Patent Description:
The human larynx is one of the most complex organs in the body. It permits respiration and vocalization and protects the tracheobronchial tree from inhaled foreign objects.

The larynx has a complex neural supply from two different branches of the vagus nerve, the superior laryngeal nerve (SLN) and the recurrent laryngeal nerve (RLN). Afferent sensory input from the supraglottic and glottic larynx is carried in the internal branch of the superior laryngeal nerve (iSLN), with some overlap from the recurrent laryngeal nerve (RLN) at the glottis. The RLN is the predominant sensory nerve supply for the infraglottic region. The RLN provides the main motor innervation to laryngeal musculature, with the exception of the cricothyroid muscle which is supplied by the external branch of the SLN (eSLN). Monitoring of RLN, SLN and vagus nerve function is important during surgical procedures where these nerves may be at risk of injury. For thyroid and parathyroid surgeries, the RLN and eSLN lie within the operative field and there have been many recent guidelines endorsing the use of intra-operative neuromonitoring techniques to minimize post-operative neural complications. The most widely used monitoring technique for the RLN relies on endotracheal tube-based surface electrodes to measure compound muscle action potentials (CMAP) resulting from thyroarytenoid muscle contraction with vocal fold adduction. CMAPs are elicited either via direct RLN stimulation with a handheld neuro-stimulator probe or indirectly when the nerve is irritated by stretch, compression, etc..

More recently, intra-operative stimulation of the vagus nerve proximal to the exit point of the recurrent laryngeal nerve, either intermittently or continuously, has been advocated. In particular, several intra-operative neuromonitoring (IONM) strategies for the recurrent laryngeal nerve (RLN) exist to mitigate nerve damage during neck procedures, such as a thyroidectomy. These procedures utilize endotracheal tubes having electrodes disposed on an outer surface thereof. The IONM strategies may be intermittent (IIONM) or continuous (CIONM) in nature. For IIONM, identification of nerve malfunction occurs after the damage has taken place and thus, this strategy is less than ideal. CIONM requires a very difficult and risky surgical procedure in that it requires the opening of the carotid sheath and dissection between the internal jugular vein and the internal carotid artery to place a simulation electrode on the vagus nerve. Moreover, the electrode can easily dislodge.

The laryngeal adductor reflex (LAR) is an involuntary protective response triggered by sensory receptor stimulation in supraglottic (and glottic) mucosa. It will be understood that the term laryngeal adductor reflex and the term laryngeal adductor response are synonymous. Afferent nerve activity travels via the internal branch of the superior laryngeal nerve (iSLN) to the brainstem. The efferent pathway is via the vagus and recurrent laryngeal nerves, resulting in vocal fold adduction and thus tracheobronchial airway protection.

There is therefore a need for an alternative system and method for CIONM to prevent nerve injury during surgical procedures, such as neck surgery, and one which overcomes the above noted deficiencies associated with conventional IONM systems and methods.

<CIT> discloses a nerve monitoring device, including a cannula, a sensor for monitoring a nerve, and an optional support element, which can be inserted into an anatomic space.

<CIT> discloses an electrode endotracheal tube for detecting electromyographic signals in the laryngeal muscles and comprising electrode wires running in a direction parallel to the central axis of the endotracheal tube.

<CIT> discloses an apparatus for monitoring EMG signals of a patient's laryngeal muscles includes an endotracheal tube having an exterior surface and a first location configured to be positioned at the patient's vocal folds. A first electrode is formed on the exterior surface of the endotracheal tube substantially below the first location. A second electrode is formed on the exterior surface of the endotracheal tube substantially above the first location. The first and second electrodes are configured to receive the EMG signals from the laryngeal muscles when the endotracheal tube is placed in a trachea of the patient.

<CIT> discloses a clamp for securing a terminal end of a wire to a surface electrode formed on a cylindrical tube including a first semicylindrical element. A second semicylindrical element is configured to be attached to the first semicylindrical element to form a tubular clamp structure that is adapted to be clamped around the cylindrical tube. The tubular clamp structure includes an interior surface configured to securely hold a terminal end of a wire against a surface electrode formed on the cylindrical tube.

The present invention provides an endotracheal tube having the features of claim <NUM> and a system having the features of claim <NUM>.

The present invention takes advantage of the laryngeal adductor reflex (LAR), previously thought to be repressed during general anesthesia, for CIONM without placement of an electrode on the vagus nerve.

More specifically and according to the present disclosure, the laryngeal adductor reflex (LAR) is realized as a new monitoring method for laryngeal and vagus nerves. The present method relies on endotracheal tube electrodes for stimulating and recording laryngeal responses and the present method monitors the entire vagal reflex arc, including sensory, motor and brainstem pathways.

The LAR represents a novel method for intraoperatively monitoring laryngeal and vagus nerves. Advantages over current monitoring techniques include simplicity, ability to continuously monitor neural function without placement of additional neural probes and ability to assess integrity of both sensory and motor pathways. The LAR monitors the entire vagus nerve reflex arc and is thus applicable to all surgeries where vagal nerve integrity may be compromised.

According to one embodiment, an endotracheal tube for intraoperatively monitoring laryngeal and vagus nerves by eliciting laryngeal adductor response (LAR) in a patient that is under general anesthesia, that is of a type that preserves LAR, and by monitoring contralateral responses of the LAR that are detected after application of electrical stimulation. The endotracheal tube includes an endotracheal tube body having a first inflatable member and electrode area that has a generally triangular shaped cross-section configured for mating with a larynx anatomy of the patient. The electrode area includes a plurality of surface based recording electrodes and at least one stimulation electrode. The plurality of surface based electrodes includes at least one first surface based recording electrode that is located along a first side of the endotracheal tube and at least one second surface based recording electrode that is located along a second side the endotracheal tube. Each of the first and second surface based recording electrodes is configured to record contralateral responses of the LAR and the at least one stimulation electrode is configured to emit electrical stimulation.

The at least one stimulation electrode is located along a posterior side of the electrode area between the first side along which the at least one first surface based recording electrode is located and the second side along which the at least one second surface based recording electrode is located. In one embodiment, the at least one stimulation electrode comprises a pair of stimulation electrodes that are spaced apart and are parallel to one another. The at least one first surface based recording electrode comprises a pair of electrodes that are spaced apart and are parallel to one another and the at least one second surface based recording electrode comprises a pair of electrodes that are spaced apart and are parallel to one another. The pair of stimulation electrodes are located along the posterior of the endotracheal tube with the triangular shape being prominent along the anterior side of the endotracheal tube (i.e., the triangular shape points anteriorly). Placement of the stimulation electrodes within the electrode area along the posterior aspect of the tube enables bilateral CIONM.

In yet another aspect of the present invention, the LAR is used to define the topography of the larynx as it relates to elicitation of the laryngeal adductor reflex using electrical mucosal stimulation under general anesthesia.

In yet another aspect of the present invention, the LAR can alternatively be monitored by using the ipsilateral (iR1) component of the reflex for both stimulation and recording purposes. This monitoring is achieved using the endotracheal tubes with electrodes as described herein.

As used herein, the term "proximal" shall mean close to the operator (less into the body) and "distal" shall mean away from the operator (further into the body). In positioning a medical device inside a patient, "distal" refers to the direction away from an insertion location and "proximal" refers to the direction close to the insertion location.

Unless otherwise specified, all numbers expressing quantities, measurements, and other properties or parameters used in the specification and claims are to be understood as being modified in all instances by the term "about. " Accordingly, unless otherwise indicated, it should be understood that the numerical parameters set forth in the following specification and attached claims are approximations. At the very least and not as an attempt to limit the application of the doctrine of equivalents to the scope of the attached claims, numerical parameters should be read in light of the number of reported significant digits and the application of ordinary rounding techniques.

In accordance with at least one exemplary embodiment, an intra-operative system and monitoring methodology for assessing the integrity of laryngeal and vagus nerves by utilizing the laryngeal adductor reflex (LAR) are provided.

As previously mentioned, the laryngeal adductor reflex (LAR) is an involuntary protective response triggered by sensory receptor stimulation in supraglottic (and glottic) mucosa. Afferent nerve activity travels via the internal branch of the superior laryngeal nerve (iSLN) to the brainstem. The efferent pathway is via the vagus and recurrent laryngeal nerves, resulting in vocal fold adduction and thus tracheobronchial airway protection. Vocal fold contractile components of the LAR consist of two parts - an early evoked R1 response with a latency between <NUM> and <NUM>, and later more variable R2 component. Prior studies had concluded that only ipsilateral R1 responses were present in humans under deep general anesthesia, with contralateral R1 and bilateral R2 responses being absent. However, as set forth below, the present Applicant recently showed using the device described herein that the contralateral R1 response is robustly present under total intravenous anesthesia, with the R2 response also present in a subset of patients. As also described herein, the LAR can alternatively be monitored by using the ipsilateral (iR1) component of the reflex for both stimulation and recording purposes. This monitoring is achieved using the endotracheal tubes with electrodes as described herein.

Detailed knowledge of the LAR has been difficult to obtain due to the perceived inability to successfully elicit all components of the reflex under general anesthesia. Studies in awake humans have been limited by laryngeal accessability issues, patient discomfort and inaccuracies in stimulation of the reflex. Whether threshold for elicitation of a bilateral LAR response differs between different laryngeal subsites remains unclear. In cats, it seems that most of the sensory receptors responsible for generating the reflex are located in the posterior laryngeal mucosa over the arytenoid cartilages (reference). However, we have very scarce data in humans and that which we do have is predominantly based on histological studies of sensory nerve receptor density. If there are topographical differences for LAR elicitation, this information could be used understand and potentially better manage conditions associated with impaired LAR functioning, including silent aspiration in the elderly and, possibly, sudden infant death syndrome. In addition, preventing complications of general anesthesia such as laryngospasm and aspiration are dependent on an understanding of which areas of the larynx are most responsible for eliciting the LAR. For example, if the posterior larynx in humans does indeed contain the highest density of sensory receptors, this is the area that should be targeted when topical local laryngeal anesthesia is applied to prevent laryngospasm. In accordance with one aspect of the present invention, the LAR is used to define the topography of the larynx as it relates to elicitation of the laryngeal adductor reflex using electrical mucosal stimulation under general anesthesia.

The general system and method described herein and according to at least one embodiment are used for a patient that is under general anesthesia of a type that does not suppress LAR. In other words, the present invention is implemented in general anesthesia regimes that preserve LAR and is not intended for use with general anesthesia that is of type that suppresses LAR. In one exemplary embodiment, the present system and method are used with patients that are under total intravenous anesthesia (TIVA).

As discussed herein, the LAR is a protective reflex that prevents aspiration by causing thyroarytenoid muscle contraction and thus vocal fold closure. It can be elicited via electrical stimulation of the iSLN or by stimulation of mechanoreceptors (or other receptors) in the laryngeal mucosa with air puffs. Recently, the LAR has been elicited by applying brief electrical stimulation directly to the laryngeal mucosa by a wire electrode passed through the laryngoscope until the mucosa is reached. In awake humans, the LAR consists of early (R1) and late (R2) bilateral responses and the R1 response has been shown to be present even during volitional vocal and respiratory tasks, attesting to the primordial and robust nature of this airway reflex.

Under general anesthesia, ipsi- and contralateral R1 responses (iR1 and cR1, respectively) have been observed in humans. However, the cR1 response tends to disappear at higher anesthetic levels of halogenated agents. The present invention provides a noninvasive, simple and reproducible methodology for eliciting the LAR under general anesthesia that relies solely on endotracheal tube-based surface electrodes. The present technique monitors not only vocal fold adduction but also the entire vagal reflex arc, incorporating for sensory, motor and brainstem pathways.

As discussed herein, LAR was successfully elicited under total intravenous anesthesia (TIVA) using surface based endotracheal tube electrodes that not only record but also stimulate. This is in contrast with previous methods in which endotracheal tube electrodes have been used only to record - but not stimulate. The present invention includes an endotracheal tube construction that improves IIONM and CIONM by improving signal specificity, increasing tissue contact with electrodes, and preventing rotation and proximal/distal movement of the endotracheal tube. The details of the improved endotracheal tube construction are discussed immediately below.

<FIG> illustrate an intubation tube <NUM> in accordance with one exemplary embodiment of the present invention. As is known, tracheal intubation (intubation) is generally the placement of a flexible plastic tube into the trachea (windpipe) to maintain an open airway or to serve as a conduit through which to administer certain drugs. Intubation is frequently performed in the critically injured, ill, or anesthetized patients to facilitate ventilation of the lungs and to prevent the possibility of asphyxiation or airway obstruction. The most common technique (referred to as orotracheal) is to pass an endotracheal tube through the mouth, the vocal apparatus into the trachea. Because intubation is an invasive and uncomfortable medical procedure, intubation is usually performed after administration of general anesthesia and a neuromuscular-blocking drug. Intubation is normally facilitated by using a conventional laryngoscope, flexible fiber optic bronchoscope, or video laryngoscope to identify the vocal cords and pass the tube between the vocal cords into the trachea instead of into the esophagus. After the trachea has been intubated, a balloon cuff is typically inflated just above the distal end of the endotracheal tube to help secure it in place.

The illustrated intubation tube <NUM> is an elongated structure (tubular body <NUM>) that includes a proximal end (not shown) that is located and positioned outside of the patient and a distal end <NUM> for insertion into the patient. The intubation tube <NUM> can be formed in any number of different sizes and can be formed to have any number of different shapes; however, a circular shape is most common. As described herein and illustrated in <FIG>, the intubation tube <NUM> can have a variable cross-sectional shape in that one or more sections of the tube can have one shape (e.g., circular), while one or more other sections can have another, different shape (e.g., triangular).

The intubation tube <NUM> includes a first inflatable member <NUM> and optionally includes a second inflatable member <NUM> that is spaced proximal to the first inflatable member <NUM>. Due to their relative positions along the length of the intubation tube <NUM>, the first inflatable member <NUM> can be referred to as being a lower balloon and the optional second inflatable member <NUM> can be referred to as being an upper balloon. The optional second inflatable member <NUM> is intended for placement at a location distal to the larynx and is configured for preventing proximal/distal movement of the intubation tube <NUM>.

Each of the first and second inflatable members <NUM>, <NUM> can be in the form of a balloon cuff that can be controllably and selectively inflated to a desired inflation level. It will be understood that the first inflatable member <NUM> can have a different shape and/or size compared to the second inflatable member <NUM>.

As described herein, an area <NUM> between the first and second inflatable members <NUM>, <NUM> of the intubation tube <NUM> can be in the form of an electrode section. More specifically, the area <NUM> is at least a recording electrode area that includes at least one first electrode <NUM> and at least one second electrode <NUM>. The at least one electrode <NUM> is in the form of an active recording electrode and the at least one second electrode <NUM> is in the form of a reference recording electrode. The electrodes <NUM>, <NUM> are described in more detail below. Alternatively and according to at least one other embodiment, the area <NUM> can include one or more stimulation electrode and thus, is not limited to only performing a recording function.

As described below, the area <NUM> preferably includes bi-lateral active electrodes that are configured to both provide stimulation and record tissue response depending upon the precise application (e.g., the location of the operative site) and therefore, there are at least two first electrodes <NUM>, with at least one electrode <NUM> being on one side of the intubation tube <NUM> within the area <NUM> and the other electrode <NUM> is on the other side of the intubation tube <NUM> within the area <NUM>.

<FIG> illustrate exemplary constructions for the intubation tube <NUM>. <FIG> shows that a cross-section of the intubation tube <NUM> at a location above the area <NUM> (and above the first inflatable member <NUM>) is circular in shape. <FIG> shows that a cross-section of the intubation tube <NUM> at a location within the area <NUM> is generally triangular in shape. <FIG> shows that a cross-section of the intubation tube <NUM> at a location below the area <NUM> (and below the second inflatable member <NUM>) is circular in shape. The generally triangular shape of the outer surface of the intubation tube <NUM> within the area <NUM> is configured to mate with the larynx anatomy and prevents rotation of the intubation tube <NUM>, while also increasing the surface area of the intubation tube <NUM> that is contact with the larynx tissue. It will be understood that the generally triangular shape of the intubation tube <NUM> can be restricted to a front portion of the intubation tube as shown in <FIG> in that it is defined by an integral protrusion (extension) that has a triangular shape and extends radially outward from the circular shaped tube portion. The posterior aspect to the intubation tube is circular in shape similar to a conventional intubation tube as shown. The modification of the front portion (by inclusion of the triangular shaped protrusion in a discrete local region of the tube) allows for decreased left/right rotation, whilst not increasing the diameter of the posterior tube portion. As set forth below, this increased surface area allows for increased electrode-tissue contact.

<FIG>, <FIG>, <FIG> and <FIG> show details concerning the electrode section <NUM>. As shown in <FIG> and described above, the intubation tube <NUM> has a generally triangular shaped cross-section in the area <NUM> (electrode section) that is defined by a first side surface (face) <NUM>, an opposing second side surface (face) <NUM>, a third side surface (face) <NUM>, and an opposing fourth side surface (face) <NUM>. A central, circular shaped bore is also formed in area <NUM>. As shown, the first and second side surfaces <NUM>, <NUM> can be planar surfaces that are angled with respect to one another, while the third and fourth side surfaces <NUM>, <NUM> can be arcuate shaped. The third side surface <NUM> has an arcuate length that is less than the fourth side surface <NUM>.

The reference recording electrode <NUM> can be a single electrode located along the third side surface <NUM> and more particularly, can be vertically oriented such that it extends longitudinally along a length of the intubation tube <NUM> within the area <NUM>. The reference recording electrode <NUM> can be centrally oriented within the third side surface <NUM>.

In the illustrated embodiment, there is a plurality of active recording electrodes <NUM>. The plurality of active recording electrodes <NUM> can be oriented parallel to one another and in series along a longitudinal length of the intubation tube <NUM> within the area <NUM> as shown. However, it will be understood that other arrangements of the active recording electrodes <NUM> are equally possible, including a vertical orientation or a matrix comprising rows and columns, and therefore, the electrodes <NUM> illustrated and described herein are merely exemplary in nature and not limiting of the scope of the present invention. More specifically and according to one embodiment, the active recording electrodes <NUM> are in the form of bilateral electrode arrays in that, as best shown in <FIG>, the active recording electrodes <NUM> can be formed of a first array <NUM> that is formed along the first side surface <NUM> and a second array <NUM> that is formed along the opposing second side surface <NUM>. Each of the first and second arrays <NUM>, <NUM> is defined by parallel spaced electrode bands disposed along the outer surface of the intubation tube <NUM> and electrically connected to one another, as shown in <FIG>. As shown, each electrode band is operatively coupled to an electrical lead so as to electrically connect the electrode bands and permits a signal indicative of an LAR response to be delivered to a signal receiver (signal processor/recorder) that can record and/or analyze the signal as described below. In other words, electrode bands are electrically connected to the signal receiver.

In at least one embodiment, each of the first and second electrode arrays <NUM>, <NUM> is configured to both provide an electrical stimulus (and thus acts as an active stimulation electrode) and also record signals, in this case, the contralateral R1 (cR1) and R2 (cR2) responses of the LAR (and thus act as an active recording electrode). The electrode arrays <NUM>, <NUM> thus are configured to provide electrical stimuli to adjacent tissue by receiving electrical signal from a signal generator, which is described below, can be the same machine that records. As described herein and according to one exemplary implementation of the present system and method, the LAR was elicited by electrical stimulation of the laryngeal mucosa on the side contralateral to the operative field using the right or left surface electrodes (i.e., the first and second electrode arrays <NUM>, <NUM>) attached to the endotracheal tube <NUM> within area <NUM>.

It will also be appreciated that as shown in <FIG>, the first and second electrode arrays <NUM>, <NUM> can be disposed entirely along the faces <NUM>, <NUM> that define the triangular shaped protrusion that extends radially outward from the circular shaped posterior portion of the intubation tube. The reference electrode <NUM> can also be positioned entirely within this triangular shaped portion as well.

When the second inflatable member <NUM> is used, the placement of the bi-lateral electrode arrays <NUM>, <NUM> between the first and second inflatable members (cuffs) <NUM>, <NUM> also improves the signal to noise ratio.

In one embodiment, the second inflatable member <NUM> includes one or more stimulation electrodes <NUM> that are disposed along an outer surface of the second inflatable member <NUM>. See <FIG> and <FIG>. As shown, each stimulation electrode <NUM> extends about the outer surface (circumference) of the second inflatable member <NUM>. The one or more stimulation electrodes <NUM> can be arranged in a latitudinal direction along the second inflatable member <NUM>.

In one embodiment, there is a single stimulation electrode <NUM> disposed along the second inflatable member <NUM>. When a single stimulation electrode <NUM> is used, it is configured such that it can provide electrical stimulation of the laryngeal mucosa on the side contralateral to the operative field and thus, has coverage over both the left vocal fold and the right vocal fold. As described herein, when the optional second inflatable member <NUM>, with the at least one stimulation electrode <NUM>, is used, the at least one stimulation electrode <NUM> then becomes the stimulating electrode of the system and the first and second electrode arrays <NUM>, <NUM> become the recording electrodes. One advantage of this type of arrangement is that it allows left and right sides to be recorded simultaneously, something not possible with the only currently available continuous monitoring technique which requires a vagus nerve electrode to be placed on the ipsilateral side to operation field prior to being able to record continuously. In other words, by moving the active stimulation electrode from the area <NUM>, the active electrodes in area <NUM>, namely, the first and second electrode arrays <NUM>, <NUM> serve only as recording electrodes, thereby providing bi-lateral recording coverage.

In one exemplary embodiment, the second inflatable member <NUM> has a bi-lateral electrode configuration in that there is one stimulation electrode <NUM> disposed along one side of the second inflatable member <NUM> and another stimulation electrode <NUM> is disposed along the other side of the second inflatable member <NUM>. Each stimulation electrode <NUM> can be oriented in a latitudinal direction along the second inflatable member <NUM>; however, other orientations are equally possible. The positions of the stimulation electrodes <NUM> are such that one stimulation electrode <NUM> is for placement into direct contact with the left vocal fold and the other stimulation electrode <NUM> is for placement into direct contact with the right vocal fold.

It will be understood that in yet another embodiment, the second inflatable member <NUM> is present along with the first inflatable member <NUM>; however, the second inflatable member <NUM> is free of any stimulation electrodes and thus, serves only as an anchoring balloon to prevent proximal and distal movement of the intubation tube <NUM>. In this embodiment, the stimulation electrode is thus one of the active electrodes <NUM> (e.g., first and second electrode arrays <NUM>, <NUM>) that is located within area <NUM> of the intubation tube <NUM> and the recording electrode is the other of the active electrodes <NUM>.

As best shown in <FIG>, each of the electrodes associated with the intubation tube <NUM> is electrically connected to a machine <NUM> that is configured to both generate stimuli and record responses to the applied stimuli (e.g., electric signals). The electrical connection between the individual electrodes and the machine <NUM> is by conventional means, such as wires or other type of connectors <NUM>. The machine <NUM> can thus be a signal generator/receiver that is suitable for the present application in that it is configured to both generate electrical stimuli (electrical signals) and record electrical signals.

One exemplary machine <NUM> is an Axon Sentinel <NUM> EP Analyzer machine (Axon Systems Inc. ; Hauppauge, NY, USA) that comprises a multi-channel device that monitors and detects electrical signals (e.g., evoked potential monitoring) and is further configured to emit electrical signals (stimulation signals). Signals received by the machine <NUM> can be amplified, filtered and then stored on a computer device, such as a desk-top or laptop, or can be stored in the cloud (network). As described below, the machine <NUM> is configured such that the electrical stimuli can be directed to one or more electrodes and the character of the electrical stimuli can be controlled by the user, e.g., the frequency, duration, etc., of the electrical stimuli can be selected and controlled.

Fifteen patients who underwent neck surgery were studied. Table <NUM> (set forth below) shows demographics, diagnosis and type of surgery for each patient. The anesthetic regimen consisted of total intravenous anesthesia (TIVA) using propofol and remifentanil in standard weight based doses.

After induction of general anesthesia, the patient was intubated with a Nerve Integrity Monitor TriVantage endotracheal tube (NIM TriVantage™, Medtronics Xomed Inc. ; Jacksonville, FL, USA) containing bilaterally imbedded conductive silver ink surface electrodes (See, <FIG>). These electrodes come into direct contact with the right and left vocal folds (<FIG>). It will be appreciated that both the intubation tube construction and the electrode construction and placement in <FIG> is different than the embodiment shown in <FIG>. More specifically, <FIG> depict an intubation tube <NUM> having a first inflatable member (balloon cuff) <NUM>, a first pair of electrodes <NUM> on one side (e.g., left) of the tube <NUM>, and a second pair of electrodes <NUM> on the other side (e.g., right) of the tube <NUM>.

Following initial intubation, the tube position was rechecked after the patient was properly positioned for the neck surgery. For stimulation and recording, an Axon Sentinel <NUM> EP Analyzer machine was utilized (Axon Systems Inc. ; Hauppauge, NY, USA). This type of device is a multi-channel device that monitors and detects electrical signals (evoked potential monitoring). Other suitable machines can equally be used. The LAR was elicited by electrical stimulation of the laryngeal mucosa on the side contralateral to the operative field using the right or left surface electrodes attached to the endotracheal tube.

It will therefore be appreciated that unlike in conventional uses, the intubation tube <NUM> shown in <FIG> was operatively connected to a machine (e.g., the Axon Sentinel <NUM> EP Analyzer machine) that is configured not only to record but also to generate and deliver stimuli to certain select electrodes. For example, the electrode(s) on one side of the tube can be selected as being a stimulating electrode(s) and the device to which the electrode(s) is electrically connected thus supplies electrical stimuli to this electrode. The electrode(s) on the other side of the tube would thus be selected and serve as the recording electrode(s). This is in direct contrast to the conventional use of the illustrated intubation tube in which both the left and right electrodes act only as recording electrodes.

A single stimulus (<NUM>-<NUM> duration) or a pair of stimuli (ISI <NUM>-<NUM>) at intensity up to 4mA was applied. In order to minimize stimulus artifact, two responses elicited by stimuli of reverse polarity were averaged. Surface electrodes ipsilateral to the surgical field (and contralateral to the stimulation side) attached to the endotracheal tube were used to record the contralateral R1 (cR1) and R2 (cR2) responses of the LAR. The cR1 and cR2 responses were defined as the short and long-latency responses, respectively, elicited in the contralateral vocal fold muscles relative to the stimulating side (<FIG>). Signals were amplified (<NUM>), filtered (bandwidth <NUM>-<NUM>), and stored on the computer for off-line analysis.

The results of the study described above are as follows. There were three males and twelve females aged between <NUM> and <NUM> years (<NUM>±<NUM>, mean±SD). In all patients, LARs were successfully elicited bilaterally. The cR1 response was reliably elicited throughout the surgery in all cases (<FIG>). A cR2 response was also seen in <NUM> patients. The mean onset latency and amplitude (measured peak to peak) of the cR1 response for the right and left vocal folds are presented in Table <NUM> (set forth below). The mean onset latency of the elicited cR2 response is also presented.

The intensity of current required to elicit the LAR varied between 2mA (<NUM> duration) to 4mA (<NUM> duration) and the intensity required to elicit the reflex for each patient was adjusted throughout the surgery to obtain reliable cR1 responses. Reversible changes in the LAR manifesting as increased latency and decreased amplitude of response from baseline were noted to occur during every surgery. In every surgery, the timing of these changes correlated temporally with surgical maneuvers that would have put stretch or compression directly on the RLN. During times when the RLN was out of the operative field, the LAR remained constant in amplitude and latency. None of the patients had intraoperative total reflex loss and, postoperatively, no patient had objective vocal cord paralysis. No intraoperative or post-operative complications relating to the stimulation or recording of the LAR were noted for any patient.

The above-described study demonstrates the feasibility of monitoring both sensory and motor pathways of the laryngeal nerves during neck surgery by eliciting the LAR in patients under total intravenous general anesthesia. This novel methodology is simple, noninvasive and widely applicable as it uses a commercially available endotracheal tube for stimulating laryngeal mucosa on one side and recording contralateral vocal fold responses on the opposite side (cR1 and cR2).

Using this methodology, the present Applicant was successfully able to assess the functional integrity of the LAR pathways throughout all included neck surgeries. This laryngeal reflex thus represents a new method for continuous monitoring of vagal and recurrent laryngeal nerve function. The LAR is a brainstem reflex that protects the larynx from aspiration. Afferent and efferent limbs of the LAR are mediated by two distinctive branches of the vagus nerve, the SLN and the RLN. The afferent limb carries information from sensory receptors in the supraglottic and glottic mucosa (likely mechanoreceptors and chemoreceptors) through the iSLN. The inferior glottis and subglottic regions of the larynx receive sensory fibers from the RLN which may also contribute to the reflex during mucosal stimulation with surface based endotracheal tube electrodes. The efferent limb of the LAR is mediated by motor fibers of the RLN.

Prior studies have shown that electrical stimulation of the iSLN induces several recordable responses in adductor muscles of the larynx. An early ipsilateral response (relative to the stimulus) called ipsilateral R1 (iR1) has been extensively recorded in anesthetized cats, dogs, pigs and humans. A short latency contralateral R1 response (cR1) that involves contralateral adduction of the vocal fold muscle has been consistently recorded in anesthetized cats, awake humans, and humans under low dose of general anesthesia. A longer latency R2 response that produces bilateral vocal cord adduction have been recorded in awake humans. Latency of iR1 in awake and anesthetized humans is typically between <NUM>-<NUM> (milliseconds). It has also been noted that the latency of the human cR1 response is approximately <NUM> longer than the latency of the iR1 response, and proposed different models of brainstem circuitry for iR1 and cR1 responses. The iR1 was proposed to project from the iSLN to motor neurons of the ipsilateral nucleus ambiguus via the ipsilateral nucleus of the tractus solitarius. In contrast, the cR1 would project from the ipsilateral nucleus of the tractus solitarius to the contralateral nucleus ambiguous via <NUM>-<NUM> additional interneuron synapses within the reticular formation, thus giving the contralateral adduction of the reflex. The presence of the cR1 response would be supported by central facilitation and consequently would be suppressed by anesthesia in a dose-dependent manner. Subsequently, due to this perceived difficulty in eliciting contralateral responses in animals (except for the cat) and humans under deep general anesthesia, other studies do not address cR1 responses despite the LAR being a bilateral reflex. In the present study, Applicant provides evidence of the feasibility of eliciting cR1 responses in patients under general anesthesia with TIVA, similar to the cR1 responses that Sasaki et al (<NUM>) were able to elicit at <NUM> MAC of isoflurane <NUM> (but not at higher alveolar concentrations). The ability to elicit the cR1 in <NUM>% of patients under TIVA attests to robust nature of this reflex as an airway protective mechanism.

Currently available methods for continuous intraoperative monitoring of the RLN rely on operative exposure of the RLN and/or vagus nerves for placement of monitoring probes. The ability to use the surface electrodes of the endotracheal tube for stimulation and recording purposes without requiring placement of additional monitoring devices within the neck is thus a tremendous advantage over other currently available techniques. The ability to obtain continuous nerve integrity feedback without actual nerve exposure also broadens the potential uses of this technique to surgical procedures where the RLN (or iSLN) is at risk but not necessarily directly visualized in the operative field. In addition, this methodology has the ability to assess intraoperative afferent laryngeal nerve function, something that is lacking in previous methodologies. Brainstem and basis crania surgeries frequently pose a significant risk to the integrity of the vagus nerve. Current methodologies for intra-operative monitoring include cranial nerve mapping of the vagus nerve and cortico-bulbar motor evoked potentials (MEP). Cranial nerve mapping is one of the most utilized methodologies but depends on surgeon participation and cannot be used continuously. Cortico-bulbar MEPs can continuously assess the integrity of nerves, nuclei and central pathways if used frequently however they provoke movement due to transcranial electrical stimulation that interrupts the surgery and thus the frequency of application is limited. In contrast, the LAR is simple to perform and does not evoke movement or cause any disruption to the surgical procedure. However, it must be noted that although it assesses integrity of the vagus nerve and nucleus ambiguous it cannot assess the integrity of supranuclear pathways. Positioning of the electrodes on the endotracheal tube is of crucial importance to the success of this reflex. The electrodes must be positioned so that they oppose the glottic mucosa for both stimulation and recording purposes. There have been prior articles describing how the tube should be positioned during thyroid surgery and these guidelines are helpful in ensuring correct tube placement. If intraoperative changes in the reflex occur (decrease in amplitude or increase in latency compared to baseline recordings) during surgery where laryngeal nerves are at risk, several factors need to be addressed. First, stimulus intensity should be increased until reflex trace returns to baseline levels because threshold for eliciting the LAR may have changed due to surgical manipulations. If increasing intensity does not recover the reflex to baseline recordings, the surgeon should be alerted and asked if the nerve is being stretched at that moment. If so, simply relaxing the tissue may allow the reflex to recover. If releasing the tissue does not result in full recovery or if the surgeon is not operating near the nerve at the time, tube position should be checked. The tube position is optimally checked by using a laryngoscope however it can also be checked without using laryngoscopy by moving the tube in a rotational or proximal-distaldirection and testing the reflex in each new tube position. Finally, if none of the above maneuvers recovers the reflex to baseline levels, true reflex changes due to impending nerve injury can be suspected. Loss of the LAR is a warning criteria for the surgeon to stop the surgery and explore the surgical field to confirm nerve injury.

Based on at least the foregoing study, intra-operative application of the LAR using endotracheal tube surface based electrodes and contralateral R1 responses is a viable method of monitoring recurrent laryngeal and vagus nerve integrity during surgery. The results from the above study indicate that the LAR was reliably elicited in <NUM>% of patients for the duration of each surgical procedure. Mean onset latency of cR1 response was <NUM> +/- <NUM> (right) and <NUM>+/-<NUM> (left). cR2 responses were noted in <NUM> patients (<NUM>%). No perioperative complications or adverse outcomes were observed.

As a result, the LAR is a novel neuro-monitoring technique for the vagus nerve and in particular, represents a novel method for intraoperatively monitoring laryngeal and vagus nerves. The LAR monitors the entire vagus nerve reflex arc and is thus applicable to all surgeries where vagal nerve integrity may be compromised. Advantages over current monitoring techniques including simplicity, ability to continuously monitor neural function without placement of additional neural probes and ability to assess integrity of both sensory and motor pathways.

<FIG> illustrate an alternative intubation tube <NUM> according to another embodiment. The intubation tube <NUM> is similar to intubation tube <NUM> and is in the form of an elongated structure (tubular body) that includes a proximal end (not shown) that is located and positioned outside of the patient and a distal end for insertion into the patient. The intubation tube <NUM> can be formed in any number of different sizes and can be formed to have any number of different shapes; however, a circular shape is most common. Like the intubation tube <NUM>, the intubation tube <NUM> can have a variable cross-sectional shape in that one or more sections of the tube can have one shape (e.g., circular), while one or more other sections can have another, different shape (e.g., triangular as described below).

Also like the intubation tube <NUM>, the intubation tube <NUM> includes a first inflatable member <NUM> (see, <FIG>) and optionally includes a second inflatable member <NUM> (see, <FIG>) that is spaced proximal to the first inflatable member <NUM>. For sake of simplicity, the first and second inflatable members <NUM><NUM> are not shown in <FIG>. It will be appreciated that an electrode section (electrode area) <NUM> shown in <FIG> is positioned between the first and second inflatable members along the elongated body of the intubation tube <NUM>.

As described herein, the electrode section or area <NUM>, which can be located between the first inflatable and second inflatable members <NUM>, <NUM> (<FIG>) of the intubation tube <NUM> can be in the form of an electrode section. More specifically, the electrode area <NUM> is configured as a multi-functional electrode section. In particular, unlike the previous embodiment in which the stimulation electrodes were placed on the second cuff (second inflatable member <NUM>), the electrode area <NUM> includes both recording and stimulation electrodes as described in detail below.

As shown, the electrode area <NUM> is generally triangularly shaped like electrode section <NUM> of the previous embodiment. As shown in <FIG>, within the electrode area <NUM> of the intubation tube <NUM>, the intubation tube has a first portion <NUM> that is generally circular in shape and an adjacent second portion <NUM> that protrudes radially outward from the first portion <NUM>.

<FIG> illustrate exemplary constructions for the intubation tube <NUM>. It will be appreciated like the previous embodiment, a cross-section of the intubation tube <NUM> at a location above the area <NUM> (and above the first inflatable member <NUM> (<FIG>)) is circular in shape. <FIG> shows that a cross-section of the intubation tube <NUM> at a location within the area <NUM> is generally triangular in shape. It will further be appreciated that like the previous embodiment, a cross-section of the intubation tube <NUM> at a location below the area <NUM> (and below the second inflatable member <NUM> (<FIG>)) is circular in shape. The generally triangular shape of the outer surface of the intubation tube <NUM> within the area <NUM> is configured to mate with the larynx anatomy and prevents rotation of the intubation tube <NUM>, while also increasing the surface area of the intubation tube <NUM> that is contact with the larynx tissue. It will be understood that the generally triangular shape of the intubation tube <NUM> can be restricted to a front portion of the intubation tube as shown in <FIG> in that it is defined by an integral protrusion (extension) that has a triangular shape and extends radially outward from the circular shaped tube portion. The posterior aspect to the intubation tube is circular in shape similar to a conventional intubation tube as shown. The modification of the front portion (by inclusion of the triangular shaped protrusion in a discrete local region of the tube) allows for decreased left/right rotation, whilst not increasing the diameter of the posterior tube portion. As set forth below, this increased surface area allows for increased electrode-tissue contact.

<FIG> show details concerning the electrode section <NUM>. As shown in <FIG> and described above, the intubation tube <NUM> has a generally triangular shaped cross-section in the area <NUM> (electrode section) that can generally be thought of as including a first side surface (face) <NUM>, an opposing second side surface (face) <NUM>, a third side surface (face) <NUM> which is an anterior portion, and an opposing fourth side surface (face) <NUM> which is a posterior portion. A central, circular shaped bore is also formed in area <NUM>. As shown, the first and second side surfaces <NUM>, <NUM> can be slightly curved or planar surfaces that are angled with respect to one another, while the third and fourth side surfaces <NUM>, <NUM> can be arcuate shaped. The third side surface <NUM> has an arcuate length that is less than the fourth side surface <NUM>.

The electrode area <NUM> includes a plurality of recording electrodes and in particular, includes at least one first electrode <NUM> in the form of an active recording electrode and the at least one second electrode <NUM> in the form of a reference recording electrode. The electrodes <NUM>, <NUM> are described in more detail below.

The electrode area <NUM> preferably includes bi-lateral active electrodes that are configured to both provide stimulation and record tissue response depending upon the precise application (e.g., the location of the operative site) and therefore, there are at least two recording electrodes, with at least one electrode being on one side of the intubation tube <NUM> within the area <NUM> and at least one electrode being on the other side of the intubation tube <NUM> within the area <NUM>.

In the illustrated embodiment, one recording electrode <NUM> is located on the first side <NUM>, while one recording electrode <NUM> is located on the opposite side <NUM>. As shown, there are preferably a pair of recording electrode <NUM> on the first side <NUM> and a pair of electrodes <NUM> on the second side <NUM>. The electrodes <NUM> can run longitudinally along the intubation tube <NUM> and are parallel to one another and similarly, the electrodes <NUM> can run longitudinally along the intubation tube <NUM> and are parallel to one another. As best shown in <FIG>, one electrode <NUM> is proximate the anterior (generally triangular shaped) protrusion, while the other electrode <NUM> is located along the circular shaped body closer to the posterior side. The same is true for the pair of electrodes <NUM> in that one can be located proximate the anterior protrusion with the other being closer to the posterior side.

<FIG> shows a side (lateral) view of the electrode area <NUM> and it can be seen that from the side view, one pair of recording electrodes (in this case electrodes <NUM>) can be seen (from the other side view, the other pair of electrodes <NUM> can be seen).

In the illustrated embodiment and in contrast to the previous embodiments, the electrode area <NUM> includes one or more stimulation electrodes <NUM> that are disposed along an outer surface of the intubation tube <NUM> within the electrode area <NUM> as shown in the figures. The illustrated embodiment includes a pair of stimulation electrodes <NUM> that are located along the fourth side <NUM> (posterior side) of the intubation tube <NUM>. Like the recording electrodes <NUM>, <NUM>, the stimulation electrodes <NUM> can run longitudinally and are spaced apart (in a parallel manner).

While the lengths of the recording electrodes <NUM>, <NUM> and the stimulation electrodes <NUM> are shown as generally be equal and the widths are shown as generally being equal, it will be appreciated that the lengths and/or widths can be different.

As a result of the posterior positioning and use of a pair of stimulating electrodes <NUM>, the stimulating electrodes <NUM> become the stimulating electrodes of the system and the first and second electrode arrays <NUM>, <NUM> become the recording electrodes. One advantage of this type of arrangement is that it allows left and right sides to be recorded simultaneously, something not possible with the only currently available continuous monitoring technique which requires a vagus nerve electrode to be placed on the ipsilateral side to operation field prior to being able to record continuously. The first and second electrode arrays <NUM>, <NUM> serve only as recording electrodes, thereby providing bi-lateral recording coverage.

In illustrated embodiment, the electrode area <NUM> also has a bi-lateral electrode configuration in that there is one stimulation electrode <NUM> disposed along one side of the electrode area <NUM> and another stimulation electrode <NUM> is disposed along the other side of the electrode area <NUM>.

The design of the intubation tube <NUM> improves IIONM and CIONM by improving signal specificity, increasing tissue contact with electrodes, and preventing rotation and proximal/distal movement of the intubation tube <NUM>.

The optional second inflatable member (balloon or cuff) <NUM> (<FIG>) can be positioned along the intubation tube <NUM> at a location that will be distal to the larynx for preventing proximal/distal movement.

As mentioned previously, the triangular outer surface of the intubation tube <NUM> between cuffs (first and second inflatable members of <FIG>) mates with the larynx anatomy and therefore, prevents rotation and increases electrode-tissue contact.

The placement of bi-lateral electrode arrays (e.g., the bi-lateral recording electrodes <NUM>, <NUM> and bi-lateral stimulation electrodes <NUM>) between the cuffs (first and second inflatable members of <FIG>) improves signal to noise ratio.

As shown in <FIG>, the stimulation electrodes <NUM> can, in the illustrated embodiment, be thought of as being posterior arytenoid rim stimulation electrodes. The illustrated intubation tube <NUM> allows for bilateral reflex recording. The illustrated intubation tube <NUM> thus includes a total of <NUM> electrodes (<NUM> pairs) with <NUM> electrodes (<NUM> pairs) being recording electrodes and <NUM> electrodes (<NUM> pair) being stimulation electrodes.

Ten patients were enrolled. All patients were intubated with a monitored endotracheal tube (NIM Trivantage tube, Medtronic Inc). Direct laryngoscopy was performed and the larynx suspended. A bipolar probe was used to stimulate different laryngeal subsites. Bipolar stimulation was used in order to minimize current spread away from the site of stimulation. Subsites included anterior and posterior membranous vocal fold, posterior supraglottis over the medial surface of the arytenoid cartilage, mid false vocal fold, epiglottic petiole, epiglottic tip and subglottis. The maximum current approved by the IRB was 10mA and all subsites were initially stimulated at this level and vocal fold responses recorded both visually and by the endotracheal tube electrodes. Subsites that, on 10mA stimulation, elicited a bilateral reflex response were stimulated starting at 3mA and increasing by 1mA increments to define where the reflex first became bilateral. Pulse duration used was <NUM>. The study was approved by the Institutional Review Board for the Icahn School of Medicine at Mount Sinai.

Ten patients were enrolled. In all patients, posterior supraglottic stimulation elicited strong bilateral contractile responses in all patients, with contractile strength increasing in an inferior to superior direction upon stimulation up the medial arytenoid cartilage. The ventricular folds and epiglottic tip elicited variable responses, most commonly ipsilateral but becoming bilateral in a subset of patients at higher currents of stimulation. Membranous vocal folds and epiglottic petiole did not elicit any reflex.

The presence of strong bilateral LAR responses upon stimulation posteriorly in <NUM>% patients implies that the stimulating electrodes for the LAR tube in a preferred embodiment would be placed posteriorly, abutting the medial surface of each arytenoid cartilage. In this preferred embodiment, the recording electrodes are best placed more anteriorly, on the lateral tube surface, in order to record responses in the lateral cricoarytenoid muscles. This topography of responses with regards to the human larynx has not been previously investigated and no data except the data generated by the present Applicant exists.

<FIG> is a cross-sectional view of an exemplary electrode section of an intubation tube in accordance with the present invention. <FIG> lists exemplary dimensions and exemplary placements for the different types of electrodes that are part of the intubation tube. In this example, each recording electrode can have a width of about <NUM> and a length of about <NUM>. As also shown, on each side of the intubation tube, the inter-electrode gap between adjacent recording electrodes is about <NUM>. Each stimulation electrode can have a width of about <NUM> and a length of about <NUM>. As shown, the inter-electrode gap between adjacent recording electrodes can be about <NUM>. It will be appreciated that the recording electrodes in <FIG> can correspond to the recording electrodes <NUM>, <NUM> in <FIG> and the stimulating electrodes can correspond to the stimulating electrodes <NUM> in <FIG>.

<FIG> and <FIG> show a vocal cord level marker (cross symbol) that assists in the positioning of the device (intubation tube) relative to the vocal cord. The marker can be a line (indicia) formed on the tube for visualization.

One hundred patients undergoing thyroidectomy (n=<NUM>) or parathyroidectomy (n=<NUM>) were included. All patients underwent pre-operative (within one month) and post-operative (within one week) laryngeal examination via flexible trans-nasal laryngoscopy. Patients with post-operative vocal fold paresis or paralysis were followed monthly until normal vocal fold function returned. Eighty patients completed Vocal Fold Handicap Index-<NUM> questionnaires pre-operatively and one week post-operatively.

Anesthesia was induced with Propofol and succinylcholine and maintained using total intravenous anesthesia (TIVA) with Propofol and opioids (remifentanil). Inhalational and topical laryngeal anesthetic agents were avoided. Intubation was performed with a Nerve Integrity Monitor TriVantage endotracheal tube (NIM TriVantageTM, Medtronics Xomed Inc. ; Jacksonville, FL, USA). The patient's neck was extended and ET position rechecked and adjusted using video laryngoscopy (GlideScope, Verathon Inc. Seattle, WA, USA) to ensure electrodes were in direct contact with right and left laryngeal mucosa. The tube was fixed with standard tape and, in <NUM>% of patients, an oral endotracheal tube fastener (Anchor-FastTM, Libertyville, IL, USA).

Nerve stimulation was performed with a monopolar handheld stimulating probe (Medtronic Xomed, Jacksonville, FL, USA) with a subdermal sternal reference needle. Single stimuli of <NUM> duration with maximum intensity <NUM> mA at repetition rate <NUM> were applied. Responses were stimulated and recorded on a NIM-Response <NUM> machine (Medtronic Xomed, Inc. , Jacksonville, Florida, U. Loss of signal (LOS) was defined as an EMG amplitude response below 100µV with an absent posterior cricoarytenoid muscular twitch response on laryngeal palpation during vagal and RLN stimulation. LOS was classified into Type <NUM> (segmental) and Type <NUM> (diffuse) injury.

The LAR was elicited by electrical stimulation of laryngeal mucosa on the side contralateral to the operative field using ET electrodes. A single-stimulus (<NUM>-<NUM> duration) at intensity ≤<NUM> mA using the minimal current necessary for supramaximal stimulation was applied. Vocal fold adduction was recorded by ET electrodes contralateral to the stimulating side. Responses were stimulated and recorded on an Axon Sentinel <NUM> EP Analyzer machine (Axon Systems Inc. ; Hauppauge, NY, U. ) or Medtronic Eclipse® system (Medtronic Xomed, Inc. , Jacksonville, FL, USA). Signals were filtered (bandwidth <NUM>-<NUM>,<NUM>) and stored for offline analysis.

All patients with a decrease in vocal fold function between pre- and post-operative laryngeal examinations were analyzed. Closing LAR values were correlated with opening values, postoperative laryngeal examination findings, voice outcomes and closing CMAP values. Descriptive analyses were performed to determine the incidence of RLN paralysis. Two-tailed P < <NUM> was considered significant. Sensitivity, specificity, and positive and negative predictive values for prediction of laryngeal functional outcome using the LAR-CIONM were calculated.

In this study, the one hundred patients (<NUM> nerves at risk) underwent neck endocrine procedures by a single surgeon (CFS) monitored continuously using LAR-CIONM in addition to IIONM. Demographics, surgical indications, surgery type and pathology are outlined in Table <NUM>. All Bethesda <NUM>/<NUM> nodules underwent molecular testing prior to surgical intervention. LAR baseline values were taken prior to skin incision. If the LAR was unable to be elicited, ET position was adjusted until a reliable reflex was obtained. LAR elicitability was <NUM>%. Mean opening and closing LAR amplitudes for patients with normal postoperative laryngeal function were <NUM>±<NUM>µV and <NUM>±<NUM>µV, respectively. By comparison, mean closing LAR amplitudes for patients with abnormal post-operative laryngeal function due to intraoperative RLN injury were significantly decreased (opening <NUM>±<NUM>µV, closing <NUM>±<NUM>µV, p=<NUM>). In every thyroid surgery transient decreases in LAR amplitude without concomitant increases in reflex latency occurred during surgical maneuvers that put traction on the RLN (<FIG>). Releasing the tissue resulted in recovery of LAR amplitude.

Table <NUM> presents nerve injury data grouped by pre-operative nerve function. Patients <NUM> and <NUM> had normal pre-operative laryngeal examinations with post-operative hypomobility of the ipsilateral vocal fold to <NUM>% of the contralateral fold. Both patients had palpable posterior cricoarytenoid muscle twitches during intraoperative vagal nerve stimulation. Patient <NUM> had a posteriorly located right <NUM> papillary thyroid carcinoma with extrathyroidal extension. A decrement in LAR amplitude occurred during sharp dissection of the nerve off the tumor (<NUM>% decrement). Normal laryngeal function returned at <NUM>-weeks post-operatively. Patient <NUM> had thyromegaly with a prominent tubercle of Zuckerkandl and exhibited a <NUM>% LAR amplitude decrement. She had left vocal fold hypomobility at day <NUM> that returned to normal by day <NUM> postoperatively.

Patients <NUM>, <NUM> and <NUM> had normal pre-operative laryngeal examinations with postoperative transient vocal fold paralysis (<NUM>% unanticipated nerve paralysis rate). All recovered baseline laryngeal function by <NUM> weeks postoperatively. Patients <NUM> and <NUM> exhibited Type <NUM> loss of CMAP signal (LOS) presumably due to traction, and patient <NUM> was a Type <NUM> nerve injury due to heat damage from adjacent cautery. All patients had > <NUM>% amplitude decrement between the opening and closing LAR values (Table <NUM>) and exhibited significant decreases on their VHI-<NUM> questionnaires (mean pre-operative <NUM>, mean <NUM>-week postoperative <NUM>) that returned to baseline by <NUM> weeks postoperatively.

Patients <NUM> and <NUM> had pre-operative vocal fold paresis with post-operative vocal fold paralysis. Both patients had posteriorly located thyroid carcinomas with features of extrathyroidal extension (ETE). For patient <NUM>, the nerve was cut off the tumor with a Type <NUM> LOS at this site and a > <NUM>% amplitude decrement between the opening and closing LAR values. Final pathology showed microscopic ETE at the site of dissection. Although the vocal fold retains good tone in a medialized position, cord mobility has not returned <NUM> months postoperatively. Pre- and post-operative VHI-<NUM> scores are comparable at <NUM>. Patient <NUM> had complete encasement of the RLN by tumor and the nerve was sacrificed. A <NUM>% LAR amplitude decrement occurred between opening and closing LAR values, with closing amplitude of <NUM>. However, opening amplitude was only 104µV and we would thus currently classify this patient as 'not monitorable' by the LAR-CIONM technique (see discussion below). An ansa cervicalis to RLN nerve anastomosis was performed. At <NUM> months postoperatively, her VHI-<NUM> score is <NUM>, having improved from an immediate postoperative score of <NUM>.

Of <NUM> nerves at risk, <NUM> (<NUM>%) were unable to be continuously monitored throughout the surgical procedure. For four of these patients (<NUM>%), the contralateral nerve (i.e. nerve not 'at-risk') was also unable to be monitored suggesting suboptimal stimulating electrode contact with laryngeal mucosa due to either the ET diameter being too small and/or significant secretions between tube and mucosa. These patients were successfully monitored with IIONM alone confirming that the recording electrodes were functional. For the other patient, the nerve not "at risk" was able to be monitored using the LAR, suggesting a tube rotation issue or inadequate ipsilateral mucosal contact.

For the nerve transection case and the cases of complete post-operative vocal fold paralysis, a closing LAR amplitude <<NUM>µV was noted in <NUM>% of cases, with no case having a closing value of zero. This residual LAR activity in cases with LOS by IIONM criteria reflects far field recordings from contraction of contralateral vocal fold musculature against ET electrodes during the bilateral reflex response. Thus, for reliable monitoring using LAR-CIONM, a minimum opening amplitude of 150µV, optimally ><NUM>µV, is necessary. If nerves at risk with opening amplitudes < <NUM>µV are excluded from analysis (n=<NUM>), LAR-CIONM monitorability was <NUM>%.

Significantly more nerves-at-risk with LAR opening-closing amplitude decrement ><NUM>% or with closing amplitude < 100µV had postoperative nerve palsies compared with nerves-at-risk without these findings (p<<NUM>). The positive predictive value (PPV), negative predictive value (NPV), sensitivity and specificity of the LAR-CIONM using these criteria are presented in Table <NUM>. Of note, if patients with opening amplitudes < <NUM>µV were excluded (n=<NUM>), there were no patients with a ><NUM>% opening-closing amplitude decrement who did not have postoperative vocal fold dysfunction and all patients with <<NUM>% decrement had normal postoperative vocal fold function. Statistically this corresponds to a PPV/NPV/sensitivity/specificity of <NUM>%.

No patient exhibited hemodynamic instability at any time during reflex elicitation. One patient exhibited severe bradycardia (<NUM> beats per minute) when the vagus nerve was stimulated intermittently at 1mA without concomitant bradycardia using LAR-CIONM. There were no complications attributable directly to the monitoring technique. One patient with pre-operative cough had a worsened cough for <NUM> hours post-extubation and one patient with no pre-operative cough developed a cough four days after surgery that lasted for two days. One patient developed symptoms of benign positional vertigo four days postoperatively which settled with repositioning maneuvers.

As discussed herein, the LAR represents a novel method to continuously monitor the vagus nerve during surgical procedures. The only commercially available vagal CIONM technique requires potentially harmful manipulation of the vagus nerve for electrode placement. Electrode dislocation intra-operatively necessitates repeat nerve manipulation and disrupts the core analysis of the Automatic Periodic Stimulation (APS®) system for detecting significant CMAP decrements. In contrast, LAR-CIONM uses non-invasive ET electrodes alone to both stimulate and record vagal responses. This methodological advantage makes the LAR-CIONM particularly attractive for minimally invasive neck surgeries and neurosurgical procedures.

LAR-CIONM is exquisitely sensitive to changes in nerve excitability induced by RLN stretch or compression, necessitating frequent relaxation of tissues during surgical procedures to assess for reversibility of observed LAR-CIONM amplitude decrements. LAR-CIONM can thus provide very early warning of potential nerve injury and may prove more effective than CMAP responses in preventing type <NUM> LOS injuries because traction injuries are reversible when prompt corrective measures are applied. Increased latency of LAR responses did not predict nerve injury in this series. This suggests that the concept of the 'combined event' to predict postoperative nerve paralysis for CMAP responses may not apply to the LAR. It is recognized that trial-to-trial, a reflex is physiologically conducted by different axon fibers with varying conduction velocities which may contribute to latency variability during LAR-CIONM. Also, slight movements of the tube relative to the mucosa during surgical tissue manipulation may intermittently favor cathodic or anodic axonal depolarization, thereby increasing LAR latency variability.

In yet another aspect of the present invention, the devices and method disclosed herein can be adapted to monitor the LAR using the ipsilateral iR1 component of the reflex for both stimulation and recording purposes.

Surface electrodes ipsilateral to the surgical field (and also ipsilateral to the stimulation side) attached to the endotracheal tube can be used to record the ipsilateral R1 (iR1) and R2 (iR2) responses of the LAR. The iR1 and iR2 responses were defined as the short and long-latency responses, respectively, elicited in the ipsilateral vocal fold muscles relative to the stimulating side. For example, the device shown in <FIG> can be adapted and configured such that posterior pair of electrodes <NUM> act as the stimulating electrodes and due to their posterior position, these electrodes <NUM> will elicit an ipsilateral response that is recoded by an ipsilateral recording electrode, such as electrode(s) <NUM> and/or <NUM>. In yet another electrode arrangement, the device of <FIG> can be modified such that that the stimulating electrodes <NUM> can be eliminated or rendered inactive and for each of the pairs of electrodes <NUM>, <NUM>, the posterior electrode of the pair acts as a stimulating electrode, while the anterior electrode of the pair acts as the recording electrode. In this manner, the recording and stimulating electrodes are located on the same side of the tube. Ipsilateral iR1 recording can be achieved by separation of the stimulation electrode(s) from the recording electrode(s) with the stimulation electrode(s) being placed posterior to the recording electrode(s). It will be understood that these teachings can also be implemented in tubes having other constructions such as the other ones described herein.

Monitoring both sensory and motor pathways of the laryngeal nerves during neck surgery can be accomplished by eliciting the LAR in patients under total intravenous general anesthesia. This novel methodology is simple, noninvasive and widely applicable as it uses a commercially available endotracheal tube for stimulating laryngeal mucosa on one side and recording ipsilateral vocal fold responses on the same side (iR1 and iR2).

It will be understood that the foregoing dimensions are only exemplary in nature and therefore are not limiting of the present invention. The size of the electrodes and the relative placements thereof can therefore differ from the foregoing example.

It is to be understood that like numerals in the drawings represent like elements through the several figures, and that not all components and/or steps described and illustrated with reference to the figures are required for all embodiments or arrangements.

Claim 1:
An endotracheal tube (<NUM>) for intraoperatively monitoring laryngeal and vagus nerves by eliciting laryngeal adductor response (LAR) in a patient that is under general anesthesia, that is of a type that preserves LAR, and by monitoring contralateral responses of the LAR that are detected after application of electrical stimulation, the endotracheal tube (<NUM>) comprising:
an endotracheal tube body (<NUM>) having a first inflatable member (<NUM>) and an electrode area (<NUM>) that includes a plurality of surface based electrodes,
- wherein the surface based electrodes includes a first surface based electrode (<NUM>) that is located along a first side of the endotracheal tube and a second surface based electrode (<NUM>) that is located along a second side of the endotracheal tube, wherein each of the first and second surface based electrodes (<NUM>, <NUM>) being configured to emit electrical stimulation and record the responses of the LAR;
- wherein the electrode area (<NUM>) has a generally triangular shaped cross-section configured for mating with a larynx anatomy of the patient;
- wherein the generally triangular shaped cross-section being defined by a first side wall and a second side wall, the first side wall including the first surface based electrode (<NUM>) which comprises a first array (<NUM>) of the surface based electrodes (<NUM>, <NUM>) and the second side wall including the second surface based electrode (<NUM>) which comprises a second array (<NUM>) of the surface based electrodes (<NUM>, <NUM>).