Download Protection of Parathyroid Function Using Carbon Nanoparticles

Original Research—Endocrine Surgery
Protection of Parathyroid Function Using
Carbon Nanoparticles during Thyroid
Surgery
Otolaryngology–
Head and Neck Surgery
149(6) 845–850
Ó American Academy of
Otolaryngology—Head and Neck
Surgery Foundation 2013
Reprints and permission:
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DOI: 10.1177/0194599813509779
http://otojournal.org
Kai Huang, MD1, Dingyuan Luo, MD1, Mingqing Huang, MD1,
Miaoyun Long, MD1, Xingzhi Peng, MD1, and
Honghao Li, MD1
No sponsorships or competing interests have been disclosed for this article.
Abstract
Objective. To investigate the hypothesis that injected carbon
nanoparticle (CN) suspension helps identify parathyroid
glands (PGs) during thyroid cancer surgery, thereby reducing
PG injury.
Study Design. A prospective, randomized controlled trial.
Setting. Sun Yet-san Memorial Hospital, Guangzhou, China.
Subjects and Methods. Thyroid cancer surgeries were performed on 72 consenting patients who were randomized
for conventional surgery (control group) or surgery with
CN suspension injection (CN group). The primary end
point was the prevalence of symptomatic hypocalcemia and
serum calcium levels \1.9 mmol/L.
Results. From 36 patients diagnosed with thyroid cancer in
each group, symptomatic hypocalcemia was found in 10
patients without CN injection and 3 patients with CN suspension injection (P = .032). In total, 5.6% of patients in the
CN group presented with muscle cramps compared with
22.2% of the control group (P = .041), which showed a significant difference.
Conclusion. Our randomized study revealed that CN suspension injection was feasible and appeared to be beneficial for
patients undergoing thyroid surgery because the incidence
of symptomatic hypocalcemia was lower compared with
controls. Therefore, this technology and technique should
be more widely considered for thyroid cancer therapy.
Additional studies with more patients and longer follow-up
times will be needed for a thorough evaluation of this
methodology.
Keywords
thyroid cancer surgery, carbon nanoparticles, parathyroid
gland injury, hypocalcemia
Received April 15, 2013; revised September 19, 2013; accepted
October 1, 2013.
A
part from dysfunction of the recurrent laryngeal
nerve (RLN), hypocalcemia caused by postoperative hypoparathyroidism is the most common complication of thyroid surgery.1 Patients with hypocalcemia
are required to take multiple medications, yet most of them
continue to experience symptoms of low calcium. The incidence of postoperative hypocalcemia varies from less than
1.6% to as high as 50%, which is often caused by the surgeon accidentally removing more than 1 of a patient’s parathyroid glands (PGs) or incidentally destroying more than 1
PG or the glandular blood supply.2,3 However, these manipulations are often due to the characteristics of the thyroid’s
anatomy (such as PGs within the thyroid), as well as the
complicated anatomical changes caused by thyroid disease
(such as serious adherence caused by inflammation). Thus,
PG injury and the consequences this generates may still be
inevitable during procedures performed by surgeons.4.
In addition to meticulous dissection during surgical procedures and formidable expertise and experience in thyroid
surgery, confirmation of the locations of the PGs via intraoperative frozen sections, parathyroid scintigraphy,5 and
methylene blue injection6 decreases the probability of
parathyroid-related complications. Nevertheless, all these
methods have not yet achieved a consensual agreement in
terms of efficacy.4 This emphasizes the appeal of having an
effective method to identify the PGs during thyroid surgery,
especially during thyroid cancer surgery, total thyroidecotomy, and/or surgeries that incorporate an extensive lymph
node dissection.
Emerging evidence shows that there are rich lymphatics
and lymphatic capillaries in the thyroid itself, whereas
there are almost none within the PGs. In addition, there are
anatomically independent external capsules for the thyroid
and parathyroid glands.7,8 Based on these findings, after
1
Department of Thyroid and Vascular Surgery, Sun Yet-san Memorial
Hospital, China
Corresponding Author:
Honghao Li, Department of Thyroid and Vascular Surgery, Sun Yet-san
Memorial Hospital, 510000, China.
Email: [email protected]
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Otolaryngology–Head and Neck Surgery 149(6)
Figure 1. Study flowchart. CN, carbon nanoparticle.
injection into the thyroid, a carbon nanoparticle (CN) suspension can color the thyroid lymphatics and capillary lymphatics completely black but not the parathyroid glands
behind the thyroid. This is important for distinguishing
these structures. Thus, CN suspension injections could be
used to protect the parathyroid glands during surgery.
However, the role of CN in reducing the prevalence of
PG injury has not been definitively established.9-11 Only a
few cases reported in Chinese have supported the technique
of injecting CN suspension to aid in the identification of
PGs, assisting surgeons to protect the PGs.9,10 Here, we
report a prospective randomized study comparing the prevalence of PG injury after thyroid cancer surgery with PG
visualization alone and with CN suspension injections. The
aim of the study is to determine if CN injections decrease
postoperative hypocalcemia by helping surgeons to differentiate parathyroid tissue from surrounding tissue, thereby
decreasing the postoperative morbidity of thyroid surgery.
Materials and Methods
Materials
cancer, previous thyroid or parathyroid surgery, preoperative
hypoparathyroidism or hypocalcemia, pregnancy or lactation, age younger than 16 years, and an inability to comply
with the follow-up protocol (Figure 1).
Patients were randomized to 2 groups (Table 1) and
were identified by visualization alone (control group) or
with the aid of intraoperative CN suspension injections (CN
group). Randomization was performed by computergenerated permuted block sequencing and allocated using
sealed envelopes to be opened at the time of admission to
the hospital. Patients were blinded to their group assignment. The primary end points were the prevalence of symptomatic hypocalcemia and serum calcium levels \1.9
mmol/L.
All surgeries were performed by the same attending surgeon (HL) to add further stability to the results of our trial.
Diagnoses were confirmed by pathological examinations
following the 2002 diagnostic standards of the American
Joint Committee on Cancer.
Surgical Procedures
Carbon nanoparticles (approval number by the China
Food and Drug Administration: H20041829; Lai Mei
Pharmaceutical Co, Chongqing, China) were used in the
form of a standard CN suspension injection (1 mL: 50 mg),
which had no reports of toxic side effects for humans.11-14
Normal saline solution was injected into the thyroid as a
control medium.
Patients
From January 2012 through January 2013, 72 patients (22
males and 50 females) underwent thyroid cancer surgery.
Approval from the ethics committee of Sun yat-sen
Memorial Hospital and informed consent were obtained
before these procedures. The inclusion criteria were thyroid
carcinoma (size of lesion between 1 and 4 cm) or an existing suspicion of the presence of neck lymph node metastasis, which would require prophylactic or therapeutic central
neck dissection. Exclusion criteria included nonthyroid
Details of the surgical procedures are as follows. After
induction of anesthesia, the airway was secured with an
endotracheal tube. The neck was entered through a transverse incision. After the platysma muscle was separated
transversely and the gap between the thyroid and anterior
cervical muscle group was opened, the anterior capsule was
carefully dissociated and the abnormal lobe was exposed.
However, the dorsal tissue to the thyroid was not separated
to reduce risk of destruction of the surrounding thyroid lymphatic network. The CN suspension or normal saline solution was injected into the lower and upper points of the
thyroid gland, with 0.1 to 0.2 mL administered for each
area, and the total amount injected would be no more than
0.4 mL per lobe. Injection into lesions was avoided. In addition, when injecting or withdrawing from the thyroid, the
syringe was pumped back to avoid mistakenly injecting into
any blood vessels. After injection, the thyroid and the surrounding lymph tissue were stained black, as well as the
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Huang et al
847
Table 1. General clinical data.
Characteristic
CN (n = 36)
Control (n = 36)
P Value
Age, mean 6 SD, y
Sex ratio, M:F
Size of tumor, mean 6 SD, mm
Disease morbidities, No. (%)
Hyperthyroidism
Thyroiditis
Procedure, No. (%)
Total thyroidectomy only
Unilateral CND
Bilateral CND
41.22 6 2.53
12:24
23.28 6 1.29
40.69 6 2.42
10:36
25.79 6 1.14
4 (11.11)
5 (13.89)
4 (11.11)
5 (13.89)
1b
1b
6 (16.67)
6 (16.67)
24 (66.67)
3 (8.33)
7 (19.44)
26 (72.22)
.479b
.881a
.611b
.15a
Abbreviations: CN, carbon nanoparticle; CND, central neck dissection; F, female; M, male.
a
Student t test.
b 2
x test.
Figure 2. (A) The inferior parathyroid gland (white arrow) and the recurrent laryngeal nerve (black arrow) at the dorsal thyroid. A clear
demarcation between the thyroid and the parathyroid gland (PG) is shown by the carbon nanoparticle suspension. (B) Lymph nodes (black
arrow) in the central neck compartment were almost entirely stained in black but not the PG (white arrow).
lymph tissue in zone VI, including other zones of lymph
tissue. At that time, PGs were identified, visibly different
from the thyroid gland and lymphatics and nodes in the central compartment (Figure 2A, B). Then, the branches of
the superior and inferior thyroid arteries were divided and
ligated close to the thyroid capsule. Recurrent laryngeal
nerves were routinely identified by visualization. The central neck dissection extends vertically from the hyoid bone
to the thoracic inlet and horizontally between the internal
carotid arteries (zone VI), if necessary. Complete thyroid
resections were performed for all cases. All parathyroid
glands were exposed. All tumor resections were pathologically confirmed via intraoperative frozen biopsy. Based on
the clinical findings and frozen section results, additional
surgical treatment such as central neck or lateral neck dissection may be necessary (Table 1). The PGs removed
were preserved in gauze with normal saline solution,
dissected in pieces as small as possible, and then reimplanted within the sternocleidomastoid before the operation
was finished.
All patients were monitored postoperatively for 6 hours.
Postoperative Evaluation and Follow-ups
Postoperative hypocalcemia was defined by postoperative
albumin-adjusted serum calcium levels of less than 1.9
mmol/L (reference range, 2.10-2.60 mmol/L; SIEMENS
Dimension RxL MaxTM, Munich, Germany) with or without clinical symptoms of hypocalcemia or subnormal serum
calcium levels (1.9-2.1 mmol/L) with neuromuscular symptoms. Neuromuscular irritability, including paresthesia,
muscle cramps, tetany, or seizures, which would tend to
follow the order from mild to serious, was documented.
According to the prospective protocol, albumin-adjusted
total serum calcium levels were measured preoperatively
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Otolaryngology–Head and Neck Surgery 149(6)
Table 2. Clinical data of symptomatic hypocalcemia.
Characteristic
Symptoms, No. (%)
Paresthesia
Muscle cramps
Tetany
sCa (\1.9 mmol/L)
CN (n = 36)
Control (n = 36)
P Value
with 4 patients in the control group, which did not achieve
statistical significance.
Follow-ups
3
2
1
3
(8.33)
(5.56)
(2.78)
(8.33)
10 (27.78)
8 (22.22)
1 (2.78)
4 (11.11)
.032
.041
1
.691
Abbreviations: CN, carbon nanoparticle; sCa, serum calcium levels. All statistical differences are shown (x2 test).
(which showed normal ranges in all cases) and on the postoperative day when symptoms of hypocalcemia occurred.
All patients with symptomatic hypocalcemia were prescribed 500 to 1000 mg of oral calcium supplements
(Wyeth Pharmaceuticals, Suzhou, China) and 0.25 mg analogue of vitamin D (Roche Pharmacy [Schweiz] Ltd,
Shanghai, China) twice a day, depending on the severity of
the clinical symptoms. Intravenous substitution of calcium
therapy was unnecessary unless serious symptomatic hypocalcemia was present.
In these patients, this was defined by postoperative clinical examination after cessation of the calcium and calcitriol
substitution therapy. A final clinical examination was performed 6 months after surgery. If clinical symptomatic
hypocalcemia returned to normal within 6 months, hypoparathyroidism was classified as transient; in all other cases, it
was classified as permanent.
Statistical Analysis
Statistical analysis was performed with a commercially
available statistic software package (SPSS 19.0 for
Windows; SPSS, Inc, an IBM Company, Chicago, Illinois).
The Pearson x2 test was used for categorical variables, and
the paired, 2-tailed t test was used for continuous variables.
P \ .05 was considered significant.
Results
Primary End-Point Analysis
Clinical symptoms of hypocalcemia were divided into 4
levels: paresthesia, muscle cramps, tetany, and seizures,
according to the severity.15,16 Fortunately, no permanent
hypocalcemia occurred in these cases. As shown in Table
2, 3 patients developed hypocalcemia (serum calcium levels
of \2.1 mmol/L with neuromuscular symptoms) in the CN
group, while there were 10 patients in the control group. No
seizures occurred after surgery. Parethesia was present in 3
patients in the CN group compared with 10 patients in the
control group (P = .032). Two of those 3 patients who
developed hypocalcemia in the CN group developed muscle
cramps after 1 or 2 days, compared with 8 of 10 patients in
the control group (P = .041), which achieved a statistically
significant difference. Tetany occurred at the same rate
between the 2 groups. Serious hypocalcemia (\1.9 mmol/L)
was apparent in only 3 patients in the CN group compared
All patients with hypocalcemia in the CN group achieved
clinical resolution at a mean (SD) time of 2.33 (0.58)
weeks, while in the control group, it was 3.8 (0.92) weeks.
During this time, no adverse events occurred.
Discussion
The parathyroids are important glands dorsal to the thyroid,
prone to injury during thyroid surgery, especially when thyroid cancer surgery is performed, necessitating total thyroidectomy and potentially lymphadenectomy.17,18 A wealth of
experience in thyroid surgery and meticulous dissection
during surgical procedures are considered the primary factors
for successfully protecting the parathyroid glands.19
However, injury might be inevitable due to the characteristics
of the thyroid anatomy, as well as the anatomical changes
caused by thyroid disease. The reasons for postoperative
hypocalcemia in papillary thyroid carcinoma (PTC) surgery
are devascularization of the parathyroid glands during surgery
owing to the close proximity of the thyroid capsule, the
accidental removal of 1 or more parathyroid glands, the
destruction of the parathyroid glands as a result of lymphadenectomy along the RLN, or hypoparathyroidism due to hematoma formation.2 Thus, numerous methods for treating these
potentially complications have been proposed.
Regarding those methods for parathyroid gland protection, the most effective one is to remove a small piece of
suspicious parathyroid gland tissue for pathological examination via intraoperative frozen sections and then perform
reimplantation if PG was proved. However, the removal
would reduce the volume of the PG and affect its function
to some extent, and even with autotransplantation, the
patient may be at risk for permanent hypoparathyroidism.
Kihara et al20 found that patients showed, after 5 years of
follow-up, a 1.4% and 21.4% incidence of permanent hypoparathyroidism after autotransplantation of 1 or 2 parathyroid glands, respectively. These results suggest that
autologous parathyroid gland transplantation cannot completely restore the gland’s normal function. A basic principle is to preserve the parathyroid glands and retain their
arteries in situ21; thus, autotransplantation might be the only
option after a surgical mistake or an unavoidable excision.
Accordingly, we prefer to preserve the PGs in situ instead
of performing autotransplantation unless something unexpected occurred, such as an accidental removal.
With respect to other intraoperative methods to localize
the parathyroid glands, methylene blue injection stains both
the parathyroid glands and sentinel lymph nodes of the
thyroid.6
Recently, CN suspension injections have been applied
for helping identify lymph nodes in lymph node dissection.12-14 The crucial components for CN suspension injections are nanocarbon granules. These have diameters of 150
nm and can enter lymphatic capillaries (diameters of 500 nm)
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Huang et al
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rather than blood vessel capillaries (diameters of 30-50 nm)
and immediately enter into drainage lymph nodes. Based on
these characteristics, CN suspension injections have been
used in lymph node dissections for breast cancer12 and gastrointestinal cancer.13,14 Furthermore, recent studies have
shown that CN suspension injection can aid in identifying
PGs, which may provide a new strategy for the identification
and protection during parathyroid surgery.9,10 It has been
shown that CN suspension has a significant lymphatic tropism when injected into the thyroid parenchyma: the thyroid
tissue is stained black as are the surrounding lymph nodes
(zone VI), except for the surrounding thyroid tissue without
lymph-vessel connections, and these effects result in an
easier identification of the parathyroid glands.
Emerging data have shown significant benefits in thyroid
cancer surgery. Hao et al11 first reported results on 100
patients with thyroid microcarcinoma who underwent cervical central neck dissection using CN suspension injections
compared with methylene blue injections. These results
showed the superiority of CN suspension vs methylene blue
injections in terms of the higher sensitivity, accuracy rate,
and lower false-negative rate of CN suspension injected.
This study revealed that CN suspension could effectively
distinguish central neck compartment lymph nodes. That is,
demarcation between nodes and PGs could be clearly visualized (Figure 2B).
In a literature review, there are different definitions of
postoperative hypoparathyroidism after thyroidectomy,
mostly based on total serum calcium levels.22-24 So, we
designed this randomized study to find out the clinical benefits of CN suspension and took total serum calcium levels
as the only measurements to predict the risk of transient or
permanent postoperative hypoparathyroidism instead of
measuring intact parathyroid hormone (iPTH), which was
strongly recommended by Asari et al.15 Asari et al pointed
out that patients with low iPTH may not present with hypoparathyroidism, and monitoring of iPTH levels would be
expensive and inconvenient when not in centers performing
endocrine (thyroid) surgery. Moreover, Lindblom et al25
found no overall significant difference between measurements of intraoperative iPTH levels and measurements of
serum calcium level concentrations on the first postoperative day for predicting hypoparathyroidism.
Our results have shown, with the aid of CN suspension,
that rates of symptomatic postoperative hypocalcemia were
significantly different between the 2 groups, which implies
that CN could easily distinguish the anatomical boundaries
among lymphoid tissue, thyroid tissue, and PGs, to some
extent. By carefully following and separating these boundaries, a lower incidence of hypocalcemia may be possible.
However, total serum calcium levels less than 1.90 mmol/L
occurred in the 2 groups and showed no significant difference. While the study may be underpowered to detect such
a difference, the severity of hypocalcemia may be associated with either the blood supply or the anatomy of the PGs
or even with other individual differences, regardless of the
usage of CN suspension.
In cases with anatomical factors or complications, dissection of PGs appears to be more difficult. In the present
study, disease morbidities such as hyperthyroidism and thyroiditis accounted for 25%, which may increase the difficulty
of dissection, along with anatomical factors, such as the
close proximity of the thyroid capsule or serious adhesion.
Only 3 patients with PG injury in the CN group developed
hypocalcemia, compared with 10 cases in the control group,
which is evidence of the effectiveness of the CN suspension.
We believe that our results show that, with the aid of the
CN suspension, it is much easier to identify and protect the
PGs to minimize intraoperative injury, as well as more feasible to perform and complete thyroid cancer surgeries.
Although we evaluated only a relatively small number of
cases, our results suggested that CN suspension injections in
thyroid cancer surgery assisted surgical identification of the
PGs, thereby allowing anatomic preservation and subsequent
function, decreasing the incidence of symptomatic postoperative hypocalcemia. This could be of great benefit to patients,
and further investigation of this new technology should be
considered for surgical management of thyroid cancer.
Author Contributions
Kai Huang, substantial contributions to conception and design,
analysis and interpretation of data, drafting the article and revising
it critically for important intellectual content, and final approval of
the version to be published; Dingyuan Luo, substantial contributions to acquisition of data, drafting the article, and final approval
of the version to be published; Mingqing Huang, substantial contributions to conception and design and acquisition of data, revising the article critically for important intellectual content, and final
approval of the version to be published; Miaoyun Long, substantial contributions to analysis and interpretation of data, drafting the
article, and final approval of the version to be published; Xingzhi
Peng, substantial contributions to conception and design, revising
the article critically for important intellectual content, and final
approval of the version to be published; Honghao Li, substantial
contributions to conception and design, revising the article critically for important intellectual content, and final approval of the
version to be published.
Disclosures
Competing interests: None.
Sponsorships: None.
Funding source: None.
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