does not appear to correlate to thepresence or severity of adverse reactions reported in theliterature." Of these 18 patients, only one patient had ahistory of allergies and was allergic to penicillin.':' Theadverse reactions that have been reported appear to beidiosyncratic in origin.

Of the 18 severe adverse reactions reported, seven pa­tients had end-stage renal disease and were undergoinghemodialysis.F:" In one series, 43 patients with chronicrenal failure underwent tests of cardiac function usingICG. IS In 4 of these 43 patients, adverse reactions to ICGdeveloped. Immunologic studies were performed, and thisshowed a significantly elevated eosinophil count in thepatients in whom adverse reactions had developed. Thissuggests that the mechanism of adverse reactions to ICGin patients with uremia is allergic hypersensitivity.

There have been two deaths attributed to ICG admin­istration.P:'? One of these deaths occurred due to an ana­phylactic reaction followed by a cardiorespiratory arrest.The patient had a history of allergy to penicillin and sul­fonamides. 13 The second death occurred in Japan, wherea different formulation of the dye is used." A 43-year-oldman had an anaphylactic reaction after 36 mg ICG wasadministered intravenously; he died despite variousemergency treatments. There is a third unreported death(personal communication; Carski TR)-a 49-year-oldwoman who underwent cardiac catheterization to measurecardiac output with ICG. An anaphylactic reaction de­veloped, she went into cardiorespiratory arrest, and sub­sequently died. A postmortem examination confirmed theclinical diagnosis.

In our study, 1923 ICG videoangiography tests wereperformed. The incidence of mild adverse reactions was1(0.15%) per 641. Two patients had nausea, and no treat­ment was required. Extravasation caused mild stinging inone patient. The rate of moderate adverse reactions was1(0.2%)per 480 ICG injections. There were four moderateadverse reactions. In two patients, urticaria developed,and two patients had a vasovagal event. Oral antihista­mines were given for urticaria, and there were no sequelae.No specific treatment was required for the vasovagalevents. One severe adverse reaction occurred; the patientrecovered fully. The rate of severe adverse reactions was1 (0.05%) per 1923. There were no deaths.

Adverse reactions to ICG occur less frequently thanwith fluorescein. The incidence of mild adverse reactionsto fluorescein is between 1% and 10%.S In our series, the

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Ophthalmology Volume 101, Number 3, March 1994

Figure 1. Structural formulaof indocyanine green.

~--~~-CH=CHCH=CHCH=CHCH=-----~

N+(CH2)4 S02 0- Na03S(CH2)4 N

rate of mild adverse reactions to ICG was 0.15%. Nauseaand vomiting are the most frequent mild adverse reactionsseen with fluorescein. Vomiting was seen in only one pa­tient in our series ofICG videoangiography tests. Extrav­asation of fluorescein can cause mode rate to severe symp­toms with tissue necrosis .F In our series, extravasation ofICG caused mild stinging in one pat ient, and no cases oftissue necrosis occurred.

The rate of moderate adverse reactions to fluoresceinis 1:63 (1.6%).8In our study, the rate of moderate reactionsto ICG was 1:480 (0.2%). The frequency rate of severeadverse reactions after fluorescein injection is I per 1900.This is a similar figure to the rate of severe adverse re­actions in our series after ICG injection.

There have been a number offatalities associated withthe use of fluorescein . The National Registry of Drug­induced Side Effects has kept a ledger of reported intra­venous fluorescein deaths in the United States since 1976.The Registry shows one fatality annually associated withthe use of the drug.

The incidence of death after fluorescein injection is1:222,000.8 Approximately a million tests using ICG havebeen performed, and three deaths have been attributedto ICG. Thus, the death rate after ICG injection is ap­proximately I:333,333. This is lower than the fatality rateafter fluorescein injection. Bear in mind, however, thatother deaths after ICG injection may not have been re­ported.

In procedures using radiocontrast media, the incidenceof severe adverse reactions is 1.6%.14 There is a fatalityrate of between I and 10 per 100,000 procedures.P Ra­diocontrast media differ from ICG in tonicity, quantityof iodine present , and dosages used. These differences mayexplain the higher rate of adverse reactions seen with ra­diocontrast media as compared with ICG.

Indocyanine green may be associated with an increasedrisk of adverse reactions and complications in patientswith a history of iodine allergy, uremia, and liver disease.Its use also is controversial in pregnancy.

Indocyanine green contains iodine, and patients whohave a history of definite iodine allergy should not begiven the dye. Iodine allergy can cause anaphylaxis. Pre­medication with prednisolone and diphenhydramine hasbeen shown to reduce the incidence of adverse reactions

532

in sensitized patients before administration of other io­dine-containing contrast media." We do not, however,recommend the use of ICG in iodine-sensitive patients.

It is not known if repeated administration ofICG pre­disposes to adverse reactions. In our study, one patientin whom a moderate adverse reaction developed had hadICG videoangiography performed previously. Of the 18patients in the literature who had severe adverse reactions,3 had been exposed to ICG previously."

Patients with uremia appear to be more at risk to ad­verse reactions due to ICG than the general population.Therefore, particular care should be exercised if ICG isgiven to patients with uremia. In our study, we did notperform ICG videoangiography in patients with uremia.

Indocyanine green is excreted exclusively by the liver,and therefore its use in patients with liver dysfunctionmay be problematic. We do not have an y experience ofdye administration in patients with liver disease, and thereare no reports of dye toxicity in patients with jaundice.However, it is excreted solely by the liver; therefore, itshould not be used in patients with liver disease.

The dye has been shown not to pass the placenta." Nostudies on fetal toxicity have been performed, and itshould not, therefore, be used during pregnancy.

Our experience has shown ICG to be a relatively safedye with a low incidence ofadverse reactions. Nonetheless,occasionally severe adverse reactions can occur. Patientsmust be selected carefully before dye administration. Ad­equate resuscitation facilities and properly trained per­sonnel must be available when the dye is used.

Indocyanine green videoangiography has been a majoradvance in the imaging of the choroidal circulation. Thesafety of ICG ensures that in the future it will continueto playa major role in ophthalmic imaging.

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