Does the use of near-infrared autofluorescence reduce the incidence of inadvertent parathyroidectomy during thyroid surgery?—a pilot study in an Australian centre

Introduction

The incidence of inadvertent parathyroidectomy in thyroid surgery has varied between 6.4% and 31% (1). Downstream ramifications of post-operative hypocalcaemia are variable but can include tetany, seizures, prolonged hospital stay, and potential for long-term dependence on calcium replacement therapy. Parathyroid glands can be difficult to identify intra-operatively, due to their variability in shape, colour, and location, and may be mistaken for thyroid tissue or fat (2). If inadvertent removal is identified at the time of surgery, it allows the opportunity for re-implantation which may reduce the incidence and/or severity of post-operative hypocalcaemia (3). Surgical experience and pattern recognition forms the mainstay of prevention, and partially accounts for the variability in documented incidence of inadvertent parathyroidectomy. There is great variability in thyroid pathology which may also contribute to difficulty in visually detecting parathyroid glands. Another technique to directly identify parathyroid tissue includes frozen section, and a rapid parathyroid hormone (PTH) assay (depending on clinical circumstance) assesses functionality, but these are time-consuming, costly, and not readily available in many institutions.

Fluorescence is an intrinsic property of certain molecules. It involves the absorption of light which ultimately triggers the movement of electrons to a lower energy level, resulting in the release of photons. The light generated is of a lower energy and longer wavelength compared to the absorbed light. The concept of fluorescence has been utilised in a range of settings such as hepatobiliary surgery, and for the assessment of tissue perfusion, including bowel anastomosis and lymphatic surgery (4,5). These settings have typically used a tracer, specifically indocyanine green (ICG), which concentrates in target tissues. ICG is activated by light in the near-infrared (NIR) spectrum, such that when the appropriate imaging system is used which can produce light in the NIR spectrum, the target tissue fluoresces and exhibits contrast to the surrounding tissues.

Whilst ICG also concentrates in parathyroids and can similarly be used as an adjunct for identification, it requires IV administration and carries small risks of anaphylaxis and liver impairment. Interestingly, parathyroid glands have been found to have intrinsic autofluorescence due to the presence of endogenous fluorophores that emit a fluorescent signal in the NIR wavelength at a peak near 820 nm (5). In 2011, Paras et al. (6) demonstrated that parathyroid glands consistently demonstrated fluorescence intensity greater than that of the thyroid and other tissues in the neck. In particular, it was two to eleven times higher than that of thyroid tissue with peak fluorescence occurring at 820–830 nm. As such, there has been increasing interest in the use of NIR systems for detecting parathyroid glands intra-operatively, without the need for contrast. The technology utilises an endoscope with a light filter at the NIR range to produce contrasting colour images that can aid differentiation of structures. Specifically, it allows for structures with a fluorescence signal around 800 nm to be enhanced.

It has been proposed that NIR systems offer a non-invasive and simple method for intra-operative detection of parathyroid tissue, which may save inadvertent removal, or allow for re-implantation of inadvertently removed glands at the time of surgery.

Several studies have examined the accuracy of utilizing NIR autofluorescence in identification of parathyroid glands, with most returning excellent results. One meta-analysis (7) returned a sensitivity and specificity over 95%. It should be noted that there is a degree of heterogeneity amongst studies, in terms of their clinical utilization of the technology (thyroid versus pathological parathyroid surgery), and in the equipment used. Nevertheless, there are growing data to support its ability to accurately identify parathyroid tissue.

Uncertainty remains as to whether NIR adjuncts are definitively superior to naked eye detection in reducing inadvertent parathyroidectomy and hypocalcaemia rates. One prospective randomized controlled trial (8) found no significant reduction in the incidence of postoperative hypoparathyroidism, whilst other studies have found a significant reduction in inadvertent resection and post-operative hypocalcaemia (9,10). This has implications for whether NIR systems should be universally recommended for all patients undergoing thyroidectomy.

In this study, we assessed our ability to identify parathyroid glands by comparing standard naked eye detection versus naked eye detection aided by NIR autofluorescence and the effect on the rate of inadvertent parathyroidectomy. We hypothesised that use of the NIR adjunct would enhance parathyroid detection rates, and result in a lower incidence of inadvertent parathyroidectomy.

Methods

This was a retrospective cohort study of hemi and total thyroidectomy operations performed at a single centre at Logan Hospital, Brisbane, Australia, where NIR has been utilized. Operations were performed by moderate to high-volume thyroid surgeons (>50/year) at a teaching hospital. This study is reported according to the STROBE reporting guidelines (available at https://www.theajo.com/article/view/10.21037/ajo-24-80/rc).

We analysed histopathology and biochemical results of all adult patients (16 years and above) who underwent hemi or total thyroidectomy over a 5-year period from 2019 to 2024. This included patients undergoing hemi and total thyroidectomy for benign or malignant disease. Patients with previous parathyroidectomy were excluded. Outcomes for routine cases utilizing naked eye detection of parathyroids were compared with cases where NIR was used as an adjunct.

Data were obtained from electronic medical records, including: patient age, gender, operation (hemi vs. total thyroidectomy), indication for operation, and whether NIR was used or not. Formal histology was reviewed to determine inadvertent parathyroidectomy rate. Post-operative calcium and PTH were also reviewed for those undergoing total thyroidectomy.

The primary measured outcome was inadvertent parathyroidectomy rate. Hypocalcaemia (defined as an albumin-corrected calcium of less than 2.1 mmol/L) rates for total thyroidectomies were analysed as a secondary outcome. All operations were performed by moderate-high volume thyroid surgeons.

NIR was performed using the ICG rigid endoscope with Rubina camera head (Karl Storz, Tuttlingen, Germany). The endoscopic system utilizes a filter to switch between white light and NIR light emitted from a light-emitting diode (LED) source (Figures 1-3). The camera was used intermittently during key portions of the case to assist dissection and preservation of parathyroid tissue where in doubt, as well as for evaluation of the extracted thyroid specimen to identify any inadvertently removed parathyroid glands. Any identified glands were then reimplanted. The final specimen was then submitted to the same anatomical pathology laboratory for analysis.

Figure 1 Intra-operative endoscopic photograph demonstrating suspected parathyroid tissue illuminated by white light (artifact in the foreground).

Figure 2 Intra-operative endoscopic photograph with NIR filter applied—parathyroid tissue fluoresces as yellow-green (artifact in the foreground). NIR, near-infrared.

Figure 3 Equipment setup with concurrent near infra-red filtered high-resolution display.

Descriptive statistics were presented with means alongside standard deviation. Data were analysed with a Fisher’s exact test to examine the differences between variables. The level of significance was taken to be P<0.05.

The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. Ethical approval for this study was obtained from the Metro South Health Human Research Ethics Committee (HREC/2023/QMS/101994). Patient confidentiality was maintained by anonymizing data, and individual consent was waived for this retrospective analysis.

Results

A total of 172 cases were identified involving at least partial thyroidectomy over the period 2019–2024. This included 42 total thyroidectomies, 116 hemithyroidectomies, and one isthmusectomy (excluded). Thirteen cases involved hemi or total thyroidectomy with central neck dissection. One hundred and seventy-one cases met criteria for inclusion (Figure 4).

Figure 4 Flow diagram outlining distribution of cases.

One hundred and fifty-four cases were performed with routine naked eye evaluation (age 51.9±15.6 years, 73% female). This included 36 total thyroidectomies and 105 hemithyroidectomies. Thirteen cases performed for hemi or total thyroidectomy included a central neck dissection. There were 26 instances of inadvertent parathyroidectomy on formal histology, resulting in a 16.8% inadvertent rate. Of the 36 total thyroidectomies (without central neck dissection) that were performed, 17 had post-operative hypocalcemia.

Seventeen cases involved use of NIR (age 51.0±12.4 years, 76% female). This included six total thyroidectomies, and 11 hemithyroidectomies. There was a single case of inadvertent parathyroidectomy. Four of six total thyroidectomies demonstrated post-operative hypocalcaemia (Table 1).

There was a lower rate (5.9%) of inadvertent parathyroidectomy in cases where NIR had been utilized, however, this difference was not significant [P=0.48; odds ratio (OR) =0.31; 95% confidence interval (CI): 0.04–2.42]. There was also no significant difference in hypocalcaemia rates (NIR 67%, naked eye detection 47%) in the total thyroidectomy population (P=0.66; OR =2.24; 95% CI: 0.36–13.78).

In the NIR group, there was a single case where a parathyroid was identified in the extracted total thyroidectomy specimen and was re-implanted. There was no hypocalcaemia seen in this case post-operatively.

Discussion

Inadvertent parathyroidectomy and post-operative hypocalcaemia can be debilitating and costly complications of thyroidectomy. Consequences may include prolonged stay in hospital, symptomatic hypocalcaemia, cardiac arrhythmias such as long QT, and need for long-term replacement. Current literature proposes inadvertent parathyroidectomy rates of 6.4–31% (1), with factors such as surgeon experience, and complexity of operation accounting for the large variability. Likewise, the rates of temporary hypocalcaemia post-total thyroidectomy range from 43% to 68% (11). Traditionally, naked eye evaluation of the thyroid bed and extracted specimen has formed the mainstay of prevention. Auto-fluorescence is a recently identified property of parathyroid tissue which has allowed for utilization of readily available technology to enhance their detection. Compared to other fluorescence technologies which require injection of tracer, the ICG camera (Karl Storz) is non-invasive, and quick and easy to setup. The equipment is commonly available in many hospitals across Australia already, given its usefulness in visualising the biliary tree, for liver transplantation and cholecystectomy amongst other indications. As such, there is minimal added cost to most departments. In our experience, the equipment is easy to assemble and troubleshoot, with minimal training required.

In our review of thyroidectomy cases over the last 5 years, we identified a small number of cases where NIR has been trialled as an adjunct with recorded data. Although there was no statistically significant difference between naked eye detection and NIR + naked eye, the results are promising, with a potential trend that NIR may reduce inadvertent parathyroidectomy rates when used over a longer period. However, post-operative hypocalcaemia is not just determined by inadvertent parathyroidectomy alone. Rather, dissection technique and preservation of parathyroid blood supply are crucial in preventing temporary hypocalcaemia. Current literature suggests that there is no significant benefit towards reducing hypoparathyroidism and hypocalcaemia rates with NIR (8). In our study, we found that there was actually a higher rate of hypocalcaemia in the NIR group (67%), although this difference was not statistically significant (P=0.66; OR =2.24; 95% CI: 0.36–13.78). With a larger sample size, we would expect the rate to be equivocal between the two groups, or potentially lower in the NIR group. NIR detection and prevention of inadvertent parathyroidectomy do not necessarily prevent ischaemic damage to parathyroid glands, which is influenced by factors such as case complexity and surgical technique. However, we anticipate that with time, surgeons may become more comfortable with incorporating the technology into routine surgery, allowing for earlier and faster identification of parathyroids, assisting in dissection to preserve parathyroid blood supply and reduce postoperative hypocalcaemia rates. The use of NIR may serve as a confirmatory test, similar to frozen section analysis, but without sacrificing part of the gland.

Some studies evaluating the effectiveness of NIR have primarily used the technology to examine the extracted thyroid specimen for inadvertently removed parathyroids, thereby allowing the opportunity to reimplant (12,13). In our institution, we utilize the technology throughout the operation to assist in confirmation of parathyroid tissue in situ. We have found value in instances where parathyroid tissue may be difficult to differentiate from nodal tissue, fat, atypical thyroid nodular tissue or found in an intracapsular position. Figure 5 demonstrates visual contrast between fat and parathyroid tissue, allowing intra-operative differentiation. This may especially be useful in cancer cases where resection margins are paramount, as is removal of any suspicious extra-thyroidal tissue. The NIR camera is yet to be trialled as an adjunct in central neck dissection, but we anticipate it to be useful in improving efficiency and reducing inadvertent parathyroidectomy while maintaining oncologic outcome. If there is tissue suspected to be normal parathyroid in the central nodal compartment, use of the NIR camera would allow for quick identification and confirmation. This may minimize reliance on frozen section analysis and avoid the risk of retained disease or unnecessary parathyroid gland sacrifice when in close proximity to pathologic lymph nodes. In this study, of the 13 patients who underwent central neck dissection (all by naked eye detection only), there were seven cases of inadvertent parathyroidectomy. We believe that NIR may play an important role in balancing parathyroid preservation with thorough resection of malignancy.

Figure 5 Endoscopic photograph demonstrating the different appearance of fat (above) and parathyroid tissue (below) with NIR filter application. NIR, near-infrared.

Furthermore, the NIR camera may have a role in assisting less experienced surgeons, and as an adjunct for teaching and training. Images displayed with high resolution clearly delineate parathyroid tissue which may provide for a less steep learning curve. Its uses in head and neck surgery have also been expanded to include localization during parathyroidectomy for hyperparathyroidism, from minimally invasive to four-gland exploration settings. In hospitals where rapid PTH assays are not available, and frozen section analysis may require advanced organization and be time-consuming, the NIR camera is a reliable technological adjunct.

At time of writing, there are two emerging systems for NIR detection in thyroid and parathyroid surgery in Australia—these are the Storz ICG camera endoscopic system as described above, and the PTeye (Medtronic, Dublin, Ireland). The PTeye uses similar NIR technology, but instead of generating an image, it provides a numeric value of tissue fluorescence relative to background thyroid tissue—this is presented visually on a monitor, with audible feedback (14). In our experience, setup of the camera stack and NIR endoscope was quick and easy. Initial cases were performed with support from a Karl Storz representative to guide equipment setup, selection of settings, and usage of endoscope. We found that minimal training was required in order for both surgeons and theatre nursing staff to become efficient and confident in the use of the technology. Overall, the time for setup was less than 5 minutes—this was further reduced by having theatre staff assist in equipment setup as the operation was proceeding.

One of the main limitations of NIR detection is the depth of penetration. Adipose tissue or thick fascia covering the gland can impede fluorescence signalling. This thus requires proper exposure of the tissue to allow for NIR analysis, risking excess dissection and devascularisation. Furthermore, the endoscope must be relatively close to the gland to induce fluorescence (some sources state 2–3 mm). Because of these aspects, the device is more adept at confirming a surgeon’s suspicions for parathyroid tissue, as opposed to being used to localize the gland. The level of fluorescence can also be variable and difficult to pick up, requiring operating room lights to be switched off temporarily. Parathyroid fluorophores persist after extraction, even up to 2 years (15). As such, even a devascularized parathyroid exhibits fluorescence, and the NIR response is not indicative of intact function. Nevertheless, it can still be used to guide careful dissection around confirmed parathyroid tissue.

The primary study limitation is the low sample size of NIR cases accrued. Use of NIR equipment was largely dependent on factors including surgeon preference, knowledge of setup and usage and availability of a company representative to assist. These factors present potential for selection bias. In the early stages of implementation for each surgeon, additional time on an operating list was required to facilitate setup and usage. This likely accounts for the small sample size of NIR cases. We found the technology easy to grasp, and expect NIR cases to increase in the future given wider adoption amongst surgeons in the department.

As a retrospective study, there were limitations in the patient populations and sample sizes able to be analysed, as well as an absence of randomisation of control and test groups. A larger prospective series in the future with increased power would clarify the effect trend. A power analysis using the preliminary results in this pilot study suggests that a sample size of at least 260 would be required to detect a difference between groups (given an 80% power). A larger, prospective randomized controlled trial is needed to assess long-term follow-up of outcomes, allow for cost-effectiveness analysis, and control for surgical complexity.

It is routine practice in our institution to utilize parathyroid preservation techniques when performing thyroidectomy, including gentle handling of parathyroid tissue and preservation of vascular pedicle. However, there is likely to exist variability across surgeons with regards to surgical dissection techniques, which could not be controlled for in this retrospective analysis. This may have influenced hypocalcaemia outcomes.

Conclusions

NIR is a safe, simple, and readily available technology that demonstrates promise in thyroid and parathyroid surgery. There were lower rates of inadvertent parathyroidectomy with use of NIR, although further studies are required to achieve a higher power to demonstrate a statistically significant effect. Increased utilization throughout a procedure may allow for early identification and confirmation of parathyroid, reducing postoperative rates of hypocalcaemia.

Acknowledgments

Acknowledgments to Rhea Daniel for assistance with data collection.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://www.theajo.com/article/view/10.21037/ajo-24-80/rc

Data Sharing Statement: Available at https://www.theajo.com/article/view/10.21037/ajo-24-80/dss

Peer Review File: Available at https://www.theajo.com/article/view/10.21037/ajo-24-80/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://www.theajo.com/article/view/10.21037/ajo-24-80/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. Ethical approval for this study was obtained from the Metro South Health Human Research Ethics Committee (HREC/2023/QMS/101994). Patient confidentiality was maintained by anonymizing data, and individual consent was waived for this retrospective analysis.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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