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The Influence of Intraoperative Parathyroid Hormone Monitoring on the Surgical Management of Hyperparathyroidism
David L. Mandell, MD;
Eric M. Genden, MD;
Jeffrey I. Mechanick, MD;
Donald A. Bergman, MD;
Edward J. Diamond, PhD;
Mark L. Urken, MD
Arch Otolaryngol Head Neck Surg. 2001;127:821-827.
ABSTRACT
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Objective To examine the role of intraoperative rapid parathyroid hormone (PTH)
monitoring in the surgical management of hyperparathyroidism.
Design Thirty-eight–month retrospective review.
Setting Tertiary care academic medical center.
Patients One hundred consecutive patients undergoing surgery for primary hyperparathyroidism.
Intervention All patients underwent preoperative technetium Tc 99m sestamibi scan
localization and intraoperative blood PTH monitoring by means of a rapid (12-minute)
immunochemiluminometric assay.
Main Outcome Measures The influence of intraoperative PTH levels on extent of surgical dissection
and achievement of postoperative normocalcemia.
Results Intraoperative PTH levels dropped an average of 64%, 75%, and 83% at
5, 10, and 20 minutes, respectively, after excision of all hyperfunctioning
parathyroid tissue. A PTH decrease of 46% or more at 10 minutes and 59% or
more at 20 minutes after excision of hyperfunctioning tissue was predictive
of postoperative normocalcemia. In 79 patients (79%), the sestamibi scan provided
accurate preoperative localization; all but 1 of these patients were treated
successfully, most often with a limited, gland-specific dissection. In 24
patients with inaccurate, negative, or misleading preoperative sestamibi scans,
23 (96%) were treated successfully with the use of the intraoperative PTH
assay.
Conclusions The rapid intraoperative PTH assay accurately predicts postoperative
success in patients with primary hyperparathyroidism. The rapid PTH assay
allows for greater confidence in performing limited dissections in well-localized
uniglandular disease. In cases of inaccurate preoperative localization, the
rapid PTH assay directly affects surgical decision making and provides greater
confidence in determining when surgical success has been achieved.
INTRODUCTION
THE EXTENT of surgical exploration required for patients with primary
hyperparathyroidism has not been clearly defined. In experienced hands, the
standard approach of bilateral cervical exploration has a surgical success
rate between 94% and 96%.1-2 However,
surgical failure and persistent postoperative hypercalcemia may result from
failure to recognize the presence of multiglandular hyperplasia (present in
up to 15% of patients),2 more than 1 adenoma
(present in approximately 3% of patients),2
or an ectopic hyperfunctioning gland.
In recent years, attempts have been made to implement "rapid" parathyroid
hormone (PTH) assays for intraoperative monitoring during surgical treatment
of primary hyperparathyroidism.3-20
Because of the short half-life of the PTH molecule (2 to 5 minutes), combined
with the tendency for normal parathyroid glands to be suppressed in cases
of parathyroid hyperfunction,5 a decrease in
the intraoperative PTH level would be expected to correlate with successful
removal of all hyperfunctioning tissue. When combined with accurate preoperative
localization by technetium Tc 99m (99mTc) sestamibi scanning, the
rapid PTH assay has been reported to prevent dissection of previously operated-on
tissue in cases of recurrent hyperparathyroidism5, 13-15
and to allow targeted unilateral surgery with shortened operative times, same-day
hospital discharge, and potential cost savings in cases of single parathyroid
adenomas.8, 12, 17
The present study is a retrospective review of the use of an intraoperative
rapid PTH immunochemiluminometric assay (ICMA) combined with preoperative
localization by sestamibi scanning in a series of patients with primary hyperparathyroidism
treated with targeted surgical exploration. The purposes of the study were
to determine the ability of the rapid PTH assay to predict surgical success
and to assess the influence of the assay on intraoperative decision making
and surgical strategy.
PATIENTS AND METHODS
The study population consisted of consecutive patients undergoing surgery
for primary hyperparathyroidism within the Department of Otolaryngology at
Mount Sinai Hospital, New York, NY, from November 5, 1997, through January
31, 2001. All operations were performed by either of 2 of us (E.M.G. and M.L.U.)
after patients gave informed consent for parathyroidectomy. Patient charts
and detailed operative reports were reviewed retrospectively, and the following
information was obtained for each patient: age at the time of surgery; sex;
preoperative total serum calcium, intact serum PTH, and serum creatinine levels;
total number of parathyroid glands removed; type of anesthesia (general vs
regional); operative time from initial incision to final closure; length of
hospital stay; and presence of coexisting thyroid gland disease. Patients
with evidence of renal failure were excluded.
All patients underwent preoperative localization with 99mTc
sestamibi nuclear imaging at Mount Sinai Hospital (Vision software; SMV America,
Twinsburg, Ohio). Two scintillation images of the neck and upper mediastinum
(1 at 15 minutes and 1 at 2 hours after injection of the radiotracer) were
obtained with the patient supine and the neck extended. The recorded dose
of radiotracer administered per patient ranged from 20 to 26 mCi (740-962
MBq). Initial uptake in the thyroid gland (seen at 15 minutes) was expected
to decrease over time, whereas a parathyroid adenoma, if present, was expected
to maintain uptake during the 2-hour time span.21
Recently, in our institution, traditional sestamibi parathyroid scintigraphic
examinations have been routinely supplemented with images obtained by single-photon
emission computed tomography, a technique that reportedly may identify smaller
(<500 mg) parathyroid adenomas with improved accuracy.22
From a surgical perspective, we have yet to notice a distinct advantage in
parathyroid adenoma detection with the use of single-photon emission computed
tomography with sestamibi, but as more data are generated, this issue will
deserve further study.
Blood was drawn for the rapid intraoperative PTH assay through a radial
arterial line at the following times: "postinduction" (immediately after induction
of general anesthesia, or immediately after completion of a regional nerve
block for cases performed with the patient under local anesthesia); "postisolation"
(immediately after dissection, but just before removal, of suspected hyperfunctioning
parathyroid tissue); and 5, 10, and 20 minutes after excision of suspected
hyperfunctioning tissue. It is generally accepted, on the basis of work by
Irvin et al,8 that a drop in rapid PTH levels
of more than 50% from baseline levels at 10 minutes after excision of hyperfunctioning
tissue is predictive of postoperative normocalcemia. However, we decided to
send 3 separate peripheral-blood samples for rapid PTH assessment at 5, 10,
and 20 minutes after excision in every patient, to make sure our experience
was consistent with that of the literature, and also simply to document and
study longitudinally the fluctuations and variations in PTH levels that might
occur during the early postexcision period.
The percentage decrease in rapid PTH levels after excision of hyperfunctioning
tissue was determined by comparing each postexcision rapid PTH level to the
highest preexcision level (either the postinduction or the postisolation level,
whichever was higher). This technique has been previously described.4
Intraoperatively, the following general principles applied. In cases
in which the preoperative sestamibi scan appeared to clearly identify a single
hyperfunctioning gland, unilateral exploration with single-gland excision
was performed. If rapid PTH levels dropped by 50% or more from either the
postinduction or postisolation levels at 10 or 20 minutes after excision of
suspected hyperfunctioning tissue, the operation was terminated. The decision
to use the 50% decrease in PTH levels as an indicator of surgical success
was based on data from Irvin et al.8 If rapid
PTH levels failed to drop to 50% or less of baseline by 20 minutes after excision
of suspected hyperfunctioning tissue, further exploration was performed.
In cases of inadequate preoperative sestamibi localization, bilateral
neck explorations were planned. Rapid PTH levels were drawn at 5, 10, and
20 minutes after excision of suspected hyperfunctioning tissue. The operation
was terminated if rapid PTH levels dropped by 50% or more8;
otherwise, further exploration was pursued.
Postoperatively, blood samples for both total and ionized calcium levels
were drawn every 6 hours until the patient was discharged from the hospital.
This relatively frequent calcium monitoring regimen was followed to ensure
that normocalcemia (and not substantial hypocalcemia) occurred in the early
postoperative period, thus helping to determine the feasibility of early (possibly
even same-day) hospital discharge after surgery. Patient discharge was based
on the demonstration of a plateau in serial total and ionized calcium levels
within the reference range after surgery. For the standard hospital assays
used in our institution, the reference range of total serum calcium level
is 8.5 to 11.0 mg/dL (2.1-2.8 mmol/L), while the reference range of ionized
calcium is 4.56 to 5.00 mg/dL (1.14-1.29 mmol/L). A telephone survey was performed
a minimum of 6 months (range, 6-33 months) after surgery in which patients
were asked to recall the last time their serum calcium level was checked,
and whether they were told the calcium level was normal or abnormal.
Rapid intraoperative PTH levels were determined by means of a commercially
available ICMA kit (QuiCk-IntraOperative Intact PTH Kit; Nichols Institute
Diagnostics, San Juan Capistrano, Calif). The assay was performed by a technician
stationed in a small anteroom directly adjacent to the operating room. The
overall turnaround time from the moment the blood sample was drawn to the
moment the rapid PTH level was reported to the surgeon was approximately 12
minutes. For the first 61 patients in the study, a 3-mL portion of each intraoperative
blood sample was sent to the central hospital laboratory for analysis with
the routine hospital PTH assay (an ICMA that requires 2 hours of incubation).
The PTH results from the standard hospital assay correlated well with results
from the rapid intraoperative assay (Pearson correlation coefficient r = 0.83; P<.01; based on 316
paired samples).
RESULTS
One hundred consecutive patients who underwent operative management
of primary hyperparathyroidism were studied. Average patient age at the time
of surgery was 58 years (range, 30-91 years). There were 69 women and 31 men.
Both the average preoperative serum calcium level (11.4 mg/dL [2.9 mmol/L];
range, 10.4-14.8 mg/dL [2.6-3.7 mmol/L]) and the average preoperative intact
serum PTH level (179 pg/mL; range, 65-800 pg/mL) were elevated above the reference
range for the assays used in all cases. The average preoperative serum creatinine
(0.9 mg/dL [80 mmol/L]; range, 0.4-1.6 mg/dL [35-141 mmol/L]) and albumin
(4.3 g/dL; range, 3.6-4.8 g/dL) levels were considered to be within the reference
range for the assays used in all cases.
Of the 100 patients in the study, 89 had a single benign hyperfunctioning
gland, 8 had 2 distinct parathyroid adenomas, 1 had multiple-gland hyperplasia,
1 had parathyroid carcinoma, and in 1 patient hyperfunctioning tissue was
not found despite extensive exploration.
There was no mortality in this series. There were no cases of recurrent
laryngeal nerve paralysis. One patient required a prolonged (20-day) postoperative
stay because of persistent hypocalcemia after 4-gland parathyroidectomy with
brachioradialis autotransplantation for multiglandular hyperplasia.
All 100 patients underwent preoperative localization with 99mTc
sestamibi scanning. The scan accurately localized hyperfunctioning tissue
to the correct side of the neck in 79% of the cases (79 true-positive scans).
There were 20 false-negative scans (20% false-negative rate). There was 1
true-negative scan, in which rapid PTH levels remained elevated and hypercalcemia
persisted postoperatively. There were 3 false-positive results. In 2 cases,
a false-positive result occurred with a contralateral true-positive result
in the same patient, leading to an unnecessary contralateral neck exploration
in which no gross parathyroid or thyroid gland disease was found. The other
false-positive result was due to a lymph node with metastatic papillary carcinoma;
in the same patient, there was a false-negative result on the contralateral
side, where a parathyroid adenoma was found. In 1 case, a false-negative result
occurred with a contralateral true-positive result in a patient with 1 parathyroid
adenoma on each side of the neck. Overall, there were 24 patients with inaccurate,
negative, or misleading preoperative localization, of whom 23 (96%) were treated
successfully with the use of the intraoperative PTH assay.
Of the 100 patients who underwent parathyroid surgery, 20 had coexistent
thyroid gland disease requiring thyroid surgery. Of these, 5 patients had
total thyroidectomy (2 patients with papillary carcinoma, 2 with multinodular
goiter, and 1 with Hurthle cell adenoma), and 15 patients had thyroid lobectomy
(8 patients with follicular adenoma, 6 with multinodular goiter, and 1 with
papillary thyroid carcinoma).
The average length of hospital stay was 1.7 days (range, 0-20 days).
Sixty-five patients (65%) were discharged home on the first postoperative
day. Thirty-seven operations (37%) were performed with the patient under regional
block anesthesia with intravenous sedation, and 7 (19%) of these patients
were ambulatory. The remaining 63 operations were performed with the patient
under general anesthesia, of whom 4 (6%) were ambulatory.
Excluding the 1 patient in whom abnormal parathyroid tissue was not
found, intraoperative rapid PTH levels dropped an average of 64%, 75%, and
83% at 5, 10, and 20 minutes, respectively, after excision of all hyperfunctioning
parathyroid tissue (Figure 1). A
rapid PTH decrease of 46% or more at 10 minutes, and 59% or more at 20 minutes,
after excision of suspected hyperfunctioning tissue was predictive of postoperative
normocalcemia. In 99 of 100 patients, normocalcemia was demonstrated at the
time of hospital discharge (average total serum calcium level, 8.7 mg/dL [2.2
mmol/L]; range, 7.4-10.3 mg/dL [1.9-2.6 mmol/L]; average ionized calcium level,
4.68 mg/dL [1.17 mmol/L]; range, 3.92-5.16 mg/dL [0.98-1.29 mmol/L]). In the
1 patient whose PTH levels did not decrease intraoperatively, hypercalcemia
persisted during the immediate postoperative period. Selective venous sampling
performed on the first postoperative day suggested the presence of a hyperfunctioning
gland in the mediastinum; however, the patient refused any further surgical
intervention and remained hypercalcemic after 9 months of postoperative follow-up.
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Figure 1. Average change in rapid parathyroid
hormone levels ( PTH) after excision of all hyperfunctioning parathyroid
tissue in 76 patients with primary hyperparathyroidism who were discharged
with normocalcemia postoperatively. Error bars represent overall range of
PTH values at each postexcision time.
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Sixty-four patients were available for long-term follow-up by telephone
survey. The most recent serum calcium levels had been drawn between 6 and
33 months after surgery (average, 14 months). Only 2 (3%) of 64 patients had
experienced recurrent hyperparathyroidism. The first patient had undergone
excision of a 0.1-g solitary left inferior parathyroid adenoma in November
1997 that had been well localized on preoperative sestamibi scan. Rapid PTH
levels dropped by 75% and 78% at 5 and 10 minutes, respectively, after adenoma
excision. Postoperative normocalcemia persisted for 2 years, at which time
hyperparathyroidism recurred. A sestamibi scan at that time localized the
abnormality to the left side of the neck, while an ultrasound scan of the
neck was negative. Extensive exploration of the left side of the neck, including
retroesophageal exploration and partial thymic excision, failed to show any
parathyroid tissue. The right side of the neck was then explored, where an
enlarged inferior parathyroid gland was found. A superior right parathyroid
gland could not be identified despite extensive exploration. After removal
of the right inferior parathyroid gland, rapid PTH levels decreased by 95%.
A small portion of the excised gland was used for brachioradialis autotransplantation.
At 3 months' follow-up, the patient remained normocalcemic. Because of the
2-year period of postoperative normocalcemia after the first operation, the
rapid PTH assay was still considered to be accurate (true positive) in this
case, and this case was not considered a surgical failure.
In the second case of recurrence, removal of a solitary left inferior
parathyroid adenoma from a patient in September 1999 resulted in a drop in
rapid PTH levels of 42%, 55%, and 64% at 5, 10, and 20 minutes, respectively,
after excision. Preoperative sestamibi scanning had shown 2 foci of increased
uptake, 1 on each side of the neck. Although a bilateral exploration had been
performed, the only parathyroid adenoma identified was on the left side (weight,
0.23 g). More extensive exploration was not undertaken because of the marked
decrease in rapid PTH levels after adenoma excision. The patient was normocalcemic
on hospital discharge on the first postoperative day; however, within 1 week
of surgery, hypercalcemia had recurred. At 8 months postoperatively, hyperparathyroidism
with hypercalcemia persisted; the patient refused further workup and recently
became unavailable for follow-up despite repeated attempts to maintain contact.
This case represents the only false-positive rapid PTH assay result
in our series and is considered a surgical failure (1 of 2 in this series).
We believe that the right-sided sestamibi localization represented a false-positive
result and that any additional adenoma would likely reside in an ectopic location.
Further workup, could it be obtained, would include repeated sestamibi and
ultrasound. If these were negative, either selective venous PTH sampling or
magnetic resonance imaging would be considered. In our department, we generally
prefer ultrasound over magnetic resonance imaging to correlate with sestamibi
results, as it is believed that ultrasound and magnetic resonance imaging
have traditionally yielded similarly accurate results in our institution,
with ultrasound representing the less expensive option.
Overall, our surgical success rate was 97% in patients with at least
6 months of follow-up.
The following represents a breakdown of the cases in our series based
on degree of complexity, to determine the way in which the rapid PTH assay
affected intraoperative decision making.
ROUTINE CASES
There were 67 cases of uncomplicated, primary hyperparathyroidism resulting
from a single parathyroid adenoma with a true-positive sestamibi scan with
a single positive site of uptake. None of these patients had a history of
endocrine-related surgery. All patients had a marked drop in rapid PTH levels
intraoperatively (average decrease of 64% [range, -18% to -96%]
at 5 minutes, 75% [range, -46% to -94%) at 10 minutes, and 84%
(range, -59% to -98%) at 20 minutes after excision), and all patients
were normocalcemic on discharge from the hospital. Among these 67 cases, 60
(90%) were able to undergo unilateral exploration. Visualization of a second
ipsilateral parathyroid gland was often not attempted. Seven patients underwent
bilateral neck explorations because of bilateral or contralateral thyroid
gland disease (6 patients) and temporary luminometer malfunction (1 patient).
Excluding the 7 patients who underwent bilateral neck explorations, 6 who
underwent attempts at endoscopic parathyroidectomy (as part of another simultaneous
study protocol), and 5 who underwent unilateral exploration with thyroid lobectomy
and parathyroidectomy, the average operative time in the remaining 49 patients
who underwent limited, single-gland dissections was 54 minutes (range, 8-84
minutes). On long-term follow-up, 2 cases of recurrent hyperparathyroidism
were identified (both were described in the "Results" section).
CASES WITH A NEGATIVE PREOPERATIVE SESTAMIBI SCAN
There were 17 patients with primary hyperparathyroidism with a negative
preoperative sestamibi scan. One patient in this group had undergone a previous
subtotal thyroidectomy, while the other 16 patients had no history of previous
endocrine-related surgery.
In 9 of these patients, an attempt was made to localize the side of
the hyperfunctioning tissue by measuring rapid PTH levels from bilateral percutaneous
internal jugular venous samples taken before skin incision, with the patient
under anesthesia (Table 1). This
technique provided accurate localization in only 3 of 9 patients; unilateral
exploration with adenoma excision was performed in these 3 patients, followed
in each instance by an appropriate decrease in rapid PTH levels. In 5 of 9
patients, right and left jugular venous samples were roughly equivalent to
one another, despite the later discovery of unilateral parathyroid disease
on surgical exploration. In one case, despite rapid PTH levels that were markedly
higher in the left jugular venous sample than the right, hyperfunctioning
parathyroid tissue could not be found despite extensive exploration. Rapid
PTH levels remained elevated throughout the procedure, and postoperative hypercalcemia
persisted. In another patient, a single adenoma was fortuitously encountered
at the onset of neck exploration with a drop in rapid PTH levels, thus obviating
the need for a contralateral exploration. In 2 patients, resection of an enlarged
parathyroid gland resulted in a drop in rapid PTH levels of only 30% and 49%,
respectively, from baseline at 20 minutes after excision; contralateral neck
exploration subsequently disclosed another enlarged parathyroid gland, after
excision of which rapid PTH levels dropped to 78% and 88%, respectively, of
baseline at 20 minutes. These 2 patients were normocalcemic on hospital discharge;
long-term follow-up is not yet available. Overall, 16 of 17 patients with
negative preoperative sestamibi localization had successful resection of hyperfunctioning
tissue (14 solitary parathyroid adenomas and 2 cases of double adenoma), with
4 unilateral and 12 bilateral explorations.
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Preoperative Rapid PTH Levels via the Internal Jugular Vein*
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REVISION SURGERY FOR RECURRENT HYPERPARATHYROIDISM
Nine patients underwent revision surgery for previous failed parathyroid
surgery. All 9 patients underwent preoperative sestamibi scanning. In 5 cases,
the combination of successful preoperative sestamibi localization with marked
postexcision decreases in intraoperative rapid PTH levels led to a limited,
unilateral neck exploration, thus avoiding the need for extensive exploration
in a previously operated-on field.
One patient had undergone previous bilateral neck exploration for primary
hyperparathyroidism at another hospital; no adenoma had been found, and hypercalcemia
persisted postoperatively. During the revision surgery in the present study,
despite a sestamibi scan showing uptake in the right lower part of the neck,
extensive bilateral exploration (including median sternotomy and mediastinal
dissection) failed to reveal an enlarged parathyroid gland, as evidenced by
a failure of rapid PTH levels to drop despite multiple biopsies. Finally,
an intrathymic parathyroid adenoma was found, and rapid PTH levels decreased
markedly after excision.
In another patient with recurrent hyperparathyroidism after excision
of a single adenoma, preoperative sestamibi localized hyperfunctioning tissue
to both sides of the neck. A parathyroid adenoma was successfully removed
on one side of the neck, with an appropriate drop in rapid PTH levels. However,
an unnecessary contralateral neck exploration was undertaken as a result of
the false-positive sestamibi scan result.
One patient had undergone 2 previous neck explorations at another institution
with removal of 1 right-sided parathyroid adenoma, 1 left-sided parathyroid
adenoma, and a left intrathyroidal parathyroid cyst, with persistent hyperparathyroidism
postoperatively. Sestamibi scanning localized the abnormality to the left
superior mediastinum, where a parathyroid adenoma was found and excised. However,
rapid PTH levels failed to decrease. After bilateral neck explorations with
no parathyroid tissue identified, attention was returned to the mediastinum,
where another left retroesophageal adenoma was identified. Rapid PTH levels
decreased markedly after excision.
In another patient with persistent hyperparathyroidism after bilateral
neck explorations at another institution, preoperative sestamibi scanning
failed to localize the abnormality, and preoperative venous sampling demonstrated
substantial elevation of PTH levels in the innominate vein. After bilateral
neck exploration failed to show parathyroid tissue, a median sternotomy was
performed. A 2.45-g parathyroid adenoma was identified within the left side
of the thymus just below the level of the innominate vein. After excision,
rapid PTH levels decreased appropriately.
MULTIPLE ADENOMAS
Six patients with primary hyperparathyroidism and no previous endocrine-related
surgery were found to have 2 distinct adenomas. In each case, 1 adenoma was
located on the right and 1 on the left side of the neck. Preoperative sestamibi
scanning successfully localized both the right and left parathyroid adenomas
in 3 of the 6 patients. In 2 patients, sestamibi scanning failed to localize
the abnormality to either side of the neck, and in 1 patient, a true-positive
sestamibi scan on one side of the neck was coupled with a false-negative result
in the contralateral side. In each case, rapid PTH levels decreased in a sequential
manner after excision of each of the adenomas (after first gland excision:
average decrease, 55%; range, 30%-85%; after second gland excision: average
decrease, 82%; range, 63%-93%). Of note, if a preoperative sestamibi scan
had not been routinely performed, the second adenoma might not have been removed
in 2 of these 6 patients, since in these cases the rapid PTH levels dropped
by more than 50% after resection of the first adenoma, and the contralateral
side was explored only because of bilateral sestamibi localization. The average
weight of the first adenoma was 0.28 g (range, 0.06 to 0.70 g); the average
weight of the second gland was 0.14 g (range, 0.06 to 0.28 g).
MULTIPLE-GLAND HYPERPLASIA
One patient with primary hyperparathyroidism demonstrated multiple-gland
hyperplasia. The rapid PTH levels tended to decrease in a delayed, sequential
manner after excision of each of the hyperplastic glands (Figure 2). The PTH levels did not decrease to less than 50% of baseline
until 20 minutes after excision of the third hyperplastic parathyroid gland.
A 4-gland parathyroidectomy was performed, with an overall decrease in rapid
PTH level of 81% from preexcision to final postexcision levels. A portion
of 1 parathyroid gland was used for brachioradialis autoimplantation. Postoperatively,
the patient experienced persistent, profound hypocalcemia requiring nearly
3 weeks of in-hospital management with both oral and intravenous calcium supplementation.
After 9 months of follow-up, hyperparathyroidism has not recurred, but the
patient still requires daily oral calcium and vitamin D supplements.
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Figure 2. Change in rapid parathyroid hormone
levels (PTH) in a patient with multiglandular parathyroid hyperplasia.
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MISCELLANEOUS
One patient with papillary thyroid carcinoma proved by fine needle aspiration
biopsy and concomitant hyperparathyroidism demonstrated sestamibi localization
to the left lower pole. In the operating room, a left paratracheal mass was
excised and found to be a lymph node with metastatic papillary carcinoma on
frozen-section analysis. Rapid PTH levels did not fall after removal of the
mass. On the right side, a large superior parathyroid adenoma was seen and
excised, after which the rapid PTH levels fell significantly. A total thyroidectomy
was also performed.
COMMENT
The earliest clinical report of a rapid intraoperative PTH assay was
described by Nussbaum et al in 1988.3 This
2-site immunoradiometric assay (IRMA) used radiolabeled anti-PTH antibody,
with radioactivity quantified in a gamma counter. Total incubation time was
shortened to just 15 minutes by raising the incubation temperature. While
accurate in predicting successful surgical removal of hyperfunctioning parathyroid
tissue, IRMA has been shown to have the following drawbacks: (1) limited assay
shelf-life because of the short half-life of the radioisotopes6
and (2) cumbersome radiation-related waste removal and safety precautions,
which hinder unit portability.6
A more recent technique for rapid PTH measurement is the ICMA. This
is a 2-site antibody assay similar to IRMA, but antibodies are labeled with
a nonradioactive agent (acridinium ester). Trigger chemicals cause the acridinium
ester to emit light, which is then measured in a luminometer. The nonradioactive
ICMA kit can be safely placed on a cart outside the operating room, eliminating
transport time and allowing immediate reporting of results to the surgeon.6
Rapid PTH assays using ICMA have reported incubation times as short
as 7 minutes,6, 13 with the results
being available to the surgeon within as little as 10 minutes of the sample
being taken.6
It is generally believed, on the basis of work by Irvin et al,8 that a drop in rapid PTH levels of greater than 50%
at 10 minutes after excision of hyperfunctioning tissue is predictive of postoperative
normocalcemia in a variety of patients with hyperparathyroidism. Patients
with no drop in intraoperative PTH levels have generally remained hypercalcemic
immediately after surgery.4, 8-9,12, 19
Several so-called false-negative results have been reported in situations
in which a delayed (up to 30 minutes) drop in PTH levels occurred.4-6,8-9,19
In addition, rapid PTH levels may initially rise within the first few minutes
after excision of a hyperfunctioning gland, possibly because of manipulation
of parathyroid tissue with augmented systemic release of PTH into the bloodstream
before excision.5
In patients with hyperparathyroidism from a variety of causes (most
commonly primary hyperparathyroidism), sestamibi scanning has been reported
to accurately localize the hyperfunctioning tissue in 75% to 94% of patients.6, 8, 12-13 In
the present study, sestamibi accurately localized the hyperfunctioning tissue
in 79% of patients. Among 24 patients in the present study with inaccurate,
negative, or misleading preoperative localization, 9 patients (38%) demonstrated
disease that might have affected the accuracy of the sestamibi scan, including
6 patients with concomitant thyroid disease, 2 patients with a history of
parathyroid surgery, and 1 patient with multiglandular hyperplasia.
Some proponents of rapid intraoperative PTH monitoring have found the
assay particularly useful in reoperative parathyroidectomy.13-15
Combined use of the rapid PTH assay with preoperative sestamibi localization
may prevent dissection of previously operated-on tissue, with its attendant
risks, in patients undergoing cervical or mediastinal reoperation.13-15 The present study,
with 9 cases of reoperative parathyroidectomy, supports these contentions.
In addition, one recent study has reported an improved operative success rate
for reoperative parathyroidectomy with the use of the rapid PTH assay when
compared with an earlier, pre–rapid PTH assay cohort of patients previously
operated on.14
The ability of the rapid PTH assay to detect the presence of multiglandular
parathyroid hyperplasia is unclear. Some studies have suggested that intraoperative
PTH levels will typically fall in a sequential manner as each of the hyperfunctioning
glands is removed.9, 20 This concept
is supported by the 1 patient with multiglandular disease in the present study
(Figure 2). However, others have
demonstrated substantial (ie, >50%) decreases in intraoperative PTH levels
after excision of the first gland in cases of multiglandular disease18-20,23;
these "false-positive" PTH assay results represent a potential cause of operative
failure should only 1 gland be removed. To avoid missed multiglandular disease,
several strategies have been proposed. One study has recommended terminating
parathyroid surgery only when postexcision PTH values (1) drop to 50% or less
of baseline and (2) decrease below the upper limit of normal for the assay.10 Others have suggested changing the degree of decline
in PTH level for prediction of operative success to more than 60% from baseline
at 15 minutes after excision,11 or to more
than 70% from baseline at 20 minutes after excision.15
One study has claimed that reelevation of rapid PTH levels at 60 to 120 minutes
after excision of a hyperfunctioning gland (after an initial decline) may
indicate the presence of multiple-gland disease,7
although waiting up to 2 hours after gland excision to test rapid PTH assay
results may be impractical in most centers.
It has been argued that the combination of intraoperative rapid PTH
monitoring with preoperative sestamibi localization, by allowing targeted
surgery in patients with hyperparathyroidism, (1) promotes the use of local
anesthesia,13, 17 (2) increases
the rate of unilateral exploration,10 (3) may
decrease the length of postoperative stay,8, 10, 17
(4) may decrease average operative time,8, 12
(5) may decrease operative failure rate to as little as 1.5%,10, 16
and (6) may have positive economic implications because of shorter operative
times8, 12 and the avoidance of
an overnight hospital stay.8, 17
However, not all authors have demonstrated an economic benefit to use of the
rapid PTH assay.10 In addition, a recent study
demonstrated the feasibility of local anesthesia and same-day hospital discharge
with bilateral neck exploration for parathyroidectomy without use of the rapid
PTH assay or routine sestamibi localization.24
In the present study, we cannot claim that overall operative time or
hospital costs are now less than before the rapid PTH assay was used in our
institution, as preassay data were not examined. In addition, only 11% of
patients in our study were discharged home the same day as the surgery. We
agree with Sofferman et al,13 who believe that
the true advantage of the intraoperative PTH assay is not in a possible reduction
in surgical time, but rather in a confirmation that the hyperparathyroid state
has been corrected while the patient is still on the operating room table.
Persistently elevated rapid PTH levels alert the surgeon to inadequate excision
of parathyroid tissue and the need for further exploration.9
The use of the intraoperative PTH assay has not often been reported
in patients with parathyroid carcinoma.3-4
In the present study, the 1 patient with parathyroid carcinoma demonstrated
a decrease of 60% and 68% in rapid PTH levels 5 and 10 minutes, respectively,
after excision of the involved gland. A month later, the patient underwent
ipsilateral thyroid lobectomy to ensure adequate tumor margins. At 4 months
after the original surgery, the patient remained normocalcemic and free of
disease.
In the present study, percutaneous rapid PTH sampling from the internal
jugular vein in the setting of negative preoperative localization studies
(in patients with no previous parathyroid surgery) demonstrated poor sensitivity
for identifying in which side of the neck an adenoma resided. These results
are in contrast to those of Irvin et al,14
who demonstrated successful lateralization in 9 of 10 patients with the use
of a similar technique. Intraoperative direct sampling of blood for rapid
PTH analysis from the superior, middle, and inferior thyroid veins bilaterally
during surgery, as reported by Saharay et al,25
may represent a more sensitive localization technique.
CONCLUSIONS
Intraoperative monitoring of PTH levels in patients with primary hyperparathyroidism
using a rapid PTH assay successfully predicts early postoperative normocalcemia.
The rapid PTH assay allows for greater confidence in performing limited dissections
in uniglandular disease that has been well localized with preoperative 99mTc sestamibi imaging. In cases of inaccurate preoperative localization,
the rapid PTH assay directly affects surgical decision making and provides
greater confidence in determining when surgical success has been achieved.
AUTHOR INFORMATION
Accepted for publication March 15, 2001.
Presented at the annual meeting of the American Head and Neck Society,
Fifth International Conference on Head and Neck Cancer, San Francisco, Calif,
August 2, 2000.
Corresponding author and reprints: Mark L. Urken, MD, Department
of Otolaryngology, Campus Box 1189, Mount Sinai School of Medicine, One Gustave
L. Levy Place, New York, NY 10029 (e-mail: mark.urken{at}mssm.edu).
From the Department of Otolaryngology (Drs Mandell, Genden, and Urken),
Division of Endocrinology (Drs Mechanick, Bergman, and Diamond), and Center
for Clinical Laboratories (Dr Diamond), Mount Sinai Medical Center, New York,
NY.
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