MEDLINE (OvidSP)

1. Recurrent Laryngeal Nerve Injuries/

2. Vocal Cord Paralysis/

3. Recurrent Laryngeal Nerve/

4. Intraoperative Complications/

5. ((vocal or laryngeal) adj3 (nerve? or pals* or paralys* or injur*)).tw.

6. rln.tw.

7. or/1‐6

8. exp Monitoring, Intraoperative/

9. Electromyography/

10. monitor*.tw.

11. neuromonitor*.tw.

12. (ionm or rlnm).tw.

13. electromyogra*.tw.

14. or/8‐13

15. Thyroidectomy/

16. Thyroid Diseases/su

17. exp Thyroid Neoplasms/su

18. Thyroid Gland/su

19. ((parathyroid or thyroid) adj3 (surg* or dissect* or resect* or cancer or neoplasm? or operat* or malign*)).tw.

20. thyroidectom*.tw.

21. or/15‐20

22. 7 and 14 and 21

[23‐33: Cochrane Handbook 2008 RCT filter ‐ sensitivity maximizing version]

23. randomized controlled trial.pt.

24. controlled clinical trial.pt.

25. randomi?ed.ab.

26. placebo.ab.

27. drug therapy.fs.

28. randomly.ab.

29. trial.ab.

30. groups.ab.

31. or/23‐30

32. exp animals/ not humans/

33. 31 not 32

34. 22 and 33

[35:Wong 2006a– systematic reviews filter – SensSpec version]

35. meta analysis.mp,pt. or review.pt. or search*.tw.

36. 22 and 35

37. 34 or 36

Embase (Ovid SP)

1. recurrent laryngeal nerve injury/

2. recurrent laryngeal nerve palsy/

3. recurrent laryngeal nerve/

4. vocal cord paralysis/

5. peroperative complication/

6. ((vocal or laryngeal) adj3 (nerve? or pals* or paralys* or injur*)).tw.

7. rln.tw.

8. or/1‐7

9. neurophysiological monitoring/

10. neuromonitoring/

11. electromyography/

12. monitor*.tw.

13. neuromonitor*.tw.

14. (ionm or rlnm).tw.

15. electromyogra*.tw.

16. or/9‐15

17. exp thyroid surgery/

18. ((parathyroid or thyroid) adj3 (surg* or dissect* or resect* or cancer or neoplasm? or operat* or malign*)).tw.

19. thyroidectom*.tw.

20. or/17‐19

21. 8 and 16 and 20

[22:Wong 2006b"sound treatment studies" filter – BS version]

22. random*.tw. or clinical trial*.mp. or exp health care quality/

23. 21 and 22

Cochrane Central Register of Controlled Trials (Cochrane Register of Studies Online)

1. MESH DESCRIPTOR Recurrent Laryngeal Nerve Injuries

2. MESH DESCRIPTOR Vocal Cord Paralysis

3. MESH DESCRIPTOR Recurrent Laryngeal Nerve

4. MESH DESCRIPTOR Intraoperative Complications

5. ((vocal or laryngeal) ADJ3 (nerve? or pals* or paralys* or injur*)):TI,AB,KY

6. rln:TI,AB,KY

7. #1 OR #2 OR #3 OR #4 OR #5 OR #6

8. MESH DESCRIPTOR Monitoring, Intraoperative EXPLODE ALL TREES

9. MESH DESCRIPTOR Electromyography

10. monitor*:TI,AB,KY

11. neuromonitor*:TI,AB,KY

12. (ionm or rlnm):TI,AB,KY

13. electromyogra*:TI,AB,KY

14. #8 OR #9 OR #10 OR #11 OR #12 OR #13

15. MESH DESCRIPTOR Thyroidectomy

16. MESH DESCRIPTOR Thyroid Diseases WITH QUALIFIERS SU

17. MESH DESCRIPTOR Thyroid Neoplasms EXPLODE ALL TREES WITH QUALIFIERS SU

18. MESH DESCRIPTOR Thyroid Gland WITH QUALIFIERS SU

19. ((parathyroid or thyroid) ADJ3 (surg* or dissect* or resect* or cancer or neoplasm? or operat* or malign*)):TI,AB,KY

20. thyroidectom*:TI,AB,KY

21. #15 OR #16 OR #17 OR #18 OR #19 OR #20

22. #7 AND #14 AND #21

WHO ICTRP Search Portal (Standard search)

laryin* AND neuromonitor* OR

vocal AND neuromonitor* OR

rln AND neuromonitor* OR

laryin* AND monitor* OR

vocal AND monitor* OR

rln AND monitor* OR

laryin* AND electromyograph* OR

vocal AND electromyograph* OR

rln AND electromyograph* OR

ionm OR

rlnm

ClinicalTrials.gov (Basic search)

(laryngeal OR vocal OR RLN OR complication OR complications) AND (monitor OR neuromonitor OR monitoring OR neuromonitoring OR electromyography OR electromyographic OR IONM OR RLNM) AND (thyroid OR parathyroid OR thyroidectomy)

'Risk of bias' domains

Random sequence generation (selection bias due to inadequate generation of a randomised sequence)

For each included trial, we described the method used to generate the allocation sequence in sufficient detail to allow an assessment of whether it should produce comparable groups.

• Low risk of bias: the trial authors achieved sequence generation using computer‐generated random numbers or a random numbers table. Drawing of lots, tossing a coin, shuffling cards or envelopes, and throwing dice are adequate if an independent person performed this who was not otherwise involved in the trial. We considered the use of the minimisation technique as equivalent to being random.

• Unclear risk of bias: insufficient information about the sequence generation process.

• High risk of bias: the sequence generation method was non‐random or quasi‐random (e.g. sequence generated by odd or even date of birth; sequence generated by some rule based on date (or day) of admission; sequence generated by some rule based on hospital or clinic record number; allocation by judgment of the clinician; allocation by preference of the participant; allocation based on the results of a laboratory test or a series of tests; or allocation by availability of the intervention).

Allocation concealment (selection bias due to inadequate concealment of allocation prior to assignment)

We described for each included trial the method used to conceal allocation to interventions prior to assignment and we assessed whether intervention allocation could have been foreseen in advance of or during recruitment, or changed after assignment.

• Low risk of bias: central allocation (including telephone, interactive voice‐recorder, web‐based and pharmacy‐controlled randomisation); sequentially numbered drug containers of identical appearance; sequentially numbered, opaque, sealed envelopes.

• Unclear risk of bias: insufficient information about the allocation concealment.

• High risk of bias: used an open random allocation schedule (e.g. a list of random numbers); assignment envelopes used without appropriate safeguards; alternation or rotation; date of birth; case record number; any other explicitly unconcealed procedure.

We also evaluated trial baseline data to incorporate assessment of baseline imbalance into the 'Risk of bias' judgment for selection bias (Corbett 2014; Egbewale 2014; Riley 2013). Chance imbalances may also affect judgments on the risk of attrition bias. In the case of unadjusted analyses, we distinguished between trials that we rated as being at low risk of bias on the basis of both randomisation methods and baseline similarity, and trials that we judged as being at low risk of bias on the basis of baseline similarity alone (Corbett 2014). We will reclassify judgements of unclear, low or high risk of selection bias as specified in Appendix 5.

Blinding of participants and study personnel (performance bias due to knowledge of the allocated interventions by participants and personnel during the trial)

We evaluated the risk of detection bias separately for each outcome (Hróbjartsson 2013). We noted whether endpoints were self‐reported, investigator‐assessed or adjudicated outcome measures (see below).

• Low risk of bias: blinding of participants and key study personnel was ensured, and it was unlikely that the blinding could have been broken; no blinding or incomplete blinding, but we judged that the outcome was unlikely to have been influenced by lack of blinding.

• Unclear risk of bias: insufficient information about the blinding of participants and study personnel; the trial does not address this outcome.

• High risk of bias: no blinding or incomplete blinding, and the outcome was likely to have been influenced by lack of blinding; blinding of trial participants and key personnel attempted, but likely that the blinding could have been broken, and the outcome was likely to be influenced by lack of blinding.

Blinding of outcome assessment (detection bias due to knowledge of the allocated interventions by outcome assessment

We evaluated the risk of detection bias separately for each outcome (Hróbjartsson 2013). We noted whether endpoints were self‐reported, investigator‐assessed or adjudicated outcome measures (see below).

• Low risk of bias: blinding of outcome assessment is ensured, and it was unlikely that the blinding could have been broken; no blinding of outcome assessment, but we judged that the outcome measurement was unlikely to have been influenced by lack of blinding.

• Unclear risk of bias: insufficient information about the blinding of outcome assessors; the trial did not address this outcome.

• High risk of bias: no blinding of outcome assessment, and the outcome measurement was likely to have been influenced by lack of blinding; blinding of outcome assessment, but likely that the blinding could have been broken, and the outcome measurement was likely to be influenced by lack of blinding.

Incomplete outcome data (attrition bias due to amount, nature or handling of incomplete outcome data)

For each included trial and/or each outcome, we described the completeness of data, including attrition and exclusions from the analyses. We stated whether the trial reported attrition and exclusions, and report the number of participants included in the analysis at each stage (compared with the number of randomised participants per intervention/comparator groups). We also noted if the trial reported the reasons for attrition or exclusion and whether missing data were balanced across groups or were related to outcomes. We considered the implications of missing outcome data per outcome such as high dropout rates (e.g. above 15%) or disparate attrition rates (e.g. difference of 10% or more between trial arms).

• Low risk of bias: no missing outcome data; reasons for missing outcome data unlikely to be related to true outcome (for survival data, censoring unlikely to introduce bias); missing outcome data balanced in numbers across intervention groups, with similar reasons for missing data across groups; for dichotomous outcome data, the proportion of missing outcomes compared with observed event risk was not enough to have a clinically relevant impact on the intervention effect estimate; for continuous outcome data, plausible effect size (mean difference or standardised mean difference) among missing outcomes was not enough to have a clinically relevant impact on observed effect size; appropriate methods, such as multiple imputation, were used to handle missing data.

• Unclear risk of bias: insufficient information to assess whether missing data in combination with the method used to handle missing data were likely to induce bias; the trial did not address this outcome.

• High risk of bias: reason for missing outcome data was likely to be related to true outcome, with either imbalance in numbers or reasons for missing data across intervention groups; for dichotomous outcome data, the proportion of missing outcomes compared with observed event risk enough to induce clinically relevant bias in the intervention effect estimate; for continuous outcome data, plausible effect size (mean difference or standardised mean difference) among missing outcomes enough to induce clinically‐relevant bias in observed effect size; 'as‐treated' or similar analysis done with substantial departure of the intervention received from that assigned at randomisation; potentially inappropriate application of simple imputation.

Selective reporting (reporting bias due to selective outcome reporting)

We assessed outcome reporting bias by integrating the results of the appendix 'Matrix of trial endpoints (publications and trial documents)' (Boutron 2014; Jones 2015; Mathieu 2009), with those of the appendix 'High risk of outcome reporting bias according to the Outcome Reporting Bias In Trials (ORBIT) classification' (Kirkham 2010). This analysis formed the basis for the judgement of selective reporting.

• Low risk of bias: the trial protocol was available and all the trial's prespecified (primary and secondary) outcomes that were of interest to this review were reported in the prespecified way; the study protocol was unavailable, but it was clear that the published reports included all expected outcomes (ORBIT classification).

• Unclear risk of bias: insufficient information about selective reporting.

• High risk of bias: not all the trial's prespecified primary outcomes were reported; one or more primary outcomes were reported using measurements, analysis methods or subsets of the data (e.g. subscales) that were not prespecified; one or more reported primary outcomes were not prespecified (unless clear justification for their reporting was provided, such as an unexpected adverse effect); one or more outcomes of interest in the Cochrane Review were reported incompletely so that we could not enter them in a meta‐analysis; the trial report failed to include results for a key outcome that we would expect to have been reported for such a trial (ORBIT classification).

Other bias

• Low risk of bias: the trial appears to be free from other sources of bias.

• Unclear risk of bias: there was insufficient information to assess whether an important risk of bias existed; insufficient rationale or evidence that an identified problem introduced bias.

• High risk of bias: the trial had a potential source of bias related to the specific trial design used; the trial was claimed to be fraudulent; or the trial had some other serious problem.

Selection bias decisions for trials reporting unadjusted analyses: comparison of results obtained using method details alone with results using method details and trial baseline information^a

Reported randomisation and allocation concealment methods

'Risk of bias' judgement using methods reporting

Information gained from study characteristics data

'Risk of bias' judgement using baseline information and methods reporting

Unclear methods

Unclear risk

Baseline imbalances present for important prognostic variable(s)

High risk

Groups appear similar at baseline for all important prognostic variables

Low risk

Limited or no baseline details

Unclear risk

Would generate a truly random sample, with robust allocation concealment

Low risk

Baseline imbalances present for important prognostic variable(s)

Unclear risk^c

Groups appear similar at baseline for all important prognostic variables

Low risk

Limited baseline details, showing balance in some important prognostic variables^b

Low risk

No baseline details

Unclear risk

Sequence is not truly random, or allocation concealment is inadequate

High risk

Baseline imbalances present for important prognostic variable(s)

High risk

Groups appear similar at baseline for all important prognostic variables

Low risk

Limited baseline details, showing balance in some important prognostic variables^b

Unclear risk

No baseline details

High risk

^aTaken from Corbett 2014; judgements highlighted in bold indicate situations in which the addition of baseline assessments would change the judgement about risk of selection bias, compared with using methods reporting alone.
^bDetails for the remaining important prognostic variables not reported.
^cImbalance identified, which appears likely to be due to chance.

Trial ID

Intervention

Comparator

Hei 2016a

RILN visualisation + IONM

RILN visualisation

Lee 2015

RILN visualisation + IONM

RILN visualisation

Barczynski 2012

RILN visualisation + IONM

RILN visualisation

Sari 2010

RILN visualisation + IONM

RILN visualisation

Barczynski 2009

RILN visualisation + IONM

RILN visualisation

IONM: intraoperative nerve monitoring; RILN: recurrent inferior laryngeal nerve

Trial ID

Intervention and comparator

Duration of follow‐up

Description of participants

Trial period
(year to year)

Country

Setting

Ethnic groups
(%)

Duration of thyroid disease

Hei 2016a

I: RILN visualisation + IONM

6 months

Participants with thyroid neoplastic (papillary, follicular and medullary carcinoma) (77%) or nontoxic nodular goitre recurrence (23%) after thyroidectomy

January 2012 to August 2014

China

Inpatient

Asian (100)

‐

C: RILN visualisation

Asian (100)

‐

Lee 2015

I: RILN visualisation + IONM

12 months

Participants with papillary thyroid carcinoma (100%)

March 2011 to September 2012

Korea

Inpatient

Asian (100)

‐

C: RILN visualisation

Asian (100)

‐

Barczynski 2012

I: RILN visualisation + IONM

6 months

Participants with Graves’ disease (5%), thyroid carcinoma (12%), toxic (15%) and nontoxic (68%) nodular goitre

September 2009 to June 2010

Poland

Inpatient

White (100)

‐

C: RILN visualisation

White (100)

‐

Sari 2010

I: RILN visualisation + IONM

12 months

Participants with Graves’ disease (9%), toxic adenoma (6%), solitary adenoma (14%), thyroid carcinoma (17%), toxic (14%) and nontoxic (39%) multinodular goitre

September 2007 to September 2009

Turkey

Inpatient

White (100)

‐

C: RILN visualisation

White (100)

‐

Barczynski 2009

I: RILN visualisation + IONM

12 months

Participants with Graves’ disease (6%), thyroid carcinoma (12%), thyroiditis (2%), toxic (10%) and nontoxic nodular goitre (70%)

January 2006 to June 2007

Poland

Inpatient

White (100)

‐

C: RILN visualisation

White (100)

‐

‐ denotes not reported

C: comparator; I: intervention; IONM: intraoperative nerve monitoring; RILN: recurrent inferior laryngeal nerve

Trial ID

Intervention and comparator

Sex
(female %)

Age
(mean/range years (SD))

BMI
(mean kg/m² (SD))

Type of thyroidectomy
(%)

Experience in thyroid surgery

Comedications/co‐interventions
(% of participants)

Comorbidities
(% of participants)

Hei 2016a

I: RILN visualisation + IONM

70

48.3 (9.1)

‐

Thyroid reoperation (100)

"1 experienced thyroid surgeon who had more than 20 years’ experience with thyroidectomy"

Extended central neck compartment dissection (94)

‐

C: RILN visualisation

84

46.8 (10.6)

‐

Thyroid reoperation (100)

Extended central neck compartment dissection (94)

‐

Lee 2015

I: RILN visualisation + IONM

92

44.2 (11.9)

‐

Robotic thyroidectomy using the bilateral axillo‐breast approach (100)

"The same surgeon with more than 10 years of experience in robotic surgery"

‐

‐

C: RILN visualisation

76

41.7 (9.0)

‐

Robotic thyroidectomy using the bilateral axillo‐breast approach (100)

‐

‐

Barczynski 2012

I: RILN visualisation + IONM

100

50.3 (15.3)

‐

Total thyroidectomy (100)

"Three experienced endocrine surgeons"

Central neck compartment dissection (13)

‐

C: RILN visualisation

100

49.7 (14.1)

‐

Total thyroidectomy (100)

Central neck compartment dissection (13)

‐

Sari 2010

I: RILN visualisation + IONM

85

47.2 (14)

26.9 (3)

Total thyroidectomy (19), lobectomy (81)

"The same surgeons in all patients"

‐

‐

C: RILN visualisation

80

48.3 (12)

27.3 (3)

Total thyroidectomy (23), lobectomy (77)

‐

.

Barczynski 2009

I: RILN visualisation + IONM

76

51.3 (14.4)

‐

Total thyroidectomy (76), Dunhill operation (19), bilateral subtotal thyroidectomy (5)

"Three experienced endocrine surgeons"

Central neck compartment dissection (12), lateral neck dissection (3)

‐

C: RILN visualisation

76

51.9 (14.7)

‐

Total thyroidectomy (74), Dunhill operation (20), bilateral subtotal thyroidectomy (6)

Central neck compartment dissection (12), lateral neck dissection (2)

‐

‐ denotes not reported

C: comparator; Dunhill operation: unilateral thyroid lobectomy and contralateral subtotal thyroid resection; I: intervention; IONM: intraoperative nerve monitoring; RILN: recurrent inferior laryngeal nerve; SD: standard deviation

Trial ID

Endpoints quoted in trial document(s)
(ClinicalTrials.gov, FDA/EMA document, manufacturer's website, published design paper)^a

Trial results available in trial register

Endpoints quoted in publication(s)^b,c

Endpoints quoted in abstract of publication(s)^b,c

Hei 2016a

N/T

Primary outcome measures: temporary and permanent RILN paralysis

Primary outcome measures: temporary and permanent RILN paralysis

Secondary outcome measure: ‐

Secondary outcome measure: ‐

Other outcome measure: ‐

Other outcome measure: ‐

Lee 2015

N/T

Primary outcome measures: transient or permanent laryngeal nerve lesions; the Voice Handicap Index and the Voice Range Profile

Primary outcome measures: transient or permanent laryngeal nerve lesions, the Voice Handicap Index and the Voice Range Profile

Secondary outcome measure: ‐

Secondary outcome measure: ‐

Other outcome measure: ‐

Other outcome measure: ‐

Barczynski 2012

Source:NCT01395134

Primary outcome measure: identification rate of the EBSLN

Yes (last verified: 1 March 2017)

Primary outcome measure: identification rate of the EBSLN

Primary outcome measure: identification rate of the EBSLN

Secondary outcome measures: anatomical variability of the external branch of the superior laryngeal nerve according to Cernea classification, incidence of EBSLN and RILN injuries assessed by videostrobolaryngoscopy (transient and permanent), changes in postoperative voice performance (pre‐ and postoperative assessment): analysis of maximum phonation time, voice level, fundamental frequency and voice quality rating on GRBAS scale

Secondary outcome measure: incidence of EBSLN and RILN injuries assessed by videostrobolaryngoscopy (transient, permanent and overall); changes in postoperative voice performance (pre‐ and postoperative assessment): analysis of maximum phonation time, voice level, fundamental frequency and voice quality rating on GRBAS scale

Secondary outcome measures: transient RILN injuries; changes in postoperative voice performance: analysis of maximum phonation time, voice level, fundamental frequency and voice quality rating on GRBAS scale

Other outcome measure: ‐

Other outcome measure: ‐

Other outcome measure: ‐

History of changes: 2 documented changes; last change 14 July 2011

Sari 2010

N/T

Primary outcome measures: identification time of RILN, operating time, persistent and transient RILN, persistent and transient hypoparathyroidism

Primary outcome measures: identification time of RILN, operating time, postoperative complications

Secondary outcome measure: ‐

Secondary outcome measure: ‐

Other outcome measure: ‐

Other outcome measure: ‐

Barczynski 2009

Source:NCT00661024

Primary outcome measure: incidence of the recurrent laryngeal nerve injury (evaluated on 2nd postoperative day and at 1, 2, 4, 6 and 12 months postoperatively, if paresis was noted on first examination)

Yes (last verified: 1 March 2017)

Primary outcome measure: transient and permanent RILN injuries

Primary outcome measure: transient and permanent RILN injuries

Secondary outcome measures: IONM‐added value to RILN identification, the value of IONM in prediction of postoperative vocal cords function (intraoperative data compared with observation of vocal cords function postoperatively on the 2nd postoperative day)

Secondary outcome measures: IONM‐added value to RILN identification, value of IONM in prediction of postoperative vocal cords function

Secondary outcome measure: ‐

Other outcome measure: ‐

Other outcome measures: technical problems and intraoperative complications related to IONM

Other outcome measure: ‐

History of changes: 2 documented changes; last change 17 April 2008

‐ denotes not reported

^aTrial document(s) refers to all available information from published design papers and sources other than regular publications (e.g. FDA/EMA documents, manufacturer's websites, trials registers).
^bPublication(s) refers to trial information published in scientific journals (primary reference, duplicate publications, companion documents or multiple reports of a primary trial).
^cPrimary and secondary outcomes refer to verbatim specifications in publication/records. Other outcome measures refer to all outcomes not specified as primary or secondary outcome measures.

EMA: European Medicines Agency; EBSLN: external branch of the superior laryngeal nerve; FDA: Food and Drug Administration (US); GRBAS: grade, roughness, breathiness, asthenia, strain; IONM: intraoperative nerve monitoring; N/T: no trial document available; RILN: recurrent inferior laryngeal nerve

Trial ID

Outcome

High risk of bias
(category A)^a

High risk of bias
(category D)^b

High risk of bias
(category E)^c

High risk of bias
(category G)^d

Hei 2016a

N/A

Lee 2015

N/A

Barczynski 2012

N/A

Sari 2010

N/A

Barczynski 2009

N/A

^aClear that outcome was measured and analysed; trial report states that outcome was analysed but reports only that result was not significant (Classification 'A', table 2, Kirkham 2010).
^bClear that outcome was measured and analysed; trial report states that outcome was analysed but report no results (Classification 'D', table 2, Kirkham 2010).
^cClear that outcome was measured but was not necessarily analysed; judgement says likely to have been analysed but not reported because of non‐significant results (Classification 'E', table 2, Kirkham 2010).
^dUnclear whether outcome was measured; not mentioned, but clinical judgement says likely to have been measured and analysed but not reported on the basis of non‐significant results (Classification 'G', table 2, Kirkham 2010).

N/A: not applicable; ORBIT: Outcome Reporting Bias In Trials

Trial ID

All‐cause mortality

Operative time

Transient RILN palsy

Health‐related quality of life

Permanent RILN palsy

Socioeconomic effects

Hei 2016a

N/R

N/R

"If RILN paralysis occurred, laryngoscopy was carried out routinely at 1, 3, and 6 months after operation and at the time that the patients felt that their voice obviously improved" (IO)

N/R

Dysfunction was defined as no recovery of function during the first 6 months after thyroid reoperation (IO)

N/R

Lee 2015

N/R

N/D

"VHI, VRP, and laryngoscopy were used to test voice function before surgery and at 2 weeks, 3 months, and 6 months after the operation" (IO)

N/R

RILN palsy was considered permanent if it persisted for 12 months (IO)

N/R

Barczynski 2012

N/D

The time from skin incision to skin closure"(IO)

"VSL was performed on day 1 postoperatively; in case of abnormal findings, reevaluation was done at 3 and 6 months postoperatively" (IO)

N/R

Vocal cord paresis for 6 months or more following the operation was regarded as permanent palsy (IO)

N/R

Sari 2010

N/D

"The time from skin preparation to closure of the skin incisions" (IO)

"In cases of dysphonia with vocal cord injury, indirect laryngoscopy was also performed 1 and 6 months later" (IO)

N/R

"Persistent nerve palsy was defined as persistent dysfunction and clinical dysphonia that lasted for 12 months postoperatively" (IO)

N/R

Barczynski 2009

N/D

"The time from skin incision to skin closure" (IO)

"Indirect laryngoscopy by a throat specialist was mandatory before surgery and on day 2 after surgery. In patients with RILN paresis, an additional examination was scheduled at 2 weeks and 1, 2, 4, 6 and 12 months after surgery, or until the vocal cord function recovered" (IO)

N/R

"Vocal cord paresis for more than 12 months after the operation was regarded as permanent palsy" (IO)

N/R

^aIn addition to definition of endpoint measurement, description of who measured the outcome (AO: adjudicated outcome measurement; IO: investigator‐assessed outcome measurement; SO: self‐reported outcome measurement)

N/D: not defined; N/R: not reported; RILN: recurrent inferior laryngeal nerve; VHI: Voice Handicap Index; VRP: Voice Range Profile; VSL: videostrobolaryngoscopy

Trial ID

Adverse events other than permanent or transient RILN palsy

Severe/serious
adverse events

Hei 2016a

Transient hypoparathyroidism: N/R

Permanent hypoparathyroidism: N/R

N/R

Lee 2015

Transient hypoparathyroidism: N/D (IO)

Permanent hypoparathyroidism: N/D (IO)

N/R

Barczynski 2012

Transient hypoparathyroidism: N/R

Permanent hypoparathyroidism: N/R

N/R

Sari 2010

Transient hypoparathyroidism: N/D (IO)

Permanent hypoparathyroidism: N/D (IO)

N/R

Barczynski 2009

Transient hypoparathyroidism: N/R

Permanent hypoparathyroidism: N/R

N/R

^aIn addition to definition of endpoint measurement, description who measured the outcome (AO: adjudicated outcome measurement; IO: investigator‐assessed outcome measurement; SO: self‐reported outcome measurement)

N/D: not defined; N/R: not reported; RILN: recurrent inferior laryngeal nerve

Trial ID

Intervention(s) and comparator(s)

Participants included in analysis
(N)

Deaths
(N)

Deaths
(% of participants)

Participants with at least one adverse event
(N)

Participants with at least one adverse event
(%)

Participants with at least one severe/serious adverse event
(N)

Participants with at least one severe/serious adverse event
(%)

Hei 2016a

I: RILN visualisation + IONM

33

‐

‐

‐

‐

‐

‐

C: RILN visualisation

37

‐

‐

‐

‐

‐

‐

Lee 2015

I: RILN visualisation + IONM

25

‐

‐

9

36

0

0

C: RILN visualisation

25

‐

‐

4

12

0

0

Barczynski 2012

I: RILN visualisation + IONM

100

0

0

‐

‐

‐

‐

C: RILN visualisation

101

0

0

‐

‐

‐

‐

Sari 2010

I: RILN visualisation + IONM

122

0

0

11

11.1

‐

‐

C: RILN visualisation

114

0

0

13

8.8

‐

‐

Barczynski 2009

I: RILN visualisation + IONM

500

0

0

‐

‐

‐

‐

C: RILN visualisation

500

0

0

‐

‐

‐

‐

‐ denotes not reported

C: comparator; I: intervention; IONM: intraoperative nerve monitoring; N: number of participants; RILN: recurrent inferior laryngeal nerve

Trial ID

Intervention(s) and comparator(s)

Participants included in analysis
(N)

Participants discontinuing trial due to an adverse event
(N)

Participants discontinuing trial due to an adverse event
(%)

Hei 2016a

I: RILN visualisation + IONM

33

0

0

C: RILN visualisation

37

0

0

Lee 2015

I: RILN visualisation + IONM

25

0

0

C: RILN visualisation

25

0

0

Barczynski 2012

I: RILN visualisation + IONM

100

0

0

C: RILN visualisation

101

0

0

Sari 2010

I: RILN visualisation + IONM

122

0

0

C: RILN visualisation

114

0

0

Barczynski 2009

I: RILN visualisation + IONM

500

0

0

C: RILN visualisation

500

0

0

‐ denotes not reported

C: comparator; I: intervention; IONM: intraoperative nerve monitoring; RILN: recurrent inferior laryngeal nerve

Trial ID

Intervention(s) and comparator(s)

Participants included in analysis
(N)

Participants with a specific adverse event
(description)

Participants with at least one specific adverse events
(N)

Participants with at least one specific adverse event
(%)

Hei 2016a

I: RILN visualisation + IONM

33

(1) Permanent RILN palsy

(2) Transient RILN palsy

(1) 0

(2) 5

(1) 0

(2) 15.2

C: RILN visualisation

37

(1) Permanent RILN palsy

(2) Transient RILN palsy

(1) 0

(2) 3

(1) 0

(2) 8.1

Lee 2015

I: RILN visualisation + IONM

25

(1) Permanent RILN palsy

(2) Transient RILN palsy

(3) Permanent hypoparathyroidism

(4) Transient hypoparathyroidism

(1) 0

(2) 0

(3) 0

(4) 9

(1) 0

(2) 0

(3) 0

(4) 36

C: RILN visualisation

25

(1) Permanent RILN palsy

(2) Transient RILN palsy

(3) Permanent hypoparathyroidism

(4) Transient hypoparathyroidism

(1) 0

(2) 0

(3) 0

(4) 4

(1) 0

(2) 0

(3) 0

(4) 12

Barczynski 2012

I: RILN visualisation + IONM

100

(1) Permanent RILN palsy

(2) Transient RILN palsy

(1) 0

(2) 3

(1) 0

(2) 3

C: RILN visualisation

101

(1) Permanent RILN palsy

(2) Transient RILN palsy

(1) 0

(2) 8

(1) 0

(2) 7.9

Sari 2010

I: RILN visualisation + IONM

122

(1) Permanent RILN palsy

(2) Transient RILN palsy

(3) Permanent hypoparathyroidism

(4) Transient hypoparathyroidism

(1) 0

(2) 3

(3) 0

(4) 11

(1) 0

(2) 2.5

(3) 0

(4) 11.1

C: RILN visualisation

114

(1) Permanent RILN palsy

(2) Transient RILN palsy

(3) Permanent hypoparathyroidism

(4) Transient hypoparathyroidism

(1) 0

(2) 3

(3) 0

(4) 13

(1) 0

(2) 2.6

(3) 0

(4) 8.8

Barczynski 2009

I: RILN visualisation + IONM

500

(1) Permanent RILN palsy

(2) Transient RILN palsy

(1) 0

(2) 19

(1) 0

(2) 3.8

C: RILN visualisation

500

(1) Permanent RILN palsy

(2) Transient RILN palsy

(1) 0

(2) 38

(1) 0

(2) 7.6

‐ denotes not reported

C: comparator; I: intervention; IONM: intraoperative nerve monitoring; RILN: recurrent inferior laryngeal nerve

Trial ID

Date trial author contacted

Date trial author replied

Hei 2016a

14 June 2017 and 18 January 2018

No answer

Lee 2015

14 June 2017 and 18 January 2018

No answer

Barczynski 2012

Co‐author of this review

Sari 2010

14 June 2017 and 18 January 2018

No answer

Barczynski 2009

Co‐author of this review

(1) Permanent RILN palsy

(2) Transient RILN palsy

(3) Health‐related quality of life

(4) Adverse events other than permanent or transient RILN palsy

(5) Operative time

(6) All‐cause mortality

(7) Socioeconoic effects

Trial limitations
(risk of bias)^a

Was random sequence generation used (i.e. no potential for selection bias)?

Yes

Yes

N/A

Yes

Yes

Yes

N/A

Was allocation concealment used (i.e. no potential for selection bias)?

Unclear

Unclear

Unclear

Unclear

Unclear

Was there blinding of participants and personnel (i.e. no potential for performance bias) or outcome not likely to be influenced by lack of blinding?

No (↓)

No (↓)

Unclear

No (↓)

Yes

Was there blinding of outcome assessment (i.e. no potential for detection bias) or was outcome measurement not likely to be influenced by lack of blinding?

Yes

Unclear

Unclear

Unclear

Yes

Was an objective outcome used?

Yes

Yes

Yes

Yes

Yes

Were more than 80% of participants enrolled in trials included in the analysis (i.e. no potential reporting bias)?^e

Yes

Yes

Yes

Yes

Yes

Were data reported consistently for the outcome of interest (i.e. no potential selective reporting)?

Yes

Yes

Yes

Yes

Yes

No other biases reported (i.e. no potential of other bias)?

Unclear

Unclear

Unclear

Unclear

Unclear

Did the trials end up as scheduled (i.e. not stopped early)?

Yes

Yes

Yes

Yes

Yes

Inconsistency^b

Point estimates did not vary widely?

Yes

Yes

Yes

Yes

N/A

To what extent did confidence intervals overlap (substantial: all confidence intervals overlap at least one of the included studies point estimate; some: confidence intervals overlap but not all overlap at least one point estimate; no: at least one outlier: where the confidence interval of some of the studies do not overlap with those of most included studies)?

Substantial

Substantial

Substantial

Substantial

N/A

Was the direction of effect consistent?

No (↓)

Yes

No (↓)

No (↓)

N/A

What was the magnitude of statistical heterogeneity (as measured by I²) ‐ low (I² < 40%), moderate (I² 40%‐60%), high I² > 60%)?

Low

Low

High (↓)

High (↓)

N/A

Was the test for heterogeneity statistically significant (P < 0.1)?

Not statistically significant

Not statistically significant

Not statistically significant

Statistically significant (↓)

N/A

Indirectness

Were the populations in included studies applicable to the decision context?

Highly applicable

Highly applicable

Highly applicable

Highly applicable

Highly applicable

Were the interventions in the included studies applicable to the decision context?

Highly applicable

Highly applicable

Highly applicable

Highly applicable

Highly applicable

Was the included outcome not a surrogate outcome?

Yes

Yes

Yes

Yes

Yes

Was the outcome timeframe sufficient?

Sufficient

Sufficient

Sufficient

Sufficient

Sufficient

Were the conclusions based on direct comparisons?

Yes

Yes

Yes

Yes

Yes

Imprecision^c

Was the confidence interval for the pooled estimate not consistent with benefit and harm?

No (↓)

No (↓)

No (↓)

No (↓)

N/A

What is the magnitude of the median sample size (high: 300 participants, intermediate: 100‐300 participants, low: < 100 participants)?^e

Intermediate

Intermediate

Intermediate

Intermediate

Intermediate

What was the magnitude of the number of included studies (large: > 10 studies, moderate: 5‐10 studies, small: < 5 studies)?^e

Small (↓)

Small (↓)

Small (↓)

Small (↓)

Small (↓)

Was the outcome a common event (e.g. occurs more than 1/100)?

No (↓)

Yes

Yes

N/A

N/A

Publication bias^d

Was a comprehensive search conducted?

Yes

Yes

Yes

Yes

Yes

Was grey literature searched?

Yes

Yes

Yes

Yes

Yes

Were no restrictions applied to study selection on the basis of language?

Yes

Yes

Yes

Yes

Yes

There was no industry influence on studies included in the review?

Yes

Yes

Yes

Yes

Yes

There was no evidence of funnel plot asymmetry?

N/A

N/A

N/A

N/A

N/A

There was no discrepancy in findings between published and unpublished trials?

N/A

N/A

N/A

N/A

N/A

^aQuestions on risk of bias are answered in relation to the majority of the aggregated evidence in the meta‐analysis rather than to individual trials.
^bQuestions on inconsistency are primarily based on visual assessment of forest plots and the statistical quantification of heterogeneity based on I² statistic.

^cWhen judging the width of the confidence interval it is recommended to use a clinical decision threshold to assess whether the imprecision is clinically meaningful.
^dQuestions address comprehensiveness of the search strategy, industry influence, funnel plot asymmetry and discrepancies between published and unpublished trials.
^eDepends on the context of the systematic review area.

(↓): key item for potential downgrading the quality of the evidence (GRADE) as shown in the footnotes of the 'Summary of finding' table(s); N/A: not applicable