Fluorescein Sodium CAS 518-47-8

Sodium fluorescein was initially mainly used for fundus retinal angiography in ophthalmology, and only later did researchers use it for brain tumor surgery.

According to its application in brain tumor surgery, it can be roughly divided into three stages: the first stage is the naked eye surgery stage, and the brain tumor biopsy operation is guided by fluorescein sodium. This stage started around 1948. Observing 46 patients with brain tumors, the researchers found that fluorescein sodium helps guide the needle biopsy of a variety of brain tumors, including meningiomas, gliomas, and metastases. Unfortunately, in the following decades, reports of fluorescein sodium for brain tumor surgery were rare.

The second stage is the surgical stage under the ordinary microscope, that is, the glioma resection is guided by sodium fluorescein under the white light microscope. Several studies around 2000 have shown that high-dose fluorescein sodium can more clearly display the border of gliomas under the white light field of view of a common operating microscope and improve the total resection rate of gliomas.

The third stage is the stage of surgery under a microscope equipped with special filters. In 2011, Acerbi et al. used a Pentero microscope (Carl Zeiss, Germany) equipped with a YELLOW 560 special filter to evaluate the safety of fluorescein (5-10 mg/kg)-guided glioma resection. The treatment is prospective Phase II clinical trial. The results of the study showed that there were no adverse reactions related to the use of fluorescein sodium; 75% of the 12 patients with grade IV gliomas achieved contrast-enhanced total tumor resection.

Since then, more and more studies have shown the safety and efficacy of sodium fluorescein-guided resection of malignant gliomas under dedicated filters.

Fluorescein sodium has been used for decades in the diagnosis of fundus diseases, with good safety and low incidence of allergic reactions. To date, only a few reports of allergic reactions have been reported. A retrospective analysis by Ha et al. of 12 005 patients who received intravenous fluorescein sodium showed that only 10 patients had allergic reactions, with an incidence rate of 0.083%. The main manifestations of the patients were hypotension, nausea and vomiting. Hypotension mostly occurred within 3 minutes after injection, and no serious consequences were caused by timely treatment.

In guiding glioma resection, most studies have shown that fluorescein sodium is safe, and reports of allergic reactions are rare. However, Dilek et al. reported an allergic reaction in a patient with severe hypotension and bradycardia, which may be related to the higher dose of fluorescein sodium (20 mg/kg). At present, under a fluorescence microscope equipped with a YELLOW 560 special filter, the usual dose of sodium fluorescein is 2-5 mg/kg, and no serious allergic reactions have been reported within this dose range. Although most patients have transient yellowing of the skin, mucous membranes and urine after using fluorescein sodium, the yellowing of the skin can subside after 6-12 hours, and the yellowing of the urine mostly returns to normal after 24-36 hours. It will not cause discomfort to the patient, nor will it cause other serious consequences.

It can be seen that the incidence of allergic reactions to fluorescein sodium is low, and usually occurs when high doses (10-20 mg/kg) are used. Using a small dose of fluorescein sodium (2-5 mg/kg) under the current special filter can achieve a good effect of intraoperative real-time fluorescence imaging-guided glioma resection, with high safety. In addition, measures such as preoperative fluorescein sodium skin test and intensive intraoperative monitoring of patients’ vital signs can further reduce the incidence of adverse reactions and improve the safety of its use.

Acerbi et al. initiated a prospective phase II clinical trial (FLUOGLIO) in 2011 to evaluate the safety and efficacy of fluorescein-guided glioma resection. The comparison and analysis of pathological examination of specimens in the fluorescent area and the non-fluorescent area showed that the sensitivity of sodium fluorescein in distinguishing high-grade gliomas was 91%, and the specificity was 100%. In a study by Rey-Dios et al., who guided stereotaxic needle biopsy with intravenous injection of 3 mg/kg fluorescein sodium, the sensitivity and specificity of fluorescein sodium-labeled tumor in 26 biopsy specimens from 6 patients with high-grade glioma were 79% and 100%.

Diaz et al.’s study showed that the sensitivity and specificity of fluorescein sodium for high-grade glioma edge recognition were 82.2% and 90.0%, respectively; Good correlation; postoperative MRI confirmed the complete resection of the tumor-enhancing part under the guidance of fluorescein sodium. Zhang et al tried to use fluorescein sodium to assist in 38 operations, and the statistical sensitivity and specificity were 94.4% and 88.6%, respectively. Neira et al. reported that the positive predictive value of the non-enhanced tumor area could reach 96% by the operator’s judgment of fluorescence imaging. These studies show that fluorescein sodium has high sensitivity and specificity for the identification of malignant glioma and the judgment of tumor boundary, which is helpful to improve the degree of tumor resection.

Chen et al conducted a cohort-controlled study to discuss the effect of high-dose fluorescein sodium (15-20 mg/kg)-guided surgery under a common surgical microscope on the rate of total tumor resection. The experimental group (intravenous injection of fluorescein sodium before dural incision, n=10) and the control group (without intravenous injection of fluorescein sodium, n=12) were all illuminated with ordinary white light during the operation. The tumor resection rates in the control group were 80% and 33%, respectively.

Several other descriptive and retrospective studies have investigated the effect of sodium fluorescein on the extent of glioma resection. Okuda et al. compared the resection of 10 cases of glioblastoma guided by high-dose sodium fluorescein (20 mg/kg) under white light and fluorescence microscope. satisfy. Schebesch et al conducted a retrospective analysis of 35 cases of brain tumor resection guided by low-dose sodium fluorescein (3-4 mg/kg) under a fluorescence operating microscope. The results showed that fluorescence imaging was helpful for the identification of tumor boundaries in 28 patients. Efficiency is 80%. Diaz et al reported that the total surgical resection rate of 12 cases of high-grade gliomas was 100% using 3 mg/kg fluorescein sodium under a fluorescence microscope. Using a similar approach, Neira et al achieved a total resection rate of 84% in 32 high-grade gliomas, 92.1% in Zhang et al, and 39 out of 47 (83%) in Francaviglia et al. ) achieved a tumor resection rate of more than 95%. In the FLUOGLIO study conducted by Acerbi et al., a preliminary preliminary study using 5-10 mg/kg fluorescein sodium to guide surgical resection showed that 9 out of 12 patients achieved complete resection (75%), and the remaining 3 patients had a minimum degree of resection of 82.8 %. In 2014, when the sample size of this study reached 20 cases, statistics showed that 16 cases (80%) of contrast-enhanced tumor lesions were completely resected, and the remaining 4 patients had a tumor resection degree of 92.6%. The latest report from the study in 2018 said that 82.6% of the 57 patients achieved complete tumor resection. Through the above studies, it is not difficult to find that compared with the traditional operation under the white light microscope, the fluorescein sodium-guided surgery can significantly improve the total surgical resection rate of malignant gliomas and improve the degree of tumor resection.

The identification of malignant glioma borders based on fluorescein sodium imaging has high sensitivity and specificity, and can improve the total tumor resection rate and tumor resection degree. Therefore, it is necessary to further explore whether it can prolong the progression-free survival of patients and overall survival. Chen et al.’s study showed that the progression-free survival of the experimental group and the control group were 7.2 months and 5.4 months, respectively, and the difference was statistically significant. However, some studies have shown that there is no statistically significant difference between sodium fluorescein and ordinary white light in improving the average survival time of patients. In the study of Acerbi et al., the 6-month progression-free survival rate of 12 patients enrolled was 71.4%, and the median survival time was 11 months. It can be seen that there are still contradictions in the existing research results, and it is necessary to carry out a prospective randomized controlled study to explore the exact effect of fluorescein sodium-guided surgery on the survival of patients with malignant glioma.

Different from the mechanism of fluorescein sodium through the blood-brain barrier to destroy non-specific leakage to the lesion area, another intraoperative fluorescent imaging agent, 5-ALA, can be specifically taken up by glioma cells, and can be metabolized into fluorescence in tumor cells. The metabolite, protoporphyrin, can generate red fluorescence under blue-violet light irradiation to visualize tumors. Although 5-ALA has shown the advantages of increasing the total resection rate of glioma (65% vs. 36%) and significantly prolonging the progression-free survival of patients (5.1 months vs. 3.6 months) in phase III randomized controlled clinical trials, but There was no statistically significant difference in overall survival between the two groups (15.2 months vs. 13.5 months).

In addition, 5-ALA still has the following shortcomings: it has not been approved by the drug regulatory authority, the access is limited, and its clinical application also has certain risks; the price is relatively expensive, which is dozens of times that of sodium fluorescein; the fluorescence mode is suitable for normal brain tissue. Indistinguishable from blood vessels, the lens needs to be switched repeatedly; there is a “bleaching” phenomenon in the fluorescence mode, and the fluorescence gradually weakens during the tumor resection, which affects the judgment of the tumor boundary; generally, oral administration is required 2-3 hours before surgery, and the medication is controlled Poor performance; postoperative patients are at risk of developing photosensitivity reactions, and should avoid sunlight and strong indoor light for 24-48 hours. These shortcomings limit the widespread use of 5-ALA. Relatively speaking, sodium fluorescein has the advantages of easy availability, low price, intravenous administration after induction of anesthesia, convenient use, good intraoperative imaging effect, and the ability to distinguish normal brain tissue and blood vessels well in fluorescence mode. It is a research hotspot and has broad application prospects in improving the resection rate of gliomas and improving the progression-free survival of patients.