Keywords
corrected serum calcium - serum parathormone - thyroid surgery
Neurological injuries and hypocalcemia are the most common complications that can
occur after thyroid surgery. Although the incidence of these complications has been
steadily declining over the years, when they occur they can lead to serious morbidity
and occasional mortality as well.
Postoperative hypocalcemia is secondary to inadvertent removal of the parathyroid
glands or their devascularization during dissection. The incidence of hypoparathyroidism
after thyroid surgery has been reported to vary from 14 to 60% for temporary hypoparathyroidism
and 1.5 to 11% for permanent hypoparathyroidism.[1] Clinical manifestations of hypocalcemia may vary from perioral, hand, and foot numbness
to muscle spasm, depression, hallucination, weak and brittle nails and easily fracturing
bones. Furthermore, there are several confounding factors such as age, gender, vitamin
D status, pH of blood, thyroid function status, and pathology (benign vs. malignant),
which can affect postoperative calcium status besides the inadvertent damage to the
parathyroids.
The present study was undertaken to evaluate the serum levels of intact parathormone
(iPTH) and corrected serum calcium (CSC) in the immediate postsurgery period and in
the follow-up period up to 1 month after thyroid surgery.
Patients and Methods
This prospective observational study was conducted over a 3-year period from April
2017 to March 2020, during which 80 patients requiring thyroid surgery were recruited.
Out of these, 44 patients underwent hemithyroidectomy and 36 were subjected to total
thyroidectomy. The exclusion criteria for patient data accrual for this study were
the following:
-
Preoperative abnormal serum iPTH (<15 or >51 pg/mL).
-
Preoperative abnormal CSC level (<8.5 or >10.5 mg/dL).
-
Patient on calcium supplement.
-
Patient with abnormal thyroid function, renal function, and hypoalbuminemia.
The intent of including patients undergoing hemithyroidectomy was to demonstrate that
there were no extraneous factors, such as anesthetic agents or perioperative medication,
that could have influenced the iPTH and CSC levels.
The diagnosis of goiter was confirmed on the basis of clinical evaluation, thyroid
ultrasound, thyroid function test, and fine-needle aspiration cytology (FNAC). All
the patients had a preoperative measurement of the serum level of intact parathormone
(iPTH), CSC, and ionized serum calcium. Repeat evaluation of these parameters was
done 1 hour, 1 day, 1 week, and 1 month after surgery.
For iPTH measurement, 2 mL of blood was collected in ice-cooled ethylenediaminetetraacetic
acid (EDTA) vial using an overnight ice-cooled syringe. The sample was immediately
centrifuged in a refrigerated centrifuge at 4°C and the lab estimation by chemiluminescence
method was done as quickly as possible. For ionic calcium, 1 mL of arterial blood
was collected in a heparinized syringe free of air. The ionic calcium estimation was
done by the ion-selective electrode (ISE) method used for arterial blood gas estimations.
CSC was estimated by the following formula: CSC = patient serum calcium (mg/dL) +0.8
(4-patient serum albumin in g/dL).
The normal lab reference range of the three parameters were the following:
Evaluation for clinical features of hypocalcemia was done by (1) asking patients about
the perioral and acral paresthesia, tingling, or numbness, (2) Trousseau's sign of
latent tetany, (3) Chvostek's sign, and (4) evidence of spontaneous carpopedal spasm
or generalized tetany. Trousseau's sign was elicited by inflating the blood pressure
cuff to pressure greater than systolic blood pressure and holding it for 3 minutes.
Spasm of muscles of the hand and forearm indicated a positive sign. Chvostek's sign
was elicited by tapping in front of the ear. Ipsilateral facial muscle spasm indicated
a positive sign.
The end point of the study was 1 month after the thyroid surgery at which time CSC,
iPTH, and ionic calcium levels were measured again. Values less than the lower limit
of reference range were considered hypocalcemic (<8.5 mg/dL of CSC or <1.0 mmol/L
of ionic calcium) or hypoparathyroid (<15 pg/mL of iPTH).
Observations
A total of 80 patients who underwent hemithyroidectomy (44) or total thyroidectomy
(36) over a 3-year period were included in the study. The mean age of the patients
was 43 years (range: 22–68 years) and the gender distribution was 19 males to 61 females
(M:F::1:3.2). All patients had a goiter and the preoperative diagnosis were the following:
(1) solitary thyroid nodule (n = 44); (2) multinodular goiter (n = 27); (3) well-differentiated thyroid cancer (n = 5), and (4) chronic lymphocytic thyroiditis (n = 4).
All patients underwent surgery under general anesthesia with muscle relaxation. The
salient features of the operative procedure were the following:
Among the 36 patients undergoing total thyroidectomy, we could reliably identify 1
or 2 parathyroid glands in 28 patients. On examination of the resected total thyroidectomy
specimen, we could identify one or two parathyroid glands in three specimens. However,
autotransplantation was not done in any of the patients because intraoperative preservation
of at least one parathyroid gland was demonstrated in the thyroid bed.
Among the 44 patients who underwent hemithyroidectomy, the mean baseline (preoperative)
iPTH levels were 35.6 ± 11.6 pg/mL. One hour after hemithyroidectomy, the mean iPTH
was 33.4 ± 10.2 pg/mL, which was a 6% drop over the baseline value. At 1 day after
surgery, the iPTH rebounded to 43.8 ± 9.8 pg/mL, it was 41.5 ± 10.4 pg/mL at 1 week,
and stabilized at 38.4 ± 9.1 pg/mL at 1 month after hemithyroidectomy ([Table 1]).
Table 1
Serum iPTH levels at baseline and at 1 hour, 1 day, 1 week, and 1 month after surgery
|
Hemithyroidectomy (n = 44)
|
Total thyroidectomy (n = 36)
|
|
iPTH baseline (pg/mL)
|
35.598 ± 11.6320
|
39.348 ± 11.9700
|
|
iPTH 1 h after surgery (pg/mL)
|
33.427 ± 10.2710 (–6%)
|
23.416 ± 17.5015 (–40%)
|
|
iPTH after 1 d (pg/mL)
|
43.883 ± 9.8528 (+23%)
|
28.615 ± 17.8183 (–27%)
|
|
iPTH after 1 wk (pg/mL)
|
41.598 ± 10.4965 (+17%)
|
30.275 ± 16.2366 (–23%)
|
|
iPTH after 1 mo (pg/mL)
|
38.445 ± 9.1708 (+8%)
|
36.133 ± 13.0558 (–8%)
|
Abbreviation: iPTH, intact parathormone.
Note: Values in bracket represent percentage change over base line values.
Among the 36 patients who underwent total thyroidectomy, the mean baseline (preoperative)
iPTH was 39.4 ± 11.9 pg/mL, which dropped by 40% to 23.4 ± 17.5 pg/mL 1 hour after
surgery and gradually recovered to 28.6 ± 17.8 pg/mL at 1 day, 30.2 ± 16.2 pg/mL at
1 week, and stabilized at 36.1 ± 13.0 pg/mL 1 month after total thyroidectomy ([Table 1], [Fig. 1]).
The mean value of CSC in the two groups followed a similar pattern. In the hemithyroidectomy
patients, the mean baseline CSC was 9.55 ± 0.77 mg/dL, which dropped by 2.8% 1 hour
after surgery and recovered to normal levels at 1 day postoperatively. Among total
thyroidectomy patients, the mean baseline CSC was 9.5 ± 0.68 pg/dL, which dropped
by 9.3% 1 hour after surgery and remained below the baseline value by 2.6% at 1 week
after surgery. Stabilization of the CSC level was seen at 1 month after total thyroidectomy
compared to 1 day after hemithyroidectomy ([Table 2], [Fig. 2]).
Table 2
Corrected serum (CS) calcium levels at baseline and at 1 hour, 1 day, 1 week, and
1 month after surgery
|
Hemithyroidectomy (n = 44)
|
Total thyroidectomy (n = 36)
|
|
CS calcium baseline (mg/dL)
|
9.550 ± 0.7793
|
9.509 ± 0.6827
|
|
CS calcium 1 h after surgery (mg/dL)
|
9.283 ± 0.8031 (–2.8%)
|
8.622 ± 0.5533 (–9.3%)
|
|
CS calcium after 1 d
|
9.694 ± 0.5536 (+1.5%)
|
9.051 ± 0.7858 (–4.8%)
|
|
CS calcium after 1 wk (mg/dL)
|
9.886 ± 0.4084 (+3.5%)
|
9.266 ± 0.6676 (–2.6%)
|
|
CS calcium after 1 mo (mg/dL)
|
9.939 ± 0.3711 (+4.1%)
|
9.547 ± 0.6025 (+0.4%)
|
Note: Values in bracket are percentage change over the baseline values.
Fig. 1 Sequential values of corrected serum calcium (CSC) after total thyroidectomy (n = 36) at baseline, 1 hour, 1 day, 1 week, and 1 month after surgery.
Fig. 2 Sequential values of iPTH after total thyroidectomy (n = 36) at baseline, 1hour, 1 day, 1 week and 1 month after surgery.
At 1 hour post total thyroidectomy, the CSC level was found to be less than 8.5 mg/dL
in 12 patients (33%), which is our defined lower limit for normal CSC range. At 1
month of follow-up, none of the patients had CSC value less than the normal range
([Table 3]).
Table 3
Follow-up of total thyroidectomy patients (n = 36) whose immediate postoperative iPTH level fell to less than 15 pg/mL and CSC
level below 8.5 mg/dL
|
At 1 h postoperative
|
At 1 mo postoperative
|
|
iPTH <15 pg/mL + CSC <8.5 mg/dL at 1 h postoperatively (both less than normal range
values)
|
4 (11%)
|
Nil
|
|
Only CSC <8.5 mg/dL (normal iPTH)
|
8 (22%)
|
Nil
|
|
Only iPTH <15 mg/dL (normal CSC)
|
1 (3%)
|
Nil
|
Abbreviation: CSC, corrected serum calcium, iPTH, intact parathormone.
On clinical evaluation on the evening of surgery, of the 36 patients who underwent
total thyroidectomy, occult clinical evidence of hypocalcemia such as perioral or
acral tingling or numbness, Trousseau's sign and Chvostek's sign could be evoked by
subtle questions or sign elicitation technique in 6 patients. Among these three patients
had CSC <8.5 mg/dL and three had CSC >8.5 mg/dL. None of the patients developed spontaneous
carpopedal spasm or generalized tetany. All patients had recovery of their clinical
signs within 2 to 4 days of surgery. Only 1 of 44 hemithyroidectomy patients complained
of perioral paresthesia on enquiry.
In none of the hemithyroidectomy patients did the iPTH level fall to <15 pg/mL, which
is the usually accepted definition for hypoparathyroidism. Among the 36 total thyroidectomy
patients, the iPTH level fell to <15 pg/mL in 5 patients (14%) immediately after surgery
although it showed a gradual recovery to near baseline levels in 3 patients. In the
remaining two patients, it was 22 and 25 pg/mL at 1 month postoperatively ([Table 3]).
Discussion
Hypocalcemia is an important potential complication after thyroid surgery. It is almost
exclusively seen after total thyroidectomy specially when central neck node dissection
(level VI cervical lymph nodes) is combined with thyroid surgery.[2] The reported incidence of post thyroidectomy hypocalcemia varies widely from 1 to
50%.[3] In the present study, none of the patients who underwent hemithyroidectomy (n = 44) experienced significant immediate postoperative hypocalcemia, while there was
an average drop of 9.3% in CSC and 40% drop in the iPTH level at 1 hour after total
thyroidectomy (n = 36). This is only to be expected because during hemithyroidectomy there can be
possible damage to a maximum of two parathyroid glands, while during total thyroidectomy,
all four parathyroid glands are at risk of unintentional removal, devascularization,
or surgical stunning due to manipulation.
An important observation in our study was the finding that biochemical hypocalcemia
did not demonstrate a linear association with symptoms of hypocalcemia or their severity.
None of our patients exhibited obvious clinical signs of hypocalcemia such as spontaneous
carpopedal spasm or generalized tetany. However, occult symptoms or signs were evident
on day 1 postoperatively in 6 (of 36) patients who underwent total thyroidectomy and
1 (of 44) patient who underwent hemithyroidectomy. These occult manifestations were
perioral and acral tingling or numbness, Trousseau's sign, or Chvostek's sign, all
of which needed to be elicited by subtle questions or drawn out by the appropriate
sign elicitation technique ([Table 4]).
Table 4
Clinical features suggestive of hypocalcemia after thyroid surgery
|
Hemithyroidectomy (n = 44)
|
Total thyroidectomy (n = 36)
|
|
|
With CSC <8.5 mg/dL (n = 12) at 1 h post-op
|
With CSC >8.5 mg/dL (n = 24) at 1 h post-op
|
|
Occult symptoms and signs of hypocalcemia (perioral and acral paresthesia, tingling
or numbness, Trousseau's or Chvostek's sign)
|
1 (2.2%)
|
3 (25%)
|
3 (12.5%)
|
|
Obvious symptoms or signs of hypocalcemia (carpopedal spasm, generalized tetany)
|
Nil
|
Nil
|
Nil
|
Abbreviation: CSC, corrected serum calcium.
Out of 12 patients of total thyroidectomy who had CSC <8.5 mg/dL at 1 hour postoperatively,
3 (25%) exhibited occult clinical features of hypocalcemia. Among the 24 patients
who had CSC >8.5 mg/dL, 3 (12.5%) also exhibited occult clinical features of hypocalcemia.
In none of these six patients, the signs of occult hypocalcemia could be demonstrated
beyond 4 days. It is well known that symptoms of hypocalcemia depend on several other
factors besides the absolute serum calcium values. These factors are (1) fraction
of ionic serum calcium, (2) pH of blood, (3) patient receiving calcium supplementation
in diet or medication, (4) hydration status, and (5) serum magnesium levels. An additional
scenario could be patients who have been chronically calcium deficient and have therefore
become acclimatized to low serum calcium levels.[4]
Postsurgical hypoparathyroidism is defined as reduction of the serum iPTH level below
15 pg/mL or decline of CSC <8.5 mg/dL or ionized calcium below 4.4 mg/dL or 1.05 mmol/L
with or without symptoms of hypocalcemia.[5] Transient hypoparathyroidism is defined as resolution of hypocalcemia without treatment
within 6 to 12 months. Permanent hypocalcemia has been reported to occur between 0
and 43%. This large variation is due to heterogeneity among reports as to the definition
and duration of hypocalcemia.[6]
The half-life of parathyroid hormone in circulation is about 5 minutes or less.[7] Therefore, intraoperative or very early postoperative measurement of serum iPTH
can be a reliable indicator of the status of parathyroid during thyroid surgery. This
property of iPTH is also utilized by surgeons for intraoperative assessment of adequacy
of parathyroid tumor removal during surgery for hyperparathyroidism. For the purpose
of this study, we utilized this attribute of iPTH for parathyroid status assessment
even 1 hour after surgery.
The present study has demonstrated that none of our post thyroidectomy patients including
the 36 who underwent total thyroidectomy had persistent hypocalcemia at 1 month after
surgery. However, there was a drop of 9.3% in the CSC level, 40% in the iPTH level,
and 10% in the iCa level at 1 hour after total thyroidectomy. This was followed by
a very rapid recovery and the CSC levels improved to –4.8% below the lower baseline
at 1 day, –2.6% at 1 week, and +0.4% at 1 month after total thyroidectomy. Similarly
the corresponding values for iPTH at 1 day, 1 week, and 1 month were –27%, –23%, and
–8% ([Figs. 1]
[2]
[3]). A total of 12 patients attained the defined level of hypocalcemia at 1 hour after
surgery. Importantly, only occult clinical features could be elicited in only three
of them as well as three who had a CSC level of >8.5 mg/dL. The immediate postoperative
drop in the iPTH and CSC levels could be attributed to one of the following three
hypotheses:
Fig. 3 Sequential values of ionic calcium after total thyroidectomy (n = 36) at baseline, 1hour, 1 day, 1 week and 1 month after surgery.
-
Inadvertent removal of two or three of the parathyroid glands.
-
Devascularization of the parathyroids during thyroid lobe mobilization.
-
Stunning effect of dissection around the parathyroid glands.
The parathyroid glands are regarded as the “calcium thermostat” of the body. It is
pertinent to note that calcitonin-producing cells in the thyroid are removed completely
during total thyroidectomy. The normal homeostasis of serum calcium levels is maintained
by a fine interplay between iPTH and calcitonin. How this balance of hormones with
antagonistic functions is affected after total thyroidectomy has not been satisfactorily
explained.
The present study has demonstrated that immediate post-thyroidectomy measurement of
iPTH can be a reliable method to assess the possible damage or removal of the parathyroid
gland after total thyroidectomy. Identification of such patients can be important
for early institution of calcium supplementation therapy and sparing the patients
from unpleasant symptoms. Such patients can be monitored till recovery of CSC, which
is likely to occur in a few weeks' time.
Another important inference from this study is that patients who demonstrate a fall
in iPTH at one hour after total thyroidectomy should have a very careful examination
of their thyroidectomy specimen before it is dipped in formalin to look for inadvertently
removed parathyroid glands. If found then auto transplantation of one or two of the
identified glands can be done under local anesthesia in the brachioradialis muscle
immediately thus sparing patient from potential permanent hypo-parathyroid state.
For the purpose of intra-operative iPTH level estimation the rapid immunochemiluminesence
assay should be performed. This can be completed within 8 to 20 minutes allowing the
surgeon to make intra-operative decisions. The intra-operative iPTH assay can be performed
in or close to the operating room to avoid delay caused by sample transport.
Conclusion
We observed a 9.3% drop in CSC, 40% drop in iPTH, and 10% drop in ionic calcium levels
at 1 hour after total thyroidectomy. The values returned to near-normal levels at
1 month postoperatively in all patients. Although occult symptoms or signs of hypocalcemia
could be evoked in first 4 days after surgery in six patients (16%) undergoing total
thyroidectomy, obvious clinical features did not appear in any of our patients. As
per expectations, drop in serum calcium or iPTH was not observed among hemithyroidectomy
patients. Early institution of calcium replacement may be started on the basis of
1 hour post-thyroidectomy iPTH levels to spare the patients from unpleasant symptoms
of hypocalcemia. Furthermore, effort should be made to identify the parathyroid glands
in the thyroidectomy specimen and consider it for autotransplantation if the 1-hour
iPTH falls to below defined hypoparathyroidism levels.
