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.Original.
CHANGES IN INTRAOPERATIVE DETERMINATION OF PTH, TOTAL
SERUM CALCIUM AND
IONIZED CALCIUM ON
SURGERY FOR PRIMARY
HYPERPARATHYROIDISM DUE TO SINGLE ADENOMA. DÍAZ - AGUIRREGOITIA, Francisco Javier * MD, PhD. DE LA QUINTANA, Aitor **, MD. GAZTAMBIDE , Sonia*** MD, PhD. BUSTURIA Maria Angeles.**** MD. PÉRDIGO, Luis F.*
MD. ECHENIQUE ELIZONDO, Miguel *, MD, PhD, FACS Institutional Affiliations: (*) Department of Surgery, Radiology an
Physic Medicine. San Sebastián. Guipuzcoa.
Basque Country University. Spain (**) Department of Surgery.. . Cruces’
Hospital. Vizcaya. And Department of Medicine. Basque Country University.
Spain. (***) Department of Endocrinology.
Cruces’ Hospital. Vizcaya. And Department of Medicine. Basque Country
University. Spain. (****) Department of Chemistry. Cruces’
Hospital. Vizcaya. Spain Correspondence ECHENIQUE ELIZONDO, Miguel MD, FACS Basque Country University. School of
Medicine P. Dr. Beguiristain, 105 20014 San Sebastian. Spain Email: gepepcelm@sc.ehu.es Phone +34-932017319 Fax +34-943017330 ABSTRACT Background: In the
setting of minimal approach Sestamibi-guided parathyroid surgery (PTS) for
primary hyperparathyroidism (PHP) we evaluated total serum calcium (TSC) and ionized calcium (IC)
kinetics and its correlation with
intra-operative iPTH monitoring. Design: Prospective
open single-blinded efficacy trial of three intraoperative (i.o.) diagnostic
monitoring methods (iPTH , TSC and IC) on a cohort of surgical patients. Patients: All patients
(n=279 - 244 valid for the study -) undergoing PTS at the Department of
General Surgery B. Cruces’ Hospital. Vizcaya from October 1999 to April 2006. Main outcome
measures: Kinetics of serum calcium, ionized calcium and iPTH during surgery and time of
prediction of cure for each method (measured in the clinic, admission, and
intraoperatively such as induction of anesthesia, and every 5 minutes after
removal of adenoma) were analyzed. Results:
Hypercalcemia and iPTH levels became corrected in 243 patients. Average iPTH
levels dropped from preoperative pathological values 294.43 +
286.38 pg/mL (mean±sd) (reference values:10-5 pg/mL) to 97.89 +
121.01 mg/dL (mean±sd) at the first i.o.determination
(minute 5), 58.58 + 58.37 pg/mL (mean±sd), second i.o. determination (minute 10), 44.62 + 54.77 pg/mL (mean±sd) at the third i.o. determination (minute
15) and 38.4 2 + 51.72 pg/mL
(mean±sd ) at fourth i.o.
determination (minute 20). Total serum calcium levels dropped from
preoperative values 10.93 + 1.04 mg/dL (mean±sd) to 10.2 + 0.97 mg/dL (mean±sd)
(reference values: 8.1-10.4 mgrs/dL)
at the first i.o. determination (minute 5),
10.17 + 1.00 pg/mL (mean±sd ) at the second i.o. determination (minute
10), 10.12 + 0.98 pg/mL (mean±sd ) at the third i.o.
determination (minute 15) and 10.09
+ 1.03 pg/mL (mean±sd ) at fourth i.o. determination (minute
20). Ionized calcium levels varied from
4.90 + 0.63 mg/dL (mean±sd) (reference values:3.9
– 4,7 mgrs/dL) at induction time to 4.84 + 0.61 mg/dL (mean±sd), at the first i.o. determination (minute
5), 4.84 + 0.66 mg/dL (mean±sd) at second i.o.
determination (minute 10), 4.82 + 0.63 mg/dL (mean±sd)
at the third i.o. determination (minute 15) and 4.82 + 0.63 pg/mL (mean±sd
) at fourth i.o. determination (minute 20). Frozen sections were conclusive for
parathyroid tissue (19.56 +
15.3 minutes after removal). Conclusions:
Intraoperative measurement of total calcium level might be of help for
predicting adequate parathyroid removal at the time of surgery when no iPTH
determinations are available. Ionized calcium does not show the same descent
pattern. INTRODUCTION Prevalence
studies of primary hyperparathyroidism (PHP) report that 0.2-0.5% of the
population in Western countries suffer this disease, which is more prevalent
in women than men (3/1) and in elderly patients (154/100,000 inhabitants)
(1,2). Primary
hyperparathyroidism etiology is commonly associated with parathyroid adenoma
but it might be caused by parathyroid hyperplasia, even in the setting of
multiple endocrine neoplasia type I (MEN I) and carcinoma (3). The gold
standard of surgery for PHP has been until the early 1990’s bilateral
cervical exploration, but the increasing sensitivity and specificity of
diagnostic methods such as Sestamibi scan alone (4) or in combination with high
resolution ultrasound (5) have moved this standard surgical approach to the
less aggressive unilateral surgical approach (6) or even the minimally
video-assisted parathyroidectomy (7). Furthermore, at the end of
the 1980’s (8) and during the 1990’s some endocrine surgeons (9-10) used
systematically intraoperative determinations of parathyroid hormone (PTH) in
order to evaluate the efficacy of the surgical procedure for correcting the
increased levels of PTH induced by the disease (11). But this technology is
not available in all Hospitals and in most of
third world countries. Minimal surgical approach with intraoperative
determinations of iPTH has become an ordinary procedure for single adenoma
(12), geriatric patients (13) and also accepted as an ambulatory procedure in
selected cases (14). Purpose of the work
Final purpose
of parathyroid
surgery (PTS) is to not only localize and remove the pathological
gland or glands decreasing therefore the levels of PTH but normalize abnormally increased calcium
levels induced by the augmented secretion of PTH. In the setting of minimal
approach Sestamibi-guided parathyroid surgery for PHP we wanted to study if
total serum calcium level (TSC) and ionized calcium (IC) monitoring could be
as effective as intraoperative parathormone (iPTH) monitoring, a method
commonly considered as the new standard in order to evaluate the efficacy of
surgical procedures for treating primary hyperparathyroidism. PATIENTS AND
METHODS
Design
Prospective open
single-blinded efficacy trial of two intraoperative diagnostic monitoring
methods (iPTH and TSCL) on a cohort of surgical patients. There was a control
group of 25 patients undergoing a hemithyroidectomy whose parathyroid glands
were identified and preserved. Setting
University
referral center with an Endocrine Surgical Unit and specialized Endocrine
Biochemistry Unit. Patients
From January
2000 to April 2006 279 patients, 199 females and 80 males, age 62.5 +
8.9 (mean±sd) years seen in the Department of Endocrinology were diagnosed
with PHP whose etiology were adenoma. Laboratory criteria for PHP diagnosis
and results in these patients: were hypercalcemia
(10.93 mg/dL ± 0.59; normal 8.1-10.4 mg/mL), increased levels of parathyroid
hormone (294 ± 286,38; normal 10 – 65 pcg/mL) in the absence of renal disease
certified with normal levels of creatinine (0.87 mg/dL ± 0.45; normal 0.5-1.1
mg/dL) and urea (41.12 mg/dL±10.21; normal 10-50 mgrs/dL). We excluded
patients with negative pre-operative localization by Sestamibi or ultrasound,
patients with hyperplasia and/or MEN I. Also were excluded after surgery 16
cases because of parathyroid hyperplasia, 13 patientes presenting double
adenomas, 2 cases of familial hypercalcemia, 1 patient with parathyroid
carcinoma and 1 patient with parathyromatosis because of recurrent
hyperparathyroidism. Thus the 244
cases included in the study were clearly defined parathyroid single
adenomas. All patients were included
in a prospective trial approved by the Hospital Ethics Committee and signed
an “had hoc” consent for the
procedure. Methods included in the trial did not increased morbidity or operative time. Localization
of parathyroid adenoma
Sestamibi scan was performed
in all patients. In 230 patients ultrasound was also employed in order to
evaluate in a different clinical trial the efficacy of ultrasound in PHP
localization. MIBI-scan preoperative location of adenoma was achieved in
235/244 (96.5%) patients. Only one patient (a parathyroid reoperation in a
laryngectomized patient) whose adenoma was not successfully found by the
Sestamibi scan, was found on us examination. Surgical
procedure
Patients were
admitted to the Hospital on the same day of operation. Surgery was performed
under general anesthesia and oro-tracheal intubation. An abbreviated Kocher’s
incision 2 to Aliquots
All aliquots
were taken from a peripheral vein placed in the other extremity to the one
used for anesthetic iv. management. Six aliquots were taken from each patient
and recorded following a protocol: the first at hospital admission, the
second during anaesthesia induction or at cut time (minute 0) and four
determinations every five minutes after adenoma removal (5,10,15 and 20
minutes). From every sample iPTH, total serum calcium and ionized calcium
levels, proteins and albumin were assayed by two different teams: One was devoted to iPTH measurement and
communicated their results to one of the surgeons while the other team was
specifically dedicated to calcium and protein assays and communicated their
results to the other surgeon of the team. Adenomas were
sent to the Pathological Department to confirm the presence of adenomas or
simply of parathyroid tissue. As soon as results were available, the surgical
team was notified. Intra-operative Assays
iPTH determination was done
using a chemoluminiscent immunometric technique. After the incubation of two
antibodies against PTH, one of them linked to a ball of
polystyrene molecule recognizes the corresponding fragment to 44-84
aminoacids. The other antibody is marked with phosphatase alkaline and
recognizes the fragment 1- For albumin, protein and
calcium levels, a standard The mean life
of iPTH is about 3-5 minutes (17) and a decrease of 50% of PTH values at
minute 10 after adenoma removal is related to successful surgical treatment
(18,19). Main
outcome measures
1-
Kinetic levels of Calcium, Ionized Calcium and PTH
(measured at admission, and intraoperatively during induction of anesthesia
or at cut time, and every 5 minutes after removal of adenoma). Statistical
analysis
All results are expressed as
mean ± standard deviation. Values of each method were determined in every
time interval and the kinetic levels are therefore time dependent. In order to compare kinetic
levels of iPTH, TSC and ionized Calcium repeated measures ANOVA analysis was
performed. RESULTS
Surgical
procedures
The study group included 244
patients and hypercalcemia and PTH levels were successfully corrected in 234
(95.9%). Unilateral exploration was performed in 229/244 patients. The
remaining four required a more invasive exploration due to
suspicious (not confirmed) multiglandular
disease, need of a hemithyroidectomy for goiter (1
case) and an extensive surgical exploration in the patient in which adenoma
removal was unsuccessful (a parathyroid reoperation in a laryngectomized
patient) with false positive ultrasound. Mean time for removal of
adenoma was 32.26 (±11.3) minutes, and the patient was in the operative field
an average of 55.49 minutes (± 17.23) minutes. Hypercalcemia
and iPTH levels became corrected in 234 patients in the immediate
postoperative period. Average iPTH levels dropped from preoperative
pathological values 294.43 + 286.38 pg/mL (mean±sd) to 97.89 +
121.01 mg/dL (mean±sd) at the first i.o.determination (minute 5), 58.58 +
58.37 pg/mL (mean±sd), second
i.o. determination (minute 10), 44.62 +
54.77 pg/mL (mean±sd) at the
third i.o. determination (minute 15) and
38.4
2 + 51.72 pg/mL (mean±sd ) at fourth i.o. determination (minute 20). Total serum
calcium levels dropped from preoperative values 10.93 + 1.04 mg/dL (mean±sd)
to 10.2 +
0.97 mg/dL (mean±sd)
at the first i.o. determination (minute 5),
10.17
+ 1.00 pg/mL (mean±sd )
at the second i.o. determination (minute 10), 10.12 + 0.98 pg/mL (mean±sd )
at the third i.o. determination (minute 15) and 10.09 + 1.03 pg/mL (mean±sd ) at
fourth i.o. determinati(reference values:3.9 – 4,7 mgrs/dL) on (minute 20).
Ionized calcium levels dropped from 4.90 +
0.63 mg/dL (mean±sd) at induction time to 4.84 + 0.61 mg/dL (mean±sd),
at the first i.o. determination (minute 5), 4.84 + 0.66 mg/dL (mean±sd) at second i.o. determination
(minute 10), 4.82 + 0.63 mg/dL (mean±sd) at the third i.o. determination
(minute 15) and 4.82 +
0.63 pg/mL (mean±sd ) at
fourth i.o. determination (minute
20). Frozen sections were conclusive
for parathyroid tissue on resected specimens (18.36 + 19.4 minutes
after removal). Calcium
levels
Total mean calcium serum levels (TCS) dropped from preoperative values
of 10.93 +
1.04 mg/dL (mean±sd) to 10.2 + 0.97 mg/dL (mean±sd) at the first i.o. determination
(minute 5), 10.17 + 1.00 pg/mL (mean±sd
) at the second i.o. determination
(minute 10), 10.12
+ 0.98 pg/mL (mean±sd ) at the third i.o. determination (minute
15) and 10.09 + 1.03 pg/mL (mean±sd )
at fourth i.o. determination (minute 20). At that
time, as shown in Figure 1, repeated measures ANOVA showed a significant
difference ( p= 0.034) when compared to basal values. When basal values where
compared to those seen in minute 10, similar analysis yielded a p = 0.03. We realize that mean calcium level is close normal values at the time of
induction of anesthesia; this is because some patients were almost
normocalcemic, and haemodilution may explain this event although patients
presented the whole hyperparathyroidism
syndrome. The fall of TSC five minutes
after removal was at least 50% in
all patients whose adenoma, double adenoma, carcinoma or parathyromatosis
were found and whose calcium values remained normal in postoperative determinations in the follow-up.
Although not considered in this study patients with double adenoma, after the second adenoma was removed, TSC dropped as in single
adenoma, but there was no change in total calcium level until that moment. Protein and albumin levels
did not affect the results of amount of TSC measured in the intraoperative
aliquots, although we have observed isolated decreases in total protein levels during surgery. There were no
significant modifications of mean TSC values in the control group patients: (9.5 ± 0.31
mg/dL at minute 0; 9.3± 0.44 mg/dL at minute 5; 9.4 ± 0.66 mg/dL at minute
10). iPTH levels
Mean iPTH showed a decrease
from pathological (294.43 ± 286.38 pg/mL) to normal values (44.62 ± 54.77
pg/mL) during the fourth intra-operatory determination (minute 15) (Figure
2), although a reduction of 50% was observed at the second
determination (minute 5). There were no significant
modifications of iPTH in control group patients: (56,47 ± 18,02 pg/dL at
minute 0; 53,6 ± 12,56 pg/dL at minute and 52,54 ± 86 pg/dL at minute 10). In
patients with double adenoma iPTH did not drop by at least 50% until the second adenoma was removed. Ionized
Calcium levels
No significant differences were observed in the sequence of aliquots determinations
for ionized calcium: 4.90 +
0.63 mg/dL (mean±sd) to 4.84 +
0.61 mg/dL (mean±sd), 4.82 + 0.63 mg/dL (mean±sd), at the first i.o. determination
(minute 5), 4.84 + 0.66 mg/dL (mean±sd) at second i.o. determination (minute
10), 4.82 + 0.63 mg/dL (mean±sd) at the third i.o. determination
(minute 15) and 4.82 + 0.63 pg/mL (mean±sd ) at fourth
i.o. determination (minute 20).
Figure 3
Pathological findings
Intraoperative pathological
findings confirmed that adenomas were removed successfully in 234 out of 244
cases and on a later stage the 10 remaining. Definitive pathological
diagnosis was made an average of 18.36 + 19.4 minutes after surgical
removal. Mean weight of adenoma was 417.53 ± 560.14 mgrs. Two resulted to be
microcystic adenomas and 3 oxyphilic adenomas. Thirteen patients were found
to have double adenomas. DISCUSSION
In a previous
publication (20) we encountered in a limited series of patients – n=35- that
total serum calcium levels dropped from previous elevated values in similar
way to iPTH descent and postulated that calcium determination could be
employed as a reference of propor parathyroid removal when intra-operative
iPTH determination is not available. However this
findings have resulted controversial and not supported by other researchers
(21) although employed methodology differs from ours. The purpose
of surgical treatment in PHP is to remove enough abnormal parathyroid tissue to reduce the
long-term destructive effects on bone as well as effects of high Calcium
and keep the patient normocalcemic. From 1930 to 1990 bilateral cervical
exploration of four glands was considered as the gold standard management for
PHP. A 95%-97% rate of success has been reported with this technical approach
(1,7, 19,22) but the operating time was excessively increased and the
hypocalcaemia rates remained near 15% (23). In the 1980’s, unilateral
cervical exploration was advocated by Wang and Tibblin (24,25). During the
1990’s the increasing accuracy of Sestamibi scan, preoperative ultrasounds
and intraoperative intact-PTH (6,26,27) measurement increased the number of
centers performing unilateral exploration avoiding nerve injuries, reducing
hypocalcemias, dropping hospital stay and increasing patient’s comfort. The accepted criteria for a
successful adenoma removal is a decrease of 50% of iPTH values at the minute
10 after adenoma removal and this was our intraoperative standard decision
making. Frozen section studies were used only to confirm the removed
parathyroid tissue. To our knowledge, there has not been published any intraoperative
calcium kinetic study in order to assure a normocalcemic status at the time
of removal of the adenoma. Although, McHenry et al, (28) reported in Whether
or not calcium levels could decrease at the moment of adenoma removal was one
of our questions at the time of the trial design but, as the controls showed
us, our hypothesis was more focused on deciding whether or not iPTH was
strictly necessary to assume that patients were cured with the removal of the
adenoma. As shown in figure 1, mean calcium levels became normal 5 minutes
after removal of adenoma and iPTH came into normal values 15 minutes after
removal of adenoma. Calcium monitoring could avoid the sophisticated iPTH
measurements and seems to be as reliable as iPTH. There is no doubt that it
is less expensive and might be used in non-reference centers. Perhaps
the changes of iPTH seen in the first determinations are due to manipulation
on the neck or over the adenoma or due to the anaesthesia employed (29). We would like to ask some
questions, even though we do not know the answers. Why do calcium levels decrease
so strikingly in the very beginning of adenoma removal? It has to be assumed
that circulating calcium can not be incorporated into bone structures so
quickly, and physiological mechanisms that could occur in such a reduced
relapse should not be advocated. Perhaps it is necessary to consider other
mechanisms apart from calcium metabolism (30) Parathyroid hormone is well
known as a modulating hormone of the tone of smooth muscle cells inducing
hypotension and vasodilatation in veins and arteries. In humans and some
animals parathormone induces hypertension (31,32) and it has been isolated a
vasopressor factor in parathyroid glands (33). Jiang et al. (34) proposed
that the vascular endothelial cells are the target for PTH and they express
its receptor. Nilsson et al. (35) have noticed paradoxical results in
endothelium-dependent vasodilatation (EDV) as in endothelium-independent
vasodilatation (EIDV) when stimulated with metacholine and sodium
nitroprusside respective in patients with PHP respect to the controls. These
authors (35) reported that endothelium is impaired in vasodilatation process
in patients with PHP and “the endothelial vasodilatory derangement is an
effect of the biochemical alterations…in patients with HPT
(hyperparathyroidism)…Endothelial vasodilatory capacity was normalized after
parathyroidectomy”. We
hypothesize that a rapid restoration of the endothelial dependent factors
could normalize the tone of arteries inducing a quick turn over of calcium in
the endothelial and smooth muscle cells of the body. Furthermore, the
hypothetical vasodilator effect post parathyroidectomy might cause some
hemodilution of ionic components of the blood might result inducing a
decrease in the levels of circulating calcium. These hypothesis have to be proven
by subsequent ongoing clinical and experimental trials on our departments. We conclude that intraoperative measurement of kinetic levels of
total serum calcium in parathyroid surgery for adenoma is a method easy to
perform, less expensive than iPTH monitoring and could become a safe
diagnostic procedure with similar efficacy to iPTH in predicting cure.
Similarly ionized calcium measurements shows no significant changes along all
determination series. Nevertheless,
further studies are needed to confirm our preliminary results. If iPTH
determination is available should be considered as the method of choice but
total serum calcium determination can be of help in the decision making
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Time 0 is induction anesthesia or cutting time. 5-20 are the sampling times
after surgical removal of the adenoma.
Figure 2 & 3: iPTH
levels at the time of surgery.
Time 0 is induction anesthesia or cutting time. 5-20 are the sampling times
after surgical removal of the adenoma. Prediction of cure is accorded as a
mean reduction of 50% of the iPTH (doted line concentration (at minute 5).
Figure 4: Ionized calcium levels at
the time of surgery. Time 0 is induction anesthesia.. 5-20 are the
sampling times after surgical removal of the adenoma.
Figure 5: Ionized calcium levels at
the time of surgery. Correlation between PTH and TCa descent ABREVIATIONS PHPT Primary hyperparathyroidism PTS Parathyroid surgery TSC Total serum calcium IC Ionized calcium Ipth Intact parathyroid hormone PTH Parathyroid hormone MIBI Technecium-99 sestamibi i.o. Intraoperative |
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Depósito Legal BI-8989-909
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