Advertisement

Systematic review with meta-analysis of studies comparing intraoperative neuromonitoring of recurrent laryngeal nerves versus visualization alone during thyroidectomy

Published:December 27, 2013DOI:https://doi.org/10.1016/j.jss.2013.12.022

      Abstract

      Background

      The role of intraoperative neuromonitoring (IONM) of the recurrent laryngeal nerve (RLN) during thyroid surgery is still debatable. The aim of this meta-analysis was to evaluate the potential improvement of IONM versus RLN visualization alone (VA) in reducing the incidence of vocal cord palsy.

      Methods

      A literature search for studies comparing IONM versus VA during thyroidectomy was performed. Studies were reviewed for primary outcome measures: overall, transient, and permanent RLN palsy per nerve and per patients at risk; and for secondary outcome measures: operative time; overall, transient and permanent RLN palsy per nerve at low and high risk; and the results regarding assistance in RLN identification before visualization.

      Results

      Twenty studies comparing thyroidectomy with and without IONM were reviewed: three prospective, randomized trials, seven prospective trials, and ten retrospective, observational studies. Overall, 23,512 patients were included, with thyroidectomy performed using IONM compared with thyroidectomy by VA. The total number of nerves at risk was 35,513, with 24,038 nerves (67.7%) in the IONM group, compared with 11,475 nerves (32.3%) in the VA group. The rates of overall RLN palsy per nerve at risk were 3.47% in the IONM group and 3.67% in the VA group. The rates of transient RLN palsy per nerve at risk were 2.62% in the IONM group and 2.72% in the VA group. The rates of permanent RLN palsy per nerve at risk were 0.79% in the IONM group and 0.92% and in the VA group. None of these differences were statistically significant, and no other differences were found.

      Conclusions

      The current review with meta-analysis showed no statistically significant difference in the incidence of RLN palsy when using IONM versus VA during thyroidectomy. However, these results must be approached with caution, as they were mainly based on data coming from non–randomized observational studies. Further studies including high-quality multicenter, prospective, randomized trials based on strict criteria of standardization and subsequent clustered meta-analysis are required to verify the outcomes of interest.

      Keywords

      1. Introduction

      Routine recurrent laryngeal nerve (RLN) visualization is considered the current gold standard of care for the prevention of nerve injury and the reduction of nerve palsy during thyroid surgery [
      • Stevens K.
      • Stojadinovic A.
      • Helou L.B.
      • et al.
      The impact of recurrent laryngeal neuromonitoring on multi-dimensional voice outcomes following thyroid surgery.
      ,
      • Rosenthal L.H.S.
      • Benninger M.S.
      • Deeb R.H.
      Vocal fold immobility: a longitudinal analysis of etiology over 20 years.
      ,
      • Jatzko G.R.
      • Lisborg P.H.
      • Müller M.G.
      • Wette V.M.
      Recurrent nerve palsy after thyroid operations: principal nerve identification and a literature review.
      ,
      • Dralle H.
      • Sekulla C.
      • Haerting J.
      • et al.
      Risk factors of paralysis and functional outcome after recurrent laryngeal nerve monitoring in thyroid surgery.
      ,
      • Snyder S.K.
      • Hendricks J.C.
      Intraoperative neurophysiology testing of the recurrent laryngeal nerve: plaudits and pitfalls.
      ]. Despite meticulous anatomical identification, however, RLN injury still exists, with the incidence of transient RLN palsy reported as 0.4%–12%, and permanent RLN palsy up to 5%–6% [
      • Angelos P.
      Recurrent laryngeal nerve monitoring: state of the art, ethical and legal issues.
      ,
      • Barczyński M.
      • Konturek A.
      • Cichoń S.
      Randomized clinical trial of visualization versus neuromonitoring of recurrent laryngeal nerves during thyroidectomy.
      ,
      • Sturgeon C.
      • Sturgeon T.
      • Angelos P.
      Neuromonitoring in thyroid surgery: attitudes, usage patterns, and predictors of use among endocrine surgeons.
      ,
      • Chan W.-F.
      • Lang B.H.
      • Lo C.Y.
      The role of intraoperative neuromonitoring of recurrent laryngeal nerve during thyroidectomy: a comparative study on 1000 nerves at risk.
      ,
      • Chiang F.Y.
      • Lee K.W.
      • Chen H.C.
      • et al.
      Standardization of intraoperative neuromonitoring of recurrent laryngeal nerve in thyroid operation.
      ,
      • Sari S.
      • Erbil Y.
      • Sümer A.
      • et al.
      Evaluation of recurrent laryngeal nerve monitoring in thyroid surgery.
      ,
      • Robertson M.L.
      • Steward D.L.
      • Gluckman J.L.
      • Welge J.
      Continuous laryngeal nerve monitoring during thyroidectomy: does it reduce risk of injury?.
      ].
      When nerves are at high risk, such as in thyroidectomies performed for substernal goiter, recurrent goiter, and advanced thyroid carcinoma, RLN palsy can occur even in experienced hands [
      • Barczyński M.
      • Konturek A.
      • Cichoń S.
      Randomized clinical trial of visualization versus neuromonitoring of recurrent laryngeal nerves during thyroidectomy.
      ,
      • Calò P.G.
      • Pisano G.
      • Medas F.
      • et al.
      Intraoperative recurrent laryngeal nerve monitoring in thyroid surgery: is it really useful?.
      ]. Impaired RLN function causes disability and reduced quality of life, and it is one of the leading reasons for malpractice litigation [
      • Kern K.A.
      Medicolegal analysis of errors in diagnosis and treatment of surgical endocrine disease.
      ,
      • Abadin S.S.
      • Kaplan E.L.
      • Angelos P.
      Malpractice litigation after thyroid surgery: the role of recurrent laryngeal nerve injuries, 1989–2009.
      ]. Thus, intraoperative neuromonitoring (IONM) has been proposed to reduce this complication by preventing RLN injuries and to aid in nerve localization before visualization [
      • Alesina P.F.
      • Rolfs T.
      • Hommeltenberg S.
      • et al.
      Intraoperative neuromonitoring does not reduce the incidence of recurrent laryngeal nerve palsy in thyroid reoperations: results of a retrospective comparative analysis.
      ,
      • Duclos A.
      • Lifante J.C.
      • Ducarroz S.
      • Soardo P.
      • Colin C.
      • Peix J.L.
      Influence of intraoperative neuromonitoring on surgeons’ technique during thyroidectomy.
      ].
      Some authors have shown that neuromonitoring reduces the rate of transient RLN palsy [
      • Barczyński M.
      • Konturek A.
      • Cichoń S.
      Randomized clinical trial of visualization versus neuromonitoring of recurrent laryngeal nerves during thyroidectomy.
      ], is useful in the case of thyroid reoperation [
      • Dralle H.
      • Sekulla C.
      • Haerting J.
      • et al.
      Risk factors of paralysis and functional outcome after recurrent laryngeal nerve monitoring in thyroid surgery.
      ], and can assist in the identification of the RLN during dissection before visualization [
      • Barczyński M.
      • Konturek A.
      • Cichoń S.
      Randomized clinical trial of visualization versus neuromonitoring of recurrent laryngeal nerves during thyroidectomy.
      ,
      • Gremillion G.
      • Fatakia A.
      • Dornelles A.
      • Amedee R.G.
      Intraoperative recurrent laryngeal nerve monitoring in thyroid surgery: is it worth the cost?.
      ,
      • Cavicchi O.
      • Caliceti U.
      • Fernandez I.J.
      • et al.
      The value of neurostimulation and intraoperative nerve monitoring of inferior laryngeal nerve in thyroid surgery.
      ]. However, the utility of neuromonitoring in decreasing the rate of permanent RLN palsy has not been proven yet [
      • Angelos P.
      Recurrent laryngeal nerve monitoring: state of the art, ethical and legal issues.
      ,
      • Shindo M.
      • Chheda N.N.
      Incidence of vocal cord paralysis with and without recurrent laryngeal nerve monitoring during thyroidectomy.
      ,
      • Atallah I.
      • Dupret A.
      • Carpentier A.S.
      • Weingertner A.S.
      • Volkmar P.
      • Rodier J.F.
      Role of the intraoperative neuromonitoring of the recurrent laryngeal nerve in high-risk thyroid surgery.
      ].
      The recent standardization of neuromonitoring methods and reporting was undertaken in an effort to provide uniformity and to minimize inappropriate variations in the application of IONM [
      • Randolph G.W.
      • Dralle H.
      • Abdullah H.
      • et al.
      with the International Intraoperative Monitoring Study Group
      Electrophysiologic recurrent laryngeal nerve monitoring during thyroid and parathyroid surgery: international standards guideline statement.
      ]. However, the role of IONM during thyroid surgery is still debatable, as no consensus exists regarding the prevention of RLN injury.
      Thus far, only two reviews with pooled analysis have been performed to compare the results of IONM of RLN versus visualization alone (VA) during thyroidectomy [
      • Higgins T.S.
      • Gupta R.
      • Ketcham A.S.
      • Sataloff R.T.
      • Wadsworth J.T.
      • Sinacori J.T.
      Recurrent laryngeal nerve monitoring versus identification alone on post-thyroidectomy true vocal fold palsy: a meta-analysis.
      ,
      • Sanabria A.
      • Ramirez A.
      • Kowalski L.P.
      • et al.
      Neuromonitoring in thyroidectomy: a meta-analysis of effectiveness from randomized controlled trials.
      ]. This dearth of research and the need for updated data on the comparison between the two techniques encouraged us to perform this new systematic review with meta-analysis, including the largest number of adult patients from all comparative studies in the literature. The aim of our research was to evaluate whether the use of IONM shows real benefits over VA, especially in terms of reducing the incidence of vocal cord palsy after thyroid surgery.

      2. Materials and methods

      To be included in our analysis, studies had to meet the following criteria: compare the characteristics and perioperative outcomes of adult patients undergoing thyroidectomy with IONM versus VA of the RLN; prospective, randomized clinical trial (RCT) or prospective or retrospective observational study comparing the two techniques; and written in English.
      Studies were not included in the meta-analysis if the outcomes of interest (as specified in the following section) were impossible to calculate, or if the standard deviation and confidence interval of the tested parameters were not reported.
      A systematic literature search was performed using the Embase, Medline, Cochrane, PubMed, and Google Scholar databases for studies comparing IONM versus VA of RLN during thyroidectomy by using the following keywords: thyroidectomy; “RLN”; “IONM”; RLN visualization or “VA”; and RLN palsy. The search was extended using the “related article” function of the databases and by scanning the references of all relevant articles. The literature search was completed in August 2013.
      Two authors (AP and GP) independently extracted the following data from each study: institution and year of publication, study type, number of patients operated on with each technique, number of nerves at risk, characteristics of patients such as age and gender, perioperative outcome, and postoperative results.
      All included studies were reviewed for the following outcomes of interest:
      • The primary outcome measures were rate of overall, transient, and permanent RLN palsy per nerve at risk and rate of overall, transient, and permanent RLN palsy per patient at risk
      • The secondary outcome measures were operative time; overall, transient, and permanent RLN palsy per nerve at low and high risk; and results regarding assistance in RLN identification before visualization.
      A laryngoscopy to check vocal cord status was performed preoperatively and postoperatively in all included studies. Patients were considered to have permanent RLN palsy if the impaired function persisted at least 6 or 12 m after thyroidectomy, depending on the author's postoperative protocol.

      2.1 Statistical analysis, synthesis, and reporting of results

      The meta-analysis was performed according to the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement [
      • Liberati A.
      • Altman D.G.
      • Tetzlaff J.
      • et al.
      The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration.
      ] and the Meta-Analysis of Observational Studies in Epidemiology checklist for observational studies [
      • Stroup D.F.
      • Berlin J.A.
      • Morton S.C.
      • et al.
      Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group.
      ]. Variables were considered for pooled analysis if they were evaluated by two or more studies. All statistical analyses were carried out using MedCalc 2011 (version 11.5.1; MedCalc Software, Ostend, Belgium) statistical software. The meta-analysis was conducted by searching for a numerical estimate of the outcomes of interest, as described elsewhere [
      • Pisanu A.
      • Reccia I.
      • Porceddu G.
      • Uccheddu A.
      Meta-analysis of prospective randomized studies comparing single-incision laparoscopic cholecystectomy (SILC) and conventional multiport laparoscopic cholecystectomy (CMLC).
      ]. For continuous outcomes, Hedges's g statistic was used to calculate the standardized mean difference (SMD) under the fixed effects model, which was adjusted for small sample bias. Under the fixed effects model, it was assumed that all studies were homogenous. This assumption was tested by the heterogeneity test, which was included to calculate the summary SMD under the random effects model, according to the method of DerSimonian and Laird [
      • DerSimonian R.
      • Laird N.
      Meta-analysis in clinical trials.
      ]. We tested for heterogeneity using the random effects model to calculate the Q-test and its associated P values. If this test yielded a P value <0.05, then the fixed effects model was considered invalid, and the random effects model was considered appropriate. The results of the individual studies were listed, and the total SMD with 95% confidence interval (CI) were given for both the fixed effects model and the random effects model. If the value 0 was not within the 95% CI, then the SMD was considered statistically significant at the 5% level (P < 0.05) (http://www.medcalc.org/manual/meta-continuous.php). This method required the standard deviations and the CIs of the tested parameters. Studies that did not report any of these parameters were excluded from the meta-analysis. The results of the different studies, with 95% CI and overall SMD, were summarized and reported using a forest plot.
      For data derived from contingency tables (qualitative outcomes), we calculated the odds ratio (OR) and 95% CI. The ORs reported in the results are of the pooled analysis method, also called pooled ORs. The Mantel–Haenszel method was used for calculating the weighted summary OR under the fixed effects model. Then, the heterogeneity test was incorporated to calculate the summary OR under the random effects model according to the method of DerSimonian and Laird [
      • DerSimonian R.
      • Laird N.
      Meta-analysis in clinical trials.
      ]. If this test yielded a P value <0.05, then the fixed effects model was considered invalid, and the random effects model was considered appropriate. The results of the individual studies were listed and the total OR with 95% CI were given for both the fixed effects model and the random effects model. If the value 1 was not within the 95% CI, then the OR was considered statistically significant at the 5% level (P < 0.05) (http://www.medcalc.org/manual/meta-oddsratio.php). The results of different studies, with 95% CI and the overall effect (summary OR) with 95% CI, were summarized on a logarithmic scale using a forest plot.

      3. Results

      The flowchart of the systematic review is shown in Figure 1. Twenty studies comparing thyroidectomy with IONM versus VA of RLN were considered suitable for the pooled analysis [
      • Stevens K.
      • Stojadinovic A.
      • Helou L.B.
      • et al.
      The impact of recurrent laryngeal neuromonitoring on multi-dimensional voice outcomes following thyroid surgery.
      ,
      • Dralle H.
      • Sekulla C.
      • Haerting J.
      • et al.
      Risk factors of paralysis and functional outcome after recurrent laryngeal nerve monitoring in thyroid surgery.
      ,
      • Barczyński M.
      • Konturek A.
      • Cichoń S.
      Randomized clinical trial of visualization versus neuromonitoring of recurrent laryngeal nerves during thyroidectomy.
      ,
      • Chan W.-F.
      • Lang B.H.
      • Lo C.Y.
      The role of intraoperative neuromonitoring of recurrent laryngeal nerve during thyroidectomy: a comparative study on 1000 nerves at risk.
      ,
      • Sari S.
      • Erbil Y.
      • Sümer A.
      • et al.
      Evaluation of recurrent laryngeal nerve monitoring in thyroid surgery.
      ,
      • Robertson M.L.
      • Steward D.L.
      • Gluckman J.L.
      • Welge J.
      Continuous laryngeal nerve monitoring during thyroidectomy: does it reduce risk of injury?.
      ,
      • Calò P.G.
      • Pisano G.
      • Medas F.
      • et al.
      Intraoperative recurrent laryngeal nerve monitoring in thyroid surgery: is it really useful?.
      ,
      • Alesina P.F.
      • Rolfs T.
      • Hommeltenberg S.
      • et al.
      Intraoperative neuromonitoring does not reduce the incidence of recurrent laryngeal nerve palsy in thyroid reoperations: results of a retrospective comparative analysis.
      ,
      • Duclos A.
      • Lifante J.C.
      • Ducarroz S.
      • Soardo P.
      • Colin C.
      • Peix J.L.
      Influence of intraoperative neuromonitoring on surgeons’ technique during thyroidectomy.
      ,
      • Gremillion G.
      • Fatakia A.
      • Dornelles A.
      • Amedee R.G.
      Intraoperative recurrent laryngeal nerve monitoring in thyroid surgery: is it worth the cost?.
      ,
      • Shindo M.
      • Chheda N.N.
      Incidence of vocal cord paralysis with and without recurrent laryngeal nerve monitoring during thyroidectomy.
      ,
      • Atallah I.
      • Dupret A.
      • Carpentier A.S.
      • Weingertner A.S.
      • Volkmar P.
      • Rodier J.F.
      Role of the intraoperative neuromonitoring of the recurrent laryngeal nerve in high-risk thyroid surgery.
      ,
      • Barczyński M.
      • Konturek A.
      • Stopa M.
      • Hubalewska-Dydejczyk A.
      • Richter P.
      • Nowak N.
      Clinical value of intraoperative neuromonitoring of the recurrent laryngeal nerves in improving outcomes of surgery for well-differentiated thyroid cancer.
      ,
      • Frattini F.
      • Mangano A.
      • Boni L.
      • Rausei S.
      • Biondi A.
      • Dionigi G.
      Intraoperative monitoring for thyroid malignancy surgery: technical notes and results from a retrospective series.
      ,
      • Dionigi G.
      • Boni L.
      • Rovera F.
      • Bacuzzi A.
      • Dionigi R.
      Neuromonitoring and video-assisted thyroidectomy: a prospective, randomized case-control evaluation.
      ,
      • Agha A.
      • Glockzin G.
      • Ghali N.
      • Iesalnieks I.
      • Schlitt H.J.
      Surgical treatment of substernal goiter: an analysis of 59 patients.
      ,
      • Netto I de P.
      • Vartarian J.G.
      • Salgado P.
      • et al.
      Vocal fold immobility after thyroidectomy with intraoperative recurrent laryngeal nerve monitoring.
      ,
      • Terris D.J.
      • Anderson S.K.
      • Watts T.L.
      • Chin E.
      Laryngeal nerve monitoring and minimally invasive thyroid surgery.
      ,
      • Witt R.L.
      Recurrent laryngeal nerve electrophysiologic monitoring in thyroid surgery: the standard of care?.
      ,
      • Yarbrough D.E.
      • Thompson G.B.
      • Kasperbauer J.L.
      • Harper C.M.
      • Grant C.S.
      Intraoperative electromyographic monitoring of the recurrent laryngeal nerve in reoperative thyroid and parathyroid surgery.
      ]. The articles included in the quantitative synthesis were published between 2004 and 2013. Seven studies were conducted in the US, three in Germany, three in Italy, two in France, two in Poland, one in Brazil, one in China, and one in Turkey. These studies included a total of 23,512 patients with thyroidectomy performed using IONM compared with thyroidectomy by VA of RLN. The total number of nerves at risk was 35,513, with 24,038 nerves at risk (67.7%) in the IONM group and 11,475 nerves at risk (32.3%) in the VA group (Table 1, Table 3). In three prospective RCTs, the patients were randomly assigned to either IONM or VA groups [
      • Barczyński M.
      • Konturek A.
      • Cichoń S.
      Randomized clinical trial of visualization versus neuromonitoring of recurrent laryngeal nerves during thyroidectomy.
      ,
      • Sari S.
      • Erbil Y.
      • Sümer A.
      • et al.
      Evaluation of recurrent laryngeal nerve monitoring in thyroid surgery.
      ,
      • Dionigi G.
      • Boni L.
      • Rovera F.
      • Bacuzzi A.
      • Dionigi R.
      Neuromonitoring and video-assisted thyroidectomy: a prospective, randomized case-control evaluation.
      ]. The other included studies were seven prospective [
      • Stevens K.
      • Stojadinovic A.
      • Helou L.B.
      • et al.
      The impact of recurrent laryngeal neuromonitoring on multi-dimensional voice outcomes following thyroid surgery.
      ,
      • Dralle H.
      • Sekulla C.
      • Haerting J.
      • et al.
      Risk factors of paralysis and functional outcome after recurrent laryngeal nerve monitoring in thyroid surgery.
      ,
      • Chan W.-F.
      • Lang B.H.
      • Lo C.Y.
      The role of intraoperative neuromonitoring of recurrent laryngeal nerve during thyroidectomy: a comparative study on 1000 nerves at risk.
      ,
      • Duclos A.
      • Lifante J.C.
      • Ducarroz S.
      • Soardo P.
      • Colin C.
      • Peix J.L.
      Influence of intraoperative neuromonitoring on surgeons’ technique during thyroidectomy.
      ,
      • Barczyński M.
      • Konturek A.
      • Stopa M.
      • Hubalewska-Dydejczyk A.
      • Richter P.
      • Nowak N.
      Clinical value of intraoperative neuromonitoring of the recurrent laryngeal nerves in improving outcomes of surgery for well-differentiated thyroid cancer.
      ,
      • Netto I de P.
      • Vartarian J.G.
      • Salgado P.
      • et al.
      Vocal fold immobility after thyroidectomy with intraoperative recurrent laryngeal nerve monitoring.
      ,
      • Terris D.J.
      • Anderson S.K.
      • Watts T.L.
      • Chin E.
      Laryngeal nerve monitoring and minimally invasive thyroid surgery.
      ] and ten retrospective comparative observational studies [
      • Robertson M.L.
      • Steward D.L.
      • Gluckman J.L.
      • Welge J.
      Continuous laryngeal nerve monitoring during thyroidectomy: does it reduce risk of injury?.
      ,
      • Calò P.G.
      • Pisano G.
      • Medas F.
      • et al.
      Intraoperative recurrent laryngeal nerve monitoring in thyroid surgery: is it really useful?.
      ,
      • Alesina P.F.
      • Rolfs T.
      • Hommeltenberg S.
      • et al.
      Intraoperative neuromonitoring does not reduce the incidence of recurrent laryngeal nerve palsy in thyroid reoperations: results of a retrospective comparative analysis.
      ,
      • Gremillion G.
      • Fatakia A.
      • Dornelles A.
      • Amedee R.G.
      Intraoperative recurrent laryngeal nerve monitoring in thyroid surgery: is it worth the cost?.
      ,
      • Shindo M.
      • Chheda N.N.
      Incidence of vocal cord paralysis with and without recurrent laryngeal nerve monitoring during thyroidectomy.
      ,
      • Atallah I.
      • Dupret A.
      • Carpentier A.S.
      • Weingertner A.S.
      • Volkmar P.
      • Rodier J.F.
      Role of the intraoperative neuromonitoring of the recurrent laryngeal nerve in high-risk thyroid surgery.
      ,
      • Frattini F.
      • Mangano A.
      • Boni L.
      • Rausei S.
      • Biondi A.
      • Dionigi G.
      Intraoperative monitoring for thyroid malignancy surgery: technical notes and results from a retrospective series.
      ,
      • Agha A.
      • Glockzin G.
      • Ghali N.
      • Iesalnieks I.
      • Schlitt H.J.
      Surgical treatment of substernal goiter: an analysis of 59 patients.
      ,
      • Witt R.L.
      Recurrent laryngeal nerve electrophysiologic monitoring in thyroid surgery: the standard of care?.
      ,
      • Yarbrough D.E.
      • Thompson G.B.
      • Kasperbauer J.L.
      • Harper C.M.
      • Grant C.S.
      Intraoperative electromyographic monitoring of the recurrent laryngeal nerve in reoperative thyroid and parathyroid surgery.
      ].
      Figure thumbnail gr1
      Fig. 1Systematic search and selection of articles for meta-analysis.
      Table 1Demographics characteristic of patients and type of operation as reported in the included studies.
      Author (y)Study typeNo. of patientsAge (y)Sex (F/M)TT/other interventions
      IONMVAIONMVAIONMVAIONMVA
      Calò et al. 2013
      • Calò P.G.
      • Pisano G.
      • Medas F.
      • et al.
      Intraoperative recurrent laryngeal nerve monitoring in thyroid surgery: is it really useful?.
      RCS751942563/188785/157742/9902/40
      Alesina et al. 2012
      • Alesina P.F.
      • Rolfs T.
      • Hommeltenberg S.
      • et al.
      Intraoperative neuromonitoring does not reduce the incidence of recurrent laryngeal nerve palsy in thyroid reoperations: results of a retrospective comparative analysis.
      RCS8915755 ± 1255 ± 1378/11131/2635/5431/126
      Gremillion et al. 2012
      • Gremillion G.
      • Fatakia A.
      • Dornelles A.
      • Amedee R.G.
      Intraoperative recurrent laryngeal nerve monitoring in thyroid surgery: is it worth the cost?.
      RCS318810/2133/55
      Stevens et al. 2012
      • Stevens K.
      • Stojadinovic A.
      • Helou L.B.
      • et al.
      The impact of recurrent laryngeal neuromonitoring on multi-dimensional voice outcomes following thyroid surgery.
      PCS395248.6 ± 12.148.1 ± 13.626/1328/2423/1629/23
      Barczynski et al. 2011
      • Barczyński M.
      • Konturek A.
      • Stopa M.
      • Hubalewska-Dydejczyk A.
      • Richter P.
      • Nowak N.
      Clinical value of intraoperative neuromonitoring of the recurrent laryngeal nerves in improving outcomes of surgery for well-differentiated thyroid cancer.
      PCS15115143.9 ± 18.144.9 ± 15.7137/14135/16151/0151/0
      Duclos et al. 2011
      • Duclos A.
      • Lifante J.C.
      • Ducarroz S.
      • Soardo P.
      • Colin C.
      • Peix J.L.
      Influence of intraoperative neuromonitoring on surgeons’ technique during thyroidectomy.
      PCS47521153.354.0361/114171/40403/72171/40
      Frattini et al. 2010
      • Frattini F.
      • Mangano A.
      • Boni L.
      • Rausei S.
      • Biondi A.
      • Dionigi G.
      Intraoperative monitoring for thyroid malignancy surgery: technical notes and results from a retrospective series.
      RCS76764139.840/3645/3176/076/0
      Sari et al. 2010
      • Sari S.
      • Erbil Y.
      • Sümer A.
      • et al.
      Evaluation of recurrent laryngeal nerve monitoring in thyroid surgery.
      RCT12311447.2 ± 1448.3 ± 12104/1991/2323/10026/88
      Atallah et al. 2009
      • Atallah I.
      • Dupret A.
      • Carpentier A.S.
      • Weingertner A.S.
      • Volkmar P.
      • Rodier J.F.
      Role of the intraoperative neuromonitoring of the recurrent laryngeal nerve in high-risk thyroid surgery.
      RCS112149
      Barczynski et al. 2009
      • Barczyński M.
      • Konturek A.
      • Cichoń S.
      Randomized clinical trial of visualization versus neuromonitoring of recurrent laryngeal nerves during thyroidectomy.
      RCT50050051.9 ± 14.751.3 ± 14.4457/43455/45371/129378/122
      Dionigi et al. 2009
      • Dionigi G.
      • Boni L.
      • Rovera F.
      • Bacuzzi A.
      • Dionigi R.
      Neuromonitoring and video-assisted thyroidectomy: a prospective, randomized case-control evaluation.
      RCT36364139.832/430/619/1721/15
      Agha et al. 2008
      • Agha A.
      • Glockzin G.
      • Ghali N.
      • Iesalnieks I.
      • Schlitt H.J.
      Surgical treatment of substernal goiter: an analysis of 59 patients.
      RCS1841
      Netto et al. 2007
      • Netto I de P.
      • Vartarian J.G.
      • Salgado P.
      • et al.
      Vocal fold immobility after thyroidectomy with intraoperative recurrent laryngeal nerve monitoring.
      PCS1041004365/3996/888/1265/3958/42
      Shindo et al. 2007
      • Shindo M.
      • Chheda N.N.
      Incidence of vocal cord paralysis with and without recurrent laryngeal nerve monitoring during thyroidectomy.
      RCS427257244/183115/142
      Terris et al. 2007
      • Terris D.J.
      • Anderson S.K.
      • Watts T.L.
      • Chin E.
      Laryngeal nerve monitoring and minimally invasive thyroid surgery.
      PCS736419/5420/44
      Chan et al. 2006
      • Chan W.-F.
      • Lang B.H.
      • Lo C.Y.
      The role of intraoperative neuromonitoring of recurrent laryngeal nerve during thyroidectomy: a comparative study on 1000 nerves at risk.
      PCS316323183/133171/152
      Witt et al. 2005
      • Witt R.L.
      Recurrent laryngeal nerve electrophysiologic monitoring in thyroid surgery: the standard of care?.
      RCS5483
      Dralle et al. 2004
      • Dralle H.
      • Sekulla C.
      • Haerting J.
      • et al.
      Risk factors of paralysis and functional outcome after recurrent laryngeal nerve monitoring in thyroid surgery.
      PCS
      Overall 16,517 patients not identified per group, but specified per nerve at risk (17,832 versus 5517 nerves at risk in IONM and VA group, respectively).
      Robertson et al. 2004
      • Robertson M.L.
      • Steward D.L.
      • Gluckman J.L.
      • Welge J.
      Continuous laryngeal nerve monitoring during thyroidectomy: does it reduce risk of injury?.
      RCS8283
      Yarbrough et al. 2004
      • Yarbrough D.E.
      • Thompson G.B.
      • Kasperbauer J.L.
      • Harper C.M.
      • Grant C.S.
      Intraoperative electromyographic monitoring of the recurrent laryngeal nerve in reoperative thyroid and parathyroid surgery.
      RCS525951.150.433/1937/22
      PCS = prospective comparative study; RCS = retrospective comparative study; TT = total thyroidectomy.
      Overall 16,517 patients not identified per group, but specified per nerve at risk (17,832 versus 5517 nerves at risk in IONM and VA group, respectively).
      Table 2Methods for IONM as reported in the included studies.
      Author (y)Operative time (min)
      Operative times are referred to total thyroidectomy.
      Device
      IONMVA
      Calò et al. 2013
      • Calò P.G.
      • Pisano G.
      • Medas F.
      • et al.
      Intraoperative recurrent laryngeal nerve monitoring in thyroid surgery: is it really useful?.
      NIM Response 2.0/3.0 Monitor (Medtronic Xomed, Jacksonville, FL)
      Alesina et al. 2012
      • Alesina P.F.
      • Rolfs T.
      • Hommeltenberg S.
      • et al.
      Intraoperative neuromonitoring does not reduce the incidence of recurrent laryngeal nerve palsy in thyroid reoperations: results of a retrospective comparative analysis.
      99 ± 4380 ± 27Neurosign (InoMed, Teningen Germany); since 2010 NIM 3.0 (Medtronic Xomed)
      Gremillion et al. 2012
      • Gremillion G.
      • Fatakia A.
      • Dornelles A.
      • Amedee R.G.
      Intraoperative recurrent laryngeal nerve monitoring in thyroid surgery: is it worth the cost?.
      99.8 ± 40.0102.4 ± 27.3Prass stimulator probe (Medtronic Xomed); EMG Contact Endotracheal Tube (IOM Products, INC, Ventura, CA)
      Stevens et al. 2012
      • Stevens K.
      • Stojadinovic A.
      • Helou L.B.
      • et al.
      The impact of recurrent laryngeal neuromonitoring on multi-dimensional voice outcomes following thyroid surgery.
      180132.5NIM (Medtronic Xomed)
      Barczynski et al. 2011
      • Barczyński M.
      • Konturek A.
      • Stopa M.
      • Hubalewska-Dydejczyk A.
      • Richter P.
      • Nowak N.
      Clinical value of intraoperative neuromonitoring of the recurrent laryngeal nerves in improving outcomes of surgery for well-differentiated thyroid cancer.
      Neurosign 100 Unit (Inomed) and NIM 2.0 Unit (Medtronic Xomed)
      Duclos et al. 2011
      • Duclos A.
      • Lifante J.C.
      • Ducarroz S.
      • Soardo P.
      • Colin C.
      • Peix J.L.
      Influence of intraoperative neuromonitoring on surgeons’ technique during thyroidectomy.
      NIM Response System (Medtronic Xomed)
      Frattini et al. 2010
      • Frattini F.
      • Mangano A.
      • Boni L.
      • Rausei S.
      • Biondi A.
      • Dionigi G.
      Intraoperative monitoring for thyroid malignancy surgery: technical notes and results from a retrospective series.
      NIM Response 2.0 System, (Medtronic Xomed)
      Sari et al. 2010
      • Sari S.
      • Erbil Y.
      • Sümer A.
      • et al.
      Evaluation of recurrent laryngeal nerve monitoring in thyroid surgery.
      65.4 ± 3179.1 ± 30Endotracheal-Based Monitoring System (NIM)
      Atallah et al. 2009
      • Atallah I.
      • Dupret A.
      • Carpentier A.S.
      • Weingertner A.S.
      • Volkmar P.
      • Rodier J.F.
      Role of the intraoperative neuromonitoring of the recurrent laryngeal nerve in high-risk thyroid surgery.
      NIM Response 2.0 (Medtronic Xomed)
      Barczynski et al. 2009
      • Barczyński M.
      • Konturek A.
      • Cichoń S.
      Randomized clinical trial of visualization versus neuromonitoring of recurrent laryngeal nerves during thyroidectomy.
      104.8 ± 26.795.7 ± 24.7Neurosign 100 system (Ionmed,)
      Dionigi et al. 2009
      • Dionigi G.
      • Boni L.
      • Rovera F.
      • Bacuzzi A.
      • Dionigi R.
      Neuromonitoring and video-assisted thyroidectomy: a prospective, randomized case-control evaluation.
      97.695.0NIM Response 2.0 system (Medtronic Xomed)
      Agha et al. 2008
      • Agha A.
      • Glockzin G.
      • Ghali N.
      • Iesalnieks I.
      • Schlitt H.J.
      Surgical treatment of substernal goiter: an analysis of 59 patients.
      IONM not specified
      Netto et al. 2007
      • Netto I de P.
      • Vartarian J.G.
      • Salgado P.
      • et al.
      Vocal fold immobility after thyroidectomy with intraoperative recurrent laryngeal nerve monitoring.
      162.5NIM-2 (Medtronic Xomed )
      Shindo et al. 2007
      • Shindo M.
      • Chheda N.N.
      Incidence of vocal cord paralysis with and without recurrent laryngeal nerve monitoring during thyroidectomy.
      NIM-2 (Medtronic Xomed)
      Terris et al. 2007
      • Terris D.J.
      • Anderson S.K.
      • Watts T.L.
      • Chin E.
      Laryngeal nerve monitoring and minimally invasive thyroid surgery.
      NIM-2
      Chan et al. 2006
      • Chan W.-F.
      • Lang B.H.
      • Lo C.Y.
      The role of intraoperative neuromonitoring of recurrent laryngeal nerve during thyroidectomy: a comparative study on 1000 nerves at risk.
      119 ± 51116 ± 37Neurosign 100 machine (Magstim Clarify Company, Withland, UK)
      Witt et al. 2005
      • Witt R.L.
      Recurrent laryngeal nerve electrophysiologic monitoring in thyroid surgery: the standard of care?.
      NIM (MedTronic, Minneapolis, MN)
      Dralle et al. 2004
      • Dralle H.
      • Sekulla C.
      • Haerting J.
      • et al.
      Risk factors of paralysis and functional outcome after recurrent laryngeal nerve monitoring in thyroid surgery.
      Neurosign 100 system (Ionmed)
      Robertson et al. 2004
      • Robertson M.L.
      • Steward D.L.
      • Gluckman J.L.
      • Welge J.
      Continuous laryngeal nerve monitoring during thyroidectomy: does it reduce risk of injury?.
      NIM EMG endoctracheal tube and NIM-2 (Medtronic Xomed )
      Yarbrough et al. 2004
      • Yarbrough D.E.
      • Thompson G.B.
      • Kasperbauer J.L.
      • Harper C.M.
      • Grant C.S.
      Intraoperative electromyographic monitoring of the recurrent laryngeal nerve in reoperative thyroid and parathyroid surgery.
      IONM not specified
      NIM = nerve integrity monitor.
      Operative times are referred to total thyroidectomy.
      Table 3Postoperative morbidity in terms of overall, transient and permanent RLN palsy per patient and per nerve at risk.
      Author (y)No. of patientsNerves at riskOverallTotal transientTotal permanent
      IONMVAIONMVAIONMVAIONMVAIONMVA
      Calò et al. 2013
      • Calò P.G.
      • Pisano G.
      • Medas F.
      • et al.
      Intraoperative recurrent laryngeal nerve monitoring in thyroid surgery: is it really useful?.
      751942149318442028142167
      Alesina et al. 2012
      • Alesina P.F.
      • Rolfs T.
      • Hommeltenberg S.
      • et al.
      Intraoperative neuromonitoring does not reduce the incidence of recurrent laryngeal nerve palsy in thyroid reoperations: results of a retrospective comparative analysis.
      89157128161848400
      Gremillion et al. 2012
      • Gremillion G.
      • Fatakia A.
      • Dornelles A.
      • Amedee R.G.
      Intraoperative recurrent laryngeal nerve monitoring in thyroid surgery: is it worth the cost?.
      318841121242301
      Stevens et al. 2012
      • Stevens K.
      • Stojadinovic A.
      • Helou L.B.
      • et al.
      The impact of recurrent laryngeal neuromonitoring on multi-dimensional voice outcomes following thyroid surgery.
      39526281554312
      Barczynski et al. 2011
      • Barczyński M.
      • Konturek A.
      • Stopa M.
      • Hubalewska-Dydejczyk A.
      • Richter P.
      • Nowak N.
      Clinical value of intraoperative neuromonitoring of the recurrent laryngeal nerves in improving outcomes of surgery for well-differentiated thyroid cancer.
      1511513023025103822
      Duclos et al. 2011
      • Duclos A.
      • Lifante J.C.
      • Ducarroz S.
      • Soardo P.
      • Colin C.
      • Peix J.L.
      Influence of intraoperative neuromonitoring on surgeons’ technique during thyroidectomy.
      4752118783823610-
      Frattini et al. 2010
      • Frattini F.
      • Mangano A.
      • Boni L.
      • Rausei S.
      • Biondi A.
      • Dionigi G.
      Intraoperative monitoring for thyroid malignancy surgery: technical notes and results from a retrospective series.
      7676152152372512
      Sari et al. 2010
      • Sari S.
      • Erbil Y.
      • Sümer A.
      • et al.
      Evaluation of recurrent laryngeal nerve monitoring in thyroid surgery.
      123114210199333300
      Atallah et al. 2009
      • Atallah I.
      • Dupret A.
      • Carpentier A.S.
      • Weingertner A.S.
      • Volkmar P.
      • Rodier J.F.
      Role of the intraoperative neuromonitoring of the recurrent laryngeal nerve in high-risk thyroid surgery.
      112149181240162291379
      Barczynski et al. 2009
      • Barczyński M.
      • Konturek A.
      • Cichoń S.
      Randomized clinical trial of visualization versus neuromonitoring of recurrent laryngeal nerves during thyroidectomy.
      5005001000100027501938812
      Dionigi et al. 2009
      • Dionigi G.
      • Boni L.
      • Rovera F.
      • Bacuzzi A.
      • Dionigi R.
      Neuromonitoring and video-assisted thyroidectomy: a prospective, randomized case-control evaluation.
      36365557131300
      Agha et al. 2008
      • Agha A.
      • Glockzin G.
      • Ghali N.
      • Iesalnieks I.
      • Schlitt H.J.
      Surgical treatment of substernal goiter: an analysis of 59 patients.
      184114-
      Netto et al. 2007
      • Netto I de P.
      • Vartarian J.G.
      • Salgado P.
      • et al.
      Vocal fold immobility after thyroidectomy with intraoperative recurrent laryngeal nerve monitoring.
      10410016915812126765
      Shindo et al. 2007
      • Shindo M.
      • Chheda N.N.
      Incidence of vocal cord paralysis with and without recurrent laryngeal nerve monitoring during thyroidectomy.
      427257671372251716921
      Terris et al. 2007
      • Terris D.J.
      • Anderson S.K.
      • Watts T.L.
      • Chin E.
      Laryngeal nerve monitoring and minimally invasive thyroid surgery.
      73649284454500
      Chan et al. 2006
      • Chan W.-F.
      • Lang B.H.
      • Lo C.Y.
      The role of intraoperative neuromonitoring of recurrent laryngeal nerve during thyroidectomy: a comparative study on 1000 nerves at risk.
      3163235014992126172046
      Witt et al. 2005
      • Witt R.L.
      Recurrent laryngeal nerve electrophysiologic monitoring in thyroid surgery: the standard of care?.
      548383107644321
      Dralle et al. 2004
      Overall 16,517 patients not divided per group, but identified per absolute numbers of nerves at risk.
      • Dralle H.
      • Sekulla C.
      • Haerting J.
      • et al.
      Risk factors of paralysis and functional outcome after recurrent laryngeal nerve monitoring in thyroid surgery.
      17,832551762619348314414349
      Robertson et al. 2004
      • Robertson M.L.
      • Steward D.L.
      • Gluckman J.L.
      • Welge J.
      Continuous laryngeal nerve monitoring during thyroidectomy: does it reduce risk of injury?.
      8283116120584513
      Yarbrough et al. 2004
      • Yarbrough D.E.
      • Thompson G.B.
      • Kasperbauer J.L.
      • Harper C.M.
      • Grant C.S.
      Intraoperative electromyographic monitoring of the recurrent laryngeal nerve in reoperative thyroid and parathyroid surgery.
      5259727911119823
      Total per patient at risk35093486211 (6.0%)233 (6.7%)125 (3.5%)158 (4.5%)42 (1.2%)54 (1.5%)
      Total per nerve at risk24,03811,475837 (3.5%)426 (3.7%)608 (2.5%)302 (2.6%)185 (0.8%)103 (0.9%)
      Overall 16,517 patients not divided per group, but identified per absolute numbers of nerves at risk.
      The mean follow-up period was 18 mo (range, 3 mo–11 y), as reported in the included studies [
      • Dralle H.
      • Sekulla C.
      • Haerting J.
      • et al.
      Risk factors of paralysis and functional outcome after recurrent laryngeal nerve monitoring in thyroid surgery.
      ,
      • Chan W.-F.
      • Lang B.H.
      • Lo C.Y.
      The role of intraoperative neuromonitoring of recurrent laryngeal nerve during thyroidectomy: a comparative study on 1000 nerves at risk.
      ,
      • Alesina P.F.
      • Rolfs T.
      • Hommeltenberg S.
      • et al.
      Intraoperative neuromonitoring does not reduce the incidence of recurrent laryngeal nerve palsy in thyroid reoperations: results of a retrospective comparative analysis.
      ,
      • Barczyński M.
      • Konturek A.
      • Stopa M.
      • Hubalewska-Dydejczyk A.
      • Richter P.
      • Nowak N.
      Clinical value of intraoperative neuromonitoring of the recurrent laryngeal nerves in improving outcomes of surgery for well-differentiated thyroid cancer.
      ,
      • Frattini F.
      • Mangano A.
      • Boni L.
      • Rausei S.
      • Biondi A.
      • Dionigi G.
      Intraoperative monitoring for thyroid malignancy surgery: technical notes and results from a retrospective series.
      ,
      • Dionigi G.
      • Boni L.
      • Rovera F.
      • Bacuzzi A.
      • Dionigi R.
      Neuromonitoring and video-assisted thyroidectomy: a prospective, randomized case-control evaluation.
      ]. Some authors defined RLN palsy as permanent at 6 mo from the time of the operation [
      • Stevens K.
      • Stojadinovic A.
      • Helou L.B.
      • et al.
      The impact of recurrent laryngeal neuromonitoring on multi-dimensional voice outcomes following thyroid surgery.
      ,
      • Dralle H.
      • Sekulla C.
      • Haerting J.
      • et al.
      Risk factors of paralysis and functional outcome after recurrent laryngeal nerve monitoring in thyroid surgery.
      ,
      • Alesina P.F.
      • Rolfs T.
      • Hommeltenberg S.
      • et al.
      Intraoperative neuromonitoring does not reduce the incidence of recurrent laryngeal nerve palsy in thyroid reoperations: results of a retrospective comparative analysis.
      ,
      • Dionigi G.
      • Boni L.
      • Rovera F.
      • Bacuzzi A.
      • Dionigi R.
      Neuromonitoring and video-assisted thyroidectomy: a prospective, randomized case-control evaluation.
      ], whereas others defined it as permanent at 12 mo from the time of the operation [
      • Chan W.-F.
      • Lang B.H.
      • Lo C.Y.
      The role of intraoperative neuromonitoring of recurrent laryngeal nerve during thyroidectomy: a comparative study on 1000 nerves at risk.
      ,
      • Sari S.
      • Erbil Y.
      • Sümer A.
      • et al.
      Evaluation of recurrent laryngeal nerve monitoring in thyroid surgery.
      ,
      • Calò P.G.
      • Pisano G.
      • Medas F.
      • et al.
      Intraoperative recurrent laryngeal nerve monitoring in thyroid surgery: is it really useful?.
      ,
      • Atallah I.
      • Dupret A.
      • Carpentier A.S.
      • Weingertner A.S.
      • Volkmar P.
      • Rodier J.F.
      Role of the intraoperative neuromonitoring of the recurrent laryngeal nerve in high-risk thyroid surgery.
      ,
      • Barczyński M.
      • Konturek A.
      • Stopa M.
      • Hubalewska-Dydejczyk A.
      • Richter P.
      • Nowak N.
      Clinical value of intraoperative neuromonitoring of the recurrent laryngeal nerves in improving outcomes of surgery for well-differentiated thyroid cancer.
      ,
      • Frattini F.
      • Mangano A.
      • Boni L.
      • Rausei S.
      • Biondi A.
      • Dionigi G.
      Intraoperative monitoring for thyroid malignancy surgery: technical notes and results from a retrospective series.
      ,
      • Witt R.L.
      Recurrent laryngeal nerve electrophysiologic monitoring in thyroid surgery: the standard of care?.
      ]. The two reviewers were found to be 100% in agreement about the data extracted from the studies. The characteristics of the included studies, demographics of the included patients, and different methods used for IONM of RLN are shown in Table 1, Table 2.

      3.1 Primary outcome measures

      3.1.1 Overall, transient, and permanent RLN palsy per nerve at risk

      The rate of overall RLN palsy per nerve at risk was 0.0347 in the IONM group versus 0.0367 in the VA group (24,038 versus 11,475 nerves at risk). This difference was not statistically significant (OR = 0.938, 95% CI = 0.828–1.063; no heterogeneity was found for Q = 17.766, P = 0.471; Fig. 2, Table 3). The rate of transient RLN palsy per nerve at risk was 0.0262 versus 0.0272 in the IONM and VA groups, respectively. However, this difference was not statistically significant (OR = 0.946, 95% CI = 0.817–1.096; no heterogeneity was found for Q = 15.604, P = 0.552; Fig. 3, Table 3). The rate of permanent RLN palsy per nerve at risk was 0.0079 versus 0.0092 in the IONM and VA groups, respectively, and this difference was also not statistically significant (OR = 0.884, 95% CI = 0.687–1.136; no heterogeneity was found for Q = 2.830, P = 1.000; Fig. 4, Table 3).
      Figure thumbnail gr2
      Fig. 2Meta-analysis of overall RLN palsy per nerve at risk. (Color version of figure is available online.)
      Figure thumbnail gr3
      Fig. 3Meta-analysis of transient RLN palsy per nerve at risk. (Color version of figure is available online.)
      Figure thumbnail gr4
      Fig. 4Meta-analysis of permanent RLN palsy per nerve at risk. (Color version of figure is available online.)

      3.1.2 Overall, transient, and permanent RLN palsy per patient at risk

      The number of patients included in the study of Dralle et al. [
      • Dralle H.
      • Sekulla C.
      • Haerting J.
      • et al.
      Risk factors of paralysis and functional outcome after recurrent laryngeal nerve monitoring in thyroid surgery.
      ] was not specified per group of treatment. Thus, the outcomes of this study were impossible to meta-analyze per patients at risk. The pooled analysis of RLN palsy per patient at risk included 3509 patients from the IONM group versus 3486 patients from the VA group. The rate of overall RLN palsy per patient at risk was 0.060 in the IONM group versus 0.067 in the VA group. This difference was not statistically significant (OR = 0.873, 95% CI = 0.716–1.063; no heterogeneity was found for Q = 20.471, P = 0.306; Fig. 5, Table 3). The rate of transient RLN palsy was 0.035 versus 0.045 in the IONM and VA groups, respectively. However, this difference was not statistically significant (OR = 0.837, 95% CI = 0.658–1.066; no heterogeneity was found for Q = 17.013, P = 0.384; Fig. 6, Table 3). The rate of permanent RLN palsy was 0.012 versus 0.015 in the IONM and VA groups, respectively, and this difference was not statistically significant (OR = 0.873, 95% CI = 0.585–1.301; no heterogeneity was found for Q = 3.264, P = 0.999; Fig. 7, Table 3).
      Figure thumbnail gr5
      Fig. 5Meta-analysis of overall RLN palsy per patient at risk. (Color version of figure is available online.)
      Figure thumbnail gr6
      Fig. 6Meta-analysis of transient RLN palsy per patient at risk. (Color version of figure is available online.)
      Figure thumbnail gr7
      Fig. 7Meta-analysis of permanent RLN palsy per patient at risk. (Color version of figure is available online.)
      Overall, six patients had bilateral vocal cord palsy: three patients in the VA group [
      • Calò P.G.
      • Pisano G.
      • Medas F.
      • et al.
      Intraoperative recurrent laryngeal nerve monitoring in thyroid surgery: is it really useful?.
      ,
      • Alesina P.F.
      • Rolfs T.
      • Hommeltenberg S.
      • et al.
      Intraoperative neuromonitoring does not reduce the incidence of recurrent laryngeal nerve palsy in thyroid reoperations: results of a retrospective comparative analysis.
      ,
      • Atallah I.
      • Dupret A.
      • Carpentier A.S.
      • Weingertner A.S.
      • Volkmar P.
      • Rodier J.F.
      Role of the intraoperative neuromonitoring of the recurrent laryngeal nerve in high-risk thyroid surgery.
      ]; one patient in the IONM group [
      • Calò P.G.
      • Pisano G.
      • Medas F.
      • et al.
      Intraoperative recurrent laryngeal nerve monitoring in thyroid surgery: is it really useful?.
      ]; and the group was not specified in the remaining two patients [
      • Chan W.-F.
      • Lang B.H.
      • Lo C.Y.
      The role of intraoperative neuromonitoring of recurrent laryngeal nerve during thyroidectomy: a comparative study on 1000 nerves at risk.
      ,
      • Agha A.
      • Glockzin G.
      • Ghali N.
      • Iesalnieks I.
      • Schlitt H.J.
      Surgical treatment of substernal goiter: an analysis of 59 patients.
      ].

      3.2 Secondary outcome measures

      3.2.1 Operative time

      The meta-analysis of mean operative time was conducted on total thyroidectomies only. Mean operative time from skin incision to skin closure was longer in the IONM group than in the VA group (97.6 versus 94.6 min, respectively; SMD = 0.102, 95% CI = −0.227–0.404). This difference was not significant, and heterogeneity was found for Q = 41.738, P < 0.0001; Table 2.

      3.2.2 Overall, transient, and permanent RLN palsy per nerve at low risk

      The meta-analysis of RLN palsy per nerve at low risk was conducted on only two studies that reported the absolute numbers of injuries to nerves considered at low risk [
      • Barczyński M.
      • Konturek A.
      • Cichoń S.
      Randomized clinical trial of visualization versus neuromonitoring of recurrent laryngeal nerves during thyroidectomy.
      ,
      • Chan W.-F.
      • Lang B.H.
      • Lo C.Y.
      The role of intraoperative neuromonitoring of recurrent laryngeal nerve during thyroidectomy: a comparative study on 1000 nerves at risk.
      ]. Nerves in thyroidectomies for low-volume, non-toxic nodular goiter and solitary thyroid nodules were those considered to be at low risk. The rate of overall RLN palsy per nerve at low risk was 0.023 in the IONM group versus 0.036 in the VA group (694 versus 714 total nerves at low risk). This difference was not statistically significant (OR = 0.334, 95% CI = 0.066–1.679; heterogeneity was found for Q = 6.122, P = 0.013; Table 4). The rate of transient RLN palsy per nerve at low risk was 0.017 versus 0.029 in the IONM and VA groups, respectively. This difference was not statistically significant (OR = 0.581, 95% CI = 0.284–1.190; no heterogeneity was found for Q = 0.254, P = 0.613; Table 4). The rate of permanent RLN palsy per nerve at low risk was 0.006 versus 0.007 in the IONM and VA groups, respectively, and this difference was also not statistically significant (OR = 0.822, 95% CI = 0.220–3.074; no heterogeneity was found for Q = 0.222, P = 0.637; Fig. 8, Table 4).
      Table 4Overall transient and permanent RLN palsy in low and high risk nerves.
      Author (y)Nerves at low riskLow risk overallLow risk transientLow risk permanentNerves at high riskHigh risk overallHigh risk transientHigh risk permanent
      IONMVAIONMVAIONMVAIONMVAIONMVAIONMVAIONMVAIONMVA
      Alesina et al. 2012
      • Alesina P.F.
      • Rolfs T.
      • Hommeltenberg S.
      • et al.
      Intraoperative neuromonitoring does not reduce the incidence of recurrent laryngeal nerve palsy in thyroid reoperations: results of a retrospective comparative analysis.
      89157848400
      Barczynski et al. 2011
      • Barczyński M.
      • Konturek A.
      • Stopa M.
      • Hubalewska-Dydejczyk A.
      • Richter P.
      • Nowak N.
      Clinical value of intraoperative neuromonitoring of the recurrent laryngeal nerves in improving outcomes of surgery for well-differentiated thyroid cancer.
      3023025103822
      Frattini et al. 2010
      • Frattini F.
      • Mangano A.
      • Boni L.
      • Rausei S.
      • Biondi A.
      • Dionigi G.
      Intraoperative monitoring for thyroid malignancy surgery: technical notes and results from a retrospective series.
      152152372512
      Atallah et al. 2009
      • Atallah I.
      • Dupret A.
      • Carpentier A.S.
      • Weingertner A.S.
      • Volkmar P.
      • Rodier J.F.
      Role of the intraoperative neuromonitoring of the recurrent laryngeal nerve in high-risk thyroid surgery.
      181240162291379
      Barczynski et al. 2009
      • Barczyński M.
      • Konturek A.
      • Cichoń S.
      Randomized clinical trial of visualization versus neuromonitoring of recurrent laryngeal nerves during thyroidectomy.
      4945081217914335064921533102459
      Chan et al. 2006
      • Chan W.-F.
      • Lang B.H.
      • Lo C.Y.
      The role of intraoperative neuromonitoring of recurrent laryngeal nerve during thyroidectomy: a comparative study on 1000 nerves at risk.
      2002064937123012931717141334
      Yarbrough et al. 2004
      • Yarbrough D.E.
      • Thompson G.B.
      • Kasperbauer J.L.
      • Harper C.M.
      • Grant C.S.
      Intraoperative electromyographic monitoring of the recurrent laryngeal nerve in reoperative thyroid and parathyroid surgery.
      727911119823
      Total per nerve at risk69471416 (2.3%)26 (3.6%)12 (1.7%)21 (2.9%)4 (0.6%)5 (0.7%)1603171575 (4.7%)104 (6.0%)55(3.4%)75(4.4%)20(1.2%)29(1.7%)
      We included data from those studies that reported the absolute numbers of RLN palsy of nerves at low and high risk.
      Figure thumbnail gr8
      Fig. 8Meta-analysis of permanent RLN palsy per nerve at low risk. (Color version of figure is available online.)

      3.2.3 Overall, transient, and permanent RLN palsy per nerve at high risk

      The meta-analysis of RLN palsy per nerve at high risk was conducted on seven studies that reported the absolute numbers of injuries to nerves considered at high risk [
      • Dralle H.
      • Sekulla C.
      • Haerting J.
      • et al.
      Risk factors of paralysis and functional outcome after recurrent laryngeal nerve monitoring in thyroid surgery.
      ,
      • Barczyński M.
      • Konturek A.
      • Cichoń S.
      Randomized clinical trial of visualization versus neuromonitoring of recurrent laryngeal nerves during thyroidectomy.
      ,
      • Chan W.-F.
      • Lang B.H.
      • Lo C.Y.
      The role of intraoperative neuromonitoring of recurrent laryngeal nerve during thyroidectomy: a comparative study on 1000 nerves at risk.
      ,
      • Alesina P.F.
      • Rolfs T.
      • Hommeltenberg S.
      • et al.
      Intraoperative neuromonitoring does not reduce the incidence of recurrent laryngeal nerve palsy in thyroid reoperations: results of a retrospective comparative analysis.
      ,
      • Atallah I.
      • Dupret A.
      • Carpentier A.S.
      • Weingertner A.S.
      • Volkmar P.
      • Rodier J.F.
      Role of the intraoperative neuromonitoring of the recurrent laryngeal nerve in high-risk thyroid surgery.
      ,
      • Barczyński M.
      • Konturek A.
      • Stopa M.
      • Hubalewska-Dydejczyk A.
      • Richter P.
      • Nowak N.
      Clinical value of intraoperative neuromonitoring of the recurrent laryngeal nerves in improving outcomes of surgery for well-differentiated thyroid cancer.
      ,
      • Frattini F.
      • Mangano A.
      • Boni L.
      • Rausei S.
      • Biondi A.
      • Dionigi G.
      Intraoperative monitoring for thyroid malignancy surgery: technical notes and results from a retrospective series.
      ]. Nerves in thyroidectomies performed for substernal goiter, recurrent goiter, thyroid carcinoma, and Graves' disease were those considered to be at high risk. The rate of overall RLN palsy per nerve at high risk was 0.047 in the IONM group versus 0.060 in the VA group (1603 versus 1715 total nerves at high risk). This difference was not statistically significant (OR = 0.829, 95% CI = 0.511–1.344; heterogeneity was found for Q = 12.810, P = 0.046; Table 4). The rate of transient RLN palsy per nerve at high risk was 0.034 versus 0.044 in the IONM and VA groups, respectively. This difference was not statistically significant (OR = 0.842, 95% CI = 0.477–1.483; heterogeneity was found for Q = 12.942, P = 0.044; Table 4). The rate of permanent RLN palsy per nerve at high risk was 0.012 versus 0.017 in the IONM and VA groups, respectively, and this difference was also not statistically significant (OR = 0.763, 95% CI = 0.432–1.347; no heterogeneity was found for Q = 1.119, P = 0.980; Fig. 9, Table 4).
      Figure thumbnail gr9
      Fig. 9Meta-analysis of permanent RLN palsy per nerve at high risk. (Color version of figure is available online.)

      3.2.4 Assistance in RLN identification before visualization

      This outcome of interest was impossible to meta-analyze, as only one study clearly reported the absolute data about localization before visualization of the RLN. Barczyński et al. [
      • Barczyński M.
      • Konturek A.
      • Cichoń S.
      Randomized clinical trial of visualization versus neuromonitoring of recurrent laryngeal nerves during thyroidectomy.
      ] reported that nerve stimulation allowed localization of 137 out of 1000 RLN nerves before visual nerve exposition, and 92 more bifurcated nerves than RLN visualization alone.

      4. Discussion

      The use of neuromonitoring in thyroid surgery has gained increasing acceptance among endocrine and head–neck surgeons because of several intraoperative advantages, and it has recently been well standardized [
      • Randolph G.W.
      • Dralle H.
      • Abdullah H.
      • et al.
      with the International Intraoperative Monitoring Study Group
      Electrophysiologic recurrent laryngeal nerve monitoring during thyroid and parathyroid surgery: international standards guideline statement.
      ]. Nevertheless, the results of neuromonitoring during thyroidectomy are still a matter to be debated.
      The primary outcome measures of our systematic review with meta-analysis show that there were no statistically significant differences in overall, transient, or permanent RLN palsy per nerve at risk when comparing the results of the IONM group with those of the VA group. Likewise, the rates of overall, transient, and permanent RLN palsy per patient at risk were similar in the IONM and VA groups. Regarding the results of the secondary outcomes, the meta-analysis of RLN palsy per nerve at low and high risk showed that the rates of overall, transient, and permanent palsy were comparable in both groups, without statistically significant differences. The length of operative time of total thyroidectomy was also similar in both groups. The outcome of interest regarding the aid in RLN identification before visualization was impossible to meta-analyze, as only one study clearly reported this outcome [
      • Barczyński M.
      • Konturek A.
      • Cichoń S.
      Randomized clinical trial of visualization versus neuromonitoring of recurrent laryngeal nerves during thyroidectomy.
      ].
      Thus, with regard to the aim of the present research, the analysis of our results can be interpreted as indicating that there is no real benefit of IONM over VA in reducing the rate of RLN palsy.
      The total number of nerves at risk was 35,513, with 24,038 nerves in the IONM group and 11,475 nerves in the VA group. The rate of overall RLN palsy per nerve at risk was 3.47% in the IONM group and 3.67% in the VA group. The rate of transient RLN palsy per nerve at risk was 2.62% versus 2.72% in the IONM and VA groups, respectively. The rate of permanent RLN palsy per nerve at risk was 0.79% versus 0.92% in the IONM and VA groups, respectively. Overall, the prevalence of RLN damage tended to be lower in the IONM group, but no statistically significant differences were found.
      In connection with these typical rates of definitive nerve palsy, it has been estimated that in the setting of a prospective, randomized trial, the calculated sample size needed to prove that rates of paralysis are lower with the use of IONM is around 9000 nerves at risk [
      • Sanabria A.
      • Ramirez A.
      • Kowalski L.P.
      • et al.
      Neuromonitoring in thyroidectomy: a meta-analysis of effectiveness from randomized controlled trials.
      ]. Other authors reported that at least 39,907 nerves at risk per arm would be necessary for thyroid cancer only to reach a statistical power with significant difference in RLN palsy rate [
      • Dralle H.
      • Sekulla C.
      • Haerting J.
      • et al.
      Risk factors of paralysis and functional outcome after recurrent laryngeal nerve monitoring in thyroid surgery.
      ]. The high number of patients required shows the difficulty of undertaking such a trial. To date, only three controlled trials comparing the two techniques have been published [
      • Barczyński M.
      • Konturek A.
      • Cichoń S.
      Randomized clinical trial of visualization versus neuromonitoring of recurrent laryngeal nerves during thyroidectomy.
      ,
      • Sari S.
      • Erbil Y.
      • Sümer A.
      • et al.
      Evaluation of recurrent laryngeal nerve monitoring in thyroid surgery.
      ,
      • Dionigi G.
      • Boni L.
      • Rovera F.
      • Bacuzzi A.
      • Dionigi R.
      Neuromonitoring and video-assisted thyroidectomy: a prospective, randomized case-control evaluation.
      ]. These trials, which include hundreds of patients, might not be adequate for performing a meta-analysis with the required statistical power, because of an inherent type II error [
      • Sanabria A.
      • Ramirez A.
      • Kowalski L.P.
      • et al.
      Neuromonitoring in thyroidectomy: a meta-analysis of effectiveness from randomized controlled trials.
      ]. On the other hand, the use of a pooled analysis including a large number of observational studies involving thousands of patients, with >35,000 nerves at risk, appears justified in the absence of adequately powered RCTs [
      • Stroup D.F.
      • Berlin J.A.
      • Morton S.C.
      • et al.
      Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group.
      ]. When calculating the primary outcomes for our research, there was no heterogeneity across the included studies, which showed no true differences in the study effect. Nevertheless, meta-analyses based on observational design studies are prone to bias such as selection, allocation, performance, and interventional biases, causing low-level evidence [
      • Higgins J.P.
      • Altman D.G.
      • Gøtzsche P.C.
      • et al.
      Cochrane Bias Methods Group; Cochrane Statistical Methods Group
      The Cochrane Collaboration’s tool for assessing of bias in randomized trials.
      ].
      To the best of our knowledge, this is the third meta-analysis to match well the results of IONM versus VA of RLN in thyroid surgery. The meta-analysis by Higgins et al. [
      • Higgins T.S.
      • Gupta R.
      • Ketcham A.S.
      • Sataloff R.T.
      • Wadsworth J.T.
      • Sinacori J.T.
      Recurrent laryngeal nerve monitoring versus identification alone on post-thyroidectomy true vocal fold palsy: a meta-analysis.
      ] included one RCT, eight comparative observational studies, and 34 noncomparative case series. The analysis included comparative studies together with noncomparative studies, which were pooled in a whole subgroup of patients. This methodology caused heterogeneity across studies, allowing only the use of the random effects model to estimate all end points. On the other hand, our meta-analysis included only comparative studies showing homogeneity with regard to the assessment of the outcomes of interest using the fixed effects model. This means that if all included studies were infinitely large, they would yield identical estimates of the effect.
      The meta-analysis by Sanabria et al. [
      • Sanabria A.
      • Ramirez A.
      • Kowalski L.P.
      • et al.
      Neuromonitoring in thyroidectomy: a meta-analysis of effectiveness from randomized controlled trials.
      ] included six RCTs. Three of those studies focused on the outcome of monitoring the external branch of the superior laryngeal nerve [
      • Lifante J.C.
      • McGill J.
      • Murry T.
      • Aviv J.E.
      • Inabnet 3rd, W.B.
      A prospective, randomized trial of nerve monitoring of the external branch of the superior laryngeal nerve during thyroidectomy under local/regional anesthesia and IV sedation.
      ,
      • Barczyński M.
      • Konturek A.
      • Stopa M.
      • Honowska A.
      • Nowak W.
      Randomized controlled trial of visualization versus neuromonitoring of the external branch of the superior laryngeal nerve during thyroidectomy.
      ,
      • Khaled A.O.
      • Irfan M.
      • Baharudin A.
      • Shahid H.
      Comparing the morbidity of external laryngeal nerve injury in thyroid surgery with and without identifying the nerve using intraoperative neuromonitoring.
      ], and three focused on the results of IONM versus VA of RLN. Thus, the total number of patients included in this pooled analysis might not be adequate to reach a statistically significant difference between groups when evaluating the outcomes of RLN palsy.
      Currently, the use of neuromonitoring in thyroid surgery is affected by some limitations, and thus, there is no consensus of its true effectiveness. Regarding the occurrence of vocal cord palsy, the outcome is excellent for patients with an intact monitoring signal at the end of the operation, which is consistent with the high negative predictive value of the procedure, reported to be as high as 97% or even 99% [
      • Dralle H.
      • Sekulla C.
      • Haerting J.
      • et al.
      Risk factors of paralysis and functional outcome after recurrent laryngeal nerve monitoring in thyroid surgery.
      ,
      • Barczyński M.
      • Konturek A.
      • Cichoń S.
      Randomized clinical trial of visualization versus neuromonitoring of recurrent laryngeal nerves during thyroidectomy.
      ].
      The outcome on vocal cord status is extremely unpredictable when there is a loss of signal at the end of a thyroidectomy because of the low positive predictive value (PPV) of the procedure, which is around 33%–37.8% [
      • Dralle H.
      • Sekulla C.
      • Haerting J.
      • et al.
      Risk factors of paralysis and functional outcome after recurrent laryngeal nerve monitoring in thyroid surgery.
      ,
      • Barczyński M.
      • Konturek A.
      • Cichoń S.
      Randomized clinical trial of visualization versus neuromonitoring of recurrent laryngeal nerves during thyroidectomy.
      ]. This means that two-thirds of nerves with a missing monitoring signal can expect normal vocal cord function after surgery [
      • Barczyński M.
      • Konturek A.
      • Cichoń S.
      Randomized clinical trial of visualization versus neuromonitoring of recurrent laryngeal nerves during thyroidectomy.
      ,
      • Chiang F.Y.
      • Lee K.W.
      • Chen H.C.
      • et al.
      Standardization of intraoperative neuromonitoring of recurrent laryngeal nerve in thyroid operation.
      ]. The relatively low sensitivity and PPV is one of the major concerns in the use of neuromonitoring. Strict criteria of standardization, as described elsewhere [
      • Randolph G.W.
      • Dralle H.
      • Abdullah H.
      • et al.
      with the International Intraoperative Monitoring Study Group
      Electrophysiologic recurrent laryngeal nerve monitoring during thyroid and parathyroid surgery: international standards guideline statement.
      ], can reduce technical pitfalls, thereby improving the PPV of neuromonitoring [
      • Dralle H.
      • Sekulla C.
      • Haerting J.
      • et al.
      Risk factors of paralysis and functional outcome after recurrent laryngeal nerve monitoring in thyroid surgery.
      ,
      • Chiang F.Y.
      • Lee K.W.
      • Chen H.C.
      • et al.
      Standardization of intraoperative neuromonitoring of recurrent laryngeal nerve in thyroid operation.
      ].
      One of the recommendations in the use of neuromonitoring is to avoid contralateral lobe resection after loss of signal in the first lobe [
      • Barczyński M.
      • Konturek A.
      • Cichoń S.
      Randomized clinical trial of visualization versus neuromonitoring of recurrent laryngeal nerves during thyroidectomy.
      ,
      • Chiang F.Y.
      • Lee K.W.
      • Chen H.C.
      • et al.
      Standardization of intraoperative neuromonitoring of recurrent laryngeal nerve in thyroid operation.
      ]. The reconsideration of surgical strategy after a missing signal in one site must be evaluated, mainly for redo surgery in patients at major risk of bilateral RLN palsy [
      • Goretzki P.E.
      • Schwarz K.
      • Brinkmann J.
      • Wirowski D.
      • Lammers B.J.
      The impact of intraoperative neuromonitoring on surgical strategy in bilateral thyroid diseases: is it worth the effort?.
      ]. Following this recommendation, however, two-thirds of patients might require unnecessary two-stage thyroidectomy [
      • Barczyński M.
      • Konturek A.
      • Cichoń S.
      Randomized clinical trial of visualization versus neuromonitoring of recurrent laryngeal nerves during thyroidectomy.
      ].
      Another highlighted limit of conventional intermittent monitoring is that RLN palsy is usually identified after it has occurred [
      • Schneider R.
      • Randolph G.W.
      • Sekulla C.
      • et al.
      Continuous intraoperative vagus nerve stimulation for identification of imminent recurrent laryngeal nerve injury.
      ]. Real-time continuous intraoperative vagus monitoring can detect an impending RLN injury with modification of the intraoperative strategy, thus avoiding nerve damage [
      • Schneider R.
      • Randolph G.W.
      • Sekulla C.
      • et al.
      Continuous intraoperative vagus nerve stimulation for identification of imminent recurrent laryngeal nerve injury.
      ,
      • Schneider R.
      • Bures C.
      • Lorenz K.
      • Dralle E.
      • Freissmuth M.
      • Hermann M.
      Evolution of nerve injury with unexpected EMG signal recovery in thyroid surgery using continuous intraoperative neuromonitoring.
      ]. However, other authors have reported that the use of continuous neuromonitoring during thyroidectomy does not reduce the rates of RLN palsy compared with neurostimulation alone [
      • Cavicchi O.
      • Caliceti U.
      • Fernandez I.J.
      • et al.
      Laryngeal neuromonitoring and neurostimulation versus neurostimulation alone in thyroid surgery: a randomized clinical trial.
      ].
      The results of this review and meta-analysis show no significant benefit of IONM over VA in reducing the rate of RLN palsy. The rates of permanent RLN palsy per nerve at risk were 0.79% versus 0.92% in the IONM and VA groups, respectively. Experienced thyroid surgeons who achieve a RLN morbidity rate <1% will have a low margin of improvement by using neuromonitoring [
      • Barczyński M.
      • Konturek A.
      • Cichoń S.
      Randomized clinical trial of visualization versus neuromonitoring of recurrent laryngeal nerves during thyroidectomy.
      ,
      • Sanabria A.
      • Ramirez A.
      • Kowalski L.P.
      • et al.
      Neuromonitoring in thyroidectomy: a meta-analysis of effectiveness from randomized controlled trials.
      ]. However, a detailed subgroup analysis conducted by Dralle et al. [
      • Dralle H.
      • Sekulla C.
      • Haerting J.
      • et al.
      Risk factors of paralysis and functional outcome after recurrent laryngeal nerve monitoring in thyroid surgery.
      ] showed a significant reduction in the incidence of permanent RLN palsy in low-volume surgeons who adopted IONM during thyroidectomy. In addition, the assistance in nerve identification before visualization could result in a significant decrease in the prevalence of transient RLN palsy [
      • Barczyński M.
      • Konturek A.
      • Cichoń S.
      Randomized clinical trial of visualization versus neuromonitoring of recurrent laryngeal nerves during thyroidectomy.
      ]. With regard to the previous considerations, it appears that additional research is necessary to understand definitively the different clinical, scientific, and neurophysiological aspects of intraoperative monitoring of the RLN during thyroidectomy [
      • Dralle H.
      • Sekulla C.
      • Lorenz K.
      • Brauckhoff M.
      • Machens A.
      the German IONM Study Group
      Intraoperative monitoring of the recurrent laryngeal nerve in thyroid surgery.
      ].

      5. Conclusions

      It was expected that thyroidectomy with IONM of the RLN would have a positive impact on nerve palsy prevention and nerve identification in some clinical circumstances. However, the results of our study could be interpreted as indicating that there are no real observed benefits of IONM over VA in reducing the rate of RLN palsy. The inherent biases of the current research suggest that the results should be approached with caution. Further studies, including high-quality multicenter prospective, randomized trials based on strict criteria of standardization and subsequent clustered meta-analysis are required to better assess the effectiveness of the IONM procedure in thyroid surgery.

      Acknowledgment

      This study was supported by a grant from the University of Cagliari, Italy (CAR 2012).
      The authors declare no conflict of interest.
      Author contributions: Pisanu A: Conception and design, acquisition and interpretation of data, drafting the article, revising for important intellectual content and approval of the final version.
      Porceddu G: Acquisition of data and analysis, revising for intellectual content, approval of the final version.
      Podda M: Analysis and interpretation of data, revising for intellectual content, approval of the final version.
      Cois A: Analysis and interpretation of data, revising for intellectual content, approval of the final version.
      Uccheddu A: Conception and design, interpretation of data, revising for important intellectual content, and approval of the final version.

      Supplementary Data

      References

        • Stevens K.
        • Stojadinovic A.
        • Helou L.B.
        • et al.
        The impact of recurrent laryngeal neuromonitoring on multi-dimensional voice outcomes following thyroid surgery.
        J Surg Oncol. 2012; 105: 4
        • Rosenthal L.H.S.
        • Benninger M.S.
        • Deeb R.H.
        Vocal fold immobility: a longitudinal analysis of etiology over 20 years.
        Laryngoscope. 2007; 117: 1864
        • Jatzko G.R.
        • Lisborg P.H.
        • Müller M.G.
        • Wette V.M.
        Recurrent nerve palsy after thyroid operations: principal nerve identification and a literature review.
        Surgery. 1994; 115: 139
        • Dralle H.
        • Sekulla C.
        • Haerting J.
        • et al.
        Risk factors of paralysis and functional outcome after recurrent laryngeal nerve monitoring in thyroid surgery.
        Surgery. 2004; 136: 1310
        • Snyder S.K.
        • Hendricks J.C.
        Intraoperative neurophysiology testing of the recurrent laryngeal nerve: plaudits and pitfalls.
        Surgery. 2005; 138: 1183
        • Angelos P.
        Recurrent laryngeal nerve monitoring: state of the art, ethical and legal issues.
        Surg Clin N Am. 2009; 89: 1157
        • Barczyński M.
        • Konturek A.
        • Cichoń S.
        Randomized clinical trial of visualization versus neuromonitoring of recurrent laryngeal nerves during thyroidectomy.
        Br J Surg. 2009; 96: 240
        • Sturgeon C.
        • Sturgeon T.
        • Angelos P.
        Neuromonitoring in thyroid surgery: attitudes, usage patterns, and predictors of use among endocrine surgeons.
        World J Surg. 2009; 33: 417
        • Chan W.-F.
        • Lang B.H.
        • Lo C.Y.
        The role of intraoperative neuromonitoring of recurrent laryngeal nerve during thyroidectomy: a comparative study on 1000 nerves at risk.
        Surgery. 2006; 140: 866
        • Chiang F.Y.
        • Lee K.W.
        • Chen H.C.
        • et al.
        Standardization of intraoperative neuromonitoring of recurrent laryngeal nerve in thyroid operation.
        World J Surg. 2010; 34: 223
        • Sari S.
        • Erbil Y.
        • Sümer A.
        • et al.
        Evaluation of recurrent laryngeal nerve monitoring in thyroid surgery.
        Int J Surg. 2010; 8: 474
        • Robertson M.L.
        • Steward D.L.
        • Gluckman J.L.
        • Welge J.
        Continuous laryngeal nerve monitoring during thyroidectomy: does it reduce risk of injury?.
        Otolaryngol Head Neck Surg. 2004; 131: 596
        • Calò P.G.
        • Pisano G.
        • Medas F.
        • et al.
        Intraoperative recurrent laryngeal nerve monitoring in thyroid surgery: is it really useful?.
        Clin Ter. 2013; 164: e193
        • Kern K.A.
        Medicolegal analysis of errors in diagnosis and treatment of surgical endocrine disease.
        Surgery. 1993; 114: 1167
        • Abadin S.S.
        • Kaplan E.L.
        • Angelos P.
        Malpractice litigation after thyroid surgery: the role of recurrent laryngeal nerve injuries, 1989–2009.
        Surgery. 2010; 148: 718
        • Alesina P.F.
        • Rolfs T.
        • Hommeltenberg S.
        • et al.
        Intraoperative neuromonitoring does not reduce the incidence of recurrent laryngeal nerve palsy in thyroid reoperations: results of a retrospective comparative analysis.
        World J Surg. 2012; 36: 1348
        • Duclos A.
        • Lifante J.C.
        • Ducarroz S.
        • Soardo P.
        • Colin C.
        • Peix J.L.
        Influence of intraoperative neuromonitoring on surgeons’ technique during thyroidectomy.
        World J Surg. 2011; 35: 773
        • Gremillion G.
        • Fatakia A.
        • Dornelles A.
        • Amedee R.G.
        Intraoperative recurrent laryngeal nerve monitoring in thyroid surgery: is it worth the cost?.
        The Ochsner J. 2012; 12: 363
        • Cavicchi O.
        • Caliceti U.
        • Fernandez I.J.
        • et al.
        The value of neurostimulation and intraoperative nerve monitoring of inferior laryngeal nerve in thyroid surgery.
        Otolaryngol Head Neck Surg. 2009; 140: 866
        • Shindo M.
        • Chheda N.N.
        Incidence of vocal cord paralysis with and without recurrent laryngeal nerve monitoring during thyroidectomy.
        Arch Otolaryngol Head Neck Surg. 2007; 133: 481
        • Atallah I.
        • Dupret A.
        • Carpentier A.S.
        • Weingertner A.S.
        • Volkmar P.
        • Rodier J.F.
        Role of the intraoperative neuromonitoring of the recurrent laryngeal nerve in high-risk thyroid surgery.
        J Otolaryngol Head Neck Surg. 2009; 38: 613
        • Randolph G.W.
        • Dralle H.
        • Abdullah H.
        • et al.
        • with the International Intraoperative Monitoring Study Group
        Electrophysiologic recurrent laryngeal nerve monitoring during thyroid and parathyroid surgery: international standards guideline statement.
        Laryngoscope. 2011; 121: S1
        • Higgins T.S.
        • Gupta R.
        • Ketcham A.S.
        • Sataloff R.T.
        • Wadsworth J.T.
        • Sinacori J.T.
        Recurrent laryngeal nerve monitoring versus identification alone on post-thyroidectomy true vocal fold palsy: a meta-analysis.
        Laryngoscope. 2011; 121: 1009
        • Sanabria A.
        • Ramirez A.
        • Kowalski L.P.
        • et al.
        Neuromonitoring in thyroidectomy: a meta-analysis of effectiveness from randomized controlled trials.
        Eur Arch Otorhinolaryngol. 2013; 270: 2175
        • Liberati A.
        • Altman D.G.
        • Tetzlaff J.
        • et al.
        The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration.
        BMJ. 2009; 339: b2700
        • Stroup D.F.
        • Berlin J.A.
        • Morton S.C.
        • et al.
        Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group.
        JAMA. 2000; 283: 2008
        • Pisanu A.
        • Reccia I.
        • Porceddu G.
        • Uccheddu A.
        Meta-analysis of prospective randomized studies comparing single-incision laparoscopic cholecystectomy (SILC) and conventional multiport laparoscopic cholecystectomy (CMLC).
        J Gastrointest Surg. 2012; 16: 1790
        • DerSimonian R.
        • Laird N.
        Meta-analysis in clinical trials.
        Control Clin Trials. 1986; 7: 177
        • Barczyński M.
        • Konturek A.
        • Stopa M.
        • Hubalewska-Dydejczyk A.
        • Richter P.
        • Nowak N.
        Clinical value of intraoperative neuromonitoring of the recurrent laryngeal nerves in improving outcomes of surgery for well-differentiated thyroid cancer.
        Pol Prezegl Chir. 2011; 83: 196
        • Frattini F.
        • Mangano A.
        • Boni L.
        • Rausei S.
        • Biondi A.
        • Dionigi G.
        Intraoperative monitoring for thyroid malignancy surgery: technical notes and results from a retrospective series.
        Updates Surg. 2010; 62: 183
        • Dionigi G.
        • Boni L.
        • Rovera F.
        • Bacuzzi A.
        • Dionigi R.
        Neuromonitoring and video-assisted thyroidectomy: a prospective, randomized case-control evaluation.
        Surg Endosc. 2009; 23: 996
        • Agha A.
        • Glockzin G.
        • Ghali N.
        • Iesalnieks I.
        • Schlitt H.J.
        Surgical treatment of substernal goiter: an analysis of 59 patients.
        Surg Today. 2008; 38: 505
        • Netto I de P.
        • Vartarian J.G.
        • Salgado P.
        • et al.
        Vocal fold immobility after thyroidectomy with intraoperative recurrent laryngeal nerve monitoring.
        Sao Paulo Med J. 2007; 125: 186
        • Terris D.J.
        • Anderson S.K.
        • Watts T.L.
        • Chin E.
        Laryngeal nerve monitoring and minimally invasive thyroid surgery.
        Arch Otolaryngol Head Neck Surg. 2007; 133: 1254
        • Witt R.L.
        Recurrent laryngeal nerve electrophysiologic monitoring in thyroid surgery: the standard of care?.
        J Voice. 2005; 19: 497
        • Yarbrough D.E.
        • Thompson G.B.
        • Kasperbauer J.L.
        • Harper C.M.
        • Grant C.S.
        Intraoperative electromyographic monitoring of the recurrent laryngeal nerve in reoperative thyroid and parathyroid surgery.
        Surgery. 2004; 136: 1107
        • Higgins J.P.
        • Altman D.G.
        • Gøtzsche P.C.
        • et al.
        • Cochrane Bias Methods Group; Cochrane Statistical Methods Group
        The Cochrane Collaboration’s tool for assessing of bias in randomized trials.
        BMJ. 2011; 343: d5928
        • Lifante J.C.
        • McGill J.
        • Murry T.
        • Aviv J.E.
        • Inabnet 3rd, W.B.
        A prospective, randomized trial of nerve monitoring of the external branch of the superior laryngeal nerve during thyroidectomy under local/regional anesthesia and IV sedation.
        Surgery. 2009; 146: 1167
        • Barczyński M.
        • Konturek A.
        • Stopa M.
        • Honowska A.
        • Nowak W.
        Randomized controlled trial of visualization versus neuromonitoring of the external branch of the superior laryngeal nerve during thyroidectomy.
        World J Surg. 2012; 36: 1340
        • Khaled A.O.
        • Irfan M.
        • Baharudin A.
        • Shahid H.
        Comparing the morbidity of external laryngeal nerve injury in thyroid surgery with and without identifying the nerve using intraoperative neuromonitoring.
        Med J Malaysia. 2012; 67: 289
        • Goretzki P.E.
        • Schwarz K.
        • Brinkmann J.
        • Wirowski D.
        • Lammers B.J.
        The impact of intraoperative neuromonitoring on surgical strategy in bilateral thyroid diseases: is it worth the effort?.
        World J Surg. 2008; 34: 1274
        • Schneider R.
        • Randolph G.W.
        • Sekulla C.
        • et al.
        Continuous intraoperative vagus nerve stimulation for identification of imminent recurrent laryngeal nerve injury.
        Head Neck. 2012; https://doi.org/10.1002/hed.23187
        • Schneider R.
        • Bures C.
        • Lorenz K.
        • Dralle E.
        • Freissmuth M.
        • Hermann M.
        Evolution of nerve injury with unexpected EMG signal recovery in thyroid surgery using continuous intraoperative neuromonitoring.
        World J Surg. 2013; 37: 364
        • Cavicchi O.
        • Caliceti U.
        • Fernandez I.J.
        • et al.
        Laryngeal neuromonitoring and neurostimulation versus neurostimulation alone in thyroid surgery: a randomized clinical trial.
        Head Neck. 2012; 34: 141
        • Dralle H.
        • Sekulla C.
        • Lorenz K.
        • Brauckhoff M.
        • Machens A.
        • the German IONM Study Group
        Intraoperative monitoring of the recurrent laryngeal nerve in thyroid surgery.
        World J Surg. 2008; 32: 1358