Background
In recent years, due to the development of instruments and techniques for thoracic surgery, uniportal thoracoscopic surgery has been increasingly used in the diagnosis and treatment of lung and thoracic diseases. Globally, uniportal thoracoscopic surgery is considered to be a feasible and safe method for the treatment of pulmonary nodules and is commonly used [
1,
2]. Consequently, localizing pulmonary nodules by tactile sense is no longer suitable due to the implementation of minimally invasive surgery. In addition, information provided solely by preoperative CT is insufficient to aid in the intraoperative detection of subcentimeter pulmonary nodules [
3,
4]. Therefore, the intraoperative localization of small pulmonary nodules remains challenging for thoracic surgeons.
Indocyanine green (ICG) is a near-infrared fluorescent dye. When stimulated by an external light source, it emits near-infrared light with a wavelength of approximately 830 nm. ICG has been approved by the U.S. Food and Drug Administration (FDA) as a safe imaging agent and has almost no risk of allergic reactions (approximately 0.003%). As a highly sensitive and specific fluorescent imaging method, ICG imaging has been introduced for general use for the diagnosis and treatment of pelvic and abdominal tumors, tumor-node-metastasis, and ocular vascular and neurological diseases [
5].
This study aimed to explore the safety and feasibility of an ICG fluorescent imaging system combined with laser positioning and CT simulation in intraoperative localization of subcentimeter pulmonary nodules.
Methods
Clinical data
A total of 32 patients admitted to the Department of Thoracic Surgery, The Fourth Affiliated Hospital of China Medical University from September 2019 to March 2020 were enrolled in this study. The inclusion criteria were (1) single or multiple pulmonary nodules with a diameter ≤ 1.5 cm; (2) nodules were located in the lung parenchyma and were ≤ 3 cm from the pleura, and preoperative CT images showed no pleural traction; and (3) no history of allergy to iodine contrast agents. All patients signed informed consent forms.
Materials and devices
Injectable ICG (2.5 mg/ml) was purchased from Dandong Yichuang Pharmaceutical Co., Ltd., China. The near-infrared fluorescence endoscopic imaging system was purchased from Optomedic Co., Ltd., China. The large-aperture spiral CT and the laser positioning systems were purchased from General Electric Co., USA and Siemens AG, Germany, respectively.
Surgical procedure
Forty minutes to one hour before the operation, a puncture was performed in the patient under laser positioning and CT guidance to a needle depth of 0.5–2 cm. The ICG agent (2.5 mg/ml, 0.3–1 ml) was injected slowly. The respiratory rate, blood pressure, and heart rate were monitored.
After general anesthesia was induced, a single 3–5 cm incision was made in the chest wall. After one-lung ventilation, the imaging system was switched to fluorescence detection to localize the nodule. A wedge excision was performed around the localized point. The sample was inspected by tactile sense and the naked eye after the surgery to verify the presence of pulmonary nodules. Based on the pathological results of the frozen section analysis, a decision was made regarding whether to perform pulmonary lobectomy.
Discussion
Due to the improvement of health awareness and the increasing number of spiral chest CT examinations, the detection rate of intrapulmonary subcentimeter nodules is continuously increasing [
6]. However, the wide use of thoracoscopic surgery leads to increasing difficulties in localizing pulmonary nodules by the conventional method of tactile sense. With the development of minimally invasive concepts, uniportal thoracoscopic surgery represents a new frontier for minimally invasive thoracic surgery [
7,
8]. Given this basis, the new generation of thoracic surgeons are eager to further reduce surgical time and trauma, thereby providing better healthcare for patients. Thus, a more precise and effective localization method for uniportal endoscopic surgery is urgently needed [
9]. Over time, different localization techniques, including the hookwire and microcoil methods, have been proposed, inevitably leading to complications such as dislodgement, systemic air embolism, pulmonary hemorrhage, and pain [
10‐
12]. Colored dyes, including methylene blue, can easily contaminate operative areas and affect surgical exposure, and because of their small molecular weight, these dyes can easily diffuse, leading to incorrect intraoperative identification or excessive resection of nodules [
13,
14].
The near-infrared dye ICG has been widely used in many fields. The Chinese Experts’ Consensus of Preoperative-assisted Localization of Pulmonary Nodules (2019 version) recommends localization methods using liquid materials, including ICG, as a 2A-level technique [
15]. Rho J et al. [
16] found that an optimal emulsion of 10% ICG and 90% lipiodol mixed through 90 passages exhibited an even distribution and the highest signal intensity under fluorescence microscopy and that all emulsion types injected were well localized around the target nodules without any side effects or procedure-related complications. Chao Zhan et al. [
17] performed preoperative ICG localization for lung lobectomy in 11 patients, and the localization failed in 2 patients due to unclear fluorescent signals. They also found that for segmentectomy, ICG fluorescence was visible at 14 s after peripheral intravenous administration. They concluded that ICG fluorescence imaging could facilitate a precise segmentectomy and reduce the surgical time and trauma. Further studies demonstrated that near-infrared fluorescence imaging could safely identify lung tumors after systemic injection of ICG; in addition, low-dose ICG was adequate for near-infrared fluorescence imaging of lung tumors. However, as passive accumulation of ICG cannot be used to distinguish between tumors and inflammation, targeted fluorescent agents should be developed to address this problem [
18].
This study showed that the optimal imaging effect was obtained when 0.4–0.5 ml of ICG (25 mg/ml) was administered at a needle depth of 1 cm. If the dose was too large or the needle depth was too shallow, ICG overflow could occur. An injection volume of less than 3 ml may not be sufficient for localization. If the injection is performed too quickly, ICG overflow may occur. In this study, 2 cases of ICG overflow were separately caused by an excessive dose and rapid injection. One case of localization failure was caused by an inadequate dose (no ICG reached the lung). The surgical time in the cases with localization failure was obviously prolonged. No patients had allergic reactions. Three patients reported pain after puncture. Complications such as pneumothorax and hemothorax did not occur.
We conclude that ICG imaging is a safe and effective technique for pulmonary nodule localization. Because of the short study time, small sample size, and lack of controls in this study, further observations and randomized controlled clinical trials should be conducted in the future. With the widespread application of near-infrared imaging devices, fluorescent imaging localization will become more widely used in thoracic surgery. Due to the continuous development of uniportal thoracoscopic surgical techniques, the combination of these two methods is expected to provide greater benefits for patients.
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