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Background: Contrast-induced nephropathy (CIN) is a common cause of acute kidney injury (AKI), and can be diagnosed when the etiology of AKI is unclear other than via a contrast agent. Fluorescent angiography (FAG) with fluorescein sodium dye is generally considered to be safe for patients with kidney diseases. However, it remains unresolved whether or not FAG can induce CIN., Methods: Patients from two tertiary hospitals who underwent FAG and had serum creatinine results within 4 weeks before FAG and 3 days after FAG between 2001 and 2017 were retrieved. Cases with concurrent iodinated contrast imaging or undergoing dialysis were excluded from the analysis. CIN was defined by two criteria: CIN criteria as >0.5 mg/dL or >25% increase in serum creatinine (sCr) level within 3 days after FAG, and contrast-induced acute kidney injury (CIAKI) criteria as ≥0.3 mg/dL increase within 2 days or ≥50% increase within 7 days after FAG., Results: A total of 979 patients were screened, and we found 124 patients with AKI after FAG. After excluding 32 patients with clear causes of AKI other than FAG, the incidence rates of CIN were 7.3% by CIN criteria and 6.4% by CIAKI criteria. CIN incidence had a U-shaped distribution according to chronic kidney disease (CKD) stages in CIN criteria, while linear association between CIN incidence and CKD stages were found in CIAKI criteria. Kaplan-Meier curves showed the CIN group was significantly associated with end-stage renal disease (ESRD) progression (log-rank P < 0.001, in both CIN criteria and CIAKI criteria), and adjusted hazard ratios by multivariable Cox regression were 2.23 [95% confidence interval (CI) 1.468-3.378] in CIN criteria and 2.17 (95% CI 1.462-3.232) in CIAKI criteria., Conclusions: According to CIN and CIAKI criteria, FAG may cause CIN and appeared to be a possible risk factor for ESRD progression. However, CIN or CIAKI criteria themselves may overestimate AKI and require meticulous attention to the interpretation of results., (© The Author(s) 2019. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

Background: Fluorescein angiography is an important and frequently used diagnostic tool in ophthalmological practice. In this case report we describe a patient who experienced an anaphylactic reaction after the injection of fluorescein. Furthermore, we report an interference with laboratory testing by fluorescein in this patient and summarize the literature on this topic., Case Presentation: An 86-year old Caucasian woman undergoing fluorescein angiography due to suspected peripapillary neovascularizations collapsed after the injection of fluorescein. The patient developed an anaphylactic reaction. With fluid resuscitation and oxygen therapy, the patient regained consciousness after a few minutes. The patient was admitted to the geriatric ward for observation, and routine blood and urine tests were performed. Urine protein concentration appeared to be falsely increased as a consequence of disturbance of the laboratory analysis by the presence of fluorescein., Conclusions: Serious complications can occur with fluorescein angiography, such as an anaphylactic reaction. In the case of anaphylaxis appropriate supportive measures including the use of oxygen and epinephrine (e.g. EpiPen), should be available to prevent morbidity and mortality from this test. Furthermore, these potential complications should be taken into consideration when choosing the healthcare setting for fluorescein angiography, such as the immediate availability of an acute medical team. Several studies have demonstrated the interference of laboratory analyses by fluorescein. The majority of these studies were published 10 to 30 years ago. By presenting this case, the authors hope to bring renewed attention to this phenomenon among clinicians, as falsely increased or decreased laboratory values can result in unnecessary diagnostics and/or therapy.

Aim: To investigate the effects of fluorescein-sodium on neural tissues., Material and Methods: Twenty-one Wistar rats were randomly divided into three experimental groups: control (group 1) and fluorescein-sodium groups with different doses (groups 2 and 3). In the control group, craniectomy following with durotomy was performed with the help of a loupe microscope, and a dry sponge was overlayed to the brain tissue. In the study groups, the open dura was covered with a sponge soaked with 0.02 mg (group 2) and with 0.2 mg (group 3) fluorescein sodium following craniectomy. Three weeks postoperatively, rats were sacrificed for the histopathologic evaluations., Results: Fluorescein-induced apoptosis occurs in a dose-dependent manner in rats' neurons. It was determined that neuron and neuroglial cell TUNEL staining was statistically different among the three groups (p < 0.001). Our results indicated that fluorescein induces apoptosis, resulting in increased nuclear factor kappa beta (NF-kβ) expression in a dose-dependent manner., Conclusion: Fluorescein sodium is used frequently during surgery for CSF fistulas. However, information in the literature about its safety is insufficient. Our study holds promise for the development of new studies on the reliability of this agent.

Water soluble "vital" dyes are commonly used clinically to evaluate health of the ocular surface; however, staining mechanisms remain poorly understood. Recent evidence suggests that sublethal damage stimulates vital dye uptake by individual living cells. Since cell damage can also stimulate reparative plasma membrane remodeling, we hypothesized that dye uptake occurs via endocytic vesicles. In support of this idea, we show here that application of oxidative stress to relatively undifferentiated monolayer cultures of human corneal epithelial cells stimulates both dye uptake and endocytosis, and that dye uptake is blocked by co-treatment with three different endocytosis inhibitors. Stress application to stratified and differentiated corneal epithelial cell cultures, which are a better model of the ocular surface, also stimulated dye uptake; however, endocytosis was not stimulated, and two of the endocytosis inhibitors did not block dye uptake. The exception was Dynasore and its more potent analogue Dyngo-4a, both small molecules developed to target dynamin family GTPases, but also having off-target effects on the plasma membrane. Significantly, while Dynasore blocked stress-stimulated dye uptake at the ocular surface of ex vivo mouse eyes when treatment was performed at the same time as eyes were stressed, it had no effect when used after stress was applied and the ocular surface was already damaged. Thus, Dynasore could not be working by inhibiting endocytosis. Employing cytotoxicity and western blotting assays, we went on to demonstrate an alternative mechanism. We show that Dynasore is remarkably protective of cells and their surface glycocalyx, preventing damage due to stress, and thus precluding dye entry. These unexpected and novel findings provide greater insight into the mechanisms of vital dye uptake and point the direction for future study. Significantly, they also suggest that Dynasore and its analogues might be used therapeutically to protect the ocular surface and to treat ocular surface disease., Competing Interests: AW, SJ and MEF are named as inventors on a patent application related to this work, submitted by the University of Southern California entitled “Method to Protect and Seal the Ocular Surface” (United States application 16/103,741, filed Aug 14, 2018). The other authors have no commercial or proprietary interest in any concept or product described in this article.

Fluorescein angiography (FA) is an important tool for the diagnosis and management of diabetic retinopathy. However, the safety of fluorescein sodium on renal functions is not fully understood. One hundred type 2 diabetes patients, within the Ophthalmology Outpatient Clinic at Alexandria Main University Hospital, Egypt, were enrolled in this prospective observational study to determine the safety of FA on renal function. Serum creatinine and cystatin C were measured pre- and 2 days post-FA. Urinary neutrophil gelatinase-associated lipocalin (uNGAL) was measured pre- and 4 hours post-FA. Renal injury was defined as a 25% increase in serum creatinine, cystatin C, or uNGAL. The study included 71 females and 29 males, with a mean age of 55.73 ± 7.29 years. Baseline serum cystatin C and uNGAL were 0.89 ± 0.34 mg/L and 21.7 ± 2.39 ng/mL, respectively. Serum cystatin C and uNGAL significantly increased after FA to 0.95 ± 0.36 and 27 ± 2.81, respectively (P <0.001). Eleven patients (11%) experienced more than a 25% rise in serum cystatin C from baseline, whereas 40 patients (40%) experienced more than a 25% increase in uNGAL levels after FA. However, the mean serum creatinine level did not change significantly after FA (P = 0.061). Only one patient experienced more than a 25% rise in serum creatinine from baseline. FA showed a significant increase in early sensitive acute kidney injury biomarkers (as serum cystatin C and uNGAL) in substantial number of patients, suggesting but still not proving, a potential harmful effect of FA on kidney functions. These findings were not demonstrated using ordinary serum creatinine.

Background: Intrathecal injection of fluorescein is a useful adjuvant method for localization of fistulas in endoscopic endonasal repair of cerebrospinal fluid (CSF) leakage. Although being neurotoxic in commercial doses, a low dose of diluted fluorescein seems to be safe on the basis the existing data in the literature., Objectives: The purpose of this study was to investigate the role of a low- dose intrathecal fluorescein injection in detection of CSF fistula and potential adverse effects of this technique., Materials and Methods: CSF rhinorrhea was repaired in 20 patients with an endoscopic endonasal technique. Intraoperative intrathecal fluorescein injection was used for localization of the site of the CSF leak. The accuracy rate of leakage site identification and the incidence of complications and recurrences were recorded., Results: Intrathecal administration of fluorescein demonstrated CSF leakage in 18 of the 20 patients (90%). There were no intraoperative complications. Definitive closure of the CSF leakage site was achieved in 16 patients (80%) after the initial reconstruction. Recurrence occurred in four cases and all patients were free of CSF leakage after the second surgical attempt., Conclusions: The present study suggested that a low dose of intraoperative intrathecal fluorescein administration is a safe and sensitive method for localization of CSF leakage sites.

Fluorescein is associated with minor adverse effects during retinal angiography, and most of these effects are not severe and not related to immunological mechanism. However, on rare occasions, anaphylatoid reaction can occur, and fatalities involving fluorescein have been described. Life threatening complications after intravenous injection of sodium fluorescein require immediate intervention. Trainings for professionals are needed to standardize treatment for this event.

Purpose: To evaluate allergy skin testing as a diagnostic tool of adverse reactions to fluorescein and whether allergy and previous sodium fluorescein angiography (SFA) act as predisposing factors., Methods: Patients with adequate indication for fluorescein angiography and normal skin responsiveness were subjected to allergy skin-prick and intradermal tests for fluorescein, followed by SFA. During SFA, adverse reactions were monitored and classified as mild, moderate or severe. Previous SFAs and adverse reactions as well as the presence of atopy were also registered., Results: One thousand and thirty-seven patients were enrolled in the study and 1284 SFAs were executed. Forty-four patients (4.3%) developed 55 adverse reactions; among them 50 (3.8%) were mild, three (0.2%) moderate and two (0.16%) severe. None of the reactors produced positive skin tests to fluorescein. Patients with atopy and previous SFAs were not more susceptible to adverse reactions., Conclusion: The vast majority of adverse reactions to fluorescein are mild and not attributed to immunological mechanisms. Allergy skin tests cannot predict non-immunological reactions but their utility remains substantial in predicting anaphylaxis during SFAs and must be performed in patients reporting risk factors in their past medical history., (© 2009 The Authors. Journal compilation © 2009 Acta Ophthalmol.)

Background: Confocal laser endomicroscopy (CLE) is rapidly emerging as a valuable tool for gastrointestinal endoscopic imaging. Fluorescent contrast agents are used to optimize imaging with CLE, and intravenous fluorescein is the most widely used contrast agent. Fluorescein is FDA-cleared for diagnostic angiography of the retina. For these indications, the safety profile of fluorescein has been well-documented; however, to date, fluorescein is not cleared for use with CLE., Aims: To estimate the rate of serious and total adverse events attributable to intravenous fluorescein when used for gastrointestinal CLE., Methods: We performed a cross sectional survey of 16 International Academic Medical Centres with active research protocols in CLE that involved intravenous fluorescein. Centres using i.v. fluorescein for CLE who were actively monitored for adverse events were included., Results: Sixteen centres performed 2272 gastrointestinal CLE procedures. The most common dose of contrast agent was 2.5-5 mL of 10% sodium fluorescein. No serious adverse events were reported. Mild adverse events occurred in 1.4% of individuals, including nausea/vomiting, transient hypotension without shock, injection site erythema, diffuse rash and mild epigastric pain. The limitation is that only immediate post procedure events were actively monitored., Conclusions: Use of intravenous fluorescein for gastrointestinal CLE appears to be safe with few acute complications.

Objective: To determine the incidence rate and correlation factors of the adverse reactions during fluorescence fundus angiography (FFA) in special patients., Methods: 256 special patients were performed FFA with Heidelberg Retinal Angiography. Fluorescein Sodium was given according to the body weight and adverse reactions during FFA were observed. The special patients enrolled in this study include those with drug allergy history, system disease, light adverse reactions such as nausea, vomiting and pruritus during the fist FFA or patients over 80 years old., Results: Adverse reactions were observed in 69 of 256 (27.0%) cases and the majority is at a mild to moderate degree. Nausea, sneezing, vomiting or pruritus occurred in 10 of 73 (13.7%) patients with drug allergy history. Nausea or vomiting occurred in 4 of 78 (5.1%) patients with systemic diseases. Different degrees of adverse reactions occurred in 54 of 56 (94.6%) cases who had nausea, vomiting or pruritus during the first FFA. Nausea occurred in 1 of 49 (2.0%) patients over 80 years old., Conclusion: FFA is a safe examination for the above special patients. The incidence rate of adverse reaction due to FFA in these special patients is similar to that in the healthy population. Observing the patients closely and strengthening the containment and salvage measures are important to improve the safety of FFA in these special patients.

Cerebrospinal fluid leak (CSF), clinical sign of a dural lesion of the skull base, is a relatively rare event that can present with a variety of symptoms. Every craniosinus fistula should be considered a serious, potentially life-threatening situation (even those cases with hidden CSF leak). Reports of experience concerning diagnosis and treatment of craniosinus fistulae have appeared in the Literature. In the last few years, the endoscopic nasal approach is proving effective as it makes diagnosis much easier and is the least invasive surgical approach, with the greatest percentage of success. Various classifications are being proposed to improve clinical evaluation of CSF leaks and to simplify the diagnostic and therapeutic approach. The most common parameters of classification are: aetiology (traumatic, iatrogenic, non-traumatic, etc.) site, type of flow (high or low pressure) and, as far as concerns treatment, the type of graft used, all of which have contributed to various diagnostic and therapeutic algorithms being proposed. Therefore, the subject seems to be widely schematized and the therapeutic attitude widely agreed. However, one of the diagnostic and therapeutic approaches is now being questioned. For some, it is the heart of the clinical approach, while for others, it is a useful tool yet too dangerous to be used on account of potential side effects: namely, the fluorescein test. This procedure, consisting of intrathecal injection of a colorant (fluorescein), is well known by the Food and Drug Administration (FDA) which neither explicitly prohibits it, nor allows it, intrathecal administration is, therefore, an off label use. As far as the Authors know, authorization of this procedure has not been forthcoming anywhere in the world although the procedure itself is widely employed. As far as concerns the use of intrathecal fluorescein, many scientific papers have been written, clearly supporting its clinical usefulness. One limit to the use of fluorescein derives from frequent reports of complications, often related to the intrathecal administration; such complications are, however, always due to an incorrect dosage. In order to perform correct monitoring of any complication related to the use of intrathecal fluorescein and to investigate in a strictly scientific fashion, the legal problem related to the off label use (intrathecal administration) of an authorised substance, the Authors coordinated an Italian multicentre study aimed at establishig the tolerability of the lumbar intrathecal administration of fluorescein. Aim of the study was to review the literature focusing on CSF leaks, to set up to date diagnostic and therapeutic indications of fluorescein and to report the preliminary results of the Italian multicentre study.

Fluorescein is a fluorochrome dye occasionally administered by intrathecal injection to identify and localize cerebrospinal fluid leaks. Although generally considered to be a benign intervention, intrathecal administration of fluorescein has resulted in adverse events. We report a case of status epilepticus after intrathecal administration of fluorescein. Anesthesia providers should be aware of complications associated with intrathecal fluorescein use and be prepared to manage neurologic complications during the perioperative period.

The Authors describe an extremely rare fatal case (sixth case in the literature) of anaphylactic shock following a fluorescein angiography. This is the first report in which the diagnosis of anaphylactic reaction to the dye was made through laboratory analyses. The diagnosis of fatal shock due to sodium fluorescein was made based on clinical, laboratory and immunohistochemical data. Mast-cell tryptase was dosed in serum and a pulmonary immunohistochemical evaluation was performed. Tryptase, a neutral protease of human mast-cells is a potentially important indicator of mast-cell involvement in anaphylactic events.