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Address for reprints: Hecheng Li, MD, PhD, Department of Thoracic Surgery, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, 197 Ruijin 2nd Rd, Shanghai, China 200025.
Pulmonary segmentectomy should be the standard surgical procedure for patients in certain clinical scenarios. However, detecting the intersegmental planes both on the pleural surface and within the lung parenchyma remains a challenge. We developed an intraoperative novel method for distinguishing intersegmental planes of the lung via transbronchial injection of iron sucrose (ClinicalTrials.gov number, NCT03516500).
Methods
We first performed a bronchial injection of iron sucrose to identify the intersegmental plane of the porcine lung. Then, we conducted a prospective study to evaluate the safety and feasibility of the technique in 20 patients who underwent anatomic segmentectomy. Iron sucrose was injected into the bronchus of target pulmonary segments, and the intersegmental planes were divided with electrocautery or stapler.
Results
The median injection of iron sucrose was 90 mL (range, 70-120 mL), and the median time from injection of iron sucrose to demarcation of intersegmental plane was 8 minutes (range, 3-25 minutes). Qualified identification of the intersegmental plane was observed in 17 cases (85%). The intersegmental plane could not be recognized in 3 cases. All patients experienced no complications related to iron sucrose injection or complications of Clavien–Dindo grade 3 or more.
Conclusions
Transbronchial injection of iron sucrose is a simple, safe, and feasible approach to identify the intersegmental plane (NCT03516500).
Based on preliminary animal and human trials, transbronchial injection of iron sucrose is a simple, safe, effective, and feasible method for identifying the intersegmental plane.
Intraoperative transbronchial injection of iron sucrose reveals a distinct intersegmental plane both on the pleural surface and in the pulmonary parenchyma for precise segmentectomy. Its outstanding advantages are that it is visible to the naked eye, requires no special equipment, and is not affected by the patient's lung function. Moreover, the indicator is easily accessible, safe, and nontoxic.
Because of early detection and diagnosis, the survival of patients with lung cancer has improved. However, when compared with other cancers, lung cancer remains the leading cause of death in China and worldwide.
Lobectomy is the standard treatment for patients with lung cancer with resectable diseases but may cause lethal respiratory dysfunction in those with poor pulmonary function.
Thus, segmentectomy was introduced as a compromise in these patients.
Unlike wedge resection, segmentectomy requires meticulous dissection of the segmental hilar with lymph nodes and provides a larger margin to the tumor as well as more accurate staging information.
Perioperative course and quality of life in a prospective randomized multicenter phase III trial, comparing standard lobectomy versus anatomical segmentectomy in patients with non-small cell lung cancer up to 2cm, stage IA (7th edition of TNM staging system).
Most important, segmentectomy was verified recently to provide 5-year survival similar to that of lobectomy in early-stage non–small cell lung cancers despite a higher local recurrent rate.
Segmentectomy versus lobectomy in small-sized peripheral non-small-cell lung cancer (JCOG0802/WJOG4607L): a multicentre, open-label, phase 3, randomised, controlled, non-inferiority trial.
In that case, segmentectomy is supposed to be applied more widely in patients with lung cancer.
Precise identification and dissection of the intersegmental plane, which ensure sufficient margin for the tumor, are key procedures of segmentectomy. The inflation-deflation method is most broadly used for its simplicity and availability but may be ineffective in patients with chronic obstructive pulmonary disease.
Another widely accepted method is intravenous indocyanine green (ICG) application, which illuminates the preserved part distinguishably regardless of pulmonary function.
A simple and effective technique for identification of intersegmental planes by infrared thoracoscopy after transbronchial injection of indocyanine green.
Fluorescence visualization of the intersegmental plane by bronchoscopic instillation of indocyanine green into the targeted segmental bronchus: determination of the optimal settings.
injection through fiberoptic bronchoscopy, are used less because of the unexpected diffusion to the preserved segment.
We introduce a nascent method for expeditious identification of the intersegmental plane without the excessive need for facilities and potential toxicity to patients.
Materials and Methods
We first performed a bronchial injection of iron sucrose to identify the intersegmental plane of the porcine lung. The pulmonary segmental bronchi of the pig were defined in accordance with a previous report.
After isolation of the superior segmental pulmonary artery and bronchus, the targeted segmental pulmonary artery and bronchus were cut off. We validated the technique of superior segmentectomy of the porcine lung using the traditional inflation and deflation method (Figure 1, A and C). Next, a 23-gauge butterfly needle was inserted into the distal portion of the superior bronchus.
We used the butterfly needle to slowly inject 35 mL iron sucrose (100 mg dissolved in 50 mL saline) into the distal superior segmental bronchus without resistance. After injection, the superior segment turns brown (Figure 1, B), and the intersegmental plane was distinguished not only on the pleural surface but also on the deep pulmonary parenchyma (Figure 1, D). All animal experimental procedures complied with laboratory animal guidelines for ethical review of animal welfare.
Figure 1Results in porcine lung model. We performed a dorsal segment resection on the porcine lung model. Two different methods to identify the segmental plane were demonstrated. A and C, The traditional inflation and deflation method was applied to validate the borderline. The border was clear on the surface but not on the parenchyma. B and D, The intersegmental plane was distinguished not only on the pleural surface but also on the deep pulmonary parenchyma after iron sucrose injection.
The safety and feasibility of using iron sucrose injection to identify the lung intersegmental plane for patients who underwent pulmonary segmentectomy were explored. The prospective study was approved by the Ethics Commission of Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (2018-12).
Patients with lung nodule(s) who were scheduled to undergo minimally invasive segmentectomy were eligible for inclusion in the study. The sample size of 20 was determined on the basis of the previous clinical study.
A simple and effective technique for identification of intersegmental planes by infrared thoracoscopy after transbronchial injection of indocyanine green.
All 20 patients provided written informed consent. The main exclusion criteria were as follows: a known allergy to iron sucrose injection; patients who have iron overdose or iron use barrier; intraoperative finding of extensive pigmentation silicosis or extensive carbon deposition in the lung because the lung in these patients may be too dark to develop the dye; and patients who have not received segmental resection. The primary outcome was safety. Any grade of treatment-related adverse events were closely monitored and recorded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.0). The secondary outcome measures were successful identification of segmental plane, surgical margin, duration of air leaks and the incidence of prolonged air leaks (defined as > 5 days), length of hospital stay, and duration of the chest tube. In addition to basic information such as gender, age, comorbidities, and malignant history, the pathological diagnosis was also recorded. The iron sucrose can be washed out in the routine pathological examination and has no impact on the pathological diagnosis.
Operative Technique
First, we needed to identify the target segment accurately. We confirmed this by preoperative image reading and 3-dimensional reconstruction, verified it intraoperatively based on arterial and anatomic location, and asked the anesthesiologist bronchoscopy to help determine the location intraoperatively if necessary.
Then, we cut the pulmonary artery and ligated the segmental bronchus. Mediastinal and hilar nodes were always dissected. During the procedure, frozen-section analysis was performed on enlarged resected nodes (>1 cm) and number 12 lymph node.
Then, we injected iron sucrose through a butterfly needle into the bronchus of the targeting segment (Figure 2, A). The dosage of iron sucrose was according to target segment volume
and the lucid delineation of the intersegmental plane. Specifically, we use one-half the volume of the target segment. For example, when the volume of a target segment was 200 mL, the injection volume was determined as 100 mL or more. After injection, the target segment turns brown, the border of the intersegmental plane is easily recognized (Figure 2, B and C), and we can use an automated suturing device (Figure 2, D) or an electrocautery setting of 60 to divide the intersegmental plane (Video 1).
Figure 2Intraoperative view of patients. We performed a lingual segment resection in patients. A, Iron sucrose was injected through a butterfly needle into the bronchus of the targeting segment. B and C, The target segment turns brown after injection, and the border of the intersegmental plane is easily recognized. D, An automated suturing device was applied to isolate the segment.
Ten male and 10 female patients participated in this study, with a median age of 53 years (range, 24-73 years). The characteristics of enrolled patients are summarized in Table 1. Segmentectomy regions included 3 left apicodorsale (S1+2), 3 right superius (S6), 3 right ventrobasale (S8), 2 right dorsale (S2), 2 right apicale (S1), 1 right dorsale + apicale propprius subsegmentum (S2 + S1a), 2 lingular division (S4 + S5), 2 left superius (S6), 1 upper-division (S1+2 + S3), and 1 left laterobase + dorsobasale (S9 + S10) segments.
Table 1Patients' characteristics
Variables
Data (n = 20)
Age (y)
Range
24-73
Median
53
Male/female
10/10
ASA Score
I
15
II
5
FEV1 (L)
Range
1.9-4.2
Median
2.7
BMI (kg/m2)
Range
17.8-26.1
Median
22.1
Smoking history
Nonsmoker
12
Smoker
5
Former smoker
3
Comorbidity
Hypertension
3
Diabetes
2
History of malignant tumor
Thyroid cancer
1
ASA, American Society of Anesthesiologists; FEV1, forced expiratory volume in 1 second; BMI, body mass index.
All patients underwent minimally invasive surgery, including 4 robotic surgeries and 16 video-assisted thoracic surgeries. The segmental plane was mostly separated with stapler, and a few were combined with cautery. The median operative time was 82 minutes (range, 40-130 minutes), and the median postoperative hospital stay was 3 days (range, 2-10 days). All patients recovered uneventfully (Table 2), and there was no prolonged air leak (>7 days). We have observed no complications related to iron sucrose injection and complications of Clavien–Dindo grade 3 or more.
Table 2Perioperative outcomes
Variables
Data (n = 20)
Operative time (min)
Range
40-130
Median
82
Blood loss (mL)
Range
30-300
Median
100
Duration of postoperative drainage (d)
Range
1-4
Median
3
Length of postoperative hospital stay (d)
Range
2-10
Median
3
Tumor size (cm)
Range
0.4-1.8
Median
0.8
Surgical margin (cm)
Range
0.5-4.5
Median
2.5
Histologic subtypes
Fibrous tissue proliferation
1
Atypical adenomatous hyperplasia
2
Adenocarcinoma in situ
1
Microinvasive adenocarcinoma
5
Invasive adenocarcinoma
11
Injection volume of iron sucrose (mL)
Range
70-120
Median
90
Time from injection of iron sucrose to demarcation of intersegmental plane(min)
The median injection of iron sucrose was 90 mL (range, 70-120 mL), and the median time from injection of iron sucrose to demarcation of intersegmental plane was 8 minutes (range, 3-25 minutes). The intersegmental plane could not be recognized in 3 cases. One was the segmentectomy of S1+2 + 3 on the left side due to insufficient injection of iron sucrose, 1 right S6 because of iron sucrose diffusion to adjacent S9 + S10, and 1 right S2 + S1a due to difficulty in inserting the needle into the involved bronchi. The recognition of the intersegmental plane for the 3 failure cases was replenished using the inflation-deflation method. The rate of a good depiction of the intersegmental plane was 85%. Moreover, this technique does not interfere with the pathological diagnosis (Figure 3).
Figure 3Gross specimens and pathological sections after iron sucrose injection in patients. The gross specimens showed the tumor and targeted segment after injection of iron sucrose. The pathological sections showed that the technique does not interfere with the diagnosis. MIA, Minimally invasive adenocarcinoma.
The median tumor size was 0.8 cm (range, 0.4-1.8 cm), and median surgical margin width was 2.5 cm (range, 0.5-4.5 cm). Final pathologic diagnoses were fibrous tissue proliferation in 1 patient, atypical adenomatous hyperplasia in 2 patients, adenocarcinoma in situ in 1 patient (p-TisN0M0), minimally invasive adenocarcinoma in 5 patients (p-T1miN0M0), and invasive adenocarcinoma in 11 patients (p-T1aN0M0 8 cases and p-T1bN0M0 3 cases).
Discussion
Iron sucrose is a brown colloidal solution widely used for iron deficiency. In this study, we showed favorable results for distinguishing the intersegmental plane with the use of iron sucrose, with an 85% rate of good delineation of the intersegmental plane. The intersegmental plane can be identified both on the pleural surface and in the pulmonary parenchyma (Figures 1 and 2). There were no postoperative complications of Clavien–Dindo grade 3 or more.
The inflation-deflation method is still most widely applied and served as the fundamental way for intersegmental plane identification.
Moreover, the duration of surgery is prolonged as a result of waiting for the deflation of preserved segment. Different from the jet injection, the iron sucrose is directly instilled into the target bronchus that has been cut off. The borderline would emerge in an average of 8 minutes and be distinguishable regardless of patients' lung function. Thus, our method can be used as a complement to the traditional inflation-deflation method, especially for those patients with poor lung function.
Intravenous application of ICG is another approach to reveal the borderline.
The fluorescent is injected into the patient's vein after the isolation of the target segmental vessels. The blood flow carries ICG to the preserved pulmonary tissue, and the illumination can be captured by a special facility. Besides demand for the equipment, the potential toxicity of ICG concerns surgeons.
A fluorescence duration of approximately 5 minutes might be insufficient in some cases. Compared with ICG application, the iron sucrose we adopted is a common nutritional supplement that can be easily acquired and is theoretically less risky and less expensive (the medication cost was < $10 for each patient). Furthermore, the intrabronchial approach avoids the side effects of drugs entering the bloodstream. Because the staining is visible through the naked eye, no additional equipment is required. Meanwhile, the permanent staining provides an adequate time for further operation.
Study Limitations
Despite its advantages, several limitations exist for the application of iron sucrose. Similar to other dye methods, it has a risk of unanticipated diffusion to the preserved segment that results from the overly forceful injection. Excessive volume of the target segment may bring about unclear borderline because of uneven staining. The combined sub-segmentectomy, during which more than 1 bronchial stump needs to be instilled dye, has a highly demanding operational requirement. The pigmentation on the pleura surface may confuse the staining performance. In addition, the injection also inflates the segment to some extent and brings a challenge to further removal.
Conclusions
We propose a novel staining technique that applies iron sucrose for intersegmental identification (Figure 4). Animal experiments and preliminary exploration of patients proved its safety, feasibility, and high efficiency. More evidence is still required to verify its improvements, when compared with traditional methods, for segmental surgery.
Figure 4A technique for identifying intersegmental plane both on the surface and in the parenchyma.
The procedures of iron sucrose instillment performed in this study were in accordance with the Declaration of Helsinki (as revised in 2013) and approved by the Ethics Committee of the Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (Registration No. 201801, ClinicalTrials.gov number, NCT03516500) in January 2018. All patients receiving treatment signed an informed consent form and agreed to the publication of their relevant data.
Conflict of Interest Statement
The authors reported no conflicts of interest.
The Journal policy requires editors and reviewers to disclose conflicts of interest and to decline handling or reviewing manuscripts for which they may have a conflict of interest. The editors and reviewers of this article have no conflicts of interest.
The authors thank Qiangru Zhu for the anesthesia and ethical care of pigs in animal experiments, and Yuqin Cao for help with the graphic abstract design.
A left S4+5 segmentectomy using the transbronchial injection of iron sucrose to distinguish the intersegmental plane. The A4+5, B4+5, and V4+5 were identified and dissected sequentially. Then, we injected iron sucrose through a butterfly needle into the distant B4+5 stump. After injection, the target segment turns brown, the border of the intersegmental plane is easily recognized, and we use an automated suturing device to divide the intersegmental plane and remove S4+5. Video available at: https://www.jtcvs.org/article/S2666-2507(23)00004-4/fulltext.
A left S4+5 segmentectomy using the transbronchial injection of iron sucrose to distinguish the intersegmental plane. The A4+5, B4+5, and V4+5 were identified and dissected sequentially. Then, we injected iron sucrose through a butterfly needle into the distant B4+5 stump. After injection, the target segment turns brown, the border of the intersegmental plane is easily recognized, and we use an automated suturing device to divide the intersegmental plane and remove S4+5. Video available at: https://www.jtcvs.org/article/S2666-2507(23)00004-4/fulltext.
Perioperative course and quality of life in a prospective randomized multicenter phase III trial, comparing standard lobectomy versus anatomical segmentectomy in patients with non-small cell lung cancer up to 2cm, stage IA (7th edition of TNM staging system).
Segmentectomy versus lobectomy in small-sized peripheral non-small-cell lung cancer (JCOG0802/WJOG4607L): a multicentre, open-label, phase 3, randomised, controlled, non-inferiority trial.
A simple and effective technique for identification of intersegmental planes by infrared thoracoscopy after transbronchial injection of indocyanine green.
Fluorescence visualization of the intersegmental plane by bronchoscopic instillation of indocyanine green into the targeted segmental bronchus: determination of the optimal settings.
The study was supported by the National Natural Science Foundation of China Grant No. 81871882; Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant No. 20172005; and Shanghai Municipal Commission of Health and Family Planning Outstanding Academic Leaders Training Program (2017BR055).
Drs Li, Zhang, Feng, and Han contributed equally to this article.
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