Intraoperative PTH values at pre-incision, time zero (immediately prior to excision of parathyroid adenoma), and 10 min post-excision. There is a greater than 50 % PTH drop at 10 min post-excision compared to the pre-incision PTH value
Intraoperative PTH values at pre-incision, time zero, 10 and 20 min post-excision. There is only a 37 % drop in PTH at 10 min post-excision; therefore a 20-min post-excision PTH level is drawn which results in a greater than 50 % PTH drop
The “>50 % PTH drop” criterion is a reliable method for patients with sporadic pHPT. However, a modification has been proposed and utilized by some endocrine surgeons to improve the specificity of the assay . The modification includes the following criteria: (1) a greater than 50 % PTH drop from the highest pre-excision value 10 min following gland excision and a PTH drop into the normal range or a >65 % PTH drop to predict operative success. If neither of these criteria are met after the 10-min post-excision PTH assay, then (2) a greater than 50 % PTH drop and a return to the normal range in 20 min are used as the criterion for operative success. The accuracy, sensitivity, and specificity for this criterion are 97 %, 97 %, and 98 %, respectively . Furthermore, this modification was reported to decrease false-positive results from 0.9 to 0.3 % without significantly increasing unnecessary neck exploration .
A retrospective review by Chiu and colleagues analyzed 352 patients who underwent parathyroidectomy for pHPT and correlated six different criteria for predicting operative success with actual 6-month postoperative PTH and calcium levels . The investigators compared the following six criteria: (1) >50 % drop from the highest intraoperative PTH level at 10 min post-excision; (2) >50 % drop from the pre-incision PTH level at 10 min post-excision; (3) >50 % drop from the highest intraoperative PTH level at 10 min post-excision and a final PTH value within normal range; (4) >50 % drop from the highest intraoperative PTH level at 10 min post-excision and a final PTH value less than the pre-incision value; (5) >50 % drop from the highest intraoperative PTH level at 5 min post-excision; and (6) >50 % drop from the pre-excision PTH level at 10 min post-excision. After comparing each criterion with 6-month lab values, they found that satisfying criterion 3 had a high operative success rate but resulted in additional unnecessary neck exploration. Criterion 2 was better at predicting postoperative eucalcemia than criterion 3 .
Limitations in the Use of Intraoperative PTH Monitoring
Peripheral intravenous access is required for determining PTH levels both pre-incision and for at least one post-excision value. Many surgeons prefer to use the foot or arm for blood sampling. However, some prefer to collect samples from the internal jugular veins for ease of access. PTH values from the internal jugular veins are known to be higher absolute values than from a peripheral vein . Although PTH levels will drop at a similar rate when compared to peripheral veins, they require a longer duration to reach the normal range. This complicates the scenario in which a surgeon relies on the 10-min post-excision PTH drop of >50 % and within normal range for operative success. The use of internal jugular veins from blood sampling therefore has the potential to increase unnecessary neck exploration or lead to longer operative times waiting for the PTH to drop to within normal range. In the case of a patient with very poor peripheral intravenous access, obtaining a blood sample from the jugular veins may be necessary. In these instances, it remains an accurate option for predicting postoperative calcium levels [26, 27].
Because operative success using intraoperative PTH monitoring is dependent on the PTH assay, errors in blood collection or laboratory processing can be devastating. The blood sample used for the PTH assay could be diluted or incorrectly measured either by the technician or an error in the system itself. It is crucial for the surgeon to understand the PTH assay technique and be able to evaluate the reported levels in the context of the clinical presentation intraoperatively. It is also important to confirm that the controls are within the expected reference range for that particular laboratory.
Delay in PTH Drop After Successful Parathyroid Adenoidectomy
After the excision of a hypersecreting parathyroid gland, occasionally the PTH does not drop enough to meet the surgeon’s criteria for success. This more frequently occurs when the surgeon relies on a >50 % drop in PTH along with return to the normal reference range. In situations such as these, the authors recommend sending a 20-min post-excision PTH level in order to avoid further neck exploration. During difficult cases in which a significant amount of dissection is required for the identification of a parathyroid adenoma, trauma to the gland and release of PTH are not uncommon. Therefore, during these instances, it may take longer for the PTH level to return to normal following excision.
Does Intraoperative PTH Predict Gland Size?
The use of intraoperative PTH monitoring guided by the “>50 % PTH drop” criterion has not been shown to predict macroscopic size of normally secreting parathyroid glands. The rate of multi-gland disease (MGD) is much lower when using intraoperative PTH monitoring to guide parathyroidectomy as opposed to gland size (3–10 % versus 13–28 %, respectively) [21, 23, 28–32]. In fact, when surgeons have used intraoperative PTH monitoring during bilateral neck exploration, they have demonstrated that 9–19 % of patients who met the criteria for operative success have another enlarged gland found on exploration . Despite the finding of macroscopic glands on further exploration, there is no evidence that operative failure, or hypercalcemia occurring within 6 months post-procedure, occurs in these patients who met the “>50 % PTH drop” criterion [21, 23, 32, 34].
Miccoli and colleagues demonstrated the use of intraoperative PTH monitoring to guide surgery as opposed to morphologic gland size in a prospective randomized study of 40 patients. They demonstrated that patients who had bilateral neck exploration with parathyroidectomy guided by gland size as opposed to intraoperative PTH monitoring had a higher incidence of multiglandular disease (10 % versus 0 %, respectively) . The operative success rate was equivalent between the two groups, despite fewer glands being removed in the group who underwent parathyroidectomy guided by function as opposed to gland morphology. The potential risks of bilateral neck exploration are not trivial, including persistent hypocalcemia, recurrent laryngeal nerve injury, and fibrosis and scarring making revision surgery more difficult. Conversely, focused parathyroidectomy guided by intraoperative PTH monitoring leads to equivalent cure rates with shorter hospital stays and reduced cost when compared to traditional bilateral neck exploration . Therefore, the use of intraoperative PTH monitoring to guide parathyroidectomy as opposed to bilateral neck exploration is an important surgical asset.
Alternative Applications for Intraoperative PTH Assays
Fine-Needle Aspiration Analysis
PTH levels obtained from fine-needle aspirates during parathyroidectomy can differentiate parathyroid from non-parathyroid tissue with a specificity of 100 % [36, 37]. To perform this technique, a 25-gauge needle attached to a 10 cc syringe is used to aspirate cells from the suspicious tissue. This aspirate is then analyzed for PTH using the same rapid PTH assay already employed in that laboratory. Pelizzo et al. measured rapid intraoperative PTH values on 50 structures presumed to be either parathyroid glands or lymph nodes that were then sent for frozen section analysis. They found that the median PTH value of parathyroid tissue was 263.25 pmol/L compared to a median PTH of 1.31 pmol/L from lymph node tissue (p < 0.0001; ).
Internal Jugular Venous Sampling
For patients in which preoperative imaging is equivocal, differential internal jugular venous sampling can help the surgeon to determine the laterality of a hypersecreting parathyroid gland. Blood samples are obtained from both internal jugular veins, preferably under ultrasound guidance prior to incision, and sent for PTH analysis. Studies have shown that the side harboring a hypersecreting parathyroid gland has an approximately 10 % higher PTH level compared to the contralateral side [38–40]. This allows the surgeon to start on the side of the neck with the higher PTH level and potentially avoid bilateral neck exploration.
Intraoperative PTH monitoring is now a commonly utilized tool in the surgical management of patients with sporadic primary hyperparathyroidism. Its use during parathyroidectomy guides the surgeon in operative decision making and is often a critical aspect of the surgery itself. The use of intraoperative PTH monitoring has several benefits over traditional bilateral neck exploration, including shorter operative times and hospital stays and the reduced potential for complications. Most surgeons recommend using a greater than 50 % PTH drop criterion from the pre-incision PTH value to a 10-min post-excision PTH value for measuring operative success. Additionally, many surgeons recommend a post-excision PTH value that returns to the normal reference range. This criterion has improved accuracy in identifying parathyroid adenomas with reduction of unnecessary bilateral neck exploration. Further investigation is required into the utility and efficacy of intraoperative PTH monitoring for parathyroid disorders other than sporadic primary hyperparathyroidism.
Intraoperative PTH monitoring is a safe and effective adjuvant to parathyroid surgery, particularly for patients with sporadic primary hyperparathyroidism. However, its effective use relies upon the surgeon’s thorough knowledge of parathyroid hormone physiology and standardization of the intraoperative protocol.