Abstract for Institutional Review Board (IRB)

Title: Frequency of Recurrent Laryngeal Nerve Palsy following Total thyroidectomy

with or without central lymph node dissection for Differentiated Thyroid Cancer.

Background:

Thyroid surgery has been associated with complications ranging from nerve injury to death.

Recurrent laryngeal nerve (RLN) injury is a well-known, potentially serious complications of

thyroid surgery. As the RLN innervates all intrinsic muscles of the larynx except the

cricothyroid muscles, injury of this nerve induces a paresis or palsy of the vocal cord. The

patient often presents with postoperative dysphonia that may or may not be associated with

deglutition problems or dyspnea. These symptoms can resolve rapidly or can persist over

time depending on the injury type (e.g., heat, compression, stripping and section).

Aim: Aim of this study is to determine the frequency of recurrent laryngeal nerve palsy

among patients undergoing total thyroidectomy for differentiated thyroid cancer.

Methodology: A prospective observational study will be conducted in the Department of

Otolaryngology - Head & Neck Surgery, at different tertiary care hospitals, Dhaka, for one

and a half years from January 2022 to June 2023, with 40 patients diagnosed with

differentiated thyroid cancer admitted in In Patient Department (IPD). The subjects will be

selected on the basis of inclusion and exclusion criteria. All of these patients will be

evaluated by the complete ENT examinations. All the data will be compiled and sorted

properly, and the numerical data will be analyzed statistically by using the Statistical

1
Package for Social Scientists (SPSS-26.0) (Evolution or trial version). Demographic

characteristics and study variables will be analyzed using descriptive statistics. The results of

the study will be expressed as mean, standard deviation (± SD), frequency, and percentages.

Means and standard deviations will be reported for continuous variables. Frequencies and

percentages will be reported for categorical variables. Student's t-test will be done to

compare the continuous variables, and the Chi-Square test will be done to compare the

categorical variables. p-value <0.05 will be considered as the level of significance.

Ethical issue: The nature and purpose of the study will be informed in detail to all

participants. Voluntary participation will be encouraged. There will be minimal physical,

psychological, and social risks to the subjects. Informed and understood written consent will

be taken from every patient before enrollment. Privacy, anonymity, and confidentiality of

data information identifying any patient will be maintained strictly. Each patient will enjoy

every right to participate or refuse or even withdraw from the study at any point in time.

Before starting this studies, ethical clearance will be taken from the Institutional Review

Board (IRB) of BSMMU. Data taken from the participants will be regarded as confidential

and kept locked under the investigator for purposeful use only.

2
1. Introduction

1.1 Introduction

The thyroid gland is the largest of the discrete endocrine organs typically weighing between

15 and 25 grams, being slightly larger in women, dependent upon age, nutritional and

hormonal status. Macroscopically the normal thyroid gland presents a bilobate structure with

a reddish-brown colour. The two lobes are connected by a central isthmus. A vestigial,

accessory pyramidal lobe is present in 40% of the population. (Scott-Brown's

Otolaryngology Head & Neck Surgery, 2018, 8th edition)

Thyroid disorders are common; serious or sinister problems are rare. They are broadly be

divided into disorders of function and disorders of structure, with a few miscellaneous

others.

Thyroid nodules are common in adults and may be palpated in 3-7% of cases. (Hegedus L,

Bonnema SJ, Bennedback FN. 2003) If ultrasound is used, the prevalence is nearer 70%.

(Perros P, Buelart K, Colley S et al. 2014) The majority of thyroid nodules are solitary, but

they may be part of a multinodular goiter. A focal or diffuse goiter can occur

physiologically, and in association with thyroiditis.

The commonest presentation of a thyroid nodule is with an asymptomatic lump. Increasingly

referrals are arising as incidental findings from radiological investigation. Pain, rapid

increase in size, hoarse voice and the presence of a lateral neck mass are all the features that

raise concern about a malignant underlying pathology, but the commonest cause for sudden

painful thyroid nodule is bleeding into a pre-existing cyst and the commonest presentation of

3
a differentiated thyroid cancer is an asymptomatic nodule. (Nix P, Nicolaides A,

Coatesworth AP 2005)

Thyroid cancer is the most common endocrine neoplasia and consists in the 0.7 - 1% of all

neoplasm and its incidence is continuously increasing with 8.7 cases every 100000

inhabitants in the USA (Aschebrook-Kilfoy B, Ward MH, Sabra MM et al. 2011)

Differentiated carcinomas (DC) are the 94% of all tumours and are divided in papillary

carcinoma (80%), follicular carcinoma (11%), Hurthle cell carcinoma (3%). Medullary

carcinoma and anaplastic carcinoma represent respectively 5% and 1% of cases. (M.

Monacelli, R. Lucchini, A. Polistena et al, 2014)

Papillary thyroid carcinoma (PTC) accounts for 80 - 85% of all thyroid malignancies, with a

reported 10-years survival of >90%. ( Lundgren CI, Hall P, Dickman PW et al, 2006).

Despite the excellent prognosis, cervical lymph node metastasis are common, with an

incidence between 40% and 90%. (Moo TA, McGill J, Alledorf J et al, 2010; Grodski S,

Cornford L, Sywak M et al, 2007). The most common sites of metastases are the central

lymph nodes of the neck (Level VI), followed by ipsilateral lateral lymph nodes. (Machens

A, Hinze R, Thomusch O et al, 2002).

There is renewed interest in the operative management of cervical lymph node metastasis

with controversies. Most surgeon agree that clinically evident metastasis require either a

modified radical neck dissection or selective neck dissection. The debate centers around the

use of routine or prophylactic central lymph node dissection (CLND) at the time of initial

thyroid operation.

4
CLND removes level VI nodes, from the hyoid bone superiorly, the carotid sheath laterally,

the suprasternal notch inferiorly, the trachea centrally and the prevertebral fascia posteriorly.

Thyroid surgery is one of the commonest neck surgeries performed worldwide. Common

indications for surgical interventions are suspicion of malignancy or malignancy,

compressive symptoms, and cosmetic problems (Cohen-kerem et al, 2000).

Thyroidectomy is globally practiced to treat a wide range of thyroid swelling and is

considered as a safe procedure in well-equipped settings with suitable experience to

anticipate and avoid the occurrence of possible surgical complications. (Doumi EA,

Mohamed IM, Abakar AM, Bakhiet MY 2009). Complications such as bleeding,

hypoparathyroidism and Recurrent Laryngeal Nerve Injury (RLNI) represent nearly half of

all the complications of thyroid surgery (Ready AR, Barnes AD. 1994). RLN injury is an

annoying but avoidable complication which results from severing, clamping or stretching of

the nerve during surgery and may result in severe untoward sequelae for patient (Souza LS,

Crespo AN, Alves de Medeiros JL, 2009). Vocal palsy is one the most common

complications after thyroid surgery. The resulting phonetic paralysis is not only serious

impairment for patients who rely on their voice professionally, but it may also lead to serious

disturbances in ventilation in cases with bilateral vocal palsy (Feng-Yu Chiang et. al. 2004).

Recurrent laryngeal nerve (RLN) injury is a well-known and potentially serious complication

of thyroid surgery. From vocal cord dysfunction to acute airway emergencies, injuries to the

RLN can lead to a variety of complications ranging in severity. Most injuries are temporary,

not life-threatening, and recover within 6 months of surgery. Despite this, RLN injuries

remain significant outcome measures because they negatively affect patient’s quality of life

5
and increase their subsequent health-care utilization. Known risk factors include re-operative

procedures, malignancy, Graves' disease, substernal goiter, hematoma exploration and

surgeon volume. Furthermore, the use of intraoperative neuromonitoring (IONM) to localize

the RLN during surgery has increased despite lack of conclusive evidence of its superiority

to prevent injury (Alexander Gunn et. al., 2020).

Anatomically, the left and right RLNs are different. The left is longer, usually 12 cm from

where it winds around the ligamentum arteriosum to the larynx, whereas the right RLN is

usually 6 cm from where it winds around the subclavian artery to the larynx. The left RLN

tends to run within the tracheoesophageal groove. Damage to a RLN with resultant paralysis

of the sole abducting muscle (posterior cricoarytenoid) of the vocal cord can cause

symptoms ranging from almost undetectable hoarseness in unilateral lesions to stridor and

acute airway obstruction in bilateral damage (Erbil Y, Barbaros U, Issever H et al, 2007).

RLN palsy following thyroid surgery is one of the leading reasons for medico-legal litigation

against surgeons.

6
1.2 Rationale of the study

Recurrent laryngeal nerve palsy is one of the common complications after thyroid surgeries.

Sequalae of the RLN palsy are hoarse voice, airway difficulty, weakened cough and

predisposition to aspiration. A key aim of thyroid surgery is to preserve recurrent laryngeal

nerve with a precise surgical technique. In this study we are going to study the incidence of

RLNI after thyroid surgeries. To date, there is limited published literature on the topic and so

far after massive search, no thesis has been published in this topic at BSMMU. So, this study

will be helpful to provide evidence-based information to the surgeons as well as patients

group

about the RLN palsy after thyroid surgery and it also help for further prevention and

management of RLN palsy.

2. Research question

What is the incidence of RLN palsy following total thyroidectomy for DTC?

7
3. Objectives

3.1 General objective:

 To know the frequency of RLN palsy after total thyroidectomy without central

clearance for DTC

 To know the frequency of RLN palsy after total thyroidectomy with central clearance

for DTC

 To know the any relationship between recurrent laryngeal nerve injury and size of

nodule

3.2 Specific objectives:

 To see frequency of recurrent laryngeal nerve injury following total thyroidectomy

for differentiated thyroid cancer.

8
4. Materials & Methods

4.1 Types of Study: Prospective observational study

4.2 Study Period: Jan 2022 to Jun 2023

4.3 Place of the Study: This study will be carried out in the Department of

Otolaryngology- Head & Neck Surgery at BSMMU, Dhaka.

4.4 Study population: Patients undergoing total thyroidectomy with the diagnosis of

differentiated thyroid cancer.

4.5 Sampling technique: Purposive

4.6 Ethical clearance: Before starting this study, the research protocol will be approved by

the institutional review board (IRB) of BSMMU

4.7 Sample size: 22

9
Calculation of sample size

The representative sample size was determined by the following statistical formula

{u [ √ π ( 1−π ) ] +v [ √ π ( 1−π 0 ) ] }
2
0
n= 2
( π−π 0 )

Where, n = Sample size

Π1 = 17%, is the value of the population proportion under the alternative hypothesis

(KC Sarita et al., 2013)

Π0 = 3%, is the value of the population proportion under the null hypothesis, (Sikdar

A. H. et. al., 2013).

u = 1.96

v = 0.84

By using formula given above,

Sample size will be 22.

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4.7 Inclusion criteria:
 Patients age 18 years or more

 Patients admitted to the Department of Otolaryngology - Head & Neck Surgery at

BSMMU, Dhaka with the diagnosis of DTC that needed total thyroidectomy.

4.8 Exclusion criteria:

 Subtotal or hemithyroidectomy as definitive procedure

 Papillary microcarcinoma <10 mm

 History of recurrent thyroid malignancy

 History of recurrent laryngeal nerve palsy

 History of distant metastatc disesase

4.9 Data Collection Tool

Pre-tested structured questionnaire will be prepared by reviewing previous studies on the

problem of interest

11
4.10 Study Procedure

This study will be carried out at the Department of Otolaryngology - Head & Neck Surgery,
at different tertiary care hospitals, Dhaka from Jan 2022 to Jun 2023, after obtaining
clearance and approval from the Institutional Review Board. Patients admitted to the
department with thyroid swelling and fulfill the inclusion and exclusion criteria will be
recruited as subjects in the study. After the selection of the subjects, the nature, purpose, and
benefit of the study will be explained to the patient and guardian in detail. They will be
encouraged to participate voluntarily. They will be allowed to withdraw from the study at
any time. Informed written consent will be taken from the participants. A detailed history
will be taken. A thorough ENT examination, including thyroid gland examination and related
systemic examinations, will be done. Preoperative arrangement & investigation like thyroid
function test, USG of the thyroid, FNAC, preoperative S. calcium, and other investigation for
general anesthesia will be done. After completing the necessary procedure for operation, the
patient will undergo total thyroidectomy with or without neck dissection. Detailed operation
findings, including the postoperative recurrent laryngeal nerve evaluation will be noted. All
the patients undergoing surgery will be evaluated with fiberoptic laryngoscopy (FOL) pre
and post operatively to see the vocal cord status.

All the information will be recorded in a preformatted questionnaire. The data will be
analyzed by computer-based software SPSS (26.0). The statistical significance will be set to
p< 0.05. Demographic characteristics and study variables will be analyzed using descriptive
statistics. The results of the study will be expressed as mean, standard deviation (± SD),
frequency, and percentages. Means and standard deviations will be reported for continuous
variables. Frequencies and percentages will be reported for categorical variables. Student's t-
test will be done to compare the continuous variables, and the Chi-Square test will be done to
compare the categorical variables.

12
4.11 Variables:

Demographic variables:
● Age
● Gender

Clinical variables:
● DTC with cN0
● DTC with cN+
● Size of the thyroid swelling

Outcome variables:
 Recurrent laryngeal nerve injury

Confounding variables:
● To minimize the biased interpretation of the data during analysis, confounding
variable, which may distort the study result, is taken into account. Associated
thyroiditis, the anatomical variation of the RLN.

13
4.12 Research tools:

FOL pre and postoperatively for the evaluation of vocal cord.

4.13 Operational Definition:

Total thyroidectomy: Removal of the entire thyroid gland. (Tongol and Mirasol, 2016).

cN0: The clinically negative (N0) neck is defined by its absence of palpable or

radiographically suspicious lymph nodes (Pittman, K.T. 2002)

cN+: Clinical N+ neck defined as cervical lymph nodes detected at the physical examination,

imaging studies (either a computed tomography scan, magnetic resonance imaging or

positron emission tomography scan), or fine needle aspiration cytology (Yoo S.S. et al.

2013). 

Vocal Fold Paralysis: This pathological condition inhibits adequate closure of the vocal

folds, causing breathy dysphonia frequently accompanied by symptoms of aspiration result

in incomplete vocal fold closure and may inhibit propagation of a symmetrical and fluid

vocal fold wave. (Benninger et al. 2016)

14
4.14 Data processing and analysis:
The data will be analyzed by computer-based software SPSS (26.0). The statistical
significance will be set to p< 0.05. Demographic characteristics and study variables will be
analyzed using descriptive statistics. The results of the study will be expressed as mean,
standard deviation (± SD), frequency, and percentages. Means and standard deviations will
be reported for continuous variables. Frequencies and percentages will be reported for
categorical variables. Student's t-test will be done to compare the continuous variables, and
the Chi-Square test will be done to compare the categorical variables.

4.15 Protocol Registration and Results System (PRS):

This study is an observational study involving human; therefore, this protocol will be
registered after approval by IRB to the clinicalTrials.gov which is a service of the US
National Institutes of Health with the following account:
Organization: Bangabandhu Sheikh Mujib Medical University (BSMMU), Shahbag, Dhaka,
Bangladesh
The data will be entered into the protocol registration site once the protocol has been
approved by the Institutional Review Board.

4.16 Ethical issue

In this study, keeping compliance with the Helsinki Declaration for Medical Research
Involving Human Subjects 1964, the nature and purpose of the study will be informed in
detail to all participants. Voluntary participation will be encouraged. There will be minimal
physical, psychological, and social risks to the subjects. Informed and understood written
consent will be taken from every patient before enrollment. Privacy, anonymity, and
confidentiality of data information identifying any patient will be maintained strictly. Each
patient will enjoy every right to participate or refuse or even withdraw from the study at any

15
point of time. Before starting this study ethical clearance will be taken from the Institutional
Review Board (IRB) of BSMMU. Data taken from the participants will be regarded as
confidential and kept locked under the investigator for purposeful use only. This protocol is
primarily selected by the academic committee of the department of otolaryngology and head-
neck surgery. Due respect will be given to all the subjects .

The informed consent will contain the following information -

▪ Explanation of the nature and purpose of the study
▪ Explanation of the procedure, benefit, and duration of the study
▪ Full understanding of the results of this research and their probable welfare implications
▪ An explanation that they will have the right to refuse or to participate in the study ▪
Refusal to participate in the study will not affect the treatment given.
▪ Consent will be taken in an understandable local language from the study subjects before
enrollment

4.17 Methods of maintaining confidentiality:

Though the study has minimal risk, so signed informed written consent will be taken from
subjects
● Research data will be coded
● Data will be stored in a locked cabinet
● Only research personnel will be allowed to access data
● There is a minimum physical, psychological, social, and legal risk
● Proper consent will be taken
● Privacy of the study subjects will be maintained
● No experimental new drug will be administered

● No placebo will be used here

4.18 Quality assurance strategy

16
This is a comparative study design and will be conducted at BSMMU for the duration from Jan
2022 to Jun 2023. For the study, subjects will be selected irrespective of sexes from admitted
patients in the department of Otolaryngology-Head & Neck Surgery at different tertiary care
hospital, Dhaka. After the determination of sample size, a minimum of ….. cases will be
selected, according to inclusion and exclusion criteria after having informed written consent will
be taken for a significance level of <0.05. During the first six months, the supervisor will be
consulted at every two months interval, and there will be arranged meetings and discussions
regarding the progress of sample collection. Over the following three months, monthly
discussions will be held on the progress of data collection and any problems with regard to data
collection will be identified and solved. During the remaining three months, meetings will be
held with the supervisor at weekly intervals to go over the details of thesis writing and
submission.

4.19 Data and Safety Monitoring Board (DSMB)

The primary purpose of an independent DSMB is to protect the research subjects through
independent analysis of emerging data from the trial. This differs from adverse event
reporting in that the DSMB can review aggregate and unblended data as the data accumulate,
identify significant issues and trends during the study, and recommend changes in the study,
including recommending early termination of the study. The DSMB will review data for both
safety and efficacy. The protections afforded by this review apply to both current subjects
and future subjects if the DSMB identifies the need to modify or even halt the trial. In
addition to the above, an independent DSMB protects the credibility of the trial by virtue of
its independence from the study sponsors and helps to ensure the validity of study results by
reviewing data on subject accrual and conducting interim reviews. DSMBs generally include
members with expertise in biostatistics, clinical trials, and the disease and treatment being
studied. Other areas of expertise, such as bioethics, may also be useful. Following will be the
members of DMSB during this study:

17
1. Prof. Dr. A. Allam Choudhury, Department of Otolaryngology – Head & Neck Surgery,
Bangabandhu Sheikh Mujib Medical University, Dhaka

2. Assistant Professor Dr. Hawlader Mohammad Mustafizur Rahaman, Department of

Otolaryngology & Head-Neck Surgery, Bangabandhu Sheikh Mujib Medical University,
Dhaka

Study Design

Flow Chart

Screening of patients by history, examination and investigations

Inclusion and exclusion criteria

Selection of study population

Data collection
3.

Statistical analysis
4.

Report writing

18
 5.

Correction of script by
6. supervisor

19
Surgical Method:

All cases will be operated under General anesthesia with endotracheal intubation. Neck will
be slightly hyperextended. A Kocher’s incision will be placed in a skin crease two
fingerbreadths above the sternal notch between the medial borders of the sternocleidomastoid
muscles. Subcutaneous fat and platysma are divided. Subplatysmal dissection plane will be
developed up to the level of the thyroid cartilage above, and the sternal notch below.
Separating strap muscles and exposing the anterior surface of the thyroid. The fascia between
the sternohyoid and sternothyroid muscles is divided along the midline with diathermy or
scissors. The infrahyoid strap muscles will be retracted laterally with a right-angled retractor.
The middle thyroid vein will be ligated. Ligate the superior thyroid artery near the external
branch of the superior laryngeal nerve. Will take great care to ligate the artery as close to the
thyroid parenchyma as possible so as to avoid injury to the nerve. The superior arterial
pedicle will be double ligated. The recurrent laryngeal nerves must remain undisturbed and
in situ. A negative drain tube will be kept in situ. The wound will be closed in a layer by
layer. In all cases, the specimen will send for histopathology.

20
Dummy Results

Table I: Patient characteristics (n= 22)

Characteristics Number/mean ±SD

Sex
Male
Female

Age, years

Preoperative diagnosis
DTC with cN0
DTC with cN+
Data are expressed as number or as mean ± standard deviation
A p-value of ˂ 0.05 considered statistically significant

Table II: Comparison of type of surgery with RLN palsy patients (n=22)
Characteristics All patients No. of cases with P-value
palsy
Sex
Male
Female
Age , years
Type of surgery
Total thyroidectomy with central
clearance
Total thyroidectomy without central
clearance

21
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