Journal Reading

Residen: dr. Dewi S. Wahyuningtias

Trainee: dr. Abdul Haris M, Sp.B
Konsultan: dr. Suwardjo, Sp.B (onk)
• The recurrent laryngeal nerve (RLN) is located close to the thyroid gland
and is the main nerve that controls vocal-fold mobility.
• Recurrent laryngeal nerve paralysis (RLNP) is one of the major morbidities
following thyroidectomy; it results in dysphonia and dysphagia in cases of
• unilateral paralysis and can be associated with airway distress and require
tracheostomy in cases of bilateral RLNP.
• Permanent postoperative RLNP occurs in approximately 0.8% to 1.0% of
cases, whereas transient paralysis occurs in 2.2% to 8.0% of cases.
• It has also been reported that following surgeries for thyroid cancer in
particular, the RLNP rate (6.5%) was higher than the average rate (4.37%)
following surgeries for all kinds of thyroid disease.
• Intraoperative nerve monitoring (IONM) was introduced to assist with
identification of the RLN during thyroidectomy. it has been reported that
IONM is used during approximately 80% of thyroid surgeries performed by
head and neck surgeons and >50% of surgeries performed by general
surgeons.
• the utility of IONM is dependent on thyroid tumor size or the extent of
cancer invasion has not yet been determined.
• this study aimed to investigate the risk of postoperative RLNP with and
 Data Source
• This retrospective cohort study utilized data from the Diagnosis Procedure
Combination inpatient database maintained by Medical Data Vision Co., Ltd. (Tokyo,
Japan).
• The database includes 297 facilities, which represent approximately 18% of the acute-
care hospitals in Japan. The database contains anonymous information from health
insurance claims submitted by approximately 18 million patients from April 2008 to
2017. It contains information pertaining to patient characteristics (e.g., age and sex),
diagnostic information (e.g., dates of diagnoses and disease codes, which were
recorded in accordance with the codes from the International Classification of
Diseases, Tenth Revision [ICD- 10]), and medical care provided (e.g., prescriptions,
laboratory tests, interventional procedures such as surgery, and dates of medical care).
• This study was approved by the Kyoto University Graduate School and Faculty of
Medicine Ethics Committee (R1261), following the STROBE statement guidelines.
• This need for obtaining individual informed patient consent was waived because this
study was a secondary analysis of an anonymous patient database.
 Study Cohort
• We extracted data for patients age ≥20 years with thyroid
cancer who underwent thyroidectomy between April 1, 2014—
when use of IONM during thyroid cancer surgery initially began
being covered by health insurance in Japan—to May 31, 2017.
• These patients were identified by the Japanese procedure code
for thyroidectomy for malignant tumors (K463).
• We excluded patients with diagnostic codes indicating the
existence of RLNP before the index surgery (ICD-10: J380, G522,
or G978); those who underwent other head and neck surgeries,
radiation therapy, or parathyroid surgery before the index
surgery; and patients who had reoperations for thyroid cancer.
 Independent Variables
• The primary exposure variable was the use of IONM (procedure code
K930) during thyroid cancer surgery.
• Additionally, we extracted the following patient data from the
database: sex, age, thyroid cancer tumor and nodal classifications
based on the seventh edition of the Union for International Cancer
Control–American Joint Committee on Cancer staging system,14 the
type of thyroid cancer surgery (lobectomy or total thyroidectomy),
performance of neck dissection (codes K000 and K469), presence of
underlying autoimmune thyroid disease (e.g., chronic thyroiditis or
Graves’ disease) defined as having the relevant diagnostic codes
before the day of the index surgery (ICD-10: E039, E050, E055, E059,
E063), the annual volume of thyroid cancer surgeries performed in
each facility, and the year in which the index surgery was performed.
 Outcomes

• The primary outcome was the occurrence of

postoperative RLNP. We defined postoperative RLNP
as having the relevant diagnostic codes from the
day of the index surgery to 30 days after the index
surgery. To distinguish postoperative paralysis
• from paralysis caused by other surgery and
recurrence, the period was limited to 30 days
postoperatively.
 Statistical Analysis
• The characteristics of the study population were summarized
using proportions for categorical variables and the median
and standard deviation for continuous variables.
• We compared relevant variables between patients who
underwent surgery with and without the use of IONM
• The Student t test and Fisher exact test were used for
continuous variables and categorical variables, respectively.
The variables compared included patient characteristics (age,
sex, and thyroid cancer tumor and nodal classifications),
procedural data (type of surgery and neck dissection),
postoperative outcomes (RLNP), the annual volume of thyroid
cancer surgeries performed in each facility, and the year in
which the index surgery was performed.
• We used the Fisher exact test to compare the rate of postoperative RLNP with IONM use, age,
sex, tumor classification, nodal classification, the type of surgery, neck dissection, surgery
volume of each facility, and the year in which the index surgery was performed.
• We performed multivariable logistic regression analyses to evaluate the association between
IONM use and postoperative RLNP, adjusting for potential confounders based on clinical
points of view (e.g., age, sex, tumor classification, nodal classification, the type of surgery,
and surgery volume of each facility).
• The results were expressed as odds ratios (OR) with 95% confidence intervals (CI).
• We conducted sensitivity analyses by changing one of the adjusting confounders of the
multivariable logistic regression analyses, nodal classification, to “neck dissection.”
• The neck dissection code in the database indicates that neck dissection was performed in
both the central and lateral compartments; however, neck dissection that was performed in
only the central compartment was not included due to the Japanese insurance system.
Moreover, we changed the period for including RLNP as having the relevant diagnostic codes
from 30 days after the index surgery to 60 days after the index surgery.
• Furthermore, we conducted subgroup analyses to investigate whether the utility of IONM
differed according to the tumor and nodal classifications.
• All statistical tests were two-sided; P < .05 was considered statistically significant. All data
analyses were performed using SAS for Windows (version 9.4; SAS Institute Inc., Cary, NC).
 RESULTS
• From a multihospital claims database, we identified
6,359 patients who underwent thyroid cancer surgery
between April 1, 2014, and May 31, 2017. Of these, we
excluded 555 patients: 340 who were diagnosed with
RLNP before the index surgery, 59 who had undergone
thyroid cancer surgery before the index surgery, and
156 who had previously undergone other head and neck
cancer surgery, radiation therapy for head and neck
cancer, or parathyroid surgery (Fig. 1). Consequently,
5,804 patients were included in the study cohort.
 Univariate Comparison of Patient
• Characteristics and Postoperative RLNP
• Incidence
• Table I presents the demographic and baseline clinical
• characteristics of the study patients. IONM was used during thyroid
cancer surgery for 849 patients, accounting for 14.6% of the study
cohort.
• Postoperative RLNP was reported in 127 cases (2.2%); in most cases, it
was unclear whether the paralysis was unilateral or bilateral. Between
the patients who underwent surgery with and without the use of
IONM, the incidence of postoperative RLNP did not differ significantly
(Table II). In the patients with T4 tumor classification and N1b nodal
classification, postoperative RLNP occurred more frequently in the
patients who underwent IONM.
 Multivariable Analyses
• Upon performing the multivariable logistic regression analysis,
we excluded 1,027 patients with missing tumor classification
data and 92 with missing nodal classification data.
• The multivariable analysis also indicated that use of IONM
during thyroid cancer surgery was not associated with
postoperative RLNP after adjusting for confounding factors
(OR: 1.13, 95% CI: 0.66-1.94; Table III).
• Meanwhile, advanced age (OR: 1.31 per 10 years, 95% CI:
1.12-1.51) and T4 tumor classification (OR: 2.31, 95% CI: 1.18-
4.52) were independently associated with higher incidences of
postoperative RLNP.
 Sensitivity Analyses
• The subgroup analyses revealed that among patients
having T1, T2, or T3 tumor classifications, use of IONM
was not significantly associated with postoperative RLNP;
whereas among patients with tumors classified as T4, use
of IONM was associated with an increased incidence of
postoperative RLNP (Table IV). Subgroup analyses
stratified by nodal classification revealed that among
patients having N0 and N1a classifications, use of IONM
was not significantly associated with RLNP; but among
patients having an N1b classification, IONM use was
associated with an increased incidence of RLNP (Table V).
• In the multivariate model including neck dissection
(instead of nodal classification), the results were
similar to those of the primary analysis (Table VI) in
that use of IONM was not significantly associated
with postoperative RLNP.
• The factors that exhibited significant associations
with RLNP in the multivariate model included older
age, having had a total thyroidectomy, and having T4
tumor classification.
• Despite the change in the period for including RLNP
with the relevant diagnostic codes from 30 days after
the index surgery to 60 days after the index surgery,
the occurrence of RLNP did not change.
 DISCUSSION

• In this observational cohort study, we investigated the association between

the use of IONM during thyroid cancer surgery and postoperative RLNP
using a nationwide claims database.
• We observed no significant association between IONM use and
postoperative RLNP. Our subgroup analyses demonstrated that among
patients with thyroid cancer classified as T4 or N1b, IONM use was
significantly associated with an increased incidence of postoperative RLNP.
• Many previous studies have examined the benefits of using IONM to reduce
the risk of postoperative RLNP; however, the results were inconsistent. Some
studies demonstrated a decreased risk of postoperative RLNP with the use
of IONM, and others observed a similar risk of RLNP regardless of IONM
use.2–5,8,9 In these previous studies, the patient populations included a
mixture of
• those having benign and malignant diseases. We hypothesized that the utility of IONM may
differ between cases of cancer and benign diseases; thus, we focused on patients with
thyroid cancer in the present study. In this regard, one recently conducted meta-analysis that
pooled the data of 595 patients with thyroid cancer from four different studies found that
there was no evidence to support IONM use to reduce postoperative RLNP. However, the
authors of this meta-analysis indicated that the sample size was small, suggesting the need
for a large-scalestudy. Furthermore, primary lesions and lymph node metastasis should be
considered risk factors for RLNP, because the completeness of surgical resection is an
important determinant of outcome in extracapsular thyroid cancer,15 and patients
undergoing central neck dissection have a significantly higher incidence of RLNP compared
with patients who do not undergo central neck dissection.16 Therefore, we hypothesized that
tumor size and the extent of invasion may affect the utility of IONM, and thereby performed
subgroup analyses according to tumor classification and the presence of lymph node
metastasis.
• Unexpectedly, in the subgroup analysis of the T4 and N1b groups, IONM use was significantly
associated with an increased incidence of postoperative RLNP. We assumed that IONM may
be used more frequently in difficult-to-manage cases, such as those in which the cancer had
invaded the recurrent laryngeal nerve, or by operators with less surgical experience. The
possibility of indication bias could be considered; however, such bias is difficult to measure,
and conducting a randomized controlled trial is the only way to control for this bias.
• We used a multihospital claims database to ensure that we obtained a large study sample.
Although we analyzed the data of 5,804 patients, the present study may still be
underpowered due to the low incidence of postoperative RLNP (n = 127).2–4,10 A meta-
analysis targeting both benign and malignant thyroid diseases that included
• 17,203 at-risk nerves demonstrated the benefits of using IONM to reduce the risk of RLNP,
but there was no statistical significance for persistent RLNP.5 Studies with larger sample sizes
may be needed to reflect a statistically significant difference for persistent RLNP, but it is
questionable whether such studies seeking “statistical significance” rather than “clinical
significance” will change the overall value of IONM.17
• There are three possible mechanisms of RLN injury that can occur during thyroidectomy:
excessive traction on the RLN; compression of the RLN by a ligature, clamp, pickup forceps,
retractor, or tissue band; or direct injury to the RLN by sharp transection or thermal injury.18
Excessive traction and compression are difficult to recognize intraoperatively by visual
identification alone. Recently, continuous IONM of the RLN has gained increasing interest as it
provides real-time feedback to surgeons to potentially avoid RLN injuries.
• Conventional IONM is intermittent and cannot provide continuous functional protection
during nonstimulation periods19; therefore, surgeons using intermittent IONM are not able
to detect excessive traction or compression during nonstimulation periods. This may be one
of the reasons why the protective effects of IONM against RLNP have not been observed in
some studies. In Japan, continuous IONM has been available since 2016; thus, in our study,
intermittent IONM probably accounted for the majority of cases wherein IONM was
performed.
• Further studies are needed to evaluate whether continuous IONM provides superior
protective effects compared with intermittent IONM or direct visualization alone.5 There
were several limitations of this study that should be considered. First, cases of RLNP without
diagnostic codes could not be identified. The accuracy of the diagnostic codes for RLNP in the
database was unknown; thus, it is possible that the occurrence of
• postoperative RLNP was underestimated. However, we anticipated that the degree of RLNP
underestimation was nondifferential between patients having had surgeries with and without
use of IONM. Thus, it is unlikely that our finding—the similar incidence of RLNP between the
two groups—was significantly affected by underestimation of RLNP. Second, it was unclear in
most cases whether RLNP had occurred bilaterally or unilaterally.
• Only 11% (14/127) of the postoperative RLNP cases could be differentiated as being bilateral or
unilateral. The clinical courses are considerably different for unilateral versus bilateral cases of
RLNP, and it may be important to distinguish between unilateral and bilateral cases, but this
could not be achieved in our study.
• Although our study did not observe any benefit of IONM use, the possibility remains that it may
prevent bilateral RLNP, a severe form of nerve palsy. Third, we could not determine whether
RLNP was transient or permanent in the included cases, as the database does not contain
information regarding the long-term outcomes of RLNP.
• Fourth, central neck dissection may be one of the factors associated with an increased risk of
RLNP, but we were unable to identify whether central neck dissection was performed for patients
with N0 nodal classification. Some N0 patients may have undergone prophylactic central neck
dissection, but not all. In the database, we could identify the code for “neck dissection,” but this
did not include cases of neck dissection performed only in the central compartment. Finally,
there were unmeasured confounding factors in this study, such as multiple operators and facility
traits, other than the hospitals’ annual surgery volumes. Surgical techniques may vary between
operators, which may affect the incidence of RLNP. Furthermore, the affordability and adaptation
of IONM may vary between facilities. Therefore, these factors could affect the frequency of use
of IONM and the occurrence of RLNP.