The current state of intermittent intraoperative neural monitoring for prevention of recurrent laryngeal nerve injury during thyroidectomy: a PRISMA-compliant systematic review of overlapping meta-analyses

Intermittent intraoperative nerve monitoring (I-IONM) made its debut in thyroid surgery in the late 1960s with promise to reduce procedure iatrogenic nerve injury [1]. I-IONM has gained popularity in recent years with ever increasing pressures on surgeons for complication-free procedures. Despite its increasing use, I-IONM is still presently considered an adjunctive tool during thyroid surgery, taking a secondary role behind the gold standard of direct recurrent laryngeal nerve (RLN) visualization [2]. Preoperative and postoperative laryngoscopic assessment of vocal cord function should also be appraised to determine baseline and postoperative function. This supplementary role of I-IONM is supported by the recommendations set forth by the German Association of Endocrine Surgeons’ guidelines for thyroid disease and supported by the International Intraoperative Monitoring Study Group’s international standards guideline statement [2, 3]. It has also been proposed that I-IONM could play a more integral role in thyroid surgery during primary operations of high-risk patients, e.g., for retrosternal goiter, toxic goiter, Hashimoto’s thyroiditis, and Graves’ disease, or in patients undergoing revision surgery for recurrent goiter or local recurrence of thyroid cancer [4‐6]. Various anatomic anomalies of the RLN such as extralaryngeal branching also pose a unique threat to the use of direct visualization and can potentially be more effectively identified with I-IONM [4]. Although many attempts have been made in recent years to statistically demonstrate the reliability of I-IONM as an essential tool for RLN identification, individual clinical studies have produced conflicting results and meta-analyses have yet to establish a uniformly acceptable conclusion. Several meta-analyses conducted in the last 5 years corroborate the current notion that I-IONM should not be incorporated into the standard of care for thyroid surgery [7‐11]. Three analyses conducted by Zheng et al., Yang et al., and Wong et al. demonstrated just the opposite, in that there were significant benefits of I-IONM use [6, 12, 13]. Individual studies such as Thomusch et al. [14] and Barczynski et al. [15] have also contributed to these conflicting results.

It has been noted that from a financial perspective, I-IONM does not become justifiably cost effective unless it is able to achieve a 50.4% reduction in injuries compared to traditional direct visualization [16, 17]. Additionally, it does not significantly reduce operative time [16, 17]. Results of statistically significant injury reduction have been largely mixed and inconsistent with no obvious trend supporting movement towards full-time I-IONM use [13] or I-IONM as purely adjunctive worth [7‐10]. Determining whether an improvement in transient vocal fold palsy (VFP) alone or a reduction in permanent VFP is required for implementing widespread I-IONM use is another point for debate.

A study by Sturgeon et al. indicated that approximately 37% of surgeons either routinely or in select cases use I-IONM during thyroid procedures [18]. I-IONM use according to Sanabria et al. and Barczynski et al. is also stratified based on equipment availability, experience, and surgeon age [11, 19]. Injury to the RLN during thyroid operations is notably one of the most severe postoperative complications patients experience [4, 9]. VFP is also the most frequent citing cause for litigation post thyroidectomy, as well as a significant detriment to patient quality of life [20]. Injuries bear a vast range of severity from unilateral transient VFP causing hoarseness to permanent bilateral VFP resulting in airway obstruction requiring tracheostomy [10]. Rates of transient VFP and permanent VFP have been reported as 9.8 and 2.3%, respectively [21].

Technological advances in I-IONM are occurring and the time is likely approaching when I-IONM will become standard practice for thyroid surgery patients. Yarborough et al. cite that I-IONM can play a vital role in three ways for surgeons: substantiating decisions in cases of aberrant anatomy and pathology, routine intraoperative RLN identification, and assessing postoperative RLN function [22]. Preserving RLN function is a top priority, and affording surgeons the proper information and opportunity to use all available technology to lower the injury rate is paramount. The aim of our review is to directly compare the previously conducted meta-analyses on the use of I-IONM versus direct RLN visualization by assessing rates of VFP. The ultimate goal of this analysis is to provide clarification of the differing conclusions about I-IONM use that have been presented in literature to date and put them in a perspective of rapidly developing innovations like continuous IONM technology or concept of staged thyroidectomy previously not evaluated in any of the meta-analyses. We hope that this review will serve to better guide the standards of clinical therapy and the use of I-IONM in future operative procedures.

This comprehensive review is aimed at comparing and summarizing meta-analyses on the rates of RLN injury between groups undergoing either direct visualization or I-IONM during thyroidectomy. The meta-analysis conducted by Pisanu et al. was determined to be of the highest methodological quality when compared to the other included studies [8]. The evidence to date supports the notion that I-IONM does not provide for significant reduction in postoperative RLN injury challenging rationale for its widespread implementation [8].

Meta-analyses have long been utilized to increase the statistical power through the combination of smaller studies in hopes of uncovering meaningful data for use in clinical practice. In the case of I-IONM, the recommendations have varied widely between individual studies and in the several analyses conducted in recent years. With the continually variable conclusions being published on the subject, it becomes very difficult for clinicians and scientists alike to form meaningful practice changing policy. It is the intent of this analysis to provide a pathway for these individuals and agencies to easily navigate these conflicting studies.

In 1997, Jadad et al. devised a system with which to sift through these analyses that have come to differing conclusions [26]. It was proposed that there are several sources that could lead to these discordant results such as inclusion criteria, extraction techniques, statistical analysis procedures, and quality assessment [26].

The meta-analysis conducted by Pisanu et al. was the study selected that best reflects the present literature [8]. It can be noted in Table 3 that Pisanu et al. included the second highest number of studies in their analysis [8]. The chosen study achieved a score of 6 in the AMSTAR checklist utilized. The score was largely lowered by the lack of quality assessment of the studies that were included. There were five studies which resulted in an AMSTAR of higher value: Higgins et al. [10], Sanabria et al. [11], Zheng et al. [13], Yang et al. [12], and Wong et al. [6]. Through the utilization of the Jadad method, and assessing the number of studies included, the databases searched, journal of publication, and methodology, the authors still deemed Pisanu et al. to be the meta-analysis of highest quality [8]. The conclusion that I-IONM should be used as a purely adjunctive measure that resulted in Pisanu et al. (p = 0.471) [8] was largely supported by the other analyses included in this present review [Malik 2016 (p > 0.05) [7], Lombardi 2016 (p > 0.05) [9], Higgins 2011 (p = 0.11) [10], Sanabria 2013 (p = 0.15) [11]], clashing with the results of three reviews (Zheng 2013, p = 0.007, Yang 2017, p = 0.041, Wong 2017, p = 0.003, 0.021, and 0.05) [6, 12, 13]. The meta-analysis conducted by Wong et al. [6] demonstrated significant rates of injury reduction in both overall and transient VFP; it should however be noted that this study focused entirely on high-risk procedures of patients undergoing re-operation or those with significant pathology such as malignancy or retrosternal goiter.

I-IONM in theory appears as an ideal tool that could provide better outcomes for patients. It has been noted that with traditional intermittent (non-continuous) IONM techniques, injuries are often discovered by the machine but only after they have already occurred [28]. Until injuries can be prevented as opposed to being simply identified, this approach does not seem to be justifiable. However, results reported by Bergenfelz et al. in a database from a Swedish multicenter audit comprising 3660 patients undergoing thyroid surgery showed that RLN injury was recognized intraoperatively in only 16 (11.3%) out of 142 patients with a damaged nerve [29]. This in agreement with recent studies showing that RLN injury most often occurs to a visually observed nerve. Hence, I-IONM has a potential to improve the intraoperative RLN management by elucidating mechanisms of nerve injury. In addition, I-IONM is an effective tool in staging planned bilateral thyroid surgeries in cases of intraoperative RLN injury on the side of initial dissection [30]. This issue is of great importance in prevention of bilateral RLN injury which occurs in approximately 0.2% of patients undergoing thyroidectomy leading to significant deterioration of quality of life and medicolegal claims [31]. Bergenfelz et al. analyzed the risk of RLN palsy in a cohort of 5252 patients undergoing thyroidectomy with and without intraoperative nerve monitoring who were registered in the Scandinavian Quality Register for Thyroid, Parathyroid and Adrenal Surgery in 2009–2013 [32]. I-IONM was used in 3277 operations (62.4%), and postoperative laryngoscopy was performed in 1757 patients (33.5%) [32]. Early VFP occurred in 217 patients (4.1%), of which 3 were bilateral, all in the group without I-IONM. Permanent VFP occurred in 62 patients (1.2%). In the multivariable analysis of 1757 patients who had postoperative laryngoscopy, the use of I-IONM was not associated with a decreased risk of early VFP [OR 0.67 (95% CI 0.44–1.01)], but decreased the risk of permanent VFP [OR 0.43 (95% CI 0.19–0.93)]. Thus, data arising from a prospective register reflect to a greater extent some details of current surgical practice landscape in thyroid surgery rather than data from meta-analysis based on mixed and often inclusive of poorly reported retrospective case series.

It was noted by Chan et al. that among a survey of members of the American Association of Endocrine Surgeons, protection from litigation was cited as a primary reason for I-IONM use [33]. The addition of costly procedures to standard operative technique can only be rationalized by an improvement in clinical outcomes and should not be on the basis of legal protection [16]. The use of I-IONM is also associated with a learning curve and is predominantly utilized by surgeons under the age of 40 [11, 19]. This learning curve can be associated with a period of higher incidence of injury which should be factored into research conducted in the future [7, 34]. Hence, training and exposure to the standardized utilization of I-IONM technique during thyroid surgery by attending to one of the hands-on courses organized worldwide and accredited by the International Neural Monitoring Study Group in Thyroid and Parathyroid Surgery should be warranted to optimize the clinical benefit. Finally, the most recent developments of IONM technology including continuous vagal IONM with intraoperative real-time electromyography of the vocalis muscles and its potential to recognize the imminent RLN injury which could be prevented by modifying surgical maneuvers seem to be a very promising tool considered to be a quantum leap forward in the prevention of the RLN injury during thyroid surgery [35]. It should be underlined that any of the published meta-analyses included continuous IONM studies as they were undertaken and published later on.

This systematic review was limited by a number of factors. Broadly speaking, the progress of IONM technology and the methods utilized varied in the included meta-analyses. It is likely that as IONM technology improves over time, there will be increasing utility for not only identifying the RLN but also preventing the RLN injury. Older studies may introduce a level of bias into meta-analyses because of the falsely depressed levels of RLN identification and non-standardized use of the I-IONM technique both for nerve identification and for prognostication of neural function. In addition, postoperative laryngoscopy was used on a select basis in many centers leading to underestimation of the true prevalence of the RLN injury. It is important in future investigations to reduce this potential bias through subgroup analysis on the basis of study year, use of the standardized approach to IONM, and postoperative laryngoscopy, as well as potentially the equipment used. With regard to the varying methodology, studies varied greatly on their search strategies, many of which did not include foreign language articles. Future meta-analysis on this topic should use a more rigorous methodology. Numerous issues with the originally included primary studies such as bias, study design, and sample heterogeneity may have had significant impacts on the final interpretations of their results.

There is a need for continuing investigation into the use of IONM as a primary method for RLN identification and prevention of postoperative complications. IONM is a developing technology, and likely with improvements, there will come a time where it does provide the necessary reduction in injuries to warrant its widespread implementation [7]. Additionally, original studies and new meta-analyses are needed to further investigate the use of IONM specifically in cases of reoperation as has been initiated by Wong et al. [6]. Many studies have shown insignificant improvement in postoperative complications in primary procedures, while demonstrating potential use in secondary operations [7, 33, 36].

To date, I-IONM has not achieved a significant level of RLN injury reduction as shown by the meta-analysis conducted by Pisanu et al. [8]. However, most recent developments of IONM technology including continuous vagal IONM and concept of staged thyroidectomy in case of loss of signal on the first side in order to prevent bilateral RLN injury may provide additional benefits which were out of the scope of this study and need to be assessed in further prospective multicenter trials.