Near-infrared fluorescence techniques to reduce hypocalcaemia after thyroidectomy

Parathyroid glands produce and secrete parathyroid hormone (PTH) to regulate serum calcium levels. Tight regulation by the parathyroid glands is essential to ensure that levels of calcium in the blood remain within a narrow physiological range. If serum calcium levels are low, the parathyroid glands produce PTH, which increases intestinal calcium absorption via vitamin D, decreases renal calcium excretion, and ultimately stimulates osteoclasts and provides intrinsic calcium from the bones. Hypoparathyroidism occurs when the amount of PTH produced by the chief cells of the parathyroid glands is no longer sufficient to maintain serum calcium levels within the normal range. This can occur after thyroidectomy if the parathyroid glands or their vasculature are injured. Hypoparathyroidism is a common complication of total thyroidectomy. Patients who undergo thyroidectomy for Graves’ disease, thyroid cancer (particularly when a central neck dissection is also performed), or revisional surgery1 are at increased risk. Overall, the risk of transient postoperative hypocalcaemia, defined as lasting less than 6 months, is as high as 5–35 per cent2 and the risk of permanent hypoparathyroidism, defined as failure of functional recovery of the parathyroid glands within 6–12 months after thyroidectomy, is 4–12 per cent3,4. Due to their small size, variable anatomical position, and potential resemblance to the surrounding tissue, intraoperative localization of the parathyroid glands can be challenging5. Surgeon expertise remains important because normal glands are not visible with preoperative imaging. During thyroidectomy, the parathyroid glands need to be dissected off the thyroid and left in situ, which puts them at risk of being directly damaged, inadvertently removed, or having their vasculature injured. The blood supply to the parathyroid glands by end arteries follows a highly variable course; 90 per cent of the blood supply for the inferior glands and 77 per cent for the superior glands originates from the inferior thyroid artery, followed by the superior thyroid artery or by a combined blood supply. Additionally, the blood supply originates directly from the thyroid gland in 4–14 per cent of parathyroid glands6. In 5 per cent of patients, the vascular supply to all four glands is at risk when total thyroidectomy is performed6 (Fig. 1). To preserve parathyroid-gland function, at least one gland needs to be left in situ and with an intact blood supply7. Variable vasculature of the parathyroid glands affects the risk of parathyroid devascularization during thyroidectomy The regulation of calcium levels within narrow limits is critical for a multitude of functions in the body, including normal muscle contractility. Hypocalcaemia leads to muscle-fibre contractions, ranging from mild fasciculations that feel like pins and needles to tetanic attacks that lead to death in the early days after thyroid surgery. Although most hypocalcaemia states can be corrected with oral calcium supplements, calcium regulation is no longer adjusted within minutes to meet the body needs. Additionally, oral uptake of calcium may no longer be sufficient in cases when more calcium is required or more calcium is lost, such as during pregnancy and lactation, in cases of diarrhoea, or after bariatric surgery with malabsorption. Permanent hypoparathyroidism has been shown to be associated with a decrease in kidney function2,8,9, neurological and musculoskeletal complications, decreased quality of life10, and even mortality2,4,8,9,11,12. Therefore, reducing the incidence of hypoparathyroidism after thyroidectomy is important. Measures include both the expertise of the surgeon and the technique used for thyroidectomy. For patients at risk, subtotal thyroidectomy may increase the likelihood that the upper glands and their perfusion are preserved. In this procedure, the dorsal part of the thyroid near the latero-dorsal attachment of the thyroid, the Berry’s ligament, remains in situ. Performing a capsular dissection close to the thyroid will also decrease the risk of inadvertent parathyroid-gland dissection and vessel damage. In about 33 per cent of patients, even a dissection close to the thyroid capsule will de-vascularize the glands. A local intrathyroidal dissection may preserve the vascular supply if this is suspected13 (Fig. 1). It is, however, hard to assess by eye whether such a measure preserves parathyroid-gland perfusion. The unique near-infrared (NIR) autofluorescence (AF), which occurs at around 820 nm when excited by light at 785 nm, can be used to identify the parathyroid glands without endocrine-surgery expertise14. Since this discovery, probe-based and camera-based NIRAF devices that easily distinguish the parathyroid glands from the surrounding tissues have been developed. Both probe- and camera-based devices have a maximum tissue penetration of 5 mm; therefore, parathyroid glands covered by other soft tissues remain undetected15. In probe-based devices, once the background baseline fluorescence is set on thyroid or strap muscles, the probe tip can be held against the tissue. Pressing a foot pedal activates NIR light. The device then measures the NIRAF signal emitted by the tissue and displays the intensity as a detection ratio (DR) compared with the baseline. A DR greater than 1.2 is consistent with parathyroid-gland tissue and is signalled by an auditory beep16. In image-based devices, the camera is held 15–25 cm from the target tissue. The images captured by the camera are processed by the device to generate a greyscale image displayed on a monitor, where the parathyroid glands appear brighter than the surrounding tissue17,18 (Fig. 2a and Fig. S1). Image-based devices can also use indocyanine green (ICG) dye, which enables visualization of parathyroid-gland perfusion (Fig. 2b,c). Perfusion-angiography estimates of parathyroid glands based on indocyanine green uptake on NIR fluorescence imaging a Strong autofluorescent parathyroid gland (thick arrow). b Upon injection of indocyanine green, the dye can be visualized as it arrives in the inferior thyroid artery (thin arrow); autofluorescence of the parathyroid gland is no longer visible (thick arrow) as the system decreases its sensitivity to fluorescence to avoid saturation. c After 15 s, perfusion of the parathyroid gland is clearly visible (thick arrow) with its fine feeding artery. In contrast to AF, which is independent of viable or de-vascularized parathyroid glands, the assessment of perfusion and thus viability of glands using ICG correlates with postoperative function19–22. Perfusion angiography estimates the perfusion of the remaining parathyroid glands based on ICG uptake on NIR fluorescence imaging after thyroidectomy, using a three-point scale: not vascularized (0), moderately vascularized (1), and well vascularized (2)20,23 (Fig. 2). Mapping angiography, on the other hand, involves ICG injection at an early stage of dissection to visualize the vascular pedicle of the parathyroid glands and help preserve the vascular supply24–26. Compared with naked-eye assessment, NIRAF imaging has been shown to enable earlier and enhanced parathyroid-gland identification18,27,28 across all levels of training and expertise29,30. For residents, in particular, real-time feedback on interpretation of the anatomical locations is helpful19,29,30. The number of parathyroid glands on pathology specimens has been shown to be significantly reduced31. This may be due to a greater parathyroid-gland sparing dissection technique when using NIRAF techniques and an increased rate of detected glands on thyroid and neck dissection specimens, with the possibility of autotransplantation32. The use of ICG as an adjunct in image-based NIRAF devices allows for vessel mapping, with the possibility to adapt the dissection path to spare the vessels. Moreover, ICG enables an objective viability check, offering autotransplantation as a solution in cases where the objective perfusion of the gland is missed. The prediction of postoperative parathyroid function after thyroidectomy based on intraoperative gland-perfusion assessment has been shown to be very good33–35, such that ICG can also be used for risk assessment and guidance. To prevent hypoparathyroidism, the decision to perform a prophylactic central neck dissection on the contralateral side, for instance, may be based on the assessed perfusion of parathyroid glands on the side of the thyroid that is addressed first. The value of NIR devices, with or without ICG, in reducing hypoparathyroidism after thyroidectomy is well studied. A total of seven RCTs (six single-centre RCTs and one multicentre RCT) have been performed to assess the use of either AF alone (five RCTs)31,36–39 or both AF and ICG (two RCTs)40,41. In most RCTs, the use of NIRAF-based devices increased the median number of parathyroid glands identified42 and decreased the rate of transient, but not permanent, hypoparathyroidism39,43. These studies were performed in high-volume centres, where expertise on the localization and preservation of parathyroid glands is likely present, and where NIRAF-based devices may not provide as much additional benefit as in less-experienced hands. A number of studies have reported false positives using NIRAF devices, including brown fat, lymph nodes (especially metastatic lymph nodes), thyroid nodules, and Vicryl sutures16,18. This emphasizes the importance of clinical correlation of the AF images. Another drawback of camera-based NIR devices is the absence of quantification. As mentioned above, perfusion assessment of parathyroid glands relies on surgeon interpretation (grading 0–2), a limitation that may be overcome with artificial intelligence in the future44. Additionally, image-based systems are susceptible to interference from ambient light, as well as the angle of the camera, making imaging in small incisions particularly challenging. Thus, probe-based devices can be advantageous because they can be used in small incisions, providing quantitative feedback without interference from ambient light45. The authors have no funding to declare. Diana Vetter (Conceptualization, Writing—original draft, Writing—review & editing), and Frédéric Triponez (Conceptualization, Supervision, Visualization, Writing—review & editing). F.T. is a consultant for Fluoptics and Medtronic. The authors declare no other conflict of interest. Supplementary material is available at BJS online.