Introduction

Intraoperative parathyroid hormone (PTH) monitoring has been used since the 1990s to guide the excision of abnormal parathyroid glands in patients with sporadic primary hyperparathyroidism (SPHPT); however, only recently has it become the standard of care for the treatment of this disease in many centers specializing in parathyroid surgery. Currently, the majority of high-volume parathyroid surgeons use intraoperative PTH monitoring, selectively or routinely, to guide parathyroidectomy in patients with SPHPT.¹

This surgical adjunct has helped to change the operative approach to parathyroidectomy from the traditional bilateral neck exploration (BNE) with visualization of all parathyroids and excision of enlarged glands based on the surgeon’s subjective judgment of gland size to a minimally invasive uniglandular parathyroidectomy with removal of only the hypersecreting gland(s), preserving all normally functioning tissue. This less invasive approach to parathyroidectomy, safely achieved with the help of intraoperative PTH monitoring (IPM), is not only as successful as BNE but also allows for surgery in an ambulatory setting with less neck dissection, shorter operative time, and fewer postoperative complications.

The goals of this chapter are (1) to discuss the practical issues regarding the use of intraoperative PTH monitoring during parathyroidectomy, (2) to suggest guidelines for interpreting intraoperative PTH levels based on the available published data and the authors’ personal experience, and (3) to give an overview of the current controversies associated with the use of this surgical adjunct.

History of Intraoperative PTH Monitoring

Since the 1990s, a significant volume of information has been gleaned regarding the application of this methodology as well as its influence on the conduct of parathyroidectomy in various parathyroid disorders. The basic premise justifying the use of such a test resides in the ability to rapidly measure the hyperfunction of abnormal parathyroid tissue in the operating room.

The discovery of parathyroid hormone and the subsequent development of assays to accurately measure levels in both the physiologic and pathologic state has been earmarked by a number of major events, which together have led to the current application of the intraoperative measurement of parathyroid hormone in managing surgical parathyroid disease. In 1923, a general surgeon, A.M. Hanson, was the first to demonstrate presence of the hormone. The extract of the hormone, which he developed from bovine parathyroid glands, was utilized successfully in treating experimental tetany.^2,3 Nearly 3½ decades following its initial discovery, two groups working independently were able to further characterize this extract as parathyroid hormone. Rasmussen and Craig from the Rockefeller Institute in New York, as well as G.D. Aurbach in Boston, extracted a stable parathyroid polypeptide and demonstrated that the hypercalcemic properties previously described resided in a single hormonal substance.^3–5 Berson and Yalow, working at the Bronx VA Hospital in 1963, in collaboration with Aurbach and John Potts from the National Institutes of Health (NIH), described a radioimmunoassay for parathyroid hormone.⁶ In an effort to raise an antibody that recognized human parathyroid hormone specifically, Eric Reiss and Janet Canterbury, working at the Michael Reese Hospital in Chicago in 1965, harvested bovine parathyroid glands and injected the extract into various experimental animals. These early efforts were unsuccessful. However, after many trials, an antibody to bovine parathyroid was obtained that had a high affinity for human PTH in experimental chickens.⁷ Utilizing this antibody, these investigators developed an assay with satisfactory identification of parathyroid hormone concentrations in humans.⁷

In 1988, Nussbaum et al. modified the original immunoradiometric assay by increasing the temperature of incubation and employing a kinetic enhancer, changes that decreased the turnover time to approximately 15 minutes.⁸ In this initial report, these investigators described the first use of PTH monitoring during parathyroidectomy, although the patients in their series underwent bilateral neck exploration and PTH was measured postoperatively. Although the reporting of this clinical experience appeared to be of interest clinically, it was not readily accepted as an alternative to the existing practice of conventional bilateral neck exploration, especially given that operative success rates in the treatment of primary hyperparathyroidism were approximately 95%. Flentje et al. modified the PTH assay by decreasing the laboratory turnaround time to 1 hour and attempted to use it perioperatively in 1990.⁹ They described PTH level changes during parathyroidectomy and although measured after the operation, it was clear that PTH levels dropped after excision of the abnormal parathyroid gland. In 1990, Chapuis et al. from Paris, reported in French his series of 13 patients in whom the PTH dropped > 70% in 20 minutes after parathyroidectomy by using the IRMA for intraoperative parathyroid hormone measurement.¹⁰

An early advocate of the utilization of intraoperative PTH monitoring in the United States was Dr. George Irvin from the University of Miami. Irvin’s initial venture into adding the intraoperative assessment of parathyroid hormone levels to his surgical practice, by his own admission, came from an operative failure in the early 1990s. Following the initial failed parathyroidectomy in this patient, a reexploration was performed at which time a contralateral thyroid lobectomy for an occult second intrathyroidal parathyroid adenoma was carried out. Utilizing a modification of the technique described by Nussbaum, Irvin was able to demonstrate rapid decline in parathyroid hormone levels measured intraoperatively following removal of the second parathyroid adenoma.¹¹ In 1991, Irvin et al. described for the first time a series of 21 patients who had their parathyroidectomy guided exclusively by IPM using an immunoradioisotopic method.¹²

With George Irvin’s help, in 1996 this rapid assay was converted to an immunochemiluminescence method, and the “quick” PTH assay became commercially available for intraoperative use, which is still the methodology used today. Following Irvin’s initial publication, which provided impressive clinical justification for the implementation of this methodology, the literature has been replete with increasing reports describing numerous investigations on the utilization of intraoperative parathyroid hormone measurement for parathyroid exploration.

Which Patients Benefit from IPM-Guided Parathyroidectomy?

IPM has been extensively described and studied in patients with sporadic primary hyperparathyroidism, whereas its use in patients with secondary and tertiary hyperparathyroidism as well as in multiple endocrine neoplasia (MEN) requires further investigation and long-term follow-up of these patients to determine which is the optimal intraoperative criteria and protocol to predict cure in these distinct forms of hyperparathyroidism.^13–17 Intraoperative PTH assays can be used to guide parathyroidectomy in isolated familial hyperparathyroidism with an acceptable accuracy.¹⁸ However, the results of this surgical adjunct in predicting operative success in patients with parathyroid cancer are not as encouraging.¹⁹ The data and suggested guidelines for the use of IPM methodology discussed in this chapter are best applied for treatment of only sporadic primary hyperparathyroidism.

Intraoperative PTH Monitoring as an Adjunct during Parathyroidectomy

The authors use the information of IPM to do the following:

The accuracy of this adjunct in correctly guiding the surgeon to the desired outcome (complete excision of hyperfunctioning glands and achievement of postoperative eucalcemia) is strongly related to the criteria used to predict such an outcome. Intraoperative PTH assays only measure PTH levels at specific time points during the procedure as determined by the surgeon. It is therefore essential to understand hormone dynamics during parathyroidectomy to properly request blood sampling during the procedure.

IPM Protocol for Intraoperative Blood Sampling

A peripheral access with a 16-gauge catheter or arterial line for blood sampling during the procedure is obtained either in the holding area or in the operating room. It is important to ensure that blood can be drawn after access is obtained, especially after the patient’s arms are tucked, as positioning may affect satisfactory sampling from an adequately placed line. This access is kept open with saline infusion throughout the procedure, and an IV extension is used to give the anesthesiologist access to the tubing for blood collection at times requested by the surgeon. It is important to instruct the anesthesia team about discarding 10 cc of blood with saline to avoid sample dilution potentially leading to falsely lower PTH levels. Three to 5 cc of whole blood are collected for PTH measurement and are placed in an EDTA tube at specific times: (1) in the operating room before the skin incision is made (preincision), (2) when all blood supply to the suspicious gland is ligated (preexcision or time zero), (3) 5 minutes, (4) 10 minutes, and (5) occasionally 20 minutes after excision of the suspected abnormal gland. When peripheral PTH values drop >50% from the highest, either preincision or preexcision levels, 10 minutes following removal of all abnormal parathyroid glands, postoperative normal or low calcium levels are predicted with excellent accuracy.²⁰ While waiting for PTH results to be reported by the laboratory (which can range between 8 and 20 minutes depending on the assay used), the surgeon may proceed with closure of the cervical incision, avoiding manipulation of the remaining parathyroid glands in an effort to minimize the chance of falsely elevating PTH levels resulting in a delay in hormone drop. Although the 10-minute PTH level fall of > 50% is the definitive measurement of postoperative success, the PTH fall of > 50% at the 5-minute interval also will be seen in the majority of surgically cured patients. Given this, some surgeons prefer to check a 5-minute level, which if reduced > 50% allows the termination of the procedure without further neck exploration or visualization of the remaining normally secreting parathyroid glands, allowing the patient to be extubated and sent to the recovery room. By this time, the 10-minute PTH level is reported, confirming operative success. Conversely, if the criterion is not met in the 10-minute sample, the neck is reexplored and the protocol for blood sampling is repeated for each additional excised gland until all hypersecreting tissue is removed as indicated by meeting the criteria.

In cases where the PTH percent drop is not quite sufficient in 10 minutes, but it is significant (~ 40%), a 20-minute sample can be collected for PTH measurement before the neck is reexplored. However, if there is no significant PTH drop in 5 or 10 minutes, the cervical incision should be reopened promptly to identify and excise additional hypersecreting tissue.

Intraoperative Scenarios and Troubleshooting

Figure 63-1 Graphic shows PTH dynamic during excision of a single parathyroid gland resulting in adequate PTH drop correctly predicting operative success for at least 6 months. PTH, parathyroid hormone; min, minutes.

Figure 63-2 Graphic shows intraoperative PTH dynamic of patient with multiglandular disease and insufficient PTH drop after excision of two parathyroid glands. Following excision of a third and final hypersecreting gland, PTH drops significantly, assuring complete excision and operative success. PTH, parathyroid hormone; min, minutes. *Note that the percentage PTH drop in this prolonged and extensive neck exploration is calculated from the last preexcision or initial preincision sample.

Figure 63-3 A, The increase in PTH level at the 0-minute sample as a result of manipulation during parathyroid gland dissection. B, An apparent insufficient PTH drop if the 0-minute sample was not collected during the parathyroidectomy of this same patient.

Figure 63-4 A, The hormone dynamic of a patient in whom the PTH dropped significantly at the 0-minute sample. B, An apparent insufficient PTH drop if preincision level would not have been measured.