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Table 6.1 (continued)
system Benets/utility Limitations
Contrast­enhanced
Provides real-time information on parathyroid gland perfusion
May help identify and preserve parathyroid gland blood supply
Can guide decision­making regarding need for autotransplantation
Helps determine which patients are at risk for postoperative hypocalcemia
Can help determine need for postoperative labs and calcium and vitamin D supplementation
Rapid cycling between uorescence imaging, white light, and uorescence overlay
Limited ability to distinguish between thyroid and parathyroid glands
Limited tissue penetration
Subjective interpretation of degree of uorescence/ perfusion
ICG contraindicated in patients with iodine allergy
Requires purchase of imaging system and dye
Unclear effect on operative duration
J. Matson et al.
of inadvertently removed glands in the resection specimen that could then be autotransplanted. Finally, there is an upfront cost to acquire the imaging system. There is conicting data on the effect on operative duration and the ability to prevent hypocalcemia, and no cost-effectiveness studies have been published, so it is unclear what the overall nancial impact of incorporating this technology into a thyroid surgery practice would be.
ICG FA has several similar limitations. The penetration is also limited to only several millimeters, so overlying soft tissue can obscure the parathyroid glands. There is also rapid enhancement of the thyroid gland by ICG as it is also a hypervascular organ. Therefore, ICG FA should not be used to distinguish between the thyroid and parathyroid glands. Furthermore, current systems depend on subjective interpretation of uorescence, which limits standardization and the ability to determine cutoffs associated
6 Use ofFluorescence Guidance inEndocrine Surgery
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with postoperative hypocalcemia and hypoparathyroidism. Quantitative uorescence is not currently integrated into imaging systems and requires customization of equipment for real-time visualization or later analysis of videos with appropriate software, which does not provide immediate feedback to the surgeon. While the capability for NIR uorescence imaging is being integrated into newer laparoscopic and robotic imaging systems, purchasing these newer models requires signicant investment. Additionally, the greatest utility in thyroid surgery is likely using systems spe­cically designed for open surgery that do not require using the unwieldy laparoscopic or robotic cameras to visualize the neck (and which also do not require sterilization of the camera between cases). ICG dye also presents an added cost, though it is insigni­cant compared to the overall operative costs. It is also contraindi­cated in patients with allergies to iodine. Finally, like NIRAF, there is conicting data on the effect of the technology on dura­tion of the operation. There is undeniably a requirement to wait for uorescence after administration of the dye, but most studies have shown this to range from less than a minute to no more than 3min [44, 45]. This may also result in time-savings if it allows surgeons to proceed with the operation and wound closure with­out waiting for intraoperative PTH levels or frozen section analy­sis or avoid unnecessary autotransplantation.
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Summary andVision forApplication
Based on early results, there has been a good deal of excitement and numerous publications about the use of uorescence image guidance in thyroid surgery. While the vast majority of studies are retrospective, single-institution case series or cohort studies, there are several large, randomized trials that seem to show superiority of NIRAF visualization of the parathyroid glands compared to traditional surgery [31, 32]. ICG FA may provide additional insight into the perfusion status of identied glands to help guide autotransplantation and the need for postoperative monitoring and supplementation. The systematic review by Demarchi etal. sum­marized 25 studies utilizing either NIRAF or dye-enhanced NIR
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J. Matson et al.
imaging in thyroid surgery; they concluded that the use of the technology was feasible and safe and several benets including improved identication and preservation of the parathyroid glands as well as early identication of mistakenly resected glands that might allow autotransplantation [44]. Together, this may result in reduced postoperative hypoparathyroidism and hypocalcemia. This is supported by the ndings of Barbieri etal.; the authors performed a meta-analysis of 13 studies looking at uorescence imaging in total thyroidectomy and included 1484 operations [46]. They found that uorescence-guided surgery resulted in improvements in both short- and medium-term hypocalcemia rates compared to traditional surgery (8% vs. 15% and 1% vs. 5%, respectively).
Taking this information into consideration, we believe that these techniques can be used in complementary fashion for opti­mal results. In any case, a pre-incision PTH level should be drawn. The utility of NIRAF seems to primarily be in the early identica­tion and preservation of parathyroid glands and in examining the resection specimen for missed glands. Therefore, once adequate exposure of the thyroid gland has been achieved through incision of the skin, soft tissue, and platysma and retraction of the strap muscles, the surgical eld should be examined with the use of a device designed for detection of parathyroid gland autouores­cence. The location of identied parathyroid glands should be noted, and they should be protected while the dissection carefully continues, periodically reexamining the eld if candidate struc­tures are found. Once the thyroid specimen has been removed, it may also be examined briey for any missed glands, noting the limitations of penetration in identifying deeper intrathyroidal glands.
The previously identied glands should be conrmed, and then
2.5mg of ICG (1 mL of reconstituted solution, 25mg vial with 10 mL of sterile water) should be administered through a peripheral IV immediately followed by a 10cc ush of normal saline or lactated ringers by the anesthesia provider while the sur­gical eld is visualized with an NIR imaging device. The parathy­roid glands should uoresce within 30–90 s if they remain well-vascularized, and the peak intensity of their uorescence as
6 Use ofFluorescence Guidance inEndocrine Surgery
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well as the rate of increase in uorescence intensity may provide evidence for the adequacy of their perfusion. Glands that appear to be devascularized (minimal or no uorescence) can be incised with a scalpel and if there is no bleeding can be considered for autotransplantation. If there are at least two well-vascularized glands, autotransplantation of any remaining glands is likely unnecessary. Similarly, in the case of at least two well- vascularized glands, providers may choose to forego postoperative PTH/cal­cium monitoring or prophylactic vitamin D and calcium supple­mentation.
If there is concern that a candidate gland may be a metastatic lymph node, this structure should be sampled and sent for frozen section analysis before autotransplantation. Otherwise, frozen section analysis and rapid PTH assays are not necessary and should be used at surgeon discretion on a case-by-case basis.
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Parathyroid Surgery
The utility of uorescence-guided surgery in identifying parathy­roid glands and determining their perfusion status may also be applied to parathyroid surgery. Parathyroid surgery is primarily performed to prevent complications or alleviate symptoms related to hypercalcemia secondary to elevated PTH levels (i.e., kidney stones, fatigue, depression, osteoporosis, and other symptoms). The most common indication for parathyroidectomy is primary hyperparathyroidism, or abnormally elevated PTH and calcium levels, which is usually due to a single hyperfunctional parathyroid adenoma. Less common causes of primary hyperparathyroidism are multiple adenomas, diffuse hyperplasia, and parathyroid carci­noma. In patients with single or multiple adenomas, their disease process can typically be cured and calcium/PTH normalized by removal of the pathologic gland(s). Patients with diffuse hyperpla­sia as well as those with secondary (caused by constant stimulation from low calcium and elevated phosphate levels in renal disease) or tertiary (hyperparathyroidism from renal disease that persists after kidney transplant) hyperparathyroidism require subtotal para­thyroidectomy, or removal of most parathyroid glands and leaving
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about 1/2 gland in situ or autotransplanted to a more easily acces­sible area such as the forearm or sternocleidomastoid. Failure to remove diseased glands may result in persistent hyperparathyroid­ism, while leaving or autotransplanting inadequately perfused glands during subtotal parathyroidectomy could result in hypo­parathyroidism and hypocalcemia. Preoperative imaging is most effective at localizing single adenomas but has far less sensitivity and specicity for multiple adenomas or diffuse hyperplasia; even in the case of a single adenoma, however, intraoperative localiza­tion may present a challenge [4750]. Using near-infrared imaging either to elicit autouorescence of the parathyroid gland or in com­bination with uorescent dye such as ICG may facilitate localiza­tion of the abnormal glands, and the latter may be used to help determine which gland is most appropriate for preservation/auto­transplantation.
J. Matson et al.
Autouorescence
Parathyroid gland autouorescence has been found to be helpful in identifying parathyroid glands during parathyroid surgery for various indications as well as during thyroid surgery. Parras etal. found a signicant difference in autouorescence intensity between parathyroid and thyroid glands (p=0.00000235) [16]. McWade etal. corroborated this (parathyroid gland autouores­cence is between 1.2 and 29 times higher than thyroid autouores­cence) and found a sensitivity for intraoperative parathyroid gland detection of 97% [51]. The clinical signicance of autouores­cence in parathyroidectomy is to help identify parathyroid glands in order to prevent persistent hyperparathyroidism due to a missed adenoma or insufcient resection in diffuse hyperplasia. Given current high cure rates at specialist centers (up to 97%), superior­ity over traditional surgery is difcult to demonstrate [52]. In their 2019 review of NIRAF in thyroid and parathyroid surgery, DiMarco and Palazzo determined that 902 patients would need to be included to demonstrate an improvement in persistent hyper­parathyroidism from 2% to 0.1% [34]. Thus far, no studies have been performed looking at that outcome. However, Demarchi
6 Use ofFluorescence Guidance inEndocrine Surgery
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et al. recently described a characteristic autouorescent pattern for parathyroid adenomas (heterogenous uorescence with a more highly uorescent cap that correlated with normal parathy­roid tissue in 74% of specimens); all patients in their study dem­onstrated cure of their primary hyperparathyroidism [53]. If this nding is conrmed in larger studies, the characteristic pattern may permit the use of NIRAF in further distinguishing normal from abnormal gland(s) and obviating the need to wait for conr­mation with a 50% reduction in PTH levels post-resection, as is the current standard.
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Fluorescent Dyes
The use of dye-based techniques to help identify the parathyroid glands has existed for half a century [21]. The combination of dye administration with NIR uorescence imaging has seen a signi­cant uptick in interest and use in the last decade. While various compounds have been explored for his purpose, including methy­lene blue and aminolevulinic acid, the dye that has been the most studied is ICG [12, 22, 24, 39].
It has been proposed that ICG FA may be particularly helpful in identifying abnormal parathyroid glands because of their potential increased blood ow. The initial case study by Chakedis et al. demonstrated that ICG FA could effectively assist with localiza­tion of a recurrent parathyroid adenoma in redo parathyroidectomy [54]. Several case series conrmed its utility in reoperative para- thyroidectomy as well as in initial parathyroid surgery [5559]. These studies showed superior sensitivity of ICG FA compared to traditional techniques such as ultrasound or sestamibi, and even compared to newer imaging modalities such as 4D CT.
When compared to NIRAF, ICG FA can also give insight into the perfusion status of the parathyroid glands (Fig. 6.5). This is important in subtotal parathyroidectomy to ensure that an ade­quately perfused remnant is selected for either preservation or auto­transplantation. Studies have demonstrated that ICG FA may be useful in this regard, as none of the patients in these reported case series developed hypoparathyroidism [39, 58, 60]. This was one of
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J. Matson et al.
abc
Fig. 6.5 A representative image of parathyroid adenoma uorescence fol­lowing injection of ICG and excitement with NIR light. All are from the same patient and injection of ICG. (a) Parathyroid adenoma (white arrow) under white light prior to injection of ICG. (b) The adenoma (white arrow) with computer-generated green overlay after peak uorescence was achieved. (c) Fluorescence of the adenoma (white arrow) and its feeding vessel (black tri­angle) seen in grayscale viewing mode. (Figure and caption reproduced from Matson etal. [45])
the proposed uses for contrast-enhanced NIR uorescence imaging in parathyroidectomy described by Solórzano etal. in their recent review of NIR uorescence in endocrine surgery of the neck [12].
Doses of ICG administered for the detection of parathyroid
glands during parathyroidectomy were variable [39]. As little as
2.5mg can be used effectively, and repeat administration of ICG can still provide adequate uorescence visualization, such as for bilateral neck exploration, with ICG FA rst performed on one side of the neck before repeating the procedure on the contralateral side [39, 45]. The parathyroid glands will typically reach peak uorescence in less than a minute; the authors’ recently published study found an average time to initial uorescence of 26.7s and average time to peak uorescence of 38.0s, with a signicant asso­ciation between time to uorescence and how quickly the anesthe­sia provider ushed the IV following injection of the dye [39, 45].
Potential Pitfalls
Like thyroid surgery, both NIRAF and dye-enhanced uorescence imaging have a potential role in parathyroid surgery. This role is variable depending on the exact indication for surgery, and the limitations vary accordingly (Table6.2).
6 Use ofFluorescence Guidance inEndocrine Surgery
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parathyroid glands is not signicant
viability
Limited tissue penetration
Potential false positives with metastatic lymph
nodes, brown fat, colloidal thyroid nodules
Requires purchase of imaging system
Limited ability to distinguish between thyroid
and parathyroid glands
Limited tissue penetration
175
Subjective interpretation of degree of
uorescence/perfusion
ICG contraindicated in patients with iodine
allergy
Distinguishes between thyroid and parathyroid glands Does not provide information on perfusion/
Distinguishes between thyroid/parathyroid glands and
surrounding tissues
system Benets/utility Limitations
Autouorescence Does not require any exogenous contrast agent Occasionally, contrast between thyroid and
Table 6.2 Utility and limitations of uorescence guidance during parathyroid surgery
May improve intraoperative identication of parathyroid
glands over traditional surgery
Potential to identify parathyroid adenomas based on
characteristic uorescence pattern in some cases
Potential to reduce rates of persistent hyperparathyroidism Unclear effect on operative duration
Contrast- enhanced Provides real-time information on parathyroid gland
perfusion
May help guide selection of remnant gland for subtotal
parathyroidectomy
May reduce hypoparathyroidism/hypocalcemia after subtotal
parathyroidectomy
May improve localization of parathyroid adenomas over
traditional preoperative imaging techniques
Dosing may be safely repeated for bilateral neck exploration Requires purchase of imaging system and dye
Uptake of ICG is rapid in both normal and pathologic glands Unclear effect on operative duration
Rapid cycling between uorescence imaging, white light,
and uorescence overlay
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The primary role of NIRAF in parathyroid surgery is in identi­cation of the parathyroid glands, similar to its role in thyroid surgery. Therefore, some of the potential issues with its use are the same: the limited depth of penetration (just a couple millime­ters) could result in missed glands, potentially causing persistent hyperparathyroidism and requiring reoperation, or could result in devascularization of glands that should be preserved, potentially resulting in hypoparathyroidism and hypocalcemia; the lack of information about perfusion status could result in selection for preservation or autotransplantation of a suboptimally perfused gland and hypocalcemia. In parathyroid surgery, it is also impor­tant to be aware of the variable autouorescence of pathologic parathyroid glands (often less brightly uorescent than normal glands or heterogenous in enhancement, and sometimes even hypouorescent compared to surrounding tissues), which is par­ticularly true for secondary hyperparathyroidism and multiple endocrine neoplasia type (MEN1).
Dye-enhanced NIR uorescence imaging may be used for either the identication of normal or abnormal parathyroid glands during parathyroidectomy or for the assessment of perfusion sta­tus of the remnant gland in subtotal parathyroidectomy. The limi­tations are essentially the same as for thyroid surgery: limited tissue penetration and ability to detect intrathyroidal or other “buried” glands, inability to differentiate thyroid and parathyroid tissue, and potentially increased costs and OR time associated with its use. However, in parathyroid surgery, there may be better delineation between thyroid and parathyroid tissue since the para­thyroid gland being localized is usually hyperplastic and therefore should theoretically have increased uptake of ICG and greater relative uorescence.
J. Matson et al.
Summary andVision forApplication
Overall, the data supporting the use of both NIRAF and ICG FA in parathyroid surgery is limited, with no randomized trials or meta-analyses supporting its use. There are several case series that seem to demonstrate superior sensitivity compared to tradi-
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tional methods of preoperative localization and multiple system­atic reviews that highlight the potential uses of these technologies. There remains a need for large cohort studies and randomized controlled trials to better support widespread adoption of these techniques.
Because the data is more limited, the optimal use of either or both NIRAF and ICG FA in parathyroid surgery is unclear. For a surgeon who already uses one or both technologies in their thy­roid operations, they may prefer to continue integrating that tech­nology into their parathyroid operations. However, the authors believe that ICG FA offers more advantages in parathyroid sur­gery over autouorescence. First, pathologic parathyroid glands have variable autouorescence, which may include heterogenous enhancement or global hypoenhancement [34]. This is particu­larly true in the diffuse hyperplasia of secondary hyperparathy­roidism and multiple endocrine neoplasia type 1 (MEN1). Second, the use of ICG can provide information on the perfusion status of the parathyroid glands and guide autotransplantation or subtotal parathyroidectomy to reduce the risk of postoperative hypopara­thyroidism. The following represents our technique.
The beginning of the operation is no different than for thyroid surgery, beginning with the anesthesia provider drawing a pre­incision PTH level followed by the surgeon making a transverse cervical neck incision and carrying the dissection down through the platysma and retracting the strap muscles. Once the thyroid gland is identied, it is retracted toward the midline from the pre­sumed site of pathology (based on preoperative imaging) or from the surgeon’s preferred initial side if addressing 4-gland disease. Gentle dissection is then performed to attempt to identify the parathyroid glands on that side without disrupting their blood sup­ply. Particular attention is given to attempting to nd the enlarged gland in the case of an assumed single adenoma. After identifying the candidate gland(s), the surgical eld is visualized through the uorescence imaging system to ensure appropriate image quality. This may require adjustment of the OR lights away from the sur­gical eld or dimming of the room lights. 2.5mg of ICG (1mL of reconstituted solution) is then injected by the anesthesia provider through a peripheral IV followed immediately by a ush of at
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