- Email: [email protected]
Importance of latency and amplitude values of recurrent laryngeal nerve during thyroidectomy in diabetic patients
International Journal of Surgery 35 (2016) 172e178
Contents lists available at ScienceDirect
International Journal of Surgery journal homepage: www.journal-surgery.net
Importance of latency and amplitude values of recurrent laryngeal nerve during thyroidectomy in diabetic patients Ibrahim Ali Ozemir a, *, Ferman Ozyalvac a, Gorkem Yildiz a, Tunc Eren a, Zeynep Aydin-Ozemir b, Orhan Alimoglu a a b
Istanbul Medeniyet University, Goztepe Training & Research Hospital, Department of General Surgery, Istanbul, Turkey Istanbul University, Istanbul Faculty of Medicine, Department of Neurology, Istanbul, Turkey
h i g h l i g h t s Diabetic patients have prolonged post-thyroidectomy latency values than non-diabetic patients. Diabetic patients have decreased post-thyroidectomy amplitude values than non-diabetic patients. Increased post-thyroidectomy latency values detected in diabetic patients compared to pre-thyroidectomy latecies. Recurrent nerve in diabetic patients is more sensitive to the surgical trauma than non-diabetics.
a r t i c l e i n f o
a b s t r a c t
Article history: Received 24 June 2016 Received in revised form 23 September 2016 Accepted 3 October 2016 Available online 5 October 2016
Background: Diabetes mellitus may cause degeneration in the myelin and/or axonal structures of peripheral nerves. The aim of this study was to investigate the effects of diabetic neuropathy on intraoperative neuromonitoring findings such as latency and amplitude values of the recurrent laryngeal nerves during thyroidectomy. To our knowledge this is the first study to report comparison of the electrophysiologic features of diabetic and non-diabetic patients. Materials and methods: One-hundred-and-eleven consecutive patients who received neuromonitoring during thyroidectomy between 2013 and 2015 were included to study. The patients were divided into two groups according to the presence of diabetes mellitus. Pre-thyroidectomy and post thyroidectomy motor response latency and amplitude values of recurrent laryngeal nerves were compared between groups. Neuromonitoring findings, demographic data and postoperative complications were evaluated. Results: The diabetic group consisted of 29 (26.1%) patients while 82 (73.9%) patients were in nondiabetic group. The mean post-thyroidectomy amplitude values (millivolts-mV) of the recurrent laryngeal nerve were significantly lower in diabetic group (0.51 ± 0.26 mV vs. 0,70 ± 0,46 mV, p < 0.05), whereas the latency values were significantly higher (2.50 ± 0.86 ms vs. 1.85 ± 0.59 ms, p < 0.01) compared to non-diabetic group. Additionally, post-thyroidectomy latency values were significantly increased compared to the pre-thyroidectomy latency values (2.50 ± 0.86 ms vs. 2.02 ± 0.43 ms) in diabetic group patients (p < 0.05). Although postoperative complication rates were higher in diabetic group (10.3% vs. 5.9%), there were no statistical significance differences. Conclusions: Prolonged latency and decreased amplitude values in recurrent laryngeal nerves of diabetic patients show that diabetic neuropathy of the recurrent laryngeal nerves develop similarly to the peripheral nerves. Increased post-thyroidectomy latency values reveal that the recurrent laryngeal nerve is more susceptible to surgical trauma in diabetic patients. © 2016 IJS Publishing Group Ltd. Published by Elsevier Ltd. All rights reserved.
Keywords: Latency Amplitude Recurrent laryngeal nerve Diabetes mellitus
1. Introduction * Corresponding author. Istanbul Medeniyet University Goztepe Training & Research Hospital, Department of General Surgery, Dr. Erkin Street, 34660, Goztepe, Kadikoy, Istanbul, Turkey. E-mail address: [email protected] (I.A. Ozemir).
Recurrent laryngeal nerve (RLN) injury is one of the most significant complication of thyroid surgery. The incidence of RLN injury during thyroid surgery ranges from 0.3 to 18.9% [1]. Visual
http://dx.doi.org/10.1016/j.ijsu.2016.10.001 1743-9191/© 2016 IJS Publishing Group Ltd. Published by Elsevier Ltd. All rights reserved.
I.A. Ozemir et al. / International Journal of Surgery 35 (2016) 172e178
identification of the RLN is one of the most important factor that provide the nerve preservation. Absence of the visual identification of the RLN is correlated with an increased rate of RLN paralysis [2e4]. Intraoperative nerve monitoring (IONM) technology was first reported by Shedd and Durham in 1965 [5]. IONM might allow rapid identification and intraoperative assessment the function of RLN [6]. It also ensures the prescience of postoperative vocal cord function and avoid the bilateral RLN injury. Although it is a controversial topic, some authors reported that neuromonitoring significantly reduces the risk of transient RLN paralysis [7e11]. Positive stimulation of the RLN during surgery accompanied by postoperative vocal cord paralysis suggests that it will be transient [12,13]. There are increased number of publications in the literature about the usage of IONM as an adjunct to visual nerve identification during thyroid surgery. It estimates of 53% among general surgeons and up to 65% among otolaryngologists use IONM during thyroidectomy [14,15]. Despite this increased usage of IONM, reports of normative electrophysiological data are limited in the literature [4,10,16,17]. It is known that neural degeneration may be occur in the myelin and axonal structures of peripheral nerves in the presence of diabetes mellitus (DM). Overall, two-thirds of diabetic patients have objective evidence for some variety of neuropathy, but only about 20% have symptoms [18]. This disease can affect both the central and the peripheral somatic and autonomic nervous system structures, presenting with various clinical manifestations. The etiology of diabetic sensorimotor peripheral neuropathy is multifactorial [19]. In diabetic neuropathy, a symmetrical polyneuropathy is usually detected starting from the distal nerve fibers, affecting sensory, motor and autonomic fibers and causing axonal type degeneration [18]. In the electrophysiological conduction studies, decrease in amplitudes, decrease in conduction speed and elongation in latencies can be seen in sensory and motor nerves of diabetic patients with neuropathy, associated with the type of fibre and the intensity of damage [20,21]. Nerve degeneration increases and the regeneration ability decreases in diabetic patients [18]. In addition to factors that cause direct nerve damages including cutting or knotting, injury associated with thermal device usage, operative trauma and the traction of the nerve also have a role in the development of vocal cord paralysis in postoperative period. It is unknown whether pre-existent diabetic neuropathy is a facilitating factor or not, for RLN injury during thyroidectomy in diabetic patients. The aim of this study was to determine the RLN motor amplitude and latency values in the patient with DM. And investigate the alteration of post-thyroidectomy motor amplitude and latency values in diabetic patients whether is it more affected from the surgical trauma than non-diabetic patients or not.
2. Methods 2.1. Patient selection This prospective study has been approved by the Istanbul Medeniyet University ethical committee, and informed consent was obtained from all participants. Two-hundred and seventythree patients underwent thyroidectomy for various reasons, and 111 patients who received IONM included to the study between June 2013 and March 2015. Unilateral thyroidectomy was performed on 17 (15.3%) of these patients while 94 (84.7%) received bilateral thyroidectomy. In total, 205 RLNs were stimulated preand post-thyroidectomy with bipolar probe and RLN motor amplitude and latency values were recorded.
173
2.2. Evaluation of the patients Demographic data including age and gender of the patients, preoperative diagnosis, the presence of DM according to criteria of American Diabetes Association [22], the presence of concomitant diseases, laboratory findings (serum thyroxine (T4), triiodothyronine (T3), thyroid stimulating hormone (TSH) and fasting blood glucose), fine-needle aspiration biopsy (FNAB) results, the type of operation performed, the presence of complications, and hospitalization duration were recorded prospectively. 2.3. Surgery All patients are operated by experienced endocrine surgeons. In terms of the standardization of the data, same protocols for inhaler and muscle relaxants were applied to the patients. Succinyl choline at a dose of 2e2.5 mg/kg or a small dose of a nondepolarizing muscle relaxant (0.5 mg/kg of rocuronium and atracurium) were used at intubation to allow for normal return of spontaneous respiration and resumption of normal muscle twitch activities within several minutes [23e26]. Muscle relaxants were not administered during thyroidectomy. Following the Kocher's incision, cervical layers dissected. After entering the thyroid region, vena thyroidea media was located, ligated and cut. Superior thyroid artery was revealed, ligated and separated with energy device. After the upper pole of the thyroid was liberated, the Simon's triangle was located and RLN was found in the trachea-oesophageal groove about the level of second tracheal ring. RLN was stimulated with a bipolar probe from the first point it was visualized after drying the surgical site. Afterward, amplitude and latency values were recorded from the electromyogram (EMG) data. Inferior thyroid artery and veins at the lower pole were ligated and cut. RLN was separated from the surrounding fatty tissue and followed until the Berry ligament, via bipolar cautery in order to reduce nerve damage. Thyroidectomy was completed after ligation and cutting the Berry ligament. RLN was re-stimulated from the first stimulated point and the post-thyroidectomy latency and amplitude values were recorded. 2.4. Intraoperative neuromonitoring IONM was applied according to a strict study protocol applying a standardized set up using the noninvasive endotracheal tube surface electrodes and using the Avalanche® (XT, Dr. Langer Medical GmbH) with a bipolar electrode that stimulates with 3-Hz pulses at 1 mA. It is reported that bipolar probes are less exposed to current spread, therefore enabling a superior discrimination of structures within the surgical field [27]. This system records EMG activity and monitors the thyroarytenoid laryngeal muscle that is innervated by the recurrent laryngeal nerve with EMG depiction, visible on a monitor and additional audio feedback. The compound muscle action potential (CMAP) in the vocal muscle was recorded before and after the resection of each sides of the thyroid gland. Alert is transmitted along the nerve, exceeds the neuromuscular junction, and reach the muscle fibers lead to movement in the vocal cords. The typically biphasic waveform represents the CMAP of the ipsilateral vocal cord muscle (Fig. 1). “Latency” is dimensioned in millisecond (ms) and defined as process between the stimulation artefact spike and onset of the initial response, defined by either negative or positive deflection from the baseline (shown as “X” in Fig. 1). The latency defines the time it takes the action potential to travel from the stimulation site to the recording site and depends mainly on the conduction time in the peripheral axons. If demyelination affects the majority of the nerve fibers more or less equally without a conduction block, stimulation
174
I.A. Ozemir et al. / International Journal of Surgery 35 (2016) 172e178
Fig. 1. RLN compound muscle action potential wave during intraoperative neuro monitorization [X:Latency period (ms), Y: peak to peak amplitude value (mV)].
above the lesion evokes relatively normal CMAP amplitude with delayed latency [28]. Acute demyelination of RLN can lead to block the transmission of action potential and cause to occur loss of signal. “Peak to peak amplitude” is defined as the distance between positive and negative peak points of the waveform on CMAP and correlated with the number of fibers participating in the depolarization during standard laryngeal EMG. It is dimensioned in millivolt (mV) (shown as “Y” in Fig. 1). When the acute axonal injury developed in the RLN, CMAP amplitude reduction is associated with proportion to the number of lost axons, but the motor conduction velocity remain relatively normal. CMAP signal loss may occur in case of total axonal injury due to the conduction block [28]. 2.5. Perioperative management and follow-up Vocal cord function was determined in all patients both preoperatively and on the 3rd postoperative day via laryngoscopy. Patients were followed up postoperatively at regular intervals (on day 3 and 14, 2nd, 3rd, 6th and 12th months). In case of postoperative vocal cord paralysis, follow-up examinations were performed on postoperative first day with either indirect laryngoscopy or flexible endoscopy. 2.6. Statistical evaluation SPSS software version 20.0 (SPSS Inc., Chicago, IL) was used to analyze the data. Descriptive statistics were applied in relevant parameters. Distributions of the numerical variables were examined by histograms and the Shapiro-Wilk test. Where appropriate, comparisons of categorical variables were performed using the chisquared test and continuous variables with median or mean values were compared using the Mann-Whitney U test. Spearman's rho correlation coefficient was used for the correlation of the analysis between the parameters. The results were reviewed in a confidence interval of 95% and a value of p < 0.05 was considered statistically significant. 3. Results A hundred and eleven patients with 205 RLN's at risk underwent thyroidectomy with intraoperative nerve monitoring and included in the study. Type of the surgery included bilateral total
thyroidectomy in 64 patients, unilateral thyroidectomyin 17 patients, bilateral total thyroidectomy with central neck dissection in 17 patients, and completion thyroidectomy was carried out in 13 patients. The mean age of the patients was 47.9 ± 11.84 years (range: 21e80), which consists of 97 (87.4%) female and 14 (12.6%) male. Twenty-nine patients (26.1%) were on continuous antidiabetic medication preoperatively due to DM. There were no differences between diabetic and non-diabetic patients according to age, gender, FNA biopsy results, types of operations and the final pathological diagnosis (Table 1). Additionally, there were no significant differences between the groups according to plasma TSH, T3 and T4 values. In the comparison of all patients, the mean pre-and post-thyroidectomy motor response amplitude values of RLN were 0.57 ± 0,36 mV (mV) (range: 0.1e2.72) and 0.65 ± 0.43 mV (range 0.13e3.45), respectively. The mean pre-thyroidectomy latency was 1.98 ± 0.52 ms (range: 0.9e3.3), whereas post-thyroidectomy latency was 1.96 ± 0.63 ms (range: 0.9e4.7). The differences between pre- and post-thyroidectomy motor response amplitude values and latencies were not statistically significant. Pre- and post-thyroidectomy motor response amplitude values of RLN recorded from the vocal muscles and compared with nondiabetic patients. Post-thyroidectomy amplitude values were significantly lower in diabetic group than those of the non-diabetic group (0.51 ± 0.26 mV vs. 0,70 ± 0,46 mV, p:0.024). Although prethyroidectomy amplitude values were lower in diabetic group (0.49 ± 0.26 mV vs. 0,60 ± 0,39 mV), there were no statistically significant differences between groups (Table 2) (Fig. 2). The comparison of the RLN motor response latency values revealed that post-thyroidectomy latency values were statistically higher in the diabetic group compared to those of the non-diabetic group (2.50 ± 0.86 ms vs. 1.85 ± 0.59 ms, p < 0.01). Although prethyroidectomy latency values were higher in diabetic group (2.02 ± 0.43 ms vs. 1.95 ± 0,57 ms), there were no statistically significant differences between groups (Table 2) (Fig. 3). Postthyroidectomy RLN motor response latency values were prolonged statistically significant compared to the pre-thyroidectomy latency values in the diabetic patient group (2.02 ± 0.43 ms vs. 2.50 ± 0.86 ms, p:0.04). Contrarily, the differences between preand post-thyroidectomy RLN motor response latency values were not statistically significant in non-diabetic group (1.85 ± 0.59 ms vs. 1.95 ± 0,57 ms) (Table 2).
I.A. Ozemir et al. / International Journal of Surgery 35 (2016) 172e178
175
Table 1 Comparison of the clinical and pathological features of diabetic and non-diabetic patients.
Agea (mean ± standard deviation) Sexb Female Male b Benign FNAB AFL/FLUS FN/SFN SM Malign
Diabetic patients n: 29 (26.1%)
Non-diabetic patients n:82 (73.9%)
Total patients n:111
Statistical analysis
51.4 ± 10.23 23 (79.3%) 6 (20.7%) 5 (17.2%) 10 (34.5%) 8 (27.6%) 4 (13.8%) 2 (6.9%)
46.7 ± 12.18 74 (90.2%) 8 (9.8%) 30 (36.6%) 13 (15.9) 15 (18.3) 10 (12.2) 14 (17.1)
47.9 ± 11.84 97 (87.4%) 14 (12.6%) 35 (31.5%) 23 (20.7%) 23 (20.7%) 14 (12.6%) 16 (14.4)
n.s. n.s. n.s.
Operation type
Final diagnose
Unilateral Thyroidectomyb
Noduler goitre Toxic noduler goitre Muti-noduler Goitre Total
6 (20.6%) e e 6 (20.6%)
8 (9.8%) 2 (2.4%) 1 (1.2%) 11 (13.4%)
14 (12.6%) 2 (1.8%) 1 (0.9%) 17 (15.3%)
n.s.
Bilateral Thyroidectomyb
Nodular goitre Multi nodular goitre Toxic nodular goitre Grave's disease Thyroid cancer Total
e 17 (58.6%) e e e 17 (58.6%)
1 (1.2%) 38 (46.3%) 1 (1.2%) 2 (2.4%) 3 (3.5%) 45 (54.9%)
1 (0.9%) 55 (49.5%) 1 (0.9%) 2 (1.8%) 3 (2.7%) 62 (55.9%)
n.s.
Redo Thyroidectomyb
Nodular goitre Multi nodular goitre Thyroid cancer Total
1 (3.4%) 2 (6.9%) 0 3 (10.3%)
5 (6.1%) 4 (4.9%) 2 (2.4%) 11 (13.4%)
6 (5.4%) 6 (5.4%) 2 (1.8%) 14 (12.6%)
n.s.
Central Dissectionb
Thyroid cancer Total
3 (10.3%) 3 (10.3%)
15 (18.3%) 15 (18.3%)
18 (16.2%) 18 (16.2%)
n.s.
Complicationsb
None Hoarsness
23 (79.4%) 3 (10.3%) e 3 (10.3%) e
69 (84.1%) 3 (3.7%) 1 (1.2%) 6 (7.3%) 3 (3.7%)
92 (82.9%) 6 (5.4%) 1 (0.9%) 9 (8.1%) 3 (2.7%)
n.s.
1.14 ± 0.35
1.45 ± 1.0
1.37 ± 0.894
n.s.
Hypocalcemia Hospitalizationa
Transient Permanent Transient Permanent
n.s: non-significant, AFL/FLUS: Atypia/follicular lesion of undetermined significance, FN/SFN: Follicular neoplasm/suspicion for a follicular neoplasm, SM: Suspicious for malignancy. a ManneWhitney U test. b Pearson Chi-square test.
Although, the incidence of temporary vocal cord paralysis based on the number of operated RLN was higher in the diabetic group compared to non-diabetic group (6.8% vs. 1.9%, respectively), statistically significant difference were not detected. Signal loss was determined during IONM in only one patient in whom permanent vocal cord paralysis developed eventually. Temporary vocal cord paralysis occurred in six patients postoperatively. Postthyroidectomy motor response latency values were prolonged at least 10% compared to pre-thyroidectomy values in five of the
patients. This prolongation rate was detected 9.1% at sixth patient. A negative correlation was determined between the prethyroidectomy amplitude values and temporary vocal cord paralysis in diabetic patients, but it was not revealed in non-diabetic group. The mean pre-thyroidectomy amplitude value was 0.31 ± 0.15 mV in diabetic patients with temporary vocal cord paralysis while it was 0.51 ± 0.29 mV in diabetic patients without vocal cord pathology (p:0.0001) (Table 3). This relationship was not observed in non-diabetic group.
Table 2 Comparison of the compound muscle action potential obtained from the vocal cord muscles as a result of pre- and post-thyroidectomy recurrent laryngeal nerve stimulation in diabetic and non-diabetic patients. Recurrent Laryngeal nerve motor response
Diabetic patients (n:29)
Non-diabetic patients (n:82)
p value
Amplitudea (mV)
0.49 ± 0.26 (min:0.1, max:1.14) 0.51 ± 0.26 (min:0.13, max:1.14) n.s.
0.6 ± 0.39 (min:0.11, max:2.72) 0,70 ± 0,46 (min:0.14, max:3.44) n.s.
n.s. p:0.024*
2.02 ± 0.43 (min:1.5, max:3.1) 2.50 ± 0.86 (min:1.5, max:4.7) p:0.04*, Z: 2.036
1.95 ± 0.57 (min:0.9, max:3.3) 1.85 ± 0.59 (min:0.9, max:4.1) n.s
n.s. p:0.001**
Latencya (ms)
Pre-thyroidectomy Post-thyroidectomy Comparison of the pre-thyroidectomy and post-thyroidectomy amplitude valuesb Pre-thyroidectomy Post-thyroidectomy Comparison of the pre-thyroidectomy and post-thyroidectomy latency valuesb
n.s: non-significant. *: p < 0.05. **: p < 0.001. a ManneWhitney U test. b Wilcoxon signed ranks test.
176
I.A. Ozemir et al. / International Journal of Surgery 35 (2016) 172e178
Fig. 2. Comparison of RLN motor amplitude values in diabetic and non-diabetic patients. Lower mean amplitude values were presented in diabetic patients.
Fig. 3. Comparison of RLN motor latency values in diabetic and non-diabetic patients. The mean latency value was prolonged in diabetic patients and it was more prolonged in post-thyroidectomy process.
4. Discussion Nueromonitoring of RLN has been increasingly used in thyroid and parathyroid surgery since 1990s [29]. It is considered a feasible and safe in addition to traditional visualization in identifying RLN [30]. It was reported that IONM might reduce the rate of temporary vocal cord paralysis [3]. The majority of studies on IONM are about
the relation between the signal loss and vocal cord paralysis. Those studies revealed high negative predictive values (NPV; 92e100%), but relatively low and variable positive predictive values (PPV; 10e90%) for IONM [4]. The significance of amplitude and latency values on IONM is another controversial subject for prescience of nerve functions in the postoperative period [1,10], but only few studies are available in the literature about the amplitude and latency values of RLN [16,31e33]. Neurolaryngology Study Group reported wide normal ranges such as 0.1e0.8 mV for amplitude values of RLN [34]. Siritharan et al. presented the mean amplitude values 0.89 ± 0.73 mV for the RLN. Kimaid et al. reported CMAP amplitude values of RLN between 0.41 and 0.58 mV [35]. Lorenz et al. reported the outcomes of 1.289 patients with 1.996 RLNs at risk underwent surgery. According to this study mean amplitude value of RLN revealed as 0.62e0.72 mV and there were no significant differences between the amplitude values of RLN in terms of age groups (<40, 40e60, >60 years). They showed that median value of amplitude in women compared to men showed significantly larger amplitude for RLN [16]. In our study, the mean pre-thyroidectomy amplitude value was detected 0.57 ± 0.36 mV, while the post-thyroidectomy amplitude value was 0.65 ± 0.43 mV. It was found to be consistent with the literature. Siritharan et al. reported the mean RLN latency value as 3.96 ± 0.69 ms in their patient group [31]. Lorenz et al. found the median latency value 2.73 ms for RLN in their study. And they found no evident influence of age, gender, and thyroid disease on IONM parameters [16]. In our study, the mean pre-thyroidectomy latency value was detected 1.98 ± 0.52 ms, while the post-thyroidectomy latency value was 1.96 ± 0.63 ms. It was thought that different latency values presented in various studies is result of different stimulation points of RLN. In order to standardize our latency values, we stimulated the RLN at the level of second tracheal ring. There are not enough data in the literature about amplitude and latency value alterations during surgery, and the importance of these intraoperative changes. Some studies revealed that prolonged latency time might be used in combination with decreased amplitude value or signal loss as an indicator of vocal cord paralysis [10,36]. Final monitoring signal can prognosticate postoperative nerve function with high reliability. In the case of non-reduced signal, the negative predictive value of IONM can be as high as 97%, while the positive predictive value when signal is lost is only 37% [3,9]. Recognizing variations of latency and amplitude measurement from pre-thyroidectomy values will alert the surgeon to the possibility of an adverse surgical maneuver such as traction or thermal injury [37]. There is no published study in the literature regarding to the latency and amplitude values of RLN in diabetic patients. It is known that metabolic, genetic, infectious, inflammatory or toxic agents may affect the latency and/or amplitude values in peripheral nerves [38]. We aimed to investigate the electrophysiological changes related with the chronic effects of diabetic neuropathyin RLN. Additionally, latency and amplitude alterations during surgery due to nerve injury were investigated by comparison with nondiabetic patients. Statistically significant decreased pre-
Table 3 Comparison of pre-thyroidectomy amplitude values of patients whom developed temporary vocal cord palsy or not, according to diabetic and non-diabetic groups. Pre-thyroidectomy RLN motor response amplitudes (mV)
No vocal pathology
Temporary vocal cord paralysis
p value
Total RLN'sa Diabetic patients' RLN'sa Non-diabetic patients' RLN'sa
0.58 ± 0.36 (n:197) 0.51 ± 0.29 (n:49) 0.59 ± 0.38 (n:148)
0.42 ± 0.22 (n:6) 0.31 ± 0.15 (n:3) 0.44 ± 0.03 (n:3)
n.s p:0.0001, r: 0.688* n.s
n.s: non-significant. *: p < 0.001. a ManneWhitneyU test.
I.A. Ozemir et al. / International Journal of Surgery 35 (2016) 172e178
thyroidectomy RLN amplitude values detected in diabetic patients is considered that existence of axonal neuropathy in RLNs due to diabetic neuropathy as in the peripheral nerves. And prolonged pre-thyroidectomy latency values in diabetic patients, was detected more prolonged after thyroidectomy compared to non-diabetic patients. These findings emphasize that diabetic neuropathy influence RLN and these nerves were more affected by operative trauma compared to non-diabetic patients' RLNs. Therefore, RLN should be less traumatized in diabetic patients and thyroidectomy should be performed with more meticulous dissection. Normal latency and amplitude values of peripheral nerves were identified in routine neurophysiology procedures and deviations from these values are regarded as pathological. Many of these deviations from the normal ranges also show reflections to clinical outcomes [38]. Electrophysiological changes on IONM of RLN were observed in this study. Post-thyroidectomy RLN latencies were prolonged compared to those of pre-thyroidectomy values, in all patients with postoperative vocal cord paralysis. This finding suggests that prolonged latency may predict the possibility of postoperative temporary vocal cord paralysis in most of the patients. Additionally, prolongation in latency period was more than 10% in 83.3% of the patients that developed postoperative vocal cord paralysis. Acute thermal or post-traction injuries may be predicted with prolonged latency as in other peripheral nerves. However, this finding should be supported by studies with more patients. Development of signal loss during thyroidectomy shows that presence of axonal injury due to nerve cut, or conduction blockade due to myelin damage. These two pathophysiologic mechanisms differ in terms of prognosis. Improvement in nerve integrity is very slow if the nerve fibre is cut, whereas regeneration can substantially be observed in cases of conduction blockade due to focal demyelinating injuries such as stretching or thermal injury [38]. Clinical implication of these two separate pathophysiological changes and the prognosis of the patients can be different. Investigation of the nerve integrity in cases of signal loss during thyroidectomy is importance in determining the type of injury, so that the prognosis of vocal functions may be predicted. 5. Conclusions Although it not statistically significant prolonged latency and decreased amplitude values in the motor response of RLNs in diabetic patients suggest that diabetic neuropathy develops at RLN similar to other peripheral nerves. Significantly prolonged postthyroidectomy latency values compared to pre-thyroidectomy values in diabetic patients suggest that the neurotransmission speed of the RLN is more susceptible to surgical trauma in diabetic patients. Therefore, more cautious and gentle dissection during thyroidectomy would decrease the postoperative vocal cord paralysis rates related to nerve damage, especially in diabetic patients. The alterations in latency and amplitude values of RLN may provide prediction for temporary vocal cord paralysis, like the signal loss in IONM. However further studies with larger patient series are essential to determine the normal ranges and pathological cut-off values for RLN amplitude and latency alterations. Ethical approval Istanbul Medeniyet University, Goztepe Education and Research Hospital Ethical Committee – 2014/0084. Sources of funding Nothing to declare.
177
Author contribution Please specify the contribution of each author to the paper, e.g. study design, data collections, data analysis, writing. Others, who have contributed in other ways should be listed as contributors. Ibrahim Ali Ozemir – Study design, data analysis, writing. Ferman Ozyalvac – Data collection. Gorkem Yildiz – Data collection. Tunc Eren – Data collection, writing. Zeynep Aydin-Ozemir – Study design, data analysis, writing. Orhan Alimoglu – Data analysis, writing. Conflict of interest statement Ibrahim Ali Ozemir and other co-authors have no conflict of interest. Guarantor Ibrahim Ali Ozemir. Trial registry number e ISRCTN Nothing to declare. Unique identifying number (UIN) researchregistry1360. References [1] H. Sun, W. Tian, K. Jiang, et al., Clinical guidelines on intraoperative neuromonitoring during thyroid and parathyroid surgery, Ann. Transl. Med. 3 (2015) 213. [2] M. Hermann, G. Alk, R. Roka, K. Glaser, M. Freissmuth, Laryngeal recurrent nerve injury in surgery for benign thyroid diseases: effect of nerve dissection and impact of individual surgeon in more than 27,000 nerves at risk, Ann. Surg. 235 (2002) 261e268. [3] H. Dralle, C. Sekulla, J. Haerting, et al., Risk factors of paralysis and functional outcome after recurrent laryngeal nerve monitoring in thyroid surgery, Surgery 136 (2004) 1310e1322. [4] H. Dralle, C. Sekulla, K. Lorenz, M. Brauckhoff, A. Machens, German IONM Study Group. Intraoperative monitoring of the recurrent laryngeal nerve and thyroid surgery, World J. Surg. 32 (2008) 1358e1366. [5] D.P. Shedd, C. Durham, Electrical identification of the recurrent laryngeal nerve. I. Response of the canine larynx to electrical stimulation of the recurrent laryngeal nerve, Ann. Surg. 163 (1966) 47e50. [6] G. Dionigi, M. Barczynski, F.Y. Chiang, et al., Why monitor the recurrent laryngeal nerve in thyroid surgery? J. Endocrinol. Invest. 33 (2010) 819e822. [7] M.L. Robertson, D.L. Steward, J.L. Gluckman, J. Welge, Continuous laryngeal nerve integrity monitoring during thyroidectomy: does it reduce risk of injury? Otolaryngol. Head. Neck Surg. 131 (2004) 596e600. [8] T.J. Loch-Wilkinson, P.L. Stalberg, S.B. Sidhu, M.S. Sywak, J.F. Wilkinson, L.W. Delbridge, Nerve stimulation in thyroid surgery: is it really useful? ANZ J. Surg. 77 (2007) 377e380. n, Randomized clinical trial of visualiza[9] M. Barczýnski, A. Konturek, S. Cicho tion versus neuromonitoring of recurrent laryngeal nerves during thyroidectomy, Br. J. Surg. 96 (2009) 240e246. [10] G.W. Randolph, H. Dralle, et al., International Intraoperative Monitoring Study Group, Electrophysiologic recurrent laryngeal nerve monitoring during thyroid and parathyroid surgery, Int. Stand. Guidel. Statement. Laryngoscope 121 (2011) 1e16. [11] E. Moroni, J. Jonas, A. Cavallaro, P.M.C. Sapienza, R. Bahr, Intraoperative neuromonitoring of the recurrent laryngeal nerve. Experience of 1000 consecutive patients, G. Chir. 28 (2007) 29e34. [12] G.W. Randolph, J.B. Kobler, J. Wilkins, Recurrent laryngeal nerve identification and assessment during thyroid surgery: laryngeal palpation, World J. Surg. 28 (2004) 755e760. [13] W.F. Chan, B.H. Lang, C.Y. Lo, The role of intraoperative neuromonitoring of recurrent laryngeal nerve during thyroidectomy: a comparative study on 1000 nerves at risk, Surgery 140 (2006) 866e872. [14] M.C. Singer, R.M. Rosenfeld, K. Sundaram, Laryngeal nerve monitoring: current utilization among head and neck surgeons, Otolaryngol. Head. Neck Surg. 146 (2012) 895e899. [15] C. Sturgeon, T. Sturgeon, P. Angelos, Neuromonitoring in thyroid surgery:
178
[16]
[17]
[18] [19]
[20]
[21]
[22]
[23]
[24]
[25] [26]
[27]
I.A. Ozemir et al. / International Journal of Surgery 35 (2016) 172e178 attitudes, usage patterns, and predictors of use among endocrine surgeons, World J. Surg. 33 (2009) 417e425. K. Lorenz, C. Sekulla, J. Schelle, B. Schmeiss, M. Brauckhoff, H. Dralle, What are normal quantitative parameters of intraoperative neuromonitoring (IONM) in thyroid surgery? Langenbecks Arch. Surg. 395 (2010) 901e909. E. Phelan, A. Potenza, C. Slough, D. Zurakowski, D. Kamani, G. Randolph, Recurrent laryngeal nerve monitoring during thyroid surgery: normative vagal and recurrent laryngeal nerve electrophysiological data, Otolaryngol. Head. Neck Surg. 147 (2012) 640e646. J.G. Llewelyn, D.R. Tomlinson, P.K. Thomas, Diabetic neuropathies, in: Peripheral Neuropathy, Elsevier, Philadelphia, 2005, pp. 1951e1992. P.J. Dyck, K.M. Kratz, J.L. Karnes, et al., The prevalence by staged severity of various types of diabetic neuropathy, retinopathy, and nephropathy in a population-based cohort: the Rochester Diabetic Neuropathy Study, Neurology 43 (1993) 817e824. J. Kimura, Diabetic neuropathy, in: J. Kimura (Ed.), Electrodiagnosis in Diseases of Nerve and Muscle, fourth ed., Oxford University Press, New York, 2013, pp. 662e664. P.J. Dyck, C.J. Overland, P.A. Low, et al., Signs and symptoms vs nerve conduction studies to diagnose diabetic sensorimotor polyneuropathy, Muscle & Nerve 42 (2010) 157e164. American Diabetes Association, Classification and Diagnosis of diabetes, in: W.T. Cefalu (Ed.), Standards of Medicalcare in Diabetes. DiabetesCare, vol. 38, 2015, pp. 8e17. F. Marusch, J. Hussock, G. Haring, T. Hachenberg, I. Gastinger, Influence of muscle relaxation on neuromonitoring of the recurrent laryngeal nerve during thyroid surgery, Br. J. Anaesth. 5 (2005) 596e600. P. Bragg, D.M. Fisher, J. Shi, et al., Comparison of twitch depression of the adductor pollicis and the respiratory muscles, Anesthesiology 80 (1994) 310e319. C. Meistelman, Effects on laryngeal muscles and intubating conditions with new generation muscles relaxants, Acta. Anaesthesiol. Belg. 48 (1997) 11e14. K.S. Chu, S.H. Wu, I.C. Lu, et al., Feasibility of intraoperative neuromonitoring during thyroid surgery after administration of nondepolarizing neuromuscular blocking agents, World J. Surg. 33 (2009) 1408e1413. D.H. Rice, B. Cone-Wesson, Intraoperative recurrent laryngeal nerve monitoring, Otolaryngol. Head. Neck Surg. 105 (1991) 372e375.
[28] J. Kimura, Principles of nerve conduction studies, in: J. Kimura (Ed.), Electrodiagnosis in Diseases of Nerve and Muscle, fourth ed., Oxford University Press, New York, 2013, pp. 74e98. [29] R. Popescu, D. Ponoran, O. Ignat, S. Constantinoiu, Monitoringthelaryngealnervesduringthyroidectomy. Initial 115 casesexperience, Chir. (Bucur) 110 (2015) 327e332. , G. Pisano, F. Medas, et al., Intraoperative recurrent laryngeal nerve [30] P.G. Calo monitoring in thyroid surgery: is it really useful? Clin. Ter 164 (2013) e193ee198. [31] N. Sritharan, M. Chase, D. Kamani, M. Randolph, G.W. Randolph, The vagus nerve, recurrent laryngeal nerve, and external branch of superior laryngeal nerve have unique latencies allowing for intraoperative documentation of intact neural function during thyroid surgery, Laryngoscope 125 (2015) E84eE89. [32] A. Deniwar, E. Kandil, G. Randolph, Electrophysiological neural monitoring of the laryngeal nerves in thyroid surgery: review of the current literature, Gland. Surg. 4 (5) (2015) 368e375. [33] G. Dionigi, F.Y. Chiang, H. Dralle, L. Boni, S. Rausei, F. Rovera, E. Piantanida, A. Mangano, M. Barczynski, G.W. Randolph, DionigiR.Safety of neural monitoring in thyroid surgery, Int. J. Surg. 11 (Suppl 1) (2013) 120e216. [34] A. Blitzer, R.L. Crumley, S.H. Dailey, et al., Recommendations of the neurolaryngology study group on laryngeal electromyography, Otolaryngol. Head. Neck Surg. 140 (2009) 782e793. [35] P.A. Kimaid, A.N. Crespo, E.M. Quagliato, A. Wolf, M.A. Viana, L.A. Resende, Laryngealelectromyography in normal brazilianpopulation, Electromyogr. Clin. Neurophysiol. 44 (2004) 243e245. [36] D.J. Genther, E.H. Kandil, S.I. Noureldine, et al., Correlation of final evoked potential amplitudes on intraoperative electromyography of the recurrent laryngeal nerve with immediate postoperative vocal fold function after thyroid and parathyroid surgery, JAMA Otolaryngol. Head. Neck Surg. 140 (2014) 124e128. [37] E. Phelan, R. Schneider, K. Lorenz, et al., Continuous vagal IONM prevents RLN paralysis by revealing initial EMG changes of impending neuropraxic injury: a prospective, multicenter study, Laryngoscope 124 (2014) 1498e1505. [38] J. Kimura, Principles of nerve conduction studies, in: Electrodiagnosis in Diseases of Nerve and Muscle, Oxford University Press, Oxford, 2013, pp. 74e98.
Contents lists available at ScienceDirect
International Journal of Surgery journal homepage: www.journal-surgery.net
Importance of latency and amplitude values of recurrent laryngeal nerve during thyroidectomy in diabetic patients Ibrahim Ali Ozemir a, *, Ferman Ozyalvac a, Gorkem Yildiz a, Tunc Eren a, Zeynep Aydin-Ozemir b, Orhan Alimoglu a a b
Istanbul Medeniyet University, Goztepe Training & Research Hospital, Department of General Surgery, Istanbul, Turkey Istanbul University, Istanbul Faculty of Medicine, Department of Neurology, Istanbul, Turkey
h i g h l i g h t s Diabetic patients have prolonged post-thyroidectomy latency values than non-diabetic patients. Diabetic patients have decreased post-thyroidectomy amplitude values than non-diabetic patients. Increased post-thyroidectomy latency values detected in diabetic patients compared to pre-thyroidectomy latecies. Recurrent nerve in diabetic patients is more sensitive to the surgical trauma than non-diabetics.
a r t i c l e i n f o
a b s t r a c t
Article history: Received 24 June 2016 Received in revised form 23 September 2016 Accepted 3 October 2016 Available online 5 October 2016
Background: Diabetes mellitus may cause degeneration in the myelin and/or axonal structures of peripheral nerves. The aim of this study was to investigate the effects of diabetic neuropathy on intraoperative neuromonitoring findings such as latency and amplitude values of the recurrent laryngeal nerves during thyroidectomy. To our knowledge this is the first study to report comparison of the electrophysiologic features of diabetic and non-diabetic patients. Materials and methods: One-hundred-and-eleven consecutive patients who received neuromonitoring during thyroidectomy between 2013 and 2015 were included to study. The patients were divided into two groups according to the presence of diabetes mellitus. Pre-thyroidectomy and post thyroidectomy motor response latency and amplitude values of recurrent laryngeal nerves were compared between groups. Neuromonitoring findings, demographic data and postoperative complications were evaluated. Results: The diabetic group consisted of 29 (26.1%) patients while 82 (73.9%) patients were in nondiabetic group. The mean post-thyroidectomy amplitude values (millivolts-mV) of the recurrent laryngeal nerve were significantly lower in diabetic group (0.51 ± 0.26 mV vs. 0,70 ± 0,46 mV, p < 0.05), whereas the latency values were significantly higher (2.50 ± 0.86 ms vs. 1.85 ± 0.59 ms, p < 0.01) compared to non-diabetic group. Additionally, post-thyroidectomy latency values were significantly increased compared to the pre-thyroidectomy latency values (2.50 ± 0.86 ms vs. 2.02 ± 0.43 ms) in diabetic group patients (p < 0.05). Although postoperative complication rates were higher in diabetic group (10.3% vs. 5.9%), there were no statistical significance differences. Conclusions: Prolonged latency and decreased amplitude values in recurrent laryngeal nerves of diabetic patients show that diabetic neuropathy of the recurrent laryngeal nerves develop similarly to the peripheral nerves. Increased post-thyroidectomy latency values reveal that the recurrent laryngeal nerve is more susceptible to surgical trauma in diabetic patients. © 2016 IJS Publishing Group Ltd. Published by Elsevier Ltd. All rights reserved.
Keywords: Latency Amplitude Recurrent laryngeal nerve Diabetes mellitus
1. Introduction * Corresponding author. Istanbul Medeniyet University Goztepe Training & Research Hospital, Department of General Surgery, Dr. Erkin Street, 34660, Goztepe, Kadikoy, Istanbul, Turkey. E-mail address: [email protected] (I.A. Ozemir).
Recurrent laryngeal nerve (RLN) injury is one of the most significant complication of thyroid surgery. The incidence of RLN injury during thyroid surgery ranges from 0.3 to 18.9% [1]. Visual
http://dx.doi.org/10.1016/j.ijsu.2016.10.001 1743-9191/© 2016 IJS Publishing Group Ltd. Published by Elsevier Ltd. All rights reserved.
I.A. Ozemir et al. / International Journal of Surgery 35 (2016) 172e178
identification of the RLN is one of the most important factor that provide the nerve preservation. Absence of the visual identification of the RLN is correlated with an increased rate of RLN paralysis [2e4]. Intraoperative nerve monitoring (IONM) technology was first reported by Shedd and Durham in 1965 [5]. IONM might allow rapid identification and intraoperative assessment the function of RLN [6]. It also ensures the prescience of postoperative vocal cord function and avoid the bilateral RLN injury. Although it is a controversial topic, some authors reported that neuromonitoring significantly reduces the risk of transient RLN paralysis [7e11]. Positive stimulation of the RLN during surgery accompanied by postoperative vocal cord paralysis suggests that it will be transient [12,13]. There are increased number of publications in the literature about the usage of IONM as an adjunct to visual nerve identification during thyroid surgery. It estimates of 53% among general surgeons and up to 65% among otolaryngologists use IONM during thyroidectomy [14,15]. Despite this increased usage of IONM, reports of normative electrophysiological data are limited in the literature [4,10,16,17]. It is known that neural degeneration may be occur in the myelin and axonal structures of peripheral nerves in the presence of diabetes mellitus (DM). Overall, two-thirds of diabetic patients have objective evidence for some variety of neuropathy, but only about 20% have symptoms [18]. This disease can affect both the central and the peripheral somatic and autonomic nervous system structures, presenting with various clinical manifestations. The etiology of diabetic sensorimotor peripheral neuropathy is multifactorial [19]. In diabetic neuropathy, a symmetrical polyneuropathy is usually detected starting from the distal nerve fibers, affecting sensory, motor and autonomic fibers and causing axonal type degeneration [18]. In the electrophysiological conduction studies, decrease in amplitudes, decrease in conduction speed and elongation in latencies can be seen in sensory and motor nerves of diabetic patients with neuropathy, associated with the type of fibre and the intensity of damage [20,21]. Nerve degeneration increases and the regeneration ability decreases in diabetic patients [18]. In addition to factors that cause direct nerve damages including cutting or knotting, injury associated with thermal device usage, operative trauma and the traction of the nerve also have a role in the development of vocal cord paralysis in postoperative period. It is unknown whether pre-existent diabetic neuropathy is a facilitating factor or not, for RLN injury during thyroidectomy in diabetic patients. The aim of this study was to determine the RLN motor amplitude and latency values in the patient with DM. And investigate the alteration of post-thyroidectomy motor amplitude and latency values in diabetic patients whether is it more affected from the surgical trauma than non-diabetic patients or not.
2. Methods 2.1. Patient selection This prospective study has been approved by the Istanbul Medeniyet University ethical committee, and informed consent was obtained from all participants. Two-hundred and seventythree patients underwent thyroidectomy for various reasons, and 111 patients who received IONM included to the study between June 2013 and March 2015. Unilateral thyroidectomy was performed on 17 (15.3%) of these patients while 94 (84.7%) received bilateral thyroidectomy. In total, 205 RLNs were stimulated preand post-thyroidectomy with bipolar probe and RLN motor amplitude and latency values were recorded.
173
2.2. Evaluation of the patients Demographic data including age and gender of the patients, preoperative diagnosis, the presence of DM according to criteria of American Diabetes Association [22], the presence of concomitant diseases, laboratory findings (serum thyroxine (T4), triiodothyronine (T3), thyroid stimulating hormone (TSH) and fasting blood glucose), fine-needle aspiration biopsy (FNAB) results, the type of operation performed, the presence of complications, and hospitalization duration were recorded prospectively. 2.3. Surgery All patients are operated by experienced endocrine surgeons. In terms of the standardization of the data, same protocols for inhaler and muscle relaxants were applied to the patients. Succinyl choline at a dose of 2e2.5 mg/kg or a small dose of a nondepolarizing muscle relaxant (0.5 mg/kg of rocuronium and atracurium) were used at intubation to allow for normal return of spontaneous respiration and resumption of normal muscle twitch activities within several minutes [23e26]. Muscle relaxants were not administered during thyroidectomy. Following the Kocher's incision, cervical layers dissected. After entering the thyroid region, vena thyroidea media was located, ligated and cut. Superior thyroid artery was revealed, ligated and separated with energy device. After the upper pole of the thyroid was liberated, the Simon's triangle was located and RLN was found in the trachea-oesophageal groove about the level of second tracheal ring. RLN was stimulated with a bipolar probe from the first point it was visualized after drying the surgical site. Afterward, amplitude and latency values were recorded from the electromyogram (EMG) data. Inferior thyroid artery and veins at the lower pole were ligated and cut. RLN was separated from the surrounding fatty tissue and followed until the Berry ligament, via bipolar cautery in order to reduce nerve damage. Thyroidectomy was completed after ligation and cutting the Berry ligament. RLN was re-stimulated from the first stimulated point and the post-thyroidectomy latency and amplitude values were recorded. 2.4. Intraoperative neuromonitoring IONM was applied according to a strict study protocol applying a standardized set up using the noninvasive endotracheal tube surface electrodes and using the Avalanche® (XT, Dr. Langer Medical GmbH) with a bipolar electrode that stimulates with 3-Hz pulses at 1 mA. It is reported that bipolar probes are less exposed to current spread, therefore enabling a superior discrimination of structures within the surgical field [27]. This system records EMG activity and monitors the thyroarytenoid laryngeal muscle that is innervated by the recurrent laryngeal nerve with EMG depiction, visible on a monitor and additional audio feedback. The compound muscle action potential (CMAP) in the vocal muscle was recorded before and after the resection of each sides of the thyroid gland. Alert is transmitted along the nerve, exceeds the neuromuscular junction, and reach the muscle fibers lead to movement in the vocal cords. The typically biphasic waveform represents the CMAP of the ipsilateral vocal cord muscle (Fig. 1). “Latency” is dimensioned in millisecond (ms) and defined as process between the stimulation artefact spike and onset of the initial response, defined by either negative or positive deflection from the baseline (shown as “X” in Fig. 1). The latency defines the time it takes the action potential to travel from the stimulation site to the recording site and depends mainly on the conduction time in the peripheral axons. If demyelination affects the majority of the nerve fibers more or less equally without a conduction block, stimulation
174
I.A. Ozemir et al. / International Journal of Surgery 35 (2016) 172e178
Fig. 1. RLN compound muscle action potential wave during intraoperative neuro monitorization [X:Latency period (ms), Y: peak to peak amplitude value (mV)].
above the lesion evokes relatively normal CMAP amplitude with delayed latency [28]. Acute demyelination of RLN can lead to block the transmission of action potential and cause to occur loss of signal. “Peak to peak amplitude” is defined as the distance between positive and negative peak points of the waveform on CMAP and correlated with the number of fibers participating in the depolarization during standard laryngeal EMG. It is dimensioned in millivolt (mV) (shown as “Y” in Fig. 1). When the acute axonal injury developed in the RLN, CMAP amplitude reduction is associated with proportion to the number of lost axons, but the motor conduction velocity remain relatively normal. CMAP signal loss may occur in case of total axonal injury due to the conduction block [28]. 2.5. Perioperative management and follow-up Vocal cord function was determined in all patients both preoperatively and on the 3rd postoperative day via laryngoscopy. Patients were followed up postoperatively at regular intervals (on day 3 and 14, 2nd, 3rd, 6th and 12th months). In case of postoperative vocal cord paralysis, follow-up examinations were performed on postoperative first day with either indirect laryngoscopy or flexible endoscopy. 2.6. Statistical evaluation SPSS software version 20.0 (SPSS Inc., Chicago, IL) was used to analyze the data. Descriptive statistics were applied in relevant parameters. Distributions of the numerical variables were examined by histograms and the Shapiro-Wilk test. Where appropriate, comparisons of categorical variables were performed using the chisquared test and continuous variables with median or mean values were compared using the Mann-Whitney U test. Spearman's rho correlation coefficient was used for the correlation of the analysis between the parameters. The results were reviewed in a confidence interval of 95% and a value of p < 0.05 was considered statistically significant. 3. Results A hundred and eleven patients with 205 RLN's at risk underwent thyroidectomy with intraoperative nerve monitoring and included in the study. Type of the surgery included bilateral total
thyroidectomy in 64 patients, unilateral thyroidectomyin 17 patients, bilateral total thyroidectomy with central neck dissection in 17 patients, and completion thyroidectomy was carried out in 13 patients. The mean age of the patients was 47.9 ± 11.84 years (range: 21e80), which consists of 97 (87.4%) female and 14 (12.6%) male. Twenty-nine patients (26.1%) were on continuous antidiabetic medication preoperatively due to DM. There were no differences between diabetic and non-diabetic patients according to age, gender, FNA biopsy results, types of operations and the final pathological diagnosis (Table 1). Additionally, there were no significant differences between the groups according to plasma TSH, T3 and T4 values. In the comparison of all patients, the mean pre-and post-thyroidectomy motor response amplitude values of RLN were 0.57 ± 0,36 mV (mV) (range: 0.1e2.72) and 0.65 ± 0.43 mV (range 0.13e3.45), respectively. The mean pre-thyroidectomy latency was 1.98 ± 0.52 ms (range: 0.9e3.3), whereas post-thyroidectomy latency was 1.96 ± 0.63 ms (range: 0.9e4.7). The differences between pre- and post-thyroidectomy motor response amplitude values and latencies were not statistically significant. Pre- and post-thyroidectomy motor response amplitude values of RLN recorded from the vocal muscles and compared with nondiabetic patients. Post-thyroidectomy amplitude values were significantly lower in diabetic group than those of the non-diabetic group (0.51 ± 0.26 mV vs. 0,70 ± 0,46 mV, p:0.024). Although prethyroidectomy amplitude values were lower in diabetic group (0.49 ± 0.26 mV vs. 0,60 ± 0,39 mV), there were no statistically significant differences between groups (Table 2) (Fig. 2). The comparison of the RLN motor response latency values revealed that post-thyroidectomy latency values were statistically higher in the diabetic group compared to those of the non-diabetic group (2.50 ± 0.86 ms vs. 1.85 ± 0.59 ms, p < 0.01). Although prethyroidectomy latency values were higher in diabetic group (2.02 ± 0.43 ms vs. 1.95 ± 0,57 ms), there were no statistically significant differences between groups (Table 2) (Fig. 3). Postthyroidectomy RLN motor response latency values were prolonged statistically significant compared to the pre-thyroidectomy latency values in the diabetic patient group (2.02 ± 0.43 ms vs. 2.50 ± 0.86 ms, p:0.04). Contrarily, the differences between preand post-thyroidectomy RLN motor response latency values were not statistically significant in non-diabetic group (1.85 ± 0.59 ms vs. 1.95 ± 0,57 ms) (Table 2).
I.A. Ozemir et al. / International Journal of Surgery 35 (2016) 172e178
175
Table 1 Comparison of the clinical and pathological features of diabetic and non-diabetic patients.
Agea (mean ± standard deviation) Sexb Female Male b Benign FNAB AFL/FLUS FN/SFN SM Malign
Diabetic patients n: 29 (26.1%)
Non-diabetic patients n:82 (73.9%)
Total patients n:111
Statistical analysis
51.4 ± 10.23 23 (79.3%) 6 (20.7%) 5 (17.2%) 10 (34.5%) 8 (27.6%) 4 (13.8%) 2 (6.9%)
46.7 ± 12.18 74 (90.2%) 8 (9.8%) 30 (36.6%) 13 (15.9) 15 (18.3) 10 (12.2) 14 (17.1)
47.9 ± 11.84 97 (87.4%) 14 (12.6%) 35 (31.5%) 23 (20.7%) 23 (20.7%) 14 (12.6%) 16 (14.4)
n.s. n.s. n.s.
Operation type
Final diagnose
Unilateral Thyroidectomyb
Noduler goitre Toxic noduler goitre Muti-noduler Goitre Total
6 (20.6%) e e 6 (20.6%)
8 (9.8%) 2 (2.4%) 1 (1.2%) 11 (13.4%)
14 (12.6%) 2 (1.8%) 1 (0.9%) 17 (15.3%)
n.s.
Bilateral Thyroidectomyb
Nodular goitre Multi nodular goitre Toxic nodular goitre Grave's disease Thyroid cancer Total
e 17 (58.6%) e e e 17 (58.6%)
1 (1.2%) 38 (46.3%) 1 (1.2%) 2 (2.4%) 3 (3.5%) 45 (54.9%)
1 (0.9%) 55 (49.5%) 1 (0.9%) 2 (1.8%) 3 (2.7%) 62 (55.9%)
n.s.
Redo Thyroidectomyb
Nodular goitre Multi nodular goitre Thyroid cancer Total
1 (3.4%) 2 (6.9%) 0 3 (10.3%)
5 (6.1%) 4 (4.9%) 2 (2.4%) 11 (13.4%)
6 (5.4%) 6 (5.4%) 2 (1.8%) 14 (12.6%)
n.s.
Central Dissectionb
Thyroid cancer Total
3 (10.3%) 3 (10.3%)
15 (18.3%) 15 (18.3%)
18 (16.2%) 18 (16.2%)
n.s.
Complicationsb
None Hoarsness
23 (79.4%) 3 (10.3%) e 3 (10.3%) e
69 (84.1%) 3 (3.7%) 1 (1.2%) 6 (7.3%) 3 (3.7%)
92 (82.9%) 6 (5.4%) 1 (0.9%) 9 (8.1%) 3 (2.7%)
n.s.
1.14 ± 0.35
1.45 ± 1.0
1.37 ± 0.894
n.s.
Hypocalcemia Hospitalizationa
Transient Permanent Transient Permanent
n.s: non-significant, AFL/FLUS: Atypia/follicular lesion of undetermined significance, FN/SFN: Follicular neoplasm/suspicion for a follicular neoplasm, SM: Suspicious for malignancy. a ManneWhitney U test. b Pearson Chi-square test.
Although, the incidence of temporary vocal cord paralysis based on the number of operated RLN was higher in the diabetic group compared to non-diabetic group (6.8% vs. 1.9%, respectively), statistically significant difference were not detected. Signal loss was determined during IONM in only one patient in whom permanent vocal cord paralysis developed eventually. Temporary vocal cord paralysis occurred in six patients postoperatively. Postthyroidectomy motor response latency values were prolonged at least 10% compared to pre-thyroidectomy values in five of the
patients. This prolongation rate was detected 9.1% at sixth patient. A negative correlation was determined between the prethyroidectomy amplitude values and temporary vocal cord paralysis in diabetic patients, but it was not revealed in non-diabetic group. The mean pre-thyroidectomy amplitude value was 0.31 ± 0.15 mV in diabetic patients with temporary vocal cord paralysis while it was 0.51 ± 0.29 mV in diabetic patients without vocal cord pathology (p:0.0001) (Table 3). This relationship was not observed in non-diabetic group.
Table 2 Comparison of the compound muscle action potential obtained from the vocal cord muscles as a result of pre- and post-thyroidectomy recurrent laryngeal nerve stimulation in diabetic and non-diabetic patients. Recurrent Laryngeal nerve motor response
Diabetic patients (n:29)
Non-diabetic patients (n:82)
p value
Amplitudea (mV)
0.49 ± 0.26 (min:0.1, max:1.14) 0.51 ± 0.26 (min:0.13, max:1.14) n.s.
0.6 ± 0.39 (min:0.11, max:2.72) 0,70 ± 0,46 (min:0.14, max:3.44) n.s.
n.s. p:0.024*
2.02 ± 0.43 (min:1.5, max:3.1) 2.50 ± 0.86 (min:1.5, max:4.7) p:0.04*, Z: 2.036
1.95 ± 0.57 (min:0.9, max:3.3) 1.85 ± 0.59 (min:0.9, max:4.1) n.s
n.s. p:0.001**
Latencya (ms)
Pre-thyroidectomy Post-thyroidectomy Comparison of the pre-thyroidectomy and post-thyroidectomy amplitude valuesb Pre-thyroidectomy Post-thyroidectomy Comparison of the pre-thyroidectomy and post-thyroidectomy latency valuesb
n.s: non-significant. *: p < 0.05. **: p < 0.001. a ManneWhitney U test. b Wilcoxon signed ranks test.
176
I.A. Ozemir et al. / International Journal of Surgery 35 (2016) 172e178
Fig. 2. Comparison of RLN motor amplitude values in diabetic and non-diabetic patients. Lower mean amplitude values were presented in diabetic patients.
Fig. 3. Comparison of RLN motor latency values in diabetic and non-diabetic patients. The mean latency value was prolonged in diabetic patients and it was more prolonged in post-thyroidectomy process.
4. Discussion Nueromonitoring of RLN has been increasingly used in thyroid and parathyroid surgery since 1990s [29]. It is considered a feasible and safe in addition to traditional visualization in identifying RLN [30]. It was reported that IONM might reduce the rate of temporary vocal cord paralysis [3]. The majority of studies on IONM are about
the relation between the signal loss and vocal cord paralysis. Those studies revealed high negative predictive values (NPV; 92e100%), but relatively low and variable positive predictive values (PPV; 10e90%) for IONM [4]. The significance of amplitude and latency values on IONM is another controversial subject for prescience of nerve functions in the postoperative period [1,10], but only few studies are available in the literature about the amplitude and latency values of RLN [16,31e33]. Neurolaryngology Study Group reported wide normal ranges such as 0.1e0.8 mV for amplitude values of RLN [34]. Siritharan et al. presented the mean amplitude values 0.89 ± 0.73 mV for the RLN. Kimaid et al. reported CMAP amplitude values of RLN between 0.41 and 0.58 mV [35]. Lorenz et al. reported the outcomes of 1.289 patients with 1.996 RLNs at risk underwent surgery. According to this study mean amplitude value of RLN revealed as 0.62e0.72 mV and there were no significant differences between the amplitude values of RLN in terms of age groups (<40, 40e60, >60 years). They showed that median value of amplitude in women compared to men showed significantly larger amplitude for RLN [16]. In our study, the mean pre-thyroidectomy amplitude value was detected 0.57 ± 0.36 mV, while the post-thyroidectomy amplitude value was 0.65 ± 0.43 mV. It was found to be consistent with the literature. Siritharan et al. reported the mean RLN latency value as 3.96 ± 0.69 ms in their patient group [31]. Lorenz et al. found the median latency value 2.73 ms for RLN in their study. And they found no evident influence of age, gender, and thyroid disease on IONM parameters [16]. In our study, the mean pre-thyroidectomy latency value was detected 1.98 ± 0.52 ms, while the post-thyroidectomy latency value was 1.96 ± 0.63 ms. It was thought that different latency values presented in various studies is result of different stimulation points of RLN. In order to standardize our latency values, we stimulated the RLN at the level of second tracheal ring. There are not enough data in the literature about amplitude and latency value alterations during surgery, and the importance of these intraoperative changes. Some studies revealed that prolonged latency time might be used in combination with decreased amplitude value or signal loss as an indicator of vocal cord paralysis [10,36]. Final monitoring signal can prognosticate postoperative nerve function with high reliability. In the case of non-reduced signal, the negative predictive value of IONM can be as high as 97%, while the positive predictive value when signal is lost is only 37% [3,9]. Recognizing variations of latency and amplitude measurement from pre-thyroidectomy values will alert the surgeon to the possibility of an adverse surgical maneuver such as traction or thermal injury [37]. There is no published study in the literature regarding to the latency and amplitude values of RLN in diabetic patients. It is known that metabolic, genetic, infectious, inflammatory or toxic agents may affect the latency and/or amplitude values in peripheral nerves [38]. We aimed to investigate the electrophysiological changes related with the chronic effects of diabetic neuropathyin RLN. Additionally, latency and amplitude alterations during surgery due to nerve injury were investigated by comparison with nondiabetic patients. Statistically significant decreased pre-
Table 3 Comparison of pre-thyroidectomy amplitude values of patients whom developed temporary vocal cord palsy or not, according to diabetic and non-diabetic groups. Pre-thyroidectomy RLN motor response amplitudes (mV)
No vocal pathology
Temporary vocal cord paralysis
p value
Total RLN'sa Diabetic patients' RLN'sa Non-diabetic patients' RLN'sa
0.58 ± 0.36 (n:197) 0.51 ± 0.29 (n:49) 0.59 ± 0.38 (n:148)
0.42 ± 0.22 (n:6) 0.31 ± 0.15 (n:3) 0.44 ± 0.03 (n:3)
n.s p:0.0001, r: 0.688* n.s
n.s: non-significant. *: p < 0.001. a ManneWhitneyU test.
I.A. Ozemir et al. / International Journal of Surgery 35 (2016) 172e178
thyroidectomy RLN amplitude values detected in diabetic patients is considered that existence of axonal neuropathy in RLNs due to diabetic neuropathy as in the peripheral nerves. And prolonged pre-thyroidectomy latency values in diabetic patients, was detected more prolonged after thyroidectomy compared to non-diabetic patients. These findings emphasize that diabetic neuropathy influence RLN and these nerves were more affected by operative trauma compared to non-diabetic patients' RLNs. Therefore, RLN should be less traumatized in diabetic patients and thyroidectomy should be performed with more meticulous dissection. Normal latency and amplitude values of peripheral nerves were identified in routine neurophysiology procedures and deviations from these values are regarded as pathological. Many of these deviations from the normal ranges also show reflections to clinical outcomes [38]. Electrophysiological changes on IONM of RLN were observed in this study. Post-thyroidectomy RLN latencies were prolonged compared to those of pre-thyroidectomy values, in all patients with postoperative vocal cord paralysis. This finding suggests that prolonged latency may predict the possibility of postoperative temporary vocal cord paralysis in most of the patients. Additionally, prolongation in latency period was more than 10% in 83.3% of the patients that developed postoperative vocal cord paralysis. Acute thermal or post-traction injuries may be predicted with prolonged latency as in other peripheral nerves. However, this finding should be supported by studies with more patients. Development of signal loss during thyroidectomy shows that presence of axonal injury due to nerve cut, or conduction blockade due to myelin damage. These two pathophysiologic mechanisms differ in terms of prognosis. Improvement in nerve integrity is very slow if the nerve fibre is cut, whereas regeneration can substantially be observed in cases of conduction blockade due to focal demyelinating injuries such as stretching or thermal injury [38]. Clinical implication of these two separate pathophysiological changes and the prognosis of the patients can be different. Investigation of the nerve integrity in cases of signal loss during thyroidectomy is importance in determining the type of injury, so that the prognosis of vocal functions may be predicted. 5. Conclusions Although it not statistically significant prolonged latency and decreased amplitude values in the motor response of RLNs in diabetic patients suggest that diabetic neuropathy develops at RLN similar to other peripheral nerves. Significantly prolonged postthyroidectomy latency values compared to pre-thyroidectomy values in diabetic patients suggest that the neurotransmission speed of the RLN is more susceptible to surgical trauma in diabetic patients. Therefore, more cautious and gentle dissection during thyroidectomy would decrease the postoperative vocal cord paralysis rates related to nerve damage, especially in diabetic patients. The alterations in latency and amplitude values of RLN may provide prediction for temporary vocal cord paralysis, like the signal loss in IONM. However further studies with larger patient series are essential to determine the normal ranges and pathological cut-off values for RLN amplitude and latency alterations. Ethical approval Istanbul Medeniyet University, Goztepe Education and Research Hospital Ethical Committee – 2014/0084. Sources of funding Nothing to declare.
177
Author contribution Please specify the contribution of each author to the paper, e.g. study design, data collections, data analysis, writing. Others, who have contributed in other ways should be listed as contributors. Ibrahim Ali Ozemir – Study design, data analysis, writing. Ferman Ozyalvac – Data collection. Gorkem Yildiz – Data collection. Tunc Eren – Data collection, writing. Zeynep Aydin-Ozemir – Study design, data analysis, writing. Orhan Alimoglu – Data analysis, writing. Conflict of interest statement Ibrahim Ali Ozemir and other co-authors have no conflict of interest. Guarantor Ibrahim Ali Ozemir. Trial registry number e ISRCTN Nothing to declare. Unique identifying number (UIN) researchregistry1360. References [1] H. Sun, W. Tian, K. Jiang, et al., Clinical guidelines on intraoperative neuromonitoring during thyroid and parathyroid surgery, Ann. Transl. Med. 3 (2015) 213. [2] M. Hermann, G. Alk, R. Roka, K. Glaser, M. Freissmuth, Laryngeal recurrent nerve injury in surgery for benign thyroid diseases: effect of nerve dissection and impact of individual surgeon in more than 27,000 nerves at risk, Ann. Surg. 235 (2002) 261e268. [3] H. Dralle, C. Sekulla, J. Haerting, et al., Risk factors of paralysis and functional outcome after recurrent laryngeal nerve monitoring in thyroid surgery, Surgery 136 (2004) 1310e1322. [4] H. Dralle, C. Sekulla, K. Lorenz, M. Brauckhoff, A. Machens, German IONM Study Group. Intraoperative monitoring of the recurrent laryngeal nerve and thyroid surgery, World J. Surg. 32 (2008) 1358e1366. [5] D.P. Shedd, C. Durham, Electrical identification of the recurrent laryngeal nerve. I. Response of the canine larynx to electrical stimulation of the recurrent laryngeal nerve, Ann. Surg. 163 (1966) 47e50. [6] G. Dionigi, M. Barczynski, F.Y. Chiang, et al., Why monitor the recurrent laryngeal nerve in thyroid surgery? J. Endocrinol. Invest. 33 (2010) 819e822. [7] M.L. Robertson, D.L. Steward, J.L. Gluckman, J. Welge, Continuous laryngeal nerve integrity monitoring during thyroidectomy: does it reduce risk of injury? Otolaryngol. Head. Neck Surg. 131 (2004) 596e600. [8] T.J. Loch-Wilkinson, P.L. Stalberg, S.B. Sidhu, M.S. Sywak, J.F. Wilkinson, L.W. Delbridge, Nerve stimulation in thyroid surgery: is it really useful? ANZ J. Surg. 77 (2007) 377e380. n, Randomized clinical trial of visualiza[9] M. Barczýnski, A. Konturek, S. Cicho tion versus neuromonitoring of recurrent laryngeal nerves during thyroidectomy, Br. J. Surg. 96 (2009) 240e246. [10] G.W. Randolph, H. Dralle, et al., International Intraoperative Monitoring Study Group, Electrophysiologic recurrent laryngeal nerve monitoring during thyroid and parathyroid surgery, Int. Stand. Guidel. Statement. Laryngoscope 121 (2011) 1e16. [11] E. Moroni, J. Jonas, A. Cavallaro, P.M.C. Sapienza, R. Bahr, Intraoperative neuromonitoring of the recurrent laryngeal nerve. Experience of 1000 consecutive patients, G. Chir. 28 (2007) 29e34. [12] G.W. Randolph, J.B. Kobler, J. Wilkins, Recurrent laryngeal nerve identification and assessment during thyroid surgery: laryngeal palpation, World J. Surg. 28 (2004) 755e760. [13] W.F. Chan, B.H. Lang, C.Y. Lo, The role of intraoperative neuromonitoring of recurrent laryngeal nerve during thyroidectomy: a comparative study on 1000 nerves at risk, Surgery 140 (2006) 866e872. [14] M.C. Singer, R.M. Rosenfeld, K. Sundaram, Laryngeal nerve monitoring: current utilization among head and neck surgeons, Otolaryngol. Head. Neck Surg. 146 (2012) 895e899. [15] C. Sturgeon, T. Sturgeon, P. Angelos, Neuromonitoring in thyroid surgery:
178
[16]
[17]
[18] [19]
[20]
[21]
[22]
[23]
[24]
[25] [26]
[27]
I.A. Ozemir et al. / International Journal of Surgery 35 (2016) 172e178 attitudes, usage patterns, and predictors of use among endocrine surgeons, World J. Surg. 33 (2009) 417e425. K. Lorenz, C. Sekulla, J. Schelle, B. Schmeiss, M. Brauckhoff, H. Dralle, What are normal quantitative parameters of intraoperative neuromonitoring (IONM) in thyroid surgery? Langenbecks Arch. Surg. 395 (2010) 901e909. E. Phelan, A. Potenza, C. Slough, D. Zurakowski, D. Kamani, G. Randolph, Recurrent laryngeal nerve monitoring during thyroid surgery: normative vagal and recurrent laryngeal nerve electrophysiological data, Otolaryngol. Head. Neck Surg. 147 (2012) 640e646. J.G. Llewelyn, D.R. Tomlinson, P.K. Thomas, Diabetic neuropathies, in: Peripheral Neuropathy, Elsevier, Philadelphia, 2005, pp. 1951e1992. P.J. Dyck, K.M. Kratz, J.L. Karnes, et al., The prevalence by staged severity of various types of diabetic neuropathy, retinopathy, and nephropathy in a population-based cohort: the Rochester Diabetic Neuropathy Study, Neurology 43 (1993) 817e824. J. Kimura, Diabetic neuropathy, in: J. Kimura (Ed.), Electrodiagnosis in Diseases of Nerve and Muscle, fourth ed., Oxford University Press, New York, 2013, pp. 662e664. P.J. Dyck, C.J. Overland, P.A. Low, et al., Signs and symptoms vs nerve conduction studies to diagnose diabetic sensorimotor polyneuropathy, Muscle & Nerve 42 (2010) 157e164. American Diabetes Association, Classification and Diagnosis of diabetes, in: W.T. Cefalu (Ed.), Standards of Medicalcare in Diabetes. DiabetesCare, vol. 38, 2015, pp. 8e17. F. Marusch, J. Hussock, G. Haring, T. Hachenberg, I. Gastinger, Influence of muscle relaxation on neuromonitoring of the recurrent laryngeal nerve during thyroid surgery, Br. J. Anaesth. 5 (2005) 596e600. P. Bragg, D.M. Fisher, J. Shi, et al., Comparison of twitch depression of the adductor pollicis and the respiratory muscles, Anesthesiology 80 (1994) 310e319. C. Meistelman, Effects on laryngeal muscles and intubating conditions with new generation muscles relaxants, Acta. Anaesthesiol. Belg. 48 (1997) 11e14. K.S. Chu, S.H. Wu, I.C. Lu, et al., Feasibility of intraoperative neuromonitoring during thyroid surgery after administration of nondepolarizing neuromuscular blocking agents, World J. Surg. 33 (2009) 1408e1413. D.H. Rice, B. Cone-Wesson, Intraoperative recurrent laryngeal nerve monitoring, Otolaryngol. Head. Neck Surg. 105 (1991) 372e375.
[28] J. Kimura, Principles of nerve conduction studies, in: J. Kimura (Ed.), Electrodiagnosis in Diseases of Nerve and Muscle, fourth ed., Oxford University Press, New York, 2013, pp. 74e98. [29] R. Popescu, D. Ponoran, O. Ignat, S. Constantinoiu, Monitoringthelaryngealnervesduringthyroidectomy. Initial 115 casesexperience, Chir. (Bucur) 110 (2015) 327e332. , G. Pisano, F. Medas, et al., Intraoperative recurrent laryngeal nerve [30] P.G. Calo monitoring in thyroid surgery: is it really useful? Clin. Ter 164 (2013) e193ee198. [31] N. Sritharan, M. Chase, D. Kamani, M. Randolph, G.W. Randolph, The vagus nerve, recurrent laryngeal nerve, and external branch of superior laryngeal nerve have unique latencies allowing for intraoperative documentation of intact neural function during thyroid surgery, Laryngoscope 125 (2015) E84eE89. [32] A. Deniwar, E. Kandil, G. Randolph, Electrophysiological neural monitoring of the laryngeal nerves in thyroid surgery: review of the current literature, Gland. Surg. 4 (5) (2015) 368e375. [33] G. Dionigi, F.Y. Chiang, H. Dralle, L. Boni, S. Rausei, F. Rovera, E. Piantanida, A. Mangano, M. Barczynski, G.W. Randolph, DionigiR.Safety of neural monitoring in thyroid surgery, Int. J. Surg. 11 (Suppl 1) (2013) 120e216. [34] A. Blitzer, R.L. Crumley, S.H. Dailey, et al., Recommendations of the neurolaryngology study group on laryngeal electromyography, Otolaryngol. Head. Neck Surg. 140 (2009) 782e793. [35] P.A. Kimaid, A.N. Crespo, E.M. Quagliato, A. Wolf, M.A. Viana, L.A. Resende, Laryngealelectromyography in normal brazilianpopulation, Electromyogr. Clin. Neurophysiol. 44 (2004) 243e245. [36] D.J. Genther, E.H. Kandil, S.I. Noureldine, et al., Correlation of final evoked potential amplitudes on intraoperative electromyography of the recurrent laryngeal nerve with immediate postoperative vocal fold function after thyroid and parathyroid surgery, JAMA Otolaryngol. Head. Neck Surg. 140 (2014) 124e128. [37] E. Phelan, R. Schneider, K. Lorenz, et al., Continuous vagal IONM prevents RLN paralysis by revealing initial EMG changes of impending neuropraxic injury: a prospective, multicenter study, Laryngoscope 124 (2014) 1498e1505. [38] J. Kimura, Principles of nerve conduction studies, in: Electrodiagnosis in Diseases of Nerve and Muscle, Oxford University Press, Oxford, 2013, pp. 74e98.