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ENDOCRINE SURGERY
parathyroid surgery. Preoperative imaging has
a role not only to inform the choice between
traditional surgery and focused surgery but
also the choice between different surgical access
and between different minimally invasive techniques. In contrast to the surgeon performing
traditional parathyroid surgery 20 years ago,
today the parathyroid surgeon depends highly
on the quality of preoperative imaging studies
to make a judicious choice for the appropriate
indications for, and application of, the currently
available surgical techniques.
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18
Intraoperative PTH Monitoring
Denise Carneiro-Pla and George L. Irvin
Introduction
Sporadic primary hyperparathyroidism
(SPHPT) is caused by the autonomous hypersecretion of one or more parathyroid glands.
The only definitive treatment of this disease is
surgical excision of all hyperfunctioning parathyroid tissue. In the past decade, intraoperative parathormone monitoring (IPM), used to
guide the surgeon during parathyroidectomy,
has changed the operative management of
SPHPT.
IPM guided parathyroidectomy was first
introduced in 1990 and has since grown in
acceptance around the world. This technique
involves the rapid measurement of plasma parathormone levels during parathyroidectomy.
Changes in these hormone levels confirm the
extent of operative excision necessary to remove
all abnormal parathyroids while preserving in
situ other normally functioning glands. Several
rapid PTH determinations are done at the surgeon’s request and timed to coordinate the
changing hormone levels occurring with the
operative events taking place during parathyroidectomy. The understanding and use of these
intraoperative hormone dynamics has changed
the operative approach from a routine bilateral
neck exploration (BNE) with excision based on
the surgeon’s judgment of grossly enlarged
glands, to a quantitative excision based on the
hypersecretion of abnormal parathyroid tissue.
Intraoperative PTH monitoring is now being
used in many medical centers and is emphasized in current training programs. Knowledge
of this technique is expected by the board of
general surgery. There have been more than
400 published articles and numerous presentations at national and international meetings on
parathyroidectomy guided by intraoperative
PTH monitoring over the past 16 years. Currently, the use of this surgical approach is considered a standard of care by many surgeons.
The purpose of this chapter is to describe in
detail the protocol for intraoperative PTH monitoring and the usefulness of this adjunct during
parathyroidectomy for SPHPT. Although less
well defined, the use of IPM to treat hyperparathyroidism associated with other etiologies such
as secondary, tertiary, isolated familial hyperparathyroidism (IFHPT), parathyroid cancer, and
multiple endocrine neoplasia (MEN) syndrome
will be also described.
History
Human parathormone has been measured since
1968 but its intraoperative use was not practical
until 1988 when Nussbaum described a method,
using a two-site antibody immunoradiometric
assay (IRMA), which measured the intact molecule of parathormone (1-84) [1]. That same
year, his group demonstrated that serum PTH
levels decreased rapidly after excision of a
J.G.H. Hubbard et al. (eds.), Endocrine Surgery, Springer Specialist Surgery Series,
DOI 10.1007/978-1-84628-881-4_18, Ó Springer-Verlag London Limited 2009
253
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ENDOCRINE SURGERY
hyperfunctioning parathyroid gland. Blood
samples were collected during parathyroidectomy and measured by the IRMA after
the procedure. These investigators suggested
that an intraoperative parathyroid hormone
assay could be used to prevent operative failures [1, 2]. In 1990, Flentje et al. modified the
PTH assay by decreasing the laboratory turnaround time to one hour and attempted to use
it perioperatively [3]. The same group
described in detail the marked changes in
PTH levels observed during parathyroidectomy. Although they measured the PTH after
the completion of the operation, it was clearly
shown that PTH dropped after excision of the
abnormal parathyroid gland. That same year,
Chapuis, using Nussbaum’s assay, described
13 patients in whom he found that the PTH
level decreased more than 70% from a baselinevalueina20-minsampletakenaftergland
excision. In one patient, the PTH decrease was
only 38%, but he stated that the preoperative
PTH level was close to the upper limit of the
normal range and his hypercalcemia was
transient [4]
Later, a study was published describing the
use of a rapid intraoperative PTH measurement using an IRMA [5]. Parathyroidectomy
guided exclusively by IPM was described in
1991, and a BNE was found to be unnecessary
since a marked decrease in the serum PTH
level confirmed complete excision of all hyperfunctioning glands resulting in operative success [5]
In 1996, the technical advantages of
immunochemiluminescence over the immunoradioisotopic methods for hormone measurement were pointed out, and the ‘‘quick’’
PTH assay became commercially available
for intraoperative use. At the present time,
there are at least four PTH assays with capabilities for intraoperative use having turnaround times ranging from 8 to 20 minutes.
The cost of these parathyroid hormone
assays for intraoperative use has decreased
over time and along with several clinical
benefits from its incorporation as a surgical
adjunct, such as shorter operative time,
ambulatory surgery, and a focused, limited
exploration resulting in an improved operative success rate, this adjunct has become a
cost-effective part of parathyroidectomy.
Which Patients Benefit from
Intraoperative PTH
Monitoring?
IPM has been extensively studied and proven to
be very accurate in predicting operative success
or failure in patients with SPHPT [6–14]. There
are studies that evaluate the use of IPM in
patients with MEN, parathyroid cancer, secondary, tertiary, and IFHPT, but the IPM accuracy
in predicting outcome in these patients has not
been fully established [14–23]
Sporadic Primary
Hyperparathyroidism
IPM was first designed to prevent operative failure due to overlooked multiglandular disease
(MGD) in patients with SPHPT. When used
intraoperatively, this surgical adjunct has been
shown to have an accuracy rate of 97–98% in
predicting postoperative calcium levels. However, when evaluating the accuracy of IPM, it is
paramount to point out that this methodology is
directly dependent on the criteria and bloodsampling times used during the parathyroidectomy. The protocol for blood sampling will be
described in detail in the next section.
The criterion used to predict postoperative
success, which is defined as eucalcemia for
6 months or more following parathyroidectomy, is a drop in the peripheral PTH level of
>50% from the highest either preincision or
preexcision level 10 minutes after all hyperfunctioning tissue has been excised and is called the
‘‘ >50% PTH drop’’ criterion in this chapter [24].
The long-term follow-up of patients with
SPHPT with parathyroidectomy guided by IPM
and fulfilling the criterion described above has
shown an operative success rate of 97% and a
late recurrence rate of 1.5% [8] These results are
similar to the best operative outcomes of parathyroidectomy performed with BNE and excision guided by parathyroid gland size and
histopathology. Furthermore, these excellent
operative success rates have been achieved
with a low incidence of multiple gland excision
(3%) [8]
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INTRAOPERATIVE PTH MONITORING
How does Intraoperative PTH
Monitoring Guide
Parathyroidectomy?
The technique for intraoperative PTH monitoring to guide parathyroidectomy is meticulous
and the success of this surgical adjunct depends
exclusively on the surgeons’ knowledge of PTH
dynamics and the protocol used during the
operative procedure.
Protocol for Blood Sampling
In the operating room or in the holding area, a
large bore catheter is placed in one of the upper
extremities, preferably in the antecubital vein.
The venous access should be tested for adequate flow after the upper extremities are positioned along the patient’s body. Often the
access will not be adequate after the patient is
positioned and since sample timing is critical,
it is important to assure that blood samples can
be drawn promptly during the operation. If
necessary, an arterial line can be used for this
purpose. After a good access is secured, an
intravenous extension is used to allow the
anesthesiologist to draw blood using a 3-way
stopcock at specific times to be determined by
the surgeon. It is very important to discard
10cc of blood before the sample is collected
for PTH measurement to avoid sample dilution
caused by the saline in the IV tubing. Blood
sample dilution can cause a false PTH reading,
for example, if the 10-minute sample is diluted
resulting in an incorrect lower PTH level, this
could result in a false PTH percentage drop
potentially causing an operative failure. On
the other hand, if the two initial plasma samples are diluted, the 10-minute PTH level might
not drop properly potentially leading to unnecessary further neck exploration. The blood
samples should be placed in an EDTA tube
and shaken to avoid coagulation.
The first sample is called ‘‘preincision’’ and
should be taken before cervical incision is made
or when intravenous access is obtained. All
samples should be measured in the same conditions, with the same PTH kits and curve calibrations. Plasma samples measured in the initial
work-up or by a previous standard laboratory
assay cannot be used to calculate the intraoperative PTH changes.
The second sample to be drawn is called
‘‘preexcision,’’ and it is collected just before the
suspected abnormal gland’s blood supply is
clamped. This sample is very important especially in cases where manipulation of the abnormal parathyroid gland increases the PTH level
significantly. A preexcision level collected too
early in the dissection could potentially miss the
peak of PTH level as a result of further manipulation of the abnormal parathyroid gland. This
could potentially lead to a false-negative result,
meaning the PTH level will not drop sufficiently
(<50%) due to a missed peak of the hormone
level. Therefore, it is important to take the sample just before the complete blood supply of the
parathyroid gland is interrupted. Often this
level has already dropped significantly from
the preincision level, which signifies that the
abnormal parathyroid gland blood supply was
already disrupted and the PTH level has already
decreased. This is the reason the preincision
and preexcision samples should be obtained in
every procedure in order to correctly calculate
the >50% drop (Fig. 18.1A,B). The third sample
is taken 5 minutes after the gland is excised.
This sample is not crucial for the decision making, but some surgeons use this sample to proceed with the closure of the cervical incision in
cases where thePTH has already dropped >50%
from the highest of the two previous samples.
This measurement helps to shorten the operative time with the 10-minute sample assuring
the complete excision of all hypersecreting
tissue.
The final sample is collected 10 minutes after
gland excision. A sufficient decrease in this
sample allows the surgeon to finish the procedure without further exploration or visualization of the remaining normally secreting glands.
On the other hand, if the hormone level fails to
drop, it signals that more hypersecreting tissue
is likely present. The surgeon is thus directed to
continue the exploration, with samples collected after each additional suspected tissue is
excised until the PTH drops adequately. The
same protocol above described with 5- and
10-minute sample measurements should be
used for each suspicious tissue excised until all
abnormal parathyroid glands are removed. We
256
ENDOCRINE SURGERY
Fig. 18.1. Graphic showing the intraoperative PTH dynamics of two patients with successful parathyroidectomies following
excision of a single hypersecreting parathyroid gland. This shows why preexcision (A) and preincision (B) samples are needed
to calculate the drop in the PTH level 10 minutes after gland excision. (A) Insufficient PTH drop in 10 minutes from the
preincision level (38%). (B) Insufficient PTH drop in 10 minutes from preexcision level (20%). A is adapted from Irvin GL,
Carneiro-Pla DM, Solorzano CC. Intraoperative parathyroid hormone assay-guided parathyroidectomy. In: Fisher JE, Bland KI,
eds., Mastery of surgery, 5th ed. Philadelphia: Lippincott, Williams & Wilkins, 2007.
may collect a sample at 20 minutes after a gland
excision when the 10-minute level has only
dropped between 40 and 49% from the highest
value. If at 20 minutes the PTH drops sufficiently, the operation is completed. On the
other hand, if at 10 minutes there is an insignificant PTH drop, continued exploration of the
neck is done without collecting the 20-minute
sample.
Some surgeons prefer to use different sites
for blood collection other than peripheral vessels, which usually are the internal or external
jugular veins, while others use various protocols
with different blood sample timings such as
15, 20, or 30 minutes post excision [25–27].
There are protocols that use only one sample
before the parathyroid gland is excised, either
preincision or preexcision usually called ‘‘baseline level’’ [29–34]. The consequences of these
variations will be described in the following
section, but it is important to be aware that it
can potentially affect the accuracy of IPM in
predicting complete excision [24].
Calculation of IPM Accuracy
Using the ‘‘>50% PTH Drop’’
Criterion
The accuracy of IPM using the ‘‘>50% PTH
drop’’ criterion in predicting postoperative calcium levels was determined using these definitions (Table 18.1): True positive (TP) is defined
257
INTRAOPERATIVE PTH MONITORING
Table 18.1. Definitions used to calculate the accuracy of ‘‘>50% PTH drop’’ criterion in predicting
postoperative calcium levels for at least 6 months
‘‘ >50% PTH drop’’ criterion
>50% PTH drop 10
<50% PTH drop 10
´
´
Operative success
(eucalcemia for 6 months )
True positive False positive
False negative True negative
Operative failure (high
calcium + high PTH <6 months)
when the intraoperative PTH level drops >50%
from the highest initial value 10 minutes after
gland excision and the patient is eucalcemic for
at least 6 months; true negative (TN) is defined
when the PTH fails to drop >50% and another
hyperfunctioning gland is found or the patient
has persistent HPT (hypercalcemia and high
PTH level within 6 months of the operation).
False negative (FN) is present when the PTH
does not drop sufficiently in 10 minutes and
the patient is eucalcemic for at least 6 months
without any additional parathyroid gland excision; false positive (FP) is when the PTH meets
the criterion for cure but the patient is hypercalcemic postoperatively.
Which IPM Criteria Should be
Used?
It is important to emphasize that all rapid
intraoperative PTH assays only measure parathormone plasma level at a specific point in
time. The variable that determines the accuracy
of IPM is the criteria applied to the intraoperative PTH levels and the protocol used, not the
intraoperative assay itself. It is important to
clarify this fact since there are many studies
that question the validity of IPM in guiding
parathyroidectomy, when the only variable in
question is the methodology and the intraoperative criteria used to predict a specific outcome
[28–33].
The criteria described in this chapter, the
‘‘ >50% PTH drop’’ criterion, which has been
used with excellent results for the past 15 years,
is a drop in the peripheral PTH level 50% from
the highest value, in either the preincision or the
preexcision sample, 10 minutes after all hyperfunctioning tissue is excised. This specific drop
predicts postoperative calcium levels with an
accuracy of 98% correctly assuring operative
success [24].
The surgeon’s decision of which IPM criteria should be used has recently become controversial leading to studies that described the
accuracy of various IPM criteria in predicting
operative success. To determine which criteria
have the best accuracy in predicting postoperative calcium levels, we have described a careful
comparison between the intraoperative criteria
available in the literature and our 341 consecutive parathyroidectomies that were guided
exclusively by the ‘‘>50% PTH drop’’ criterion
which requires the least PTH drop to predict
cure [24]. The other referenced criteria were
more strict using in addition to the >50% PTH
drop: (1) a return of PTH to the normal range
at 10 minutes, (2) final PTH value below
the preincision level, (3) drop of >50% from
only the preincision, or (4) drop of >50% from
only the preexcision level. The overall accuracy, positive and negative predictive value
of these criteria, and the incidence of TP, TN,
FP, and FN of each one of them are shown in
Tables 18.2 and 18.3. These results were deter-
mined based on the postoperative outcome of
patients with parathyroidectomy guided by the
least strict criterion. All patients had 6 months
or longer follow-up (average 33, range 6–105)
and all operative failures were included in the
study. The patient selection and their postoperative outcome confirmed the real incidence of MGD in this population. Patients
who were eucalcemic for at least 6 months
with only one gland excised were considered
to have single gland disease and the ones who
had more than one hyperperfunctioning parathyroid gland identified either by IPM or by
operative failure after single gland excision
were considered to have MGD. As shown in
Table 18.3,usingthe‘‘>50% PTH drop’’ criter-
ion which was the least strict of all criteria
studied, MGD was missed due to FP IPM
results in three (0.9%) patients. Unnecessary
further neck exploration could have been
potentially done due to FN results in another
ENDOCRINE SURGERY
Table 18.2. IPM accuracy in predicting postoperative calcium levels with different criteria [24]
Negative
Specificity
(TN/
TN + FP)
Positive predictive
value (TP/TP + FP)
IPM criteria
‘‘ >50% PTH drop’’
Sensitivity
(TP/
TP + FN)
97% 96% 99% 88% 97%
criterion:
50% from highest
0
at 10
(1) 50% from preinc.
0
at 10
(2) 50% from highest
0
+ within NR
at 10
(3) 50% from highest
0
+ below
at 10
83% 99% 99% 56% 86%
75% 98% 99% 42% 79%
94% 97% 99% 77% 95%
preinc.
(4) 50% from highest
0
at 5
(5) 50% from preexc.
0
at 10
TP, true positive; TN, true negative; FP, false positive; FN, false negative; preinc., preincision; NR, normal range; preexc., preexcision.
Reprinted from Surgery, vol. 134, Carneiro DM, Solorzano CC, Nader MC, Ramirez M, Irvin GL 3rd, Comparison of intraoperative iPTH assay (QPTH)
criteria in guiding parathyroidectomy: which criterion is the most accurate?, 973–9; discussion 97–81, Copyright 2003, with permission from
Elsevier.
88% 97% 99% 64% 90%
85% 97% 100% 58% 87%
predictive
value (TN/
TN + FN)
Overall accuracy (TP + TN/
TP + TN + FP + FN)
258
2.6% of patients. This criterion had a low incidence of FP and the lowest incidence of FN
results therefore presenting with the highest
overall accuracy in predicting postoperative
calcium levels [24].
Table 18.3. Incidence of false-positive and false-negative
results when using different criteria compared to the
‘‘ >50% PTH drop’’ criterion
FP
IPM criteria
>50% PTH drop: 50% from highest at 10
(1) 50% from pre-inc. at 10
0
(2) 50% from highest at 100+ within NR 0.4 24
(3) 50% from highest at 100+ below
pre-inc.
(4) 50% from highest at 5
(5) 50% from pre-excision at 10
FP, false positive; FN, false negative
*Statistically significant p value <0.05; NR, normal range. Adapted
from Surgery, vol. 134, Carneiro DM, Solorzano CC, Nader MC,
Ramirez M, Irvin GL 3rd, Comparison of intraoperative iPTH assay
(QPTH) criteria in guiding parathyroidectomy: which criterion is the
most accurate?, 973–9; discussion 979–81, Copyright 2003, with
permission from Elsevier.
0
0
0
(%)FN(%)
0.9 2.6
0.3 16
0.6 6
0.6 11
0.6 15
Others have used a similar study design to
analyze which criteria have the best accuracy
[34–36]. These studies have suggested that
IPM with the ‘‘>50% PTH drop’’ criterion was
not accurate in predicting operative success
because a more strict criteria was used intraoperatively to guided the surgeon to further
exploration and another enlarged parathyroid
was found and excised. These authors claimed
that the ‘‘>50% PTH drop’’ criterion failed to
show the presence of MGD in 43% of these
patients which were identified as having more
than one enlarged gland by the use of a more
*
strict criteria (additional intraoperative drop to
*
the normal range or below preincision). If the
*
‘‘ >50% PTH drop’’ criterion fails to identify
MGD as suggested by theses studies because
*
an additional enlarged gland was found, a
*
higher incidence of operative failure should be
present when the ‘‘>50% PTH drop’’ criterion is
used. The operative failure rate with the ‘‘>50%
PTH drop’’ criterion is only 3% which was often
predicted intraoperatively. These failures were
usually not caused by missed MGD, but inability
to find and excised the abnormal gland(s) [6–8,
24]. To support these operative results, other
259
INTRAOPERATIVE PTH MONITORING
published outcomes from various centers that
use the same criterion do not show a higher
incidence of operative failure due to missed
multiglandular disease [9–14, 37, 38]. Therefore, the incidence of MGD when a more strict
criteria is used should be questioned. Indirectly,
we can conclude that those additional glands
found and excised in patients subjected to
more strict criteria were not autonomously
hypersecreting since they were not excised in
our patients, because the ‘‘>50% PTH drop’’
criterion was met, and these patients were successfully treated.
Since operative failure using the ‘‘>50% PTH
drop’’ criterion is not higher, some predict that
these enlarged glands left in situ would cause a
higher incidence of early recurrent HPT. When
the incidence of recurrent HPT was studied, this
condition occurred in 1.5% of the patients followed over an average of 3years which is similar
to the published recurrent disease incidence in
patients that underwent BNE (1.5–5%) [8].
Clark et al., in an important study, described
the results of a randomized trial in which
patients were treated with BNE with resection
of all enlarged glands or limited parathyroidectomy guided by IPM. The patients from the IPM
group, in whom parathyroidectomy was guided
by parathyroid function had a lower incidence
of MGD (15% less), suggesting that maybe the
additional enlarged glands removed during
BNE were not hyperfunctioning [38]. The published operative outcome of patients with parathyroidectomy guided by IPM and the ‘‘>50%
PTH drop’’ criterion shows that these additional
‘‘enlarged’’ glands were not hyperfunctioning
at the time of surgery, and so far they are not
autonomously hypersecreting causing hypercalcemia now averaging 4 years after
parathyroidectomy.
Additional Uses and
Advantages of the
Intraoperative PTH Assay
Differential Internal Jugular Venous
Sampling
This technique, which is positive in 70–76% of
cases, can guide the surgeon to the side of the
neck harboring the hypersecreting parathyroid
gland when the preoperative localization studies are negative or equivocal [39–41]. Samples
from the internal jugular and peripheral veins
are taken before skin incision for rapid PTH
measurement. Figure 18.2 demonstrates a positive differential jugular venous test in a patient
with a right-sided hypersecreting parathyroid
Fig. 18.2. Positive jugular venous sampling performed in the operating room guiding the surgeon the side of the neck harboring
the hypersecreting parathyroid gland in patient with negative MIBI scan allowing successful unilateral neck exploration. Reprinted
with modification from Operative Techniques in General Surgery, vol. 1, Irvin GL III, Carneiro DM. Rapid parathyroid hormone assayguided exploration, pp. 18–27, Copyright 1999, with permission from Elsevier.