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Washington University School of Medicine,
1
Department of Pathology and Immunology and
2
Department of Surgery; and
3
Department of Laboratories, Barnes-Jewish Hospital, St. Louis, MO 63110.
aAddress correspondence to this author at: Department of Pathology and Immunology, Campus Box 8118, Washington University School of Medicine, Washington University Medical Center, 660 S. Euclid Ave., St. Louis, MO 63110-1093. Fax 314-362-1461; e-mail mscott{at}labmed.wustl.edu.
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Methods: We performed rapid PTH assays with the DPC Turbo PTH assay on the DPC IMMULITE automated analyzer. The number of intraoperative frozen sections, type of anesthesia, surgical approach, length of hospital stay, and pre- and postoperative calcium values were compared between a group of 49 patients undergoing parathyroidectomy where the intraoperative PTH assay was used in conjunction with preoperative imaging, and a historical control group of 55 patients before the use of these two technologies in our institution.
Results: Comparison of the Turbo PTH assay to the standard IMMULITE PTH assay gave the following: y = 1.08x - 4.36 (r = 0.97; n = 48). For the 49 patients, the median turnaround time for each intraoperative PTH determination was 19 min (range, 14–40 min). The median decrease in PTH values from baseline was 88% (range, 33–99%). Thirty-seven patients required two PTH determinations, 7 required three, 4 had four, and 1 required five determinations. The average laboratory cost for the rapid intraoperative PTH assays was <$100 per patient (range, $55 to $113). Compared with the control group, the experimental group had significantly fewer frozen sections (1.4 vs 2.5; P <0.0001), shorter hospital stays (17 discharged on the day of surgery vs none discharged on the day of surgery; P <0.0001), greater use of local anesthesia (33% vs 0%; P <0.001), and more unilateral, rather than bilateral neck explorations (65% vs 0%; P <0.001).
Conclusions: The combination of intraoperative Turbo PTH assay and preoperative 99mTc-sestamibi scans can lead to significant decreases in laboratory and surgical pathology costs, hospital stays, and exposure to general anesthesia by facilitating concise parathyroidectomy surgery.
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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85% of cases, primary hyperparathyroidism is a result of a solitary
adenoma, with the remainder attributable to parathyroid hyperplasia
and, very rarely, parathyroid carcinoma (1). The diagnosis
of primary hyperparathyroidism relies on increased serum calcium values
in the presence of inappropriately high parathyroid hormone (PTH)
values in addition to clinical symptoms (1). In most cases,
the recommended therapy is parathyroidectomy (1). The
"classic" approach to surgical treatment has been bilateral,
open-neck exploration under general anesthesia with intraoperative,
frozen-section histopathologic examination of the parathyroid glands.
Historically, patients stayed an average of 24–48 h in the hospital
postoperatively (2), and failure rates for this approach
have been reported be >10% in some institutions (3).
Recent advances in surgical techniques have led to the use of concise
parathyroidectomy, which is performed with smaller, less invasive
incisions, leading to fewer postoperative complications (4).
However, even these minimal surgical approaches can require bilateral
exploration, overnight stays, and the use of general anesthesia
(4). Furthermore, the failure of standard intraoperative
frozen-section diagnosis to agree with definitive histology in up to
10% of cases can impact intra- and postoperative management
(5)(6)(7). Therefore, we sought an improved means of assessing
the intraoperative success of surgery to improve on the limitations of
intraoperative frozen section. Recently, we implemented two new technologies in an attempt to further simplify parathyroidectomy surgery and simultaneously decrease costs: preoperative 99mTc-sestamibi parathyroid imaging (8)(9)(10)(11) and a rapid intact PTH quantitative assay performed during the surgical procedure (12)(13)(14)(15). Preoperative 99mTc-sestamibi parathyroid scanning has been shown to identify adenomatous or hyperactive glands in up to 90% of cases (9)(10)(11), thus reducing the need for routine bilateral neck exploration (2). However, this approach can miss a second diseased gland present in 2–5% of patients (11). Rapid intraoperative PTH assays may circumvent this problem by serving as "biological frozen sections" (12)(16) to confirm removal of all hyperfunctioning parathyroid tissue. The 5-min half-life of intact PTH allows it to serve as a practical intraoperative marker, and previous studies suggested that a 50% decrease in PTH values from the presurgical value after removal of the diseased gland(s) reliably predicts postoperative normocalcemia (12)(13)(15). Previous studies have clearly shown that this approach leads to successful clinical outcomes, and some suggest that it can lead to decreased costs through less exposure to anesthesia, minimized reliance on frozen-section histology, and shorter hospital stays (17). However, the initial "intraoperative" PTH assay from Nichols has a per patient cost of $700 to $1000 (18) because of the nature of the assay design, which necessitates the use of an entire prepackaged reagent set (up to nine patient determinations) for an individual patient (14).
In this study we examined the performance of a new, less costly automated intraoperative PTH assay. We also asked whether use of the IMMULITE Turbo rapid PTH assay, in conjunction with preoperative imaging and concise parathyroidectomy, would lead to shorter hospital stays, decrease surgical pathology costs, and afford more anesthesia options for patients. We directly examined those outcomes, which had been hypothesized to improve after the institution of a rapid intraoperative PTH assay together with preoperative imaging, by comparing them with a previously described cohort at our institution that underwent concise, minimally invasive parathyroidectomies without intraoperative PTH determination (4).
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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statistical analysis
A two-tailed t-test assuming unequal variance was used
to test the significance of difference between plasma or serum calcium
and the number of frozen sections between the groups. A two-sample
Wilcoxon rank-sum test was also used to test significance of difference
among frozen sections. The Fisher exact test was used to calculate
P for other outcomes examined with STATA, Ver. 6.0.
standard immulite intact pth assay
The standard PTH assay was performed using the IMMULITE automated
analyzer, a solid-phase, two-site chemiluminescent immunometric assay
(DPC) according to the manufacturer’s recommendations. The solid
phase, a polystyrene bead enclosed within an IMMULITE Test Unit, is
coated with an affinity-purified goat polyclonal anti-PTH antibody
specific for residues 44–84. The soluble antibody is an
affinity-purified goat anti-PTH antibody specific for residues 1–34
that is conjugated to alkaline phosphatase. The assay has a 60-min
incubation and an analytical range of 5–1500 ng/L. For routine
analysis, collected tubes containing no anticoagulant are placed on ice
and transported immediately to the laboratory where the sample is
allowed to clot for 30 min and then centrifuged at 4 °C. If not
assayed immediately, serum specimens are frozen at -20 °C. Plasma
from blood samples collected in potassium EDTA tubes is also suitable.
The manufacturer’s stated reference range for PTH is 12–72 ng/L for
both IMMULITE methods examined here.
rapid intraoperative pth assay
The Turbo PTH assay was also performed on the IMMULITE automated
analyzer, using the same antibodies and assay configuration. The
"Turbo" mode of the IMMULITE uses different software, allowing more
rapid processing of results. When operated in the Turbo mode, standard
incubation assays cannot be performed simultaneously. The Turbo
IMMULITE PTH assay has an incubation time of 14 min and an analytical
range of 10–1200 ng/L (data not shown).
Samples are drawn in the operating room before incision and 10–12 min after excision of the suspected diseased parathyroid gland(s). After collection into potassium EDTA anticoagulant tubes in the operating room, samples are immediately transported to the IMMULITE operator in the main laboratory, where a 1-mL aliquot of whole blood is centrifuged for 60 s and the potassium EDTA plasma is transferred to IMMULITE sample cups. To accomplish maximum efficiency, the laboratory is notified by the surgical staff the day before the procedure to allow adequate time for preoperative calibration and running of quality-control samples. During surgery, the operating room calls the laboratory as the sample is drawn, and the sample is hand-delivered to the laboratory, which is one floor below the surgical unit.
plasma and serum calcium assays
Plasma and serum calcium concentrations were determined on one of
two instruments, the Dimension RxL (Dade Behring) or the Hitachi 747
(Roche Diagnostics), according to the manufacturers’ recommendations.
Both the Dimension RxL and Hitachi 747 calcium methods are
modifications of the calcium o-cresolphthalein complexone
reaction (19). Our reference interval for plasma and serum
calcium is 86–103 mg/L.
parathyroid scintigraphy
Parathyroid scintigraphy is performed by intravenous
administration of 20 mCi of 99mTc-sestamibi. The
equipment setup requires a gamma camera capable of single
positron-emission computed tomography (SPECT) acquisition, a
high-resolution collimator, and 140 keV with a 20% energy window. Ten
minutes after injection of the 99mTc-sestamibi, a
10-min anterior image of the neck and upper mediastinum is begun while
the patient is lying supine. After the immediate planar image, a SPECT
study of the neck and upper mediastinum is acquired. Two hours after
the initial injection, the SPECT images of the anterior neck and upper
mediastinum are repeated. The initial uptake of
99mTc-sestamibi in parathyroid and thyroid tissue
is attributable to the high blood flow to these organs. The clearance
of the tracer from thyroid tissue occurs more rapidly than from
parathyroid tissue (20)(21).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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. Although the Turbo assay is not as precise as the standard DPC
PTH assay, the Turbo assay clearly has suitable intrarun imprecision
(3.3–7.5%) for intraoperative use in detecting a >50% decrease in
serum PTH values. Regression analysis of potassium EDTA plasma values
from the DPC standard and Turbo PTH assays for 49 patients gave the
following equation: Turbo = 1.08 x standard - 4.36
(r = 0.97; Sy|x = 19.4; mean
x = 60.9; mean y = 61.5; Fig. 1
).
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patient and control group characteristics
Characteristics of the control and experimental populations are
shown in Table 2
. Preoperative calcium and PTH values were not statistically
different between the groups (Table 2
). Both groups also had similar
age, sex, and pathologic diagnoses. The pathologic diagnoses were
initially made by frozen-section analysis and confirmed by examination
of paraffin-embedded sections. It is important to note that the
designation of "hypercellular" is often used at our institution
when not all glands are available for examination. The most reliable
distinction between adenoma and hyperplasia is made only after
examining one or more glands in addition to an enlarged, hypercellular
gland (22)(23).
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Forty-four of the experimental group underwent sestamibi scans vs 9 in the control group. Of the five patients in the experimental group who did not have preoperative scans, one was a carcinoma patient who had emergency surgery because of hypercalcemia crisis, three were siblings with multiple endocrine neoplasia who had additional exploratory surgery, and one patient had renal failure with hypercellular glands. It is also important to note that the nine preoperative imaging studies in the control group were performed before the referral of the patients to the Department of Surgery. Of the patients with preoperative scans, 34 (77%) of the experimental group vs all 9 (100%) of the control group had positive scans. Four (9%) of the experimental group had negative scans, and six (14%) had an equivocal scan.
pth values
In the control group (n = 52), the preoperative PTH values
had a mean of 167.2 ng/L, a median of 113 ng/L, and a range of 43–1300
ng/L. PTH values performed at an outside institution were not available
for three patients. The mean preoperative PTH value of the experimental
group was 193.9 ng/L, the median was 117 ng/L, and the range was
58–1415 ng/L (Table 2
). In the one patient with "normal" PTH
concentrations, disease was confirmed by clinical symptoms, plasma
calcium values (calcium, 109 mg/L), and postoperative histology.
A total of 117 intraoperative PTH measurements were performed for these
49 patients. The mean number of intraoperative PTH determinations per
patient in the experimental group was 2.3, with a median of 2, and a
range of 2–5. The five determinations were performed in a patient who
had an equivocal preoperative scan and parathyroid glands that were
difficult to locate. The mean turnaround time for PTH results from
receipt of the sample in the laboratory was 19.6 min (median, 19 min;
range, 14–40 min; n = 112). Five samples were excluded from the
laboratory turnaround time analysis because they were entered into the
laboratory information system after centrifugation had begun, which
produced unlikely intralaboratory turnaround times of 
15 min. An
estimate of the length of surgery in this setting is the time from
receipt of the first preoperative sample to the last intraoperative
postresection result. In the experimental group, the mean turnaround
time was 60.0 min, the median was 48 min, and the range was 27–145 min
for 46 patients. The patient with parathyroid carcinoma, a patient sent
to the recovery room before the last PTH result, and a patient whose
pre- and postexcision samples arrived in the laboratory simultaneously
were excluded from this analysis.
Of the 49 patients in the experimental group, 46 had a >50% decrease
in their first postresection PTH value (Fig. 2
). Twelve patients had a second postresection PTH value
determined, 4 had a third postresection value, and 1 had a fourth. Of
these 12 patients, only 6 actually failed to exhibit a 
50% decrease
in PTH values in the first postresection sample (Fig. 2
). Three of
these six exhibited a 50% decrease in the third sample. Of the other
three, one patient had a 49% decrease, the parathyroid carcinoma
patient had only a 33% decrease, whereas another patient had only a
10% decrease in the final intraoperative PTH value. Subsequent removal
of additional hypercellular parathyroid glands was performed on this
latter patient without the use of the intraoperative PTH assay. These
patients emphasize the usefulness of the rapid PTH assay for indicating
incomplete surgery with the first postexcision value. For all patients,
the final postresection PTH mean was 40.9 ng/L (84% decrease), the
median was 26 ng/L, and the range was <5–231 ng/L (10–99%
decrease).
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Including the costs of quality-control materials, calibrators, and performing the quality-control and calibration assays, the direct cost to the laboratories was $51.32, $72.07, $92.82, or $113.57 for two, three, four, or five intraoperative PTH determinations per patient.
plasma and serum calcium concentrations
The mean serum or plasma calcium concentration for the
experimental population was 117 mg/L vs 113 mg/L for the control group
(P = 0.11; Table 2
). Two in the experimental group and
seven in the control group had preoperative serum and plasma calcium
concentrations within reference values. However, hyperparathyroidism
was confirmed for all nine by clinical symptoms, measurement of serum
PTH, and histology. All other patients had increased calcium values. Of
the 49 patients in the experimental group, 46 had a >50% decrease in
their PTH values (Fig. 2
), and 42 of these had postoperative calcium
values within reference values 1–9 months postoperatively (Table 3
). Four patients were hypocalcemic up to 7 months
postoperatively (77, 82, 84, and 84 mg/L). Thus, the predictive value
for a >50% decrease in intraoperative PTH value for normo- or slight
hypocalcemia was 100%. Three patients exhibited a <50% decrease
(Fig. 2
and Table 3
). One was the parathyroid carcinoma patient (33%
decrease), who remained hypercalcemic (137.0 mg/L) 9 months after
surgery. The other two patients were normocalcemic postoperatively and
exhibited a 49% and a 10% decrease in intraoperative PTH values. The
latter was the patient mentioned previously who underwent additional
neck exploration without additional intraoperative PTH values. There
was no statistical difference in postoperative calcium values between
the two groups (P = 0.48; Table 4
).
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frozen-section usage
The experimental group showed significantly less (P
<0.0001, Wilcoxon rank-sum; P <0.002, t-test)
frozen-section usage with a mean of 1.4 per patient vs 2.5 per patient
for the control group (Table 4
). The 95% confidence interval for the
mean difference (1.11) in frozen sections between the groups was
0.468–1.748. Furthermore, 10 patients in the experimental group had no
frozen sections of excised tissue, whereas all patients in the control
group had at least one frozen section performed.
surgical approach and type of anesthesia
In the experimental group, 33% of the patients had only local
anesthesia, whereas all patients in the control group received general
anesthesia (Table 4
). Furthermore, 65% of the patients in the
experimental group had a unilateral neck dissection vs none in the
control group.
length of hospital stay
Seventeen patients (35%) in the experimental group underwent
same-day surgery compared with none in the control group (P
<0.0001). In addition, fewer patients in the experimental group than
the control group had overnight hospitalizations or hospitalizations
>48 h (Table 4
).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The use of a rapid intraoperative assay to assess successful removal of the diseased gland(s), even without preoperative imaging, has been well established (13)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34). A >50% decrease in PTH values from the preresection intraoperative value 10 min after removal of the diseased gland is a strong predictor of successful surgery (12)(13)(15). Preoperative parathyroid imaging to enable minimally invasive or unilateral parathyroidectomy has shown success rates comparable to those for bilateral dissection in selected cases when the imaging results are unequivocal (35)(36)(37). The combination of both of these technologies has thus been suggested as a means to minimize pathology costs and to allow a simple surgical procedure and the option of local anesthesia. Other studies incorporating a rapid intraoperative PTH assay with ultrasound as the imaging technique (7)(12) or various combinations of scanning and localization techniques, such as the gamma probe (29), have also shown similar success. Although prior studies comparing the classic approach with techniques using preoperative scanning and intraoperative PTH determinations showed equivalent rates of successful surgery, few directly examined the impact of these added services on reductions in hospital stay, general anesthesia usage, frozen section analysis, and overall costs. One recent study (20) concluded that intraoperative PTH assays in conjunction with preoperative imaging did lead to shorter hospital stays and lower overall costs.
When we compared two groups of patients with similar sex, age, and
diagnoses, we found that 44 of 49 (90%) patients in the experimental
group and 49 of 55 (89%) patients in the control group achieved
normocalcemia postoperatively. Thus, the use of minimal excision
surgery with bilateral exploration and concise parathyroidectomy guided
by preoperative imaging and intraoperative rapid PTH assays had
identical physiologic outcomes. Confirming the hypothesis that the use
of these two technologies would lead to direct cost savings in surgical
pathology costs, we found that frozen-section usage of the experimental
group was significantly lower than that of the control group.
Furthermore, 10 of the 49 patients had no frozen sections performed. At
a cost of $203 (patient charge, $406) per frozen section, not including
the cost of analysis of permanent paraffin-embedded sections, the
combination of preoperative imaging, concise surgery, and
intraoperative PTH analysis led to an average savings of >$200 per
patient in surgical pathology costs alone. As surgeons become more
accustomed to using the intraoperative PTH assay, we expect that
frozen-section use will almost disappear when a >50% decrease in PTH
values is observed. Indeed, like others
(12)(13)(15)(17), we
found that a 50% decrease was essentially 100% predictive of curing
hypercalcemia.
The combined use of imaging and intraoperative PTH assays allowed 32 (66%) of the experimental group to undergo unilateral neck dissection in contrast to all patients having bilateral dissection before implementation of these technologies. The ability to offer these patients the choice of local or general anesthesia was directly related to unilateral surgery. In the experimental group, 16 of the 32 patients undergoing unilateral neck dissection chose the local anesthesia, thereby decreasing their overall costs. Particularly significant from a cost perspective was that all of the patients with local anesthesia and one with general anesthesia had same-day surgery vs none in the control group.
In conclusion, through the use of this new rapid PTH assay, we were
able to meet the turnaround-time demands of surgery, allowing removal
of diseased gland(s) in a cost-efficient and clinically successful
manner. The Turbo DPC PTH assay provides surgeons precise and accurate
PTH results in <20 min at a reagent cost that is $600 less per
patient than the original rapid PTH assay and leads to a frozen-section
savings of $200 per patient. Taken together, this cost-effective
intraoperative PTH assay, in conjunction with preoperative imaging,
helps facilitate simpler surgeries, the option of local anesthesia, and
shorter hospital stays when compared with minimally invasive surgery
without preoperative imaging and rapid intraoperative PTH assessment.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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probe detection, and the rapid parathyroid hormone assay to the surgical management of hyperparathyroidism. Arch Surg 2000;135:550-557.The following articles in journals at HighWire Press have cited this article:
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  S.-K. Meyer, M. Zorn, K. Frank-Raue, M. W Buchler, P. Nawroth, and T. Weber Clinical impact of two different intraoperative parathyroid hormone assays in primary and renal hyperparathyroidism Eur. J. Endocrinol., February 1, 2009; 160(2): 275 - 281. [Abstract] [Full Text] [PDF]
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 L. J. Sokoll, F. H. Wians Jr, and A. T. Remaley Rapid Intraoperative Immunoassay of Parathyroid Hormone and Other Hormones: A New Paradigm for Point-of-Care Testing Clin. Chem., July 1, 2004; 50(7): 1126 - 1135. [Abstract] [Full Text] [PDF]
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C. Bieglmayer, G. Prager, and B. Niederle Kinetic Analyses of Parathyroid Hormone Clearance as Measured by Three Rapid Immunoassays during Parathyroidectomy Clin. Chem., October 1, 2002; 48(10): 1731 - 1738. [Abstract] [Full Text] [PDF]
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 N. C. Lee and J. A. Norton Multiple-Gland Disease in Primary Hyperparathyroidism: A Function of Operative Approach? Arch Surg, August 1, 2002; 137(8): 896 - 900. [Abstract] [Full Text] [PDF]
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 P. C. Kao, J. A. van Heerden, D. R. Farley, G. B. Thompson, and R. L. Taylor Intraoperative Monitoring of Parathyroid Hormone with a Rapid Automated Assay that is Commercially Available Ann. Clin. Lab. Sci., July 1, 2002; 32(3): 244 - 251. [Abstract] [Full Text] [PDF]
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