- Email: [email protected]
Intraoperative Parathyroid Hormone Measurement During Minimally Invasive Parathyroidectomy: Does it “Value-Add” to Decision-Making?
ORIGINAL SCIENTIFIC ARTICLES
Intraoperative Parathyroid Hormone Measurement During Minimally Invasive Parathyroidectomy: Does it “Value-Add” to Decision-Making? Peter Stalberg, MD, PhD, Stan Sidhu, MB, PhD, Mark Sywak, MB, Bruce Robinson, MD, Margaret Wilkinson, MS, Leigh Delbridge, MD Routine use of intraoperative parathyroid hormone levels (IOPTH) during minimally invasive parathyroidectomy (MIP) has been challenged simply because the test works best when needed least, ie, once a solitary adenoma has been resected, and is less accurate with multiple gland disease. It has also been shown not to be cost-effective. The aim of this study was to determine if IOPTH “value-added” to decision-making during MIP. STUDY DESIGN: The study group comprised 100 consecutive patients with sporadic hyperparathyroidism and an unequivocally positive sestamibi scan who were undergoing MIP in our unit from June 2004 until October 2005, from whom blood was collected for parathyroid hormone measurement preoperatively, preexcision, and at 10 and 30 minutes postremoval. No action was taken on the results of the test. RESULTS: Ninety-eight patients were cured by MIP alone. Two patients had persistent hyperparathyroidism, one of whom was cured with subsequent open reexploration and removal of a second adenoma, and the other remains hypercalcemic despite additional open neck exploration. IOPTH in both patients failed to fall in retrospect, only the first would have been cured by conversion at the time of operation. The value-added accuracy of IOPTH was really only 1%. In an additional nine patients, IOPTH at 10 minutes had failed to fall by ⬎ 50% from the highest level, those patients (9%) would have been subjected to an unnecessary conversion on the basis of a false-negative result. CONCLUSIONS: IOPTH does not substantially value-add to decision-making during MIP. Most patients will be cured with appropriate selection for MIP based on preoperative localization studies. (J Am Coll Surg 2006;203:1–6. © 2006 by the American College of Surgeons) BACKGROUND:
In a recent review article in this Journal, Quan-Yang Duh1 questioned the role of intraoperative parathyroid hormone measurement as a necessary tool in predicting cure when performing minimally invasive parathyroidectomy (MIP) for primary hyperparathyroidism (pHPT). MIP, defined as removal of an abnormal parathyroid gland through an incision of ⬍ 2.5 cm in length, includes a number of different techniques, such as the mini-incision–
focused procedure,2-4 video-assisted parathyroidectomy,5-7 and cervical endoscopic procedures.8-10 The number of patients undergoing surgical treatment of pHPT has increased markedly11 largely because of the perceived advantages of MIP.12 Because most pHPT is a result of a solitary parathyroid adenoma,13 provided such adenomas have been correctly localized, bilateral neck exploration is not required. Intraoperative intact parathyroid hormone (IOPTH) measurement has been shown to be a highly accurate technique14,15 with a 98% to 100% positive predictive value for single parathyroid adenoma. Some authors have claimed that introduction of IOPTH has considerably improved outcomes in their units.16-18 Claims of accuracy need to be examined in their true context. The real question is not how accurate IOPTH is in isolation, but how much value it adds to the decision-
Competing Interests Declared: None. Received January 19, 2006; Revised March 26, 2006; Accepted March 29, 2006. From the Endocrine Surgical Unit, University of Sydney (Stalberg, Sidhu, Sywak, Delbridge) and Kolling Institute of Medical Research (Robinson, Wilkinson), Royal North Shore Hospital, Sydney, New South Wales, Australia. Correspondence address: Leigh W Delbridge, MD, FRACS, Department of Surgery, Endocrine Surgical Unit, University of Sydney, Wallace Freeborn Block, Royal North Shore Hospital, St Leonards, 2065 NSW, Australia. email: [email protected]
© 2006 by the American College of Surgeons Published by Elsevier Inc.
1
ISSN 1072-7515/06/$32.00 doi:10.1016/j.jamcollsurg.2006.03.022
2
Stalberg et al
Intraoperative Parathyroid Hormone Measurement
Abbreviations and Acronyms
IOPTH iPTH MGD MIP pHPT
⫽ ⫽ ⫽ ⫽ ⫽
intraoperative intact parathyroid hormone intact parathyroid hormone multiglandular disease minimally invasive parathyroidectomy primary hyperparathyroidism
making flow of information associated with successful performance of MIP. In our unit, MIP commenced as a complex video-assisted technique and IOPTH measurements. It has since evolved into a truly minimalist procedure: the scan-directed removal of a single adenoma through a 2.0-cm lateral incision as an ambulatory sameday or 23-hour procedure using standard surgical techniques and without use of any intraoperative monitoring. The aim of this study was to critically evaluate the acclaimed need for IOPTH during MIP with regard to intraoperative decision-making, and the effects on patient outcomes. METHODS Study group
This is a retrospective cohort study. The study group comprises the last 100 consecutive patients undergoing MIP in the University of Sydney, Endocrine Surgical Unit and covered the period from June 2004 to October 2005, with a minimum followup of 6 months to exclude persistent hyperparathyroidism. The study was approved by the Ethics Review Committee of the University of Sydney. All information was collected prospectively and stored on the University of Sydney Endocrine Surgery Database. All patients gave informed consent to the collection and storage of such data. Patient selection
All patients presenting to the unit with pHPT, defined as an inappropriate level of serum iPTH (intact parathyroid hormone: upper limit 50 pg/mL) in the presence of hypercalcemia (serum calcium ⬎ 10.5 mg/dL) without hypocalciuria, were assessed as to their suitability for MIP. Patients were selected as suitable for this technique on the basis of an unequivocal single site of uptake on parathyroid nuclear scan using technetium 99m-labeled sestamibi on single photon emission tomography.19 Subsequent focused ultrasonography was then performed, either by a radiologist preoperatively, or
J Am Coll Surg
by the surgeon at operation, solely to guide incision placement and to aid anatomic dissection. Patients with negative sestamibi localization studies, or with a study indicating multiple sites of uptake, underwent standard four-gland bilateral neck exploration through a cervical collar incision. Absence of concordance between sestamibi scan and ultrasonography did not contraindicate MIP, but did heighten awareness of the possible need for conversion. Of the 100 patients in this study, 7 had ultrasonography that was unable to localize a parathyroid adenoma in the neck. Patients with any of the known hereditary HPT syndromes, and patients with secondary HPT were excluded from being considered for MIP. During the study period, a total of 188 parathyroidectomies were performed in the unit. Of the 88 patients not eligible for MIP, 46 had single gland disease, 32 had multiglandular disease (MGD) and 10 had secondary HPT. Of the 46 patients with single gland disease, 25 had coincidental thyroid pathology, 14 had nonlocalizing sestamibi scan, 4 had a previous operation, 2 were lithium-induced HPT, and 1 had MEN1. The success rate in these 88 patients was 83 of 88. The causes of failure included three with missed MGD, one reoperation for MGD, and one had MEN1. Fully informed consent to MIP was obtained from all patients, who were told of the risk of conversion to open procedure and the 2% risk of failure with persistent hyperparathyroidism necessitating subsequent parathyroid reexploration. Surgical technique and IOPTH measurements
MIP was undertaken using the lateral-focused miniincision technique described previously.20 This technique involves use of a 2-cm lateral incision placed directly over the site of the adenoma and overlying the medial border of the sternomastoid. All dissection and removal of the adenoma is carried out through that incision with use of a headlight to provide appropriate anatomic visualization. The procedure can be performed with either general anesthesia or local anesthesia with a superficial cervical block supplemented by local infiltration. Neither the nuclear probe nor IOPTH was used to guide decision-making during the operation. For this study, preincision, preexcision, 10-minute, and 30-minute iPTH levels were taken, and measured on the routine laboratory using the Immulite 2000 Intact PTH assay (DPC). Immulite 2000 is a solid-phase, two-site chemiluminescent enzyme-labeled immunometric assay. Samples were run
Vol. 203, No. 1, July 2006
Stalberg et al
that afternoon, and the results were made available to the surgeon to assist with appropriately informed patient discharge. All blood samples were collected into ethylenediaminetetraacetic acid plasma tubes and kept on ice until analysis. The previously accepted and used guidelines for IOPTH levels for intraoperative decisionmaking17 were applied in retrospect. A true positive IOPTH result is defined as ⱖ 50% drop in iPTH level at 10 minutes from the highest preexcision or preincision value in a patient that returned to normal or low serum calcium levels lasting for 3 months after the MIP. A true-negative result is present when iPTH level fails to drop according to this guideline, and the patient remains or returns to hypercalcemia within 3 months after parathyroidectomy. A false-positive result is when the hormone level drops ⱖ 50% at 10 minutes, but the patient has persistent hypercalcemia at followup. A falsenegative result is defined as when the iPTH level does not drop ⬍ 50% at 10 minutes but the patient returns to normal or low calcium levels lasting at least 3 months. Statistical analysis
All values of mean and SEM was calculated using StatView software (Abacus Concepts Inc). RESULTS Mean age at operation was 59.7 years (for women, 60.8 years, range 22.4 to 85.8; for men, 56.6 years, range 37.5 to 75.9), and the female:male ratio was 3:1. All patients had unequivocal pHPT as defined by corrected serum calcium above the upper limit together with an inappropriate serum level of iPTH and absence of hypocalciuria. Cure was defined as normocalcemia at 6-month followup. All patients had single gland disease as defined by single uptake on parathyroid sestamibi scan. All patients were operated on using the focused lateral 2-cm incision approach. The cure rate in this study was 98%, without taking into consideration the results of IOPTH measurements when performing the operation. Two patients remained hypercalcemic after the first operation, and in neither of these patients was there a ⬎ 50% decrease in iPTH at either 10 or 30 minutes. The first patient had concordant preoperative localization studies and underwent removal of a left superior parathyroid adenoma weighing 1,300 mg, and remained hypercalcemic. She has subsequently been cured by removal of a second adenoma (right inferior, weighing 245 mg) using standard bilateral neck exploration. The second patient re-
Intraoperative Parathyroid Hormone Measurement
3
mained hypercalcemic after removal of what was macroscopically believed to be an adenoma, but which was subsequently shown on histologic examination to be a branchial cleft remnant associated with a normal right superior parathyroid gland (false-positive localization on both sestamibi and ultrasonography). The patient underwent subsequent bilateral neck exploration with the finding of three normal parathyroid glands; right inferior, left superior and inferior, all confirmed on histologic examination, and remains hypercalcemic. Looking at all iPTH data retrospectively leads to the conclusion that only the first patient would have been cured by using intraoperative iPTH monitoring during the first operation. The value-added accuracy of cure using IOPTH in this study was only 1%. In nine patients (9%), IOPTH failed to fall at 10 minutes, despite subsequent confirmation of cure and all these patients would have been subjected to unnecessary conversion based on a false-negative IOPTH at 10 minutes. When looking at the IOPTH at 30 minutes, the false-negative rate was reduced to 4%. None of the patients with falsenegative samples had any biochemical signs of renal failure (mean creatinine 73.9 ⫾ 3.0; normal range 60 to 100 mol/L), and all were cured by MIP removing a single parathyroid adenoma (mean weight 607 ⫾ 169 mg). In the 89 remaining patients, IOPTH fell to curative values after removal of a single parathyroid adenoma. Followup time ranges from 6 to 20 months without recurrent disease. Overall ability of IOPTH measurements to predict cure was 100%, relying on the 10-minute IOPTH would only have value added to the cure rate by 1% at the time of initial operation, and would have subjected nine patients to unnecessary conversion to open exploration. iPTH data are presented in Figure 1. DISCUSSION MIP for pHPT is a safe and effective procedure with excellent cure rates in experienced hands.3,21,22 It has been shown that MIP leads to lower hospital costs, lower incidence of hypocalcemia, and low complication rates, compared with the standard approach of bilateral neck exploration through a collar incision.14,18,23-25 There have been claims that several intraoperative adjuncts have an impact on cure rate after MIP, it is not clear from the literature how any of these techniques contribute in a substantial way to warrant their use. In this article, we present our experience from the last
4
Stalberg et al
Intraoperative Parathyroid Hormone Measurement
%
% drop from the highest preincision/preexcision IOPTH value
100
75
50
False-negatives 25
True-positives 0
n mi 30
20 m
in
in 10 m
pr pr einc ee isi xc on i si / on
time
A %
% drop from the highest preincision/preexcision IOPTH value
100
Patient #2
75
Patient #1 50
25
n mi 30
n mi 20
mi
n
time 10
pr pr einc ee isi xc on isi / on
0
B Figure 1. Intraoperative intact parathyroid hormone (IOPTH) measurements showing the drop from the highest preincision/ preexcision value at 10 and 30 min after resection of a single adenoma. (A) Group of true positives (n ⫽ 89) and group of false negatives (n ⫽ 9). Values are mean and SEM. (B) Two true negatives, patient numbers 1 and 2.
100 consecutive MIPs performed in our unit, where IOPTH data were collected prospectively but not acted on at the time of operation. During the time period of the study, we performed a total of 188 parathyroidectomies in the unit, with an overall success rate of 96% and have performed 683 MIPs since its introduction in 1998. All patients in this study had a preoperative sesta-
J Am Coll Surg
mibi scan suggestive of single gland disease. Ultrasonography of the neck was added to guide the incision; in seven patients the ultrasound was negative and this did not contraindicate MIP. We found that using preoperative sestamibi imaging showing an unequivocal single site of uptake, followed by MIP, leads to a cure rate of pHPT in 98 of 100 patients. The value-added effect of using IOPTH would only have been 1%, adding up to a final cure rate of 99%. On the other hand, use of IOPTH would have led to either 9% unnecessary conversions based on the false-negative 10-minute samples, or 4% unnecessary conversions based on the falsenegative 30-minute samples, but then associated with prolonged operative time if the anesthesia had been delayed to allow analysis of a delayed 30-minute sample. IOPTH is claimed to avoid failures during MIP for pHPT from missed MGD.26-29 IOPTH has been reported to have a considerable false-positive and falsenegative rate when applying the defined criterion for biologic recovery of hyperfunctioning parathyroid tissue to intraoperative decision-making (30 in our study, IOPTH was 100% accurate in predicting cure in patients with unequivocal sestamibi scans, but carried a substantial false-negative rate of 9% at 10 minutes, and 4% at 30 minutes). Such false-negative results cannot be explained by any of the known causes of prolonged iPTH half-life, as none of the patients showed any biochemical signs of renal failure.31,32 It is known that the immunometric assay cross-reacts with the 7–84 subunit of PTH, the importance of which is largely unclear with regard to pHPT.33 It is possible that the newer wholePTH assay will shed more light on this issue,33 but additional studies are needed. The question arises as to whether these patients with false-negative results are prone to have missed MGD. The low incidence of MGD might possibly be related to patient selection, as patients with positive imaging for a single adenoma are less likely to have MGD.28 Put into perspective, our overall incidence of MGD during the study period was 18% (33 of 177) when excluding secondary HPT and MEN. It is known that an abnormally sized gland can be found on the other side in about 15% of patients with a unilateral single adenoma removed during MIP,27 and it seems possible that some large parathyroid glands do not oversecrete PTH and do not cause disease. Normal parathyroid gland weight and size can also be larger than previously thought.34 In addition, our group has shown that there seems to be an absence of
Vol. 203, No. 1, July 2006
Stalberg et al
correlation between calcium-PTH response curve and size of the parathyroid tumor.35 Several authors claim that the widely accepted use of IOPTH measurements is necessary for MIP to have high cure rates,15,16,18 our data do not support this. We have a cure rate of 98% when performing MIP, without using any additional technical adjuncts, a cure rate equivalent to those surgeons who stated that they would never perform MIP without IOPTH because they want to cure every patient every time.18 A recent study claimed that the introduction of IOPTH improved cure rate by 10%,16 this was based on historic data in association with changed surgical staffing. Some authors have suggested concordance between ultrasonography and sestamibi scan to use a focused approach without using IOPTH with a reported success rate of 95%.36 If we had applied this to our study, 93 patients would have had MIP without IOPTH measurements. The same two patients would have been failures because both had positive preoperative imaging, leading to a cure rate of 98%. Relying on an unequivocal sestamibi scan in our setting, where the scan has a truepositive rate for single gland disease of 98 of 114, seems more cost-effective because 7 more patients could have a successful MIP procedure with the same cure rate of 98%. It has also been suggested that routine use of IOPTH should be offered to expand the percentage of patients who might be suitable for MIP, eg, those with an equivocal scan or a negative scan with positive ultrasonography. Our unit has a policy of only offering MIP to those who fit a clearly defined protocol (53% of all patients with PHPT), ie, an unequivocally positive sestamibi scan. The question of the role of IOPTH in expanding indications for MIP clearly requires additional study. We and others have challenged the use of IOPTH based on low cost-effectiveness, and lack of improved cure rates.37-40 Data from this study suggest that the success rate when MIP is performed by an experienced endocrine surgeon is essentially a result of appropriate patient selection based on preoperative localization studies, not on IOPTH measurements. Subjecting patients to unnecessary conversion to open operation or prolonged operating times cannot be cost-effective. Neither is it appropriate to propose that IOPTH, although not required for the experienced endocrine surgeons, is of value to the less-experienced surgeon in attempting to locate a parathyroid adenoma. In our unit, patients undergo MIP as a simple, cost-effective ambulatory proce-
Intraoperative Parathyroid Hormone Measurement
5
dure, fully informed of the 2% failure rate. Measurement of a single postoperative iPTH level simply assists informed discharge for those very few patients who will require subsequent readmission for bilateral neck reexploration.30 Author Contributions
Study conception and design: Sidhu, Sywak, Robinson, Delbridge Acquisition of data: Stalberg, Wilkinson, Delbridge Analysis and interpretation of data: Stalberg, Delbridge Drafting of manuscript: Stalberg Critical revision: Sidhu, Sywak, Robinson, Wilkinson, Delbridge Supervision: Delbridge REFERENCES 1. Duh QY. What’s new in general surgery: endocrine surgery. J Am Coll Surg 2005;201:746–753. 2. Delbridge LW, Dolan SJ, Hop TT, et al. Minimally invasive parathyroidectomy: 50 consecutive cases. Med J Aust 2000;172: 418–422. 3. Udelsman R, Donovan PI, Sokoll LJ. One hundred consecutive minimally invasive parathyroid explorations. Ann Surg 2000; 232:331–339. 4. van Vroonhoven TJ, van Dalen A. Successful minimally invasive surgery in primary hyperparathyroidism after combined preoperative ultrasound and computed tomography imaging. J Intern Med 1998;243:581–587. 5. Gauger PG, Reeve TS, Delbridge LW. Endoscopically assisted, minimally invasive parathyroidectomy. Br J Surg 1999;86: 1563–1566. 6. Miccoli P, Bendinelli C, Vignali E, et al. Endoscopic parathyroidectomy: report of an initial experience. Surgery 1998;124: 1077–1079; discussion 1079⫺1080. 7. Miccoli P, Berti P, Conte M, et al. Minimally invasive videoassisted parathyroidectomy: lesson learned from 137 cases. J Am Coll Surg 2000;191:613–618. 8. Gagner M. Endoscopic subtotal parathyroidectomy in patients with primary hyperparathyroidism. Br J Surg 1996;83:875. 9. Henry JF, Defechereux T, Gramatica L, de Boissezon C. Minimally invasive videoscopic parathyroidectomy by lateral approach. Langenbecks Arch Surg 1999;384:298–301. 10. Yeung HC, Ng WT, Kong CK. Endoscopic thyroid and parathyroid surgery. Surg Endosc 1997;11:1135. 11. Sackett WR, Barraclough B, Reeve TS, Delbridge LW. Worldwide trends in the surgical treatment of primary hyperparathyroidism in the era of minimally invasive parathyroidectomy. Arch Surg 2002;137:1055–1059. 12. Delbridge L. Minimally invasive parathyroidectomy: the Australian experience. Asian J Surg 2003;26:76–81. 13. Tezelman S, Shen W, Shaver JK, et al. Double parathyroid adenomas. Clinical and biochemical characteristics before and after parathyroidectomy. Ann Surg 1993;218:300–307; discussion 307⫺309. 14. Chen H, Sokoll LJ, Udelsman R. Outpatient minimally invasive parathyroidectomy: a combination of sestamibi-
6
15. 16.
17.
18. 19. 20. 21.
22. 23.
24.
25. 26. 27.
Stalberg et al
Intraoperative Parathyroid Hormone Measurement
SPECT localization, cervical block anesthesia, and intraoperative parathyroid hormone assay. Surgery 1999;126:1016–1021. Irvin GL III, Sfakianakis G, Yeung L, et al. Ambulatory parathyroidectomy for primary hyperparathyroidism. Arch Surg 1996;131:1074–1078. Chen H, Pruhs Z, Starling JR, Mack E. Intraoperative parathyroid hormone testing improves cure rates in patients undergoing minimally invasive parathyroidectomy. Surgery 2005;138:583– 587; discussion 587⫺590. Irvin GL III, Solorzano CC, Carneiro DM. Quick intraoperative parathyroid hormone assay: surgical adjunct to allow limited parathyroidectomy, improve success rate, and predict outcome. World J Surg 2004;28:1287–1292. Udelsman R. Six hundred fifty-six consecutive explorations for primary hyperparathyroidism. Ann Surg 2002;235:665–670; discussion 670⫺672. Shon IH, Roach PJ, Bernard E, et al. Superimposed double parathyroid adenoma on Tc-99m MIBI imaging: the value of oblique images. Clin Nucl Med 2001;26:876–877. Agarwal G, Barraclough BH, Reeve TS, Delbridge LW. Minimally invasive parathyroidectomy using the ‘focused’ lateral approach. II. Surgical technique. ANZ J Surg 2002;72:147–151. Agarwal G, Barraclough BH, Robinson BG, et al. Minimally invasive parathyroidectomy using the ‘focused’ lateral approach. I. Results of the first 100 consecutive cases. ANZ J Surg 2002; 72:100–104. Chen H, Zeiger MA, Gordon TA, Udelsman R. Parathyroidectomy in Maryland: effects of an endocrine center. Surgery 1996; 120:948–952; discussion 952⫺953. Bergenfelz A, Lindblom P, Tibblin S, Westerdahl J. Unilateral versus bilateral neck exploration for primary hyperparathyroidism: a prospective randomized controlled trial. Ann Surg 2002; 236:543–551. Goldstein RE, Blevins L, Delbeke D, Martin WH. Effect of minimally invasive radioguided parathyroidectomy on efficacy, length of stay, and costs in the management of primary hyperparathyroidism. Ann Surg 2000;231:732–742. Sidhu S, Neill AK, Russell CF. Long-term outcome of unilateral parathyroid exploration for primary hyperparathyroidism due to presumed solitary adenoma. World J Surg 2003;27:339–342. Kaczirek K, Riss P, Wunderer G, et al. Quick PTH assay cannot predict incomplete parathyroidectomy in patients with renal hyperparathyroidism. Surgery 2005;137:431–435. Siperstein A, Berber E, Mackey R, et al. Prospective evaluation of sestamibi scan, ultrasonography, and rapid PTH to predict the success of limited exploration for sporadic primary hyperparathyroidism. Surgery 2004;136:872–880.
J Am Coll Surg
28. Sugg SL, Krzywda EA, Demeure MJ, Wilson SD. Detection of multiple gland primary hyperparathyroidism in the era of minimally invasive parathyroidectomy. Surgery 2004;136:1303– 1309. 29. Weber KJ, Misra S, Lee JK, et al. Intraoperative PTH monitoring in parathyroid hyperplasia requires stricter criteria for success. Surgery 2004;136:1154–1159. 30. Starr FL, DeCresce R, Prinz RA. Normalization of intraoperative parathyroid hormone does not predict normal postoperative parathyroid hormone levels. Surgery 2000;128:930–935; discussion 935⫺936. 31. Libutti SK, Alexander HR, Bartlett DL, et al. Kinetic analysis of the rapid intraoperative parathyroid hormone assay in patients during operation for hyperparathyroidism. Surgery 1999;126: 1145–1150; discussion 1150⫺1151. 32. Lokey J, Pattou F, Mondragon-Sanchez A, et al. Intraoperative decay profile of intact (1–84) parathyroid hormone in surgery for renal hyperparathyroidism—a consecutive series of 80 patients. Surgery 2000;128:1029–1034. 33. Yamashita H, Gao P, Cantor T, et al. Comparison of parathyroid hormone levels from the intact and whole parathyroid hormone assays after parathyroidectomy for primary and secondary hyperparathyroidism. Surgery 2004;135:149–156. 34. Yao K, Singer FR, Roth SI, et al. Weight of normal parathyroid glands in patients with parathyroid adenomas. J Clin Endocrinol Metab 2004;89:3208–3213. 35. Mun HC, Conigrave A, Wilkinson M, Delbridge L. Surgery for hyperparathyroidism: does morphology or function matter most? Surgery 2005;138:1111–1120; discussion 1120. 36. Arici C, Cheah WK, Ituarte PH, et al. Can localization studies be used to direct focused parathyroid operations? Surgery 2001; 129:720–729. 37. Jacobson SR, van Heerden JA, Farley DR, et al. Focused cervical exploration for primary hyperparathyroidism without intraoperative parathyroid hormone monitoring or use of the gamma probe. World J Surg 2004;28:1127–1131. 38. Sebag F, Shen W, Brunaud L, et al. Intraoperative parathyroid hormone assay and parathyroid reoperations. Surgery 2003; 134:1049–1055; discussion 1056. 39. Agarwal G, Barakate MS, Robinson B, et al. Intraoperative quick parathyroid hormone versus same-day parathyroid hormone testing for minimally invasive parathyroidectomy: a costeffectiveness study. Surgery 2001;130:963–970. 40. Mozzon M, Mortier PE, Jacob PM, et al. Surgical management of primary hyperparathyroidism: the case for giving up quick intraoperative PTH assay in favor of routine PTH measurement the morning after. Ann Surg 2004;240:949–953; discussion 953⫺954.
Intraoperative Parathyroid Hormone Measurement During Minimally Invasive Parathyroidectomy: Does it “Value-Add” to Decision-Making? Peter Stalberg, MD, PhD, Stan Sidhu, MB, PhD, Mark Sywak, MB, Bruce Robinson, MD, Margaret Wilkinson, MS, Leigh Delbridge, MD Routine use of intraoperative parathyroid hormone levels (IOPTH) during minimally invasive parathyroidectomy (MIP) has been challenged simply because the test works best when needed least, ie, once a solitary adenoma has been resected, and is less accurate with multiple gland disease. It has also been shown not to be cost-effective. The aim of this study was to determine if IOPTH “value-added” to decision-making during MIP. STUDY DESIGN: The study group comprised 100 consecutive patients with sporadic hyperparathyroidism and an unequivocally positive sestamibi scan who were undergoing MIP in our unit from June 2004 until October 2005, from whom blood was collected for parathyroid hormone measurement preoperatively, preexcision, and at 10 and 30 minutes postremoval. No action was taken on the results of the test. RESULTS: Ninety-eight patients were cured by MIP alone. Two patients had persistent hyperparathyroidism, one of whom was cured with subsequent open reexploration and removal of a second adenoma, and the other remains hypercalcemic despite additional open neck exploration. IOPTH in both patients failed to fall in retrospect, only the first would have been cured by conversion at the time of operation. The value-added accuracy of IOPTH was really only 1%. In an additional nine patients, IOPTH at 10 minutes had failed to fall by ⬎ 50% from the highest level, those patients (9%) would have been subjected to an unnecessary conversion on the basis of a false-negative result. CONCLUSIONS: IOPTH does not substantially value-add to decision-making during MIP. Most patients will be cured with appropriate selection for MIP based on preoperative localization studies. (J Am Coll Surg 2006;203:1–6. © 2006 by the American College of Surgeons) BACKGROUND:
In a recent review article in this Journal, Quan-Yang Duh1 questioned the role of intraoperative parathyroid hormone measurement as a necessary tool in predicting cure when performing minimally invasive parathyroidectomy (MIP) for primary hyperparathyroidism (pHPT). MIP, defined as removal of an abnormal parathyroid gland through an incision of ⬍ 2.5 cm in length, includes a number of different techniques, such as the mini-incision–
focused procedure,2-4 video-assisted parathyroidectomy,5-7 and cervical endoscopic procedures.8-10 The number of patients undergoing surgical treatment of pHPT has increased markedly11 largely because of the perceived advantages of MIP.12 Because most pHPT is a result of a solitary parathyroid adenoma,13 provided such adenomas have been correctly localized, bilateral neck exploration is not required. Intraoperative intact parathyroid hormone (IOPTH) measurement has been shown to be a highly accurate technique14,15 with a 98% to 100% positive predictive value for single parathyroid adenoma. Some authors have claimed that introduction of IOPTH has considerably improved outcomes in their units.16-18 Claims of accuracy need to be examined in their true context. The real question is not how accurate IOPTH is in isolation, but how much value it adds to the decision-
Competing Interests Declared: None. Received January 19, 2006; Revised March 26, 2006; Accepted March 29, 2006. From the Endocrine Surgical Unit, University of Sydney (Stalberg, Sidhu, Sywak, Delbridge) and Kolling Institute of Medical Research (Robinson, Wilkinson), Royal North Shore Hospital, Sydney, New South Wales, Australia. Correspondence address: Leigh W Delbridge, MD, FRACS, Department of Surgery, Endocrine Surgical Unit, University of Sydney, Wallace Freeborn Block, Royal North Shore Hospital, St Leonards, 2065 NSW, Australia. email: [email protected]
© 2006 by the American College of Surgeons Published by Elsevier Inc.
1
ISSN 1072-7515/06/$32.00 doi:10.1016/j.jamcollsurg.2006.03.022
2
Stalberg et al
Intraoperative Parathyroid Hormone Measurement
Abbreviations and Acronyms
IOPTH iPTH MGD MIP pHPT
⫽ ⫽ ⫽ ⫽ ⫽
intraoperative intact parathyroid hormone intact parathyroid hormone multiglandular disease minimally invasive parathyroidectomy primary hyperparathyroidism
making flow of information associated with successful performance of MIP. In our unit, MIP commenced as a complex video-assisted technique and IOPTH measurements. It has since evolved into a truly minimalist procedure: the scan-directed removal of a single adenoma through a 2.0-cm lateral incision as an ambulatory sameday or 23-hour procedure using standard surgical techniques and without use of any intraoperative monitoring. The aim of this study was to critically evaluate the acclaimed need for IOPTH during MIP with regard to intraoperative decision-making, and the effects on patient outcomes. METHODS Study group
This is a retrospective cohort study. The study group comprises the last 100 consecutive patients undergoing MIP in the University of Sydney, Endocrine Surgical Unit and covered the period from June 2004 to October 2005, with a minimum followup of 6 months to exclude persistent hyperparathyroidism. The study was approved by the Ethics Review Committee of the University of Sydney. All information was collected prospectively and stored on the University of Sydney Endocrine Surgery Database. All patients gave informed consent to the collection and storage of such data. Patient selection
All patients presenting to the unit with pHPT, defined as an inappropriate level of serum iPTH (intact parathyroid hormone: upper limit 50 pg/mL) in the presence of hypercalcemia (serum calcium ⬎ 10.5 mg/dL) without hypocalciuria, were assessed as to their suitability for MIP. Patients were selected as suitable for this technique on the basis of an unequivocal single site of uptake on parathyroid nuclear scan using technetium 99m-labeled sestamibi on single photon emission tomography.19 Subsequent focused ultrasonography was then performed, either by a radiologist preoperatively, or
J Am Coll Surg
by the surgeon at operation, solely to guide incision placement and to aid anatomic dissection. Patients with negative sestamibi localization studies, or with a study indicating multiple sites of uptake, underwent standard four-gland bilateral neck exploration through a cervical collar incision. Absence of concordance between sestamibi scan and ultrasonography did not contraindicate MIP, but did heighten awareness of the possible need for conversion. Of the 100 patients in this study, 7 had ultrasonography that was unable to localize a parathyroid adenoma in the neck. Patients with any of the known hereditary HPT syndromes, and patients with secondary HPT were excluded from being considered for MIP. During the study period, a total of 188 parathyroidectomies were performed in the unit. Of the 88 patients not eligible for MIP, 46 had single gland disease, 32 had multiglandular disease (MGD) and 10 had secondary HPT. Of the 46 patients with single gland disease, 25 had coincidental thyroid pathology, 14 had nonlocalizing sestamibi scan, 4 had a previous operation, 2 were lithium-induced HPT, and 1 had MEN1. The success rate in these 88 patients was 83 of 88. The causes of failure included three with missed MGD, one reoperation for MGD, and one had MEN1. Fully informed consent to MIP was obtained from all patients, who were told of the risk of conversion to open procedure and the 2% risk of failure with persistent hyperparathyroidism necessitating subsequent parathyroid reexploration. Surgical technique and IOPTH measurements
MIP was undertaken using the lateral-focused miniincision technique described previously.20 This technique involves use of a 2-cm lateral incision placed directly over the site of the adenoma and overlying the medial border of the sternomastoid. All dissection and removal of the adenoma is carried out through that incision with use of a headlight to provide appropriate anatomic visualization. The procedure can be performed with either general anesthesia or local anesthesia with a superficial cervical block supplemented by local infiltration. Neither the nuclear probe nor IOPTH was used to guide decision-making during the operation. For this study, preincision, preexcision, 10-minute, and 30-minute iPTH levels were taken, and measured on the routine laboratory using the Immulite 2000 Intact PTH assay (DPC). Immulite 2000 is a solid-phase, two-site chemiluminescent enzyme-labeled immunometric assay. Samples were run
Vol. 203, No. 1, July 2006
Stalberg et al
that afternoon, and the results were made available to the surgeon to assist with appropriately informed patient discharge. All blood samples were collected into ethylenediaminetetraacetic acid plasma tubes and kept on ice until analysis. The previously accepted and used guidelines for IOPTH levels for intraoperative decisionmaking17 were applied in retrospect. A true positive IOPTH result is defined as ⱖ 50% drop in iPTH level at 10 minutes from the highest preexcision or preincision value in a patient that returned to normal or low serum calcium levels lasting for 3 months after the MIP. A true-negative result is present when iPTH level fails to drop according to this guideline, and the patient remains or returns to hypercalcemia within 3 months after parathyroidectomy. A false-positive result is when the hormone level drops ⱖ 50% at 10 minutes, but the patient has persistent hypercalcemia at followup. A falsenegative result is defined as when the iPTH level does not drop ⬍ 50% at 10 minutes but the patient returns to normal or low calcium levels lasting at least 3 months. Statistical analysis
All values of mean and SEM was calculated using StatView software (Abacus Concepts Inc). RESULTS Mean age at operation was 59.7 years (for women, 60.8 years, range 22.4 to 85.8; for men, 56.6 years, range 37.5 to 75.9), and the female:male ratio was 3:1. All patients had unequivocal pHPT as defined by corrected serum calcium above the upper limit together with an inappropriate serum level of iPTH and absence of hypocalciuria. Cure was defined as normocalcemia at 6-month followup. All patients had single gland disease as defined by single uptake on parathyroid sestamibi scan. All patients were operated on using the focused lateral 2-cm incision approach. The cure rate in this study was 98%, without taking into consideration the results of IOPTH measurements when performing the operation. Two patients remained hypercalcemic after the first operation, and in neither of these patients was there a ⬎ 50% decrease in iPTH at either 10 or 30 minutes. The first patient had concordant preoperative localization studies and underwent removal of a left superior parathyroid adenoma weighing 1,300 mg, and remained hypercalcemic. She has subsequently been cured by removal of a second adenoma (right inferior, weighing 245 mg) using standard bilateral neck exploration. The second patient re-
Intraoperative Parathyroid Hormone Measurement
3
mained hypercalcemic after removal of what was macroscopically believed to be an adenoma, but which was subsequently shown on histologic examination to be a branchial cleft remnant associated with a normal right superior parathyroid gland (false-positive localization on both sestamibi and ultrasonography). The patient underwent subsequent bilateral neck exploration with the finding of three normal parathyroid glands; right inferior, left superior and inferior, all confirmed on histologic examination, and remains hypercalcemic. Looking at all iPTH data retrospectively leads to the conclusion that only the first patient would have been cured by using intraoperative iPTH monitoring during the first operation. The value-added accuracy of cure using IOPTH in this study was only 1%. In nine patients (9%), IOPTH failed to fall at 10 minutes, despite subsequent confirmation of cure and all these patients would have been subjected to unnecessary conversion based on a false-negative IOPTH at 10 minutes. When looking at the IOPTH at 30 minutes, the false-negative rate was reduced to 4%. None of the patients with falsenegative samples had any biochemical signs of renal failure (mean creatinine 73.9 ⫾ 3.0; normal range 60 to 100 mol/L), and all were cured by MIP removing a single parathyroid adenoma (mean weight 607 ⫾ 169 mg). In the 89 remaining patients, IOPTH fell to curative values after removal of a single parathyroid adenoma. Followup time ranges from 6 to 20 months without recurrent disease. Overall ability of IOPTH measurements to predict cure was 100%, relying on the 10-minute IOPTH would only have value added to the cure rate by 1% at the time of initial operation, and would have subjected nine patients to unnecessary conversion to open exploration. iPTH data are presented in Figure 1. DISCUSSION MIP for pHPT is a safe and effective procedure with excellent cure rates in experienced hands.3,21,22 It has been shown that MIP leads to lower hospital costs, lower incidence of hypocalcemia, and low complication rates, compared with the standard approach of bilateral neck exploration through a collar incision.14,18,23-25 There have been claims that several intraoperative adjuncts have an impact on cure rate after MIP, it is not clear from the literature how any of these techniques contribute in a substantial way to warrant their use. In this article, we present our experience from the last
4
Stalberg et al
Intraoperative Parathyroid Hormone Measurement
%
% drop from the highest preincision/preexcision IOPTH value
100
75
50
False-negatives 25
True-positives 0
n mi 30
20 m
in
in 10 m
pr pr einc ee isi xc on i si / on
time
A %
% drop from the highest preincision/preexcision IOPTH value
100
Patient #2
75
Patient #1 50
25
n mi 30
n mi 20
mi
n
time 10
pr pr einc ee isi xc on isi / on
0
B Figure 1. Intraoperative intact parathyroid hormone (IOPTH) measurements showing the drop from the highest preincision/ preexcision value at 10 and 30 min after resection of a single adenoma. (A) Group of true positives (n ⫽ 89) and group of false negatives (n ⫽ 9). Values are mean and SEM. (B) Two true negatives, patient numbers 1 and 2.
100 consecutive MIPs performed in our unit, where IOPTH data were collected prospectively but not acted on at the time of operation. During the time period of the study, we performed a total of 188 parathyroidectomies in the unit, with an overall success rate of 96% and have performed 683 MIPs since its introduction in 1998. All patients in this study had a preoperative sesta-
J Am Coll Surg
mibi scan suggestive of single gland disease. Ultrasonography of the neck was added to guide the incision; in seven patients the ultrasound was negative and this did not contraindicate MIP. We found that using preoperative sestamibi imaging showing an unequivocal single site of uptake, followed by MIP, leads to a cure rate of pHPT in 98 of 100 patients. The value-added effect of using IOPTH would only have been 1%, adding up to a final cure rate of 99%. On the other hand, use of IOPTH would have led to either 9% unnecessary conversions based on the false-negative 10-minute samples, or 4% unnecessary conversions based on the falsenegative 30-minute samples, but then associated with prolonged operative time if the anesthesia had been delayed to allow analysis of a delayed 30-minute sample. IOPTH is claimed to avoid failures during MIP for pHPT from missed MGD.26-29 IOPTH has been reported to have a considerable false-positive and falsenegative rate when applying the defined criterion for biologic recovery of hyperfunctioning parathyroid tissue to intraoperative decision-making (30 in our study, IOPTH was 100% accurate in predicting cure in patients with unequivocal sestamibi scans, but carried a substantial false-negative rate of 9% at 10 minutes, and 4% at 30 minutes). Such false-negative results cannot be explained by any of the known causes of prolonged iPTH half-life, as none of the patients showed any biochemical signs of renal failure.31,32 It is known that the immunometric assay cross-reacts with the 7–84 subunit of PTH, the importance of which is largely unclear with regard to pHPT.33 It is possible that the newer wholePTH assay will shed more light on this issue,33 but additional studies are needed. The question arises as to whether these patients with false-negative results are prone to have missed MGD. The low incidence of MGD might possibly be related to patient selection, as patients with positive imaging for a single adenoma are less likely to have MGD.28 Put into perspective, our overall incidence of MGD during the study period was 18% (33 of 177) when excluding secondary HPT and MEN. It is known that an abnormally sized gland can be found on the other side in about 15% of patients with a unilateral single adenoma removed during MIP,27 and it seems possible that some large parathyroid glands do not oversecrete PTH and do not cause disease. Normal parathyroid gland weight and size can also be larger than previously thought.34 In addition, our group has shown that there seems to be an absence of
Vol. 203, No. 1, July 2006
Stalberg et al
correlation between calcium-PTH response curve and size of the parathyroid tumor.35 Several authors claim that the widely accepted use of IOPTH measurements is necessary for MIP to have high cure rates,15,16,18 our data do not support this. We have a cure rate of 98% when performing MIP, without using any additional technical adjuncts, a cure rate equivalent to those surgeons who stated that they would never perform MIP without IOPTH because they want to cure every patient every time.18 A recent study claimed that the introduction of IOPTH improved cure rate by 10%,16 this was based on historic data in association with changed surgical staffing. Some authors have suggested concordance between ultrasonography and sestamibi scan to use a focused approach without using IOPTH with a reported success rate of 95%.36 If we had applied this to our study, 93 patients would have had MIP without IOPTH measurements. The same two patients would have been failures because both had positive preoperative imaging, leading to a cure rate of 98%. Relying on an unequivocal sestamibi scan in our setting, where the scan has a truepositive rate for single gland disease of 98 of 114, seems more cost-effective because 7 more patients could have a successful MIP procedure with the same cure rate of 98%. It has also been suggested that routine use of IOPTH should be offered to expand the percentage of patients who might be suitable for MIP, eg, those with an equivocal scan or a negative scan with positive ultrasonography. Our unit has a policy of only offering MIP to those who fit a clearly defined protocol (53% of all patients with PHPT), ie, an unequivocally positive sestamibi scan. The question of the role of IOPTH in expanding indications for MIP clearly requires additional study. We and others have challenged the use of IOPTH based on low cost-effectiveness, and lack of improved cure rates.37-40 Data from this study suggest that the success rate when MIP is performed by an experienced endocrine surgeon is essentially a result of appropriate patient selection based on preoperative localization studies, not on IOPTH measurements. Subjecting patients to unnecessary conversion to open operation or prolonged operating times cannot be cost-effective. Neither is it appropriate to propose that IOPTH, although not required for the experienced endocrine surgeons, is of value to the less-experienced surgeon in attempting to locate a parathyroid adenoma. In our unit, patients undergo MIP as a simple, cost-effective ambulatory proce-
Intraoperative Parathyroid Hormone Measurement
5
dure, fully informed of the 2% failure rate. Measurement of a single postoperative iPTH level simply assists informed discharge for those very few patients who will require subsequent readmission for bilateral neck reexploration.30 Author Contributions
Study conception and design: Sidhu, Sywak, Robinson, Delbridge Acquisition of data: Stalberg, Wilkinson, Delbridge Analysis and interpretation of data: Stalberg, Delbridge Drafting of manuscript: Stalberg Critical revision: Sidhu, Sywak, Robinson, Wilkinson, Delbridge Supervision: Delbridge REFERENCES 1. Duh QY. What’s new in general surgery: endocrine surgery. J Am Coll Surg 2005;201:746–753. 2. Delbridge LW, Dolan SJ, Hop TT, et al. Minimally invasive parathyroidectomy: 50 consecutive cases. Med J Aust 2000;172: 418–422. 3. Udelsman R, Donovan PI, Sokoll LJ. One hundred consecutive minimally invasive parathyroid explorations. Ann Surg 2000; 232:331–339. 4. van Vroonhoven TJ, van Dalen A. Successful minimally invasive surgery in primary hyperparathyroidism after combined preoperative ultrasound and computed tomography imaging. J Intern Med 1998;243:581–587. 5. Gauger PG, Reeve TS, Delbridge LW. Endoscopically assisted, minimally invasive parathyroidectomy. Br J Surg 1999;86: 1563–1566. 6. Miccoli P, Bendinelli C, Vignali E, et al. Endoscopic parathyroidectomy: report of an initial experience. Surgery 1998;124: 1077–1079; discussion 1079⫺1080. 7. Miccoli P, Berti P, Conte M, et al. Minimally invasive videoassisted parathyroidectomy: lesson learned from 137 cases. J Am Coll Surg 2000;191:613–618. 8. Gagner M. Endoscopic subtotal parathyroidectomy in patients with primary hyperparathyroidism. Br J Surg 1996;83:875. 9. Henry JF, Defechereux T, Gramatica L, de Boissezon C. Minimally invasive videoscopic parathyroidectomy by lateral approach. Langenbecks Arch Surg 1999;384:298–301. 10. Yeung HC, Ng WT, Kong CK. Endoscopic thyroid and parathyroid surgery. Surg Endosc 1997;11:1135. 11. Sackett WR, Barraclough B, Reeve TS, Delbridge LW. Worldwide trends in the surgical treatment of primary hyperparathyroidism in the era of minimally invasive parathyroidectomy. Arch Surg 2002;137:1055–1059. 12. Delbridge L. Minimally invasive parathyroidectomy: the Australian experience. Asian J Surg 2003;26:76–81. 13. Tezelman S, Shen W, Shaver JK, et al. Double parathyroid adenomas. Clinical and biochemical characteristics before and after parathyroidectomy. Ann Surg 1993;218:300–307; discussion 307⫺309. 14. Chen H, Sokoll LJ, Udelsman R. Outpatient minimally invasive parathyroidectomy: a combination of sestamibi-
6
15. 16.
17.
18. 19. 20. 21.
22. 23.
24.
25. 26. 27.
Stalberg et al
Intraoperative Parathyroid Hormone Measurement
SPECT localization, cervical block anesthesia, and intraoperative parathyroid hormone assay. Surgery 1999;126:1016–1021. Irvin GL III, Sfakianakis G, Yeung L, et al. Ambulatory parathyroidectomy for primary hyperparathyroidism. Arch Surg 1996;131:1074–1078. Chen H, Pruhs Z, Starling JR, Mack E. Intraoperative parathyroid hormone testing improves cure rates in patients undergoing minimally invasive parathyroidectomy. Surgery 2005;138:583– 587; discussion 587⫺590. Irvin GL III, Solorzano CC, Carneiro DM. Quick intraoperative parathyroid hormone assay: surgical adjunct to allow limited parathyroidectomy, improve success rate, and predict outcome. World J Surg 2004;28:1287–1292. Udelsman R. Six hundred fifty-six consecutive explorations for primary hyperparathyroidism. Ann Surg 2002;235:665–670; discussion 670⫺672. Shon IH, Roach PJ, Bernard E, et al. Superimposed double parathyroid adenoma on Tc-99m MIBI imaging: the value of oblique images. Clin Nucl Med 2001;26:876–877. Agarwal G, Barraclough BH, Reeve TS, Delbridge LW. Minimally invasive parathyroidectomy using the ‘focused’ lateral approach. II. Surgical technique. ANZ J Surg 2002;72:147–151. Agarwal G, Barraclough BH, Robinson BG, et al. Minimally invasive parathyroidectomy using the ‘focused’ lateral approach. I. Results of the first 100 consecutive cases. ANZ J Surg 2002; 72:100–104. Chen H, Zeiger MA, Gordon TA, Udelsman R. Parathyroidectomy in Maryland: effects of an endocrine center. Surgery 1996; 120:948–952; discussion 952⫺953. Bergenfelz A, Lindblom P, Tibblin S, Westerdahl J. Unilateral versus bilateral neck exploration for primary hyperparathyroidism: a prospective randomized controlled trial. Ann Surg 2002; 236:543–551. Goldstein RE, Blevins L, Delbeke D, Martin WH. Effect of minimally invasive radioguided parathyroidectomy on efficacy, length of stay, and costs in the management of primary hyperparathyroidism. Ann Surg 2000;231:732–742. Sidhu S, Neill AK, Russell CF. Long-term outcome of unilateral parathyroid exploration for primary hyperparathyroidism due to presumed solitary adenoma. World J Surg 2003;27:339–342. Kaczirek K, Riss P, Wunderer G, et al. Quick PTH assay cannot predict incomplete parathyroidectomy in patients with renal hyperparathyroidism. Surgery 2005;137:431–435. Siperstein A, Berber E, Mackey R, et al. Prospective evaluation of sestamibi scan, ultrasonography, and rapid PTH to predict the success of limited exploration for sporadic primary hyperparathyroidism. Surgery 2004;136:872–880.
J Am Coll Surg
28. Sugg SL, Krzywda EA, Demeure MJ, Wilson SD. Detection of multiple gland primary hyperparathyroidism in the era of minimally invasive parathyroidectomy. Surgery 2004;136:1303– 1309. 29. Weber KJ, Misra S, Lee JK, et al. Intraoperative PTH monitoring in parathyroid hyperplasia requires stricter criteria for success. Surgery 2004;136:1154–1159. 30. Starr FL, DeCresce R, Prinz RA. Normalization of intraoperative parathyroid hormone does not predict normal postoperative parathyroid hormone levels. Surgery 2000;128:930–935; discussion 935⫺936. 31. Libutti SK, Alexander HR, Bartlett DL, et al. Kinetic analysis of the rapid intraoperative parathyroid hormone assay in patients during operation for hyperparathyroidism. Surgery 1999;126: 1145–1150; discussion 1150⫺1151. 32. Lokey J, Pattou F, Mondragon-Sanchez A, et al. Intraoperative decay profile of intact (1–84) parathyroid hormone in surgery for renal hyperparathyroidism—a consecutive series of 80 patients. Surgery 2000;128:1029–1034. 33. Yamashita H, Gao P, Cantor T, et al. Comparison of parathyroid hormone levels from the intact and whole parathyroid hormone assays after parathyroidectomy for primary and secondary hyperparathyroidism. Surgery 2004;135:149–156. 34. Yao K, Singer FR, Roth SI, et al. Weight of normal parathyroid glands in patients with parathyroid adenomas. J Clin Endocrinol Metab 2004;89:3208–3213. 35. Mun HC, Conigrave A, Wilkinson M, Delbridge L. Surgery for hyperparathyroidism: does morphology or function matter most? Surgery 2005;138:1111–1120; discussion 1120. 36. Arici C, Cheah WK, Ituarte PH, et al. Can localization studies be used to direct focused parathyroid operations? Surgery 2001; 129:720–729. 37. Jacobson SR, van Heerden JA, Farley DR, et al. Focused cervical exploration for primary hyperparathyroidism without intraoperative parathyroid hormone monitoring or use of the gamma probe. World J Surg 2004;28:1127–1131. 38. Sebag F, Shen W, Brunaud L, et al. Intraoperative parathyroid hormone assay and parathyroid reoperations. Surgery 2003; 134:1049–1055; discussion 1056. 39. Agarwal G, Barakate MS, Robinson B, et al. Intraoperative quick parathyroid hormone versus same-day parathyroid hormone testing for minimally invasive parathyroidectomy: a costeffectiveness study. Surgery 2001;130:963–970. 40. Mozzon M, Mortier PE, Jacob PM, et al. Surgical management of primary hyperparathyroidism: the case for giving up quick intraoperative PTH assay in favor of routine PTH measurement the morning after. Ann Surg 2004;240:949–953; discussion 953⫺954.