Chemical toxicity of indocyanine green damages retinal pigment epithelium. Invest Ophthalmol Vis Sci.

PURPOSE. To investigate the chemical toxicity of indocyanine green (ICG). METHODS. Surface active and precipitating effects of ICG were quantitatively analyzed by determining bovine serum albumin dissolved or precipitated in the presence or absence of salt solutions. The effects of precipitation on serum and cytotoxicity were evaluated by measuring the viability of retinal pigment epithelium (RPE) in vitro. RESULTS. ICG functioned as a surfactant without salts, but with nearly physiological concentrations of balanced salts, it functioned as a unique precipitating factor. This rendered the soluble molecules in serum that are indispensable in the culture of RPE cells insoluble during a 12-hour exposure, resulting in poor cell survival in vitro. Cytotoxicity in serum-free medium was also shown during brief exposures. CONCLUSIONS. Commonly used dosages of ICG directly applied into the vitreous cavity, which not only contact the retina but also invade the space between the retina and RPE through a macular hole, may be sufficient to induce retinal disorders after the damaging chemical property of ICG has disturbed the microenvironment. (Invest Ophthalmol Vis Sci. 2005;46: 2531-2539) DOI:10.1167/iovs.04-1521 B efore 1990, there was no treatment available for macular holes. Kelly and Wendel 1 first reported that vitreous surgery improved visual acuity in some eyes with macular holes, and since then an effective internal limiting membrane (ILM) peeling technique has been used to improve outcomes. 2 However, it is generally very difficult to perform efficient and complete removal of the ILM, because the ILM is thin and transparent. After indocyanine green (ICG) was introduced for selective staining of the ILM, 3 ICG-facilitated ILM peeling appeared to be beneficial, because it facilitated functional and anatomic success. 4 -10 Although some reports have shown no negative effects and/or excellent anatomic results and visual retinal function after ICG-assisted ILM peeling for macular hole surgery, 18,21 Unusual atrophic changes in the retinal pigment epithelium (RPE) at the site of the macular hole and undesirable postoperative visual acuity were reported, despite successful anatomic closure of the macular hole. 22 After macular hole surgery with ICG-guided ILM peeling, hypertrophic and atrophic RPE changes were apparent. 26 ICG injected into the vitreous cavity showed b-and a-wave amplitude, and latency abnormalities, suggesting impairment of retinal function. 27 ICG caused cytotoxicity in cultured RPE cells in a dose-and time-dependent manner, and necrotic cell death occurred. 29 ICG injected into the subretinal space caused destructive degeneration of photoreceptors and RPE, 32 Although all these data obviously indicate toxic effects of ICG on retinal function, we hardly consider these results to be caused by ICG alone. ICG-induced cytotoxicity in cultured RPE was reduced with the removal of sodium from the solvent. 33 Toxic effects of ICG on cultured RPE cells have been related to osmolarity of the solvent. 34 Factors such as sodium or osmolarity modulate the degree of toxicity, implying that some chemical mechanisms may be involved in the effects. The dye ICG is an amphipathic molecule and has both hydrophilic (two anions and one ammonium cation) and hydrophobic (mainly aromatic series) properties, suggesting that ICG is a surface active compound and may have unknown chemical and toxic properties that affect the retina. In the present study, we demonstrated unique chemical properties of ICG-acting as a precipitating factor in the presence of salts, but as a surface active compound in the absence of salts. Our data support the proposition that the clinically used dosage of ICG in buffered salt conditions directly applied into the vitreous cavity and subretinal space through a macular hole may be sufficient to induce retinal disorder. From th