Patent Application
20140018788
All publications and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.
The present disclosure is directed generally to devices, systems and methods for treating patients having sympathetically mediated disease associated at least in part with augmented peripheral chemoreflex, heightened sympathetic activation, or autonomic imbalance by ablating at least one peripheral chemoreceptor (e.g., a carotid body) or an associated nerve.
It is known that an imbalance of the autonomic nervous system is associated with several disease states. Restoration of autonomic balance has been a target of several medical treatments including modalities such as pharmacological, device-based, and electrical stimulation. For example, beta blockers are a class of drugs used to reduce sympathetic activity to treat cardiac arrhythmias and hypertension; Gelfand and Levin (U.S. Pat. No. 7,162,303) describe a device-based treatment used to decrease renal sympathetic activity to treat heart failure, hypertension, and renal failure; Yun and Yuarn-Bor (U.S. Pat. No. 7,149,574; U.S. Pat. No. 7,363,076; U.S. Pat. No. 7,738,952) describe a method of restoring autonomic balance by increasing parasympathetic activity to treat disease associated with parasympathetic attrition; Kieval, Burns and Serdar (U.S. Pat. No. 8,060,206) describe an electrical pulse generator that stimulates a baroreceptor, increasing parasympathetic activity, in response to high blood pressure; Hlavka and Elliott (US 2010/0070004) describe an implantable electrical stimulator in communication with an afferent neural pathway of a carotid body chemoreceptor to control dyspnea via electrical neuromodulation. US 2012/0172680 describes carotid body ablation for treating sympathetically mediated diseases.
Ablating a carotid body in a human patient is risky and difficult. A carotid body is typically about the size of a grain of rice, located near other glands, nerves, muscles and other organs, and moves with movement of the jaw and neck, respiration and blood pulsation. Conventional open surgical techniques to access the carotid body directly through the neck that are referred to as open surgery are challenging due to the nerves, muscles, arteries, veins and other organs near the carotid body. In the modern medicine open surgery is only used to access a carotid body for removal of carotid body tumors that are immediately life threatening.
There is a desire for minimally invasive surgical techniques and instruments configured to ablate at least a portion of the carotid body. Endovascular catheter assemblies are known for performing minimally invasive procedures and surgeries, including endovascular ablation of nerves, on the heart, kidney, pulmonary artery, renal artery and other body organs typically located below the neck. These catheter assemblies tend to be too short, too large, lack necessary features needed for retention and targeting of energy delivery and otherwise not suited to reaching the neck and, particularly, the narrow blood vessels in the neck. Endovascular catheter assemblies are also known for treating arteries in the neck such as to treat aneurysms in the wall of a blood vessel.
It is not conventional to use traditional minimally invasive surgical ablation instruments and techniques to treat organs in the neck, particularly at and near the bifurcation of carotid artery where the carotid body is located. One difficulty with applying endovascular catheter ablation techniques to an organ in the neck, other than an artery or vein in the torso or abdomen, is the long and tortuous path through the vascular system that a catheter is generally advanced to reach the neck. Another difficulty can be properly positioning the distal end of the catheter in an artery to act on the target organ that is external to the artery. Another difficulty is avoiding damage to carotid endothelium that can lead to formation of thrombus, avoiding excessive heating and scarring of blood vessel walls that can lead to stenosis, or disturbing atherosclerotic plaque that can cause embolization of brain arteries and stroke. The organ may move with respect to the artery, the narrow arteries in the neck and the complex geometries of these arteries present challenges to a minimally invasive technique to reach the carotid body. Ablation procedures may take tens of seconds and even minutes and in the highly mobile are of the neck catheter can be displaced during energy application.
While catheter probes with stimulation electrodes have been proposed for electrically stimulating the carotid body, these approaches do not describe ablating or otherwise permanently changing the carotid body. Nor do they describe devices and systems that are used to accomplish the same. Ablating, modulating or otherwise permanently changing the carotid body or its function requires the application of energy, chemicals or other forces sufficient to damage the carotid body or its associated nerves and potentially tissue and blood vessel walls near the carotid body. Damaging the carotid body, nerves and nearby tissue is not necessary or desired if the object of a treatment is to electrically stimulate the carotid body. Applying a relatively low level of energy to electrically stimulate the carotid body will unlikely damage a blood vessel or surrounding tissue, even if the energy is applied to a broader area than the carotid body. The level of energy and force or the chemicals needed to ablate the carotid body is substantially higher than the levels needed for stimulation. Applying energy, chemicals and forces (e.g., thermal energy) sufficient to damage the carotid body raises concerns that the damage could extend to nearby non-target nerves and other organs, rupture the wall of the blood vessel, disturb and dislodge plaque or create blood clots that could flow to the brain.
In view of the need to damage the carotid body, there are strict requirements for positioning and retaining the tip of an ablating catheter in a carotid artery for the duration of the procedure, and for narrowly targeting the delivery of the energy, chemicals or force to the carotid body. Recognizing and identifying the requirements for positioning an ablating tip, or energy application element, of a catheter was a first step for an endovascular catheter assembly for ablating the carotid body. A second step included the invention of endovascular catheter assemblies that satisfied the requirements. Then parameters for energy application were developed that preserve the blood vessel and surrounding non-target tissues but substantially ablate the carotid body or an associated nerve.
Methods, devices, and systems have been conceived for endovascular transmural ablation of a carotid body with a catheter having two arms to facilitate positioning and apposition of ablation elements on an intercarotid septum. Endovascular transmural ablation of a carotid body herein generally refers to delivering a device through a patient's vasculature to a blood vessel proximate to a target ablation site (carotid body, intercarotid plexus, carotid body nerves) of the patient and placing an ablation element associated with the device against the internal wall of the vessel adjacent to the peripheral chemosensor and activating the ablation element to ablate the peripheral chemosensor.
A system has been conceived comprising a catheter having a means for coupling with a carotid bifurcation for transmural carotid body ablation and an ablation energy console. The system may additionally comprise a connector cable for connecting the ablation energy console with the catheter, a computer controlled software algorithm for controlling delivery of ablation energy, a delivery sheath, or a guide wire. Ablation energy can be thermal energy such as heating (e.g., RF, ultrasound, laser) or freezing (e.g., cryogenic element).
A carotid body may be ablated by placing an ablation element within and against the wall of a carotid artery adjacent to the carotid body of interest, then delivering ablation energy from the ablation element causing a change in temperature of periarterial space containing the carotid body to an extent and duration sufficient to ablate the carotid body.
Placing the ablation element (e.g., radiofrequency electrode) at a suitable location for carotid body ablation may be facilitated by a structure at a distal region of an ablation device (e.g., endovascular catheter) that comprises two arms configured to couple with a carotid bifurcation. The structure comprising two arms may comprise an ablation element on one arm or an ablation element on each of the two arms, or multiple ablation elements on one or each of the arms. The ablation element(s) may be positioned on the arms such that when the structure is coupled to a carotid bifurcation the ablation elements are placed at a suitable location (e.g., at or between about 0 to 15 mm, 4 to 15 mm, or 4 to 10 mm from a carotid bifurcation on an inner wall of an external carotid artery and internal carotid artery and within a vessel wall arc having an arc length of about 25% of the vessel circumference facing the opposing ablation element) on a target ablation site for effective carotid body ablation. The structure may further facilitate apposition of ablation element(s) with tissue.
Devices have been conceived that couple with a carotid bifurcation to facilitate orientation, positioning and apposition of one or more ablation elements at a target ablation site or sites suitable for carotid body ablation. The devices may be configured to measure tissue impedance across an intercarotid septum.
In another exemplary procedure a location of periarterial space associated with a carotid body is identified, then an ablation element is placed against the interior wall of a carotid artery adjacent to the identified location, then ablation parameters are selected and the ablation element is activated thereby ablating the carotid body, whereby the position of the ablation element and the selection of ablation parameters provides for ablation of the carotid body without substantial collateral damage to adjacent functional structures.
In further example the location of the periarterial space associated with a carotid body is identified, as well as the location of important non-target nerve structures not associated with the carotid body, then an ablation element is placed against the interior wall of a carotid artery adjacent to the identified location, ablation parameters are selected and the ablation element is then activated thereby ablating the carotid body, whereby the position of the ablation element and the selection of ablation parameters provides for ablation of the target carotid body without substantial collateral damage to important non-target nerve structures in the vicinity of the carotid body.
Selectable carotid body ablation parameters may include ablation element temperature, duration of ablation element activation, ablation power, ablation element force of contact with a vessel wall, ablation element size, ablation modality, and ablation element position within a vessel.
The location of the perivascular space associated with a carotid body may be determined by means of a non-fluoroscopic imaging procedure prior to carotid body ablation, where the non-fluoroscopic location information is translated to a coordinate system based on fluoroscopically identifiable anatomical and/or artificial landmarks.
A function of a carotid body may be stimulated (e.g., excited with electric signal or chemical) and at least one physiological parameter is recorded prior to and during the stimulation, then the carotid body is ablated, and the stimulation is repeated, whereby the change in recorded physiological parameter(s) prior to and after ablation is an indication of the effectiveness of the ablation.
A function of a carotid body may be temporarily blocked and at least one physiological parameter(s) is recorded prior to and during the blockade, then the carotid body is ablated, and the blockade is repeated, whereby the change in recorded physiological parameter(s) prior to and after ablation is an indication of the effectiveness of the ablation.
A device configured to prevent embolic debris from entering the brain may be deployed in an internal carotid artery associated with a carotid body, then an ablation element is placed within and against the wall of an external carotid artery or an internal carotid artery associated with the carotid body, the ablation element is activated resulting in carotid body ablation, the ablation element is then withdrawn, then the embolic prevention device is withdrawn, whereby the embolic prevention device in the internal carotid artery prevents debris resulting from the use of the ablation element form entering the brain.
A method has been conceived in which the location of the perivascular space associated with a carotid body is identified, then an ablation element is placed in a predetermined location against the interior wall of vessel adjacent to the identified location, then ablation parameters are selected and the ablation element is activated and then deactivated, the ablation element is then repositioned in at least one additional predetermine location against the same interior wall and the ablation element is then reactivated using the same or different ablation parameters, whereby the positions of the ablation element and the selection of ablation parameters provides for ablation of the carotid body without substantial collateral damage to adjacent functional structures.
A method has been conceived by which a location of perivascular space associated with a carotid body is identified, an ablation element configured for tissue freezing is placed against an interior wall of a vessel adjacent to the identified location, ablation parameters are selected for reversible cryo-ablation and the ablation element is activated, effectiveness of the ablation is then determined by at least one physiological response to the ablation, and if the determination is that the physiological response is favorable, then the ablation element is reactivated using the ablation parameters selected for permanent carotid body ablation.
A system has been conceived comprising a vascular catheter configured with an ablation element in the vicinity of the distal end, and a connection between the ablation element and a source of ablation energy at the proximal end, whereby the distal end of the catheter is constructed to be inserted into a peripheral artery of a patient and then maneuvered into an internal or external carotid artery using standard fluoroscopic guidance techniques and positioned in a predetermined position at a carotid bifurcation.
A system has been conceived comprising a vascular catheter configured with an ablation element in vicinity of a distal end configured for carotid body ablation and further configured for at least one of the following: neural stimulation, neural blockade, carotid body stimulation and carotid body blockade; and a connection between the ablation element and a source of ablation energy, stimulation energy and/or blockade energy.
A system has been conceived comprising a vascular catheter configured with an ablation element and at least one electrode configured for at least one of the following: neural stimulation, neural blockade, carotid body stimulation and carotid body blockade; and a connection between the ablation element to a source of ablation energy, and a connection between the ablation element and/or electrode(s) to a source of stimulation energy and/or blockade energy.
A system has been conceived comprising a vascular catheter with an ablation element mounted in the vicinity of a distal end configured for tissue heating, whereby, the ablation element comprises at least one electrode and at least one temperature sensor, a connection between the ablation element electrode(s) and temperature sensor(s) to an ablation energy source, with the ablation energy source being configured to maintain the ablation element at a temperature in the range of 36 to 100 degrees centigrade, during ablation using signals received from the temperature sensor(s). For example, in an embodiment the at least one ablation element in contact with blood is maintained at a temperature between 36 and 50 degrees centigrade to minimize coagulation while targeted periarterial tissue is heated to a temperature between 50 and 100 degrees centigrade, such as to 50 to 55 degrees centigrade, to ablate tissue but avoid boiling of water and steam and gas expansion in the tissue.
A system has been conceived comprising a vascular catheter with an ablation element mounted in vicinity of a distal end configured for tissue heating, whereby, the ablation element comprises at least one electrode and at least one temperature sensor and at least one irrigation channel, and a connection between the ablation element electrode(s) and temperature sensor(s) and irrigation channel(s) to an ablation energy source, with the ablation energy source being configured to maintain the ablation element at a temperature in the range of 36 to 100 degrees centigrade during ablation using signals received from the temperature sensor(s) and by providing irrigation to the vicinity of the ablation element. For example, in an embodiment the at least one ablation element in contact with blood is maintained at a temperature between 36 and 50 degrees centigrade to minimize coagulation while targeted periarterial tissue is heated to a temperature between 50 and 100 degrees centigrade to ablate tissue but avoid boiling of water and steam and gas expansion in the tissue.
A carotid artery catheter has been conceived with a user-actuated structure on a distal region, where actuation of the structure is facilitated by a pull wire within the catheter in communication between the distal region and a handle containing an actuator at the proximal end, and an ablation element mounted in the vicinity of the distal end, whereby the user-actuated structure is configured to provide the user with a means for placing the ablation element against the wall of a carotid artery and means to place arms of the catheter on both sides of carotid septum.
A carotid artery catheter has been conceived with a structure comprising at least two arms configured for user actuation on a distal region of the catheter, a radiopaque ablation element mounted on at least one arm of the structure and at least one radiopaque element on the opposite arm of the structure, whereby the structure provides a user with a means for creating apposition between the ablation element against a wall of a carotid artery, and the combination of the radiopaque ablation element and the radiopaque element provide the user with a substantially unambiguous fluoroscopic determination of the location of the ablation element within a carotid artery.
A system for endovascular transmural ablation of a carotid body has been conceived comprising a carotid artery catheter with an ablation element mounted on a distal region of the catheter, a means for pressing the ablation element against a wall of a carotid artery at a specific location, a means for connecting the ablation element to a source of ablation energy mounted at a proximal region of the catheter, and a console comprising a source of ablation energy, a means for controlling the ablation energy, a user interface configured to provide the user with a selection of ablation parameters, indications of the status of the console and the status of the ablation activity, a means to activate and deactivate an ablation, and an umbilical to provide a means for connecting the catheter to the console.
A method has been conceived to reduce or inhibit chemoreflex generated by a carotid body in a human patient, to reduce afferent nerve sympathetic activity of carotid body nerves to treat a sympathetically mediated disease, the method comprising: positioning a catheter in a vascular system of the patient such that a distal section of the catheter is in a lumen proximate to a carotid body of the patient; pressing an ablation element against a wall of the lumen adjacent to the carotid body, supplying energy to the ablation element wherein the energy is supplied by an energy supply apparatus outside of the patient; applying the energy from the energy supply to the ablation element to ablate tissue proximate to or included in the carotid body; and removing the ablation device from the patient; wherein a carotid body chemoreflex function is inhibited or sympathetic afferent nerve activity of carotid body nerves is reduced due to the ablation.
A method has been conceived to treat a patient having a sympathetically mediated disease by reducing or inhibiting chemoreflex function generated by a carotid body including steps of inserting a catheter into the patient's vasculature, positioning a portion of the catheter proximate a carotid body (e.g., in a carotid artery), positioning an ablation element toward a target ablation site (e.g., carotid body, intercarotid septum, carotid plexus, carotid body nerves, carotid sinus nerve), holding position of the catheter, applying ablative energy to the target ablation site via the ablation element, and removing the catheter from the patient's vasculature, wherein the ablative energy is sufficient to cool or heat tissue sufficiently to substantially reduce chemoreflex or afferent nerve signals from the carotid body while avoiding ablation of nearby important non-target nerve structures.
The methods and systems disclosed herein may be applied to satisfy clinical needs related to treating cardiac, metabolic, and pulmonary diseases associated, at least in part, with augmented chemoreflex (e.g., high chemosensor sensitivity or high chemosensor activity) and related sympathetic activation. The treatments disclosed herein may be used to restore autonomic balance by reducing sympathetic activity, as opposed to increasing parasympathetic activity. It is understood that parasympathetic activity can increase as a result of the reduction of sympathetic activity (e.g., sympathetic withdrawal) and normalization of autonomic balance. Furthermore, the treatments may be used to reduce sympathetic activity by modulating a peripheral chemoreflex. Furthermore, the treatments may be used to reduce afferent neural stimulus, conducted via afferent carotid body nerves, from a carotid body to the central nervous system. Enhanced peripheral and central chemoreflex is implicated in several pathologies including hypertension, cardiac tachyarrhythmias, sleep apnea, dyspnea, chronic obstructive pulmonary disease (COPD), diabetes and insulin resistance, and CHF. Mechanisms by which these diseases progress may be different, but they may commonly include contribution from increased afferent neural signals from a carotid body. Central sympathetic nervous system activation is common to all these progressive and debilitating diseases. Peripheral chemoreflex may be modulated, for example, by modulating carotid body activity. The carotid body is the sensing element of the afferent limb of the peripheral chemoreflex. Carotid body activity may be modulated, for example, by substantially ablating a carotid body or afferent nerves emerging from the carotid body. Such nerves can be found in a carotid body itself, in a carotid plexus, in an intercarotid septum, in periarterial space of a carotid bifurcation and internal and external carotid arteries. Therefore, a therapeutic method has been conceived that comprises a goal of restoring or partially restoring autonomic balance by reducing or removing carotid body input into the central nervous system.
One aspect of the disclosure is an endovascular carotid septum ablation catheter comprising first and second diverging arms, the first arm comprising an ablation element and configured so that the ablation element is in contact with a carotid septal wall in one of an external carotid artery and an internal carotid artery when the catheter is coupled with a common carotid artery bifurcation, the second arm configured to be disposed in the other of the internal carotid artery and external carotid artery when the catheter is coupled with the bifurcation.
One aspect of the disclosure is an endovascular carotid septum ablation catheter comprising first and second diverging arms, the first arm comprising a first ablation element and configured so that the first ablation element is in contact with an external carotid artery wall when the catheter is coupled with a common carotid artery bifurcation, the second arm comprising a second ablation element and configured so that the second ablation element is in contact with an internal carotid artery when the catheter is coupled with the bifurcation, wherein the first and second ablation elements are positioned on the first and second arms so that when the catheter is coupled with the bifurcation, a straight line passing through the first and second ablation elements passes through a carotid septum.
One aspect of the disclosure is a method of ablating a carotid septum, comprising advancing a first diverging arm of an ablation catheter into an external carotid artery and a second diverging arm of the ablation catheter into an internal carotid artery so that a first ablation element on the first diverging arm is in apposition with a carotid septum wall in the external carotid artery and a second ablation element on the second diverging arm is positioned in the internal carotid artery; and ablating carotid septal tissue by delivering ablation energy between the first and second ablation elements so that the ablation energy passes through a carotid septum.
In the following detailed description, reference is made to the accompanying drawings, which form a part hereof, and in which is shown by way of illustration exemplary embodiments in which the disclosure may be practiced. These embodiments are described in sufficient detail to enable those skilled in the art to practice the inventions, and it is to be understood that the embodiments may be combined, or that other embodiments may be utilized and that structural, logical and electrical changes may be made without departing from the spirit and scope of the present disclosure.
References to “an”, “one”, or “various” embodiments in this disclosure are not necessarily to the same embodiment, and such references contemplate more than one embodiment. The following detailed description provides exemplary embodiments.
Systems, devices, and methods have been conceived for carotid body ablation (that is, full or partial ablation of one or both carotid bodies, carotid body nerves, intercarotid septums, or peripheral chemoreceptors) to treat patients having a sympathetically mediated disease (e.g., cardiac, renal, metabolic, or pulmonary disease such as hypertension, congestive heart failure, atrial fibrillation, ventricular tachycardia, dyspnea, sleep apnea, sleep disordered breathing, diabetes, insulin resistance, atrial fibrillation, chronic kidney disease, polycystic ovarian syndrome, post MI mortality) at least partially resulting from augmented peripheral chemoreflex (e.g., peripheral chemoreceptor hypersensitivity, peripheral chemosensor hyperactivity), heightened sympathetic activation, or an unbalanced autonomic tone.
A reduction of peripheral chemoreflex or reduction of afferent nerve signaling from a carotid body (CB) resulting in a reduction of central sympathetic tone is a main therapy pathway of the methods described herein. Higher than normal chronic or intermittent activity of afferent carotid body nerves is considered enhanced chemoreflex. Other therapeutic benefits such as increase of parasympathetic tone, vagal tone and specifically baroreflex and baroreceptor activity, as well as reduction of dyspnea, hyperventilation, hypercapnea, respiratory alkalosis and breathing rate may be expected in some patients. Secondary to reduction of breathing rate additional increase of parasympathetic tone can be expected in some patients. Reduced breathing rate can lead to increased tidal lung volume, reduced dead space and increased efficiency of gas exchange. Reduced dyspnea and reduced dead space can independently lead to improved ability to exercise. Shortness of breath (dyspnea) and exercise limitations are common debilitating symptoms in CHF and COPD. Augmented peripheral chemoreflex (e.g., carotid body activation) leads to increases in sympathetic nervous system activity, which is in turn primarily responsible for the progression of chronic disease as well as debilitating symptoms and adverse events seen in our intended patient populations. Carotid bodies contain cells that are sensitive to partial pressure of oxygen and carbon dioxide in blood plasma. Carotid bodies also may respond to blood flow, pH acidity, glucose level in blood and possibly other variables. Thus carotid body ablation may be a treatment for patients, for example having hypertension, heart disease or diabetes, even if chemosensitive cells are not activated.
The disclosure herein includes methods of endovascular transmural carotid body ablation, which in some embodiments includes inserting a catheter in the patient's vascular system, positioning a distal region of the catheter in a vessel proximate a carotid body (e.g., in a common carotid artery, internal carotid artery, external carotid artery, at a carotid bifurcation, proximate an intercarotid septum), coupling the distal region of the catheter to a carotid bifurcation, positioning an ablation element proximate to a target site (e.g., a carotid body, afferent nerves associated with a carotid body, a peripheral chemosensor, an intercarotid septum), and delivering an ablation agent from the ablation element to ablate the target site. Exemplary methods and devices configured to perform these methods are described herein.
To inhibit or suppress a peripheral chemoreflex, anatomical targets for ablation (also referred to as target tissue, targeted tissue, target ablation sites, or target sites) may include at least a portion of at least one carotid body, an aortic body, nerves associated with a peripheral chemoreceptor (e.g., carotid body nerves, carotid sinus nerve, carotid plexus), small blood vessels feeding a peripheral chemoreceptor, carotid body parenchyma, chemosensitive cells (e.g., glomus cells), tissue in a location where a carotid body is suspected to reside (e.g., a location based on pre-operative imaging or anatomical likelihood), an intercarotid septum, a portion of an intercarotid septum or a combination thereof. As used herein, ablation of a carotid body or carotid body ablation may refer to ablation of any of these target ablation sites.
As shown in
Inventors have conducted extensive human cadaver anatomy studies to understand variability in geometry and relative position of carotid arteries, carotid bodies, carotid nerves, and important non-target nerves. This information is an important part of the inventive step to determine aspects of a procedure and device that could effectively ablate a targeted tissue (e.g., carotid body, carotid body nerves, substantial portion of a carotid body) while safely avoiding iatrogenic injury of important non-target nerves. Inventors have discovered that a volume of tissue, which is referred to herein as an intercarotid septum, carotid septum, or septum, may be a suitable target for ablation in a carotid body ablation (“CBA”) procedure. Endovascular catheter assemblies, such as those described herein, were designed to be configured to ablate at least a significant portion of, and containing an ablation within or substantially within, an intercarotid septum. An exemplary intercarotid septum 114, shown in
As used herein, a “wall” of an external or internal carotid artery, or any other vessel, is not limited to the endothelial layer, but includes any other tissue or non-tissue associated with the vessel. For example, a wall includes plaque or any other material deposited thereon. As used herein, a “wall” of a blood vessel is anything that at least partially defines the lumen through which blood flows. For example, when an electrode is in apposition with a wall of a blood vessel, it may be in contact with an endothelial layer, plaque, etc.
Carotid body nerves are anatomically defined herein as carotid plexus nerves 122 (see
An ablation may be focused exclusively on targeted tissue, or be focused on the targeted tissue while safely ablating tissue proximate to the targeted tissue (e.g., to ensure the targeted tissue is ablated or as an approach to gain access to the targeted tissue). An ablation may be as big as a peripheral chemoreceptor (e.g., carotid body or aortic body) itself, somewhat smaller, or bigger and can include tissue surrounding the chemoreceptor such as blood vessels, adventitia, fascia, small blood vessels perfusing the chemoreceptor, or nerves connected to and innervating the glomus cells. An intercarotid plexus or carotid sinus nerve may be a target of ablation with an understanding that some baroreceptor nerves will be ablated together with carotid body nerves. Baroreceptors are distributed in the human arteries and have high degree of redundancy.
Tissue may be ablated to inhibit or suppress a chemoreflex of only one of a patient's two carotid bodies. Alternatively, a carotid body ablation procedure may involve ablating tissue to inhibit or suppress a chemoreflex of both of a patient's carotid bodies. For example a therapeutic method may include ablation of one carotid body, measurement of resulting chemosensitivity, sympathetic activity, respiration or other parameter related to carotid body hyperactivity and ablation of the second carotid body if needed to further reduce chemosensitivity following unilateral ablation. The decision to ablate one or both carotid bodies may be based on pre-procedure testing or on patient's anatomy.
An embodiment of a therapy may substantially reduce chemoreflex without excessively reducing the baroreflex of the patient. The proposed ablation procedure may be targeted to substantially spare the carotid sinus, baroreceptors distributed in the walls of carotid arteries (e.g., internal carotid artery), and at least some of the carotid sinus baroreceptor nerves that conduct signals from said baroreceptors. For example, the baroreflex may be substantially spared by targeting a limited volume of ablated tissue possibly enclosing the carotid body, tissues containing a substantial number of carotid body nerves, tissues located in periadventitial space of a medial segment of a carotid bifurcation, or tissue located at the attachment of a carotid body to an artery. Said targeted ablation is enabled by visualization of the area or carotid body itself, for example by CT, CT angiography, MRI, ultrasound sonography, IVUS, OCT, intracardiac echocardiography (ICE), trans-esophageal echocardiography (TEE), fluoroscopy, blood flow visualization, or injection of contrast, and positioning of an instrument in the carotid body or in close proximity while avoiding excessive damage (e.g., perforation, stenosis, thrombosis) to carotid arteries, baroreceptors, carotid sinus nerves or other important non-target nerves such as vagus nerve or sympathetic nerves located primarily outside of the carotid septum. CT angiography and ultrasound sonography have been demonstrated to locate carotid bodies in most patients. Thus imaging a carotid body before ablation may be instrumental in (a) selecting candidates if a carotid body is present, large enough and identified and (b) guiding therapy by providing a landmark map for an operator to guide an ablation instrument to the carotid septum, center of the carotid septum, carotid body nerves, the area of a blood vessel proximate to a carotid body, or to an area where carotid body itself or carotid body nerves may be anticipated. Note that although a landmark map may be useful, the need for it may be reduced or eliminated by using devices configured to create and contain an ablation within an intercarotid septum, such as the devices disclosed herein, therefor reducing costly pre-procedural planning and operator dependency on following a landmark map. It may also help exclude patients in whom the carotid body is located substantially outside of the carotid septum in a position close to a vagus nerve, hypoglossal nerve, jugular vein or some other structure that can be endangered by ablation. In one embodiment only patients with carotid body substantially located within the intercarotid septum are selected for ablation therapy. Pre-procedure imaging can also be instrumental in choosing the right catheter depending on a patient's anatomy. For example a catheter with more space between arms can be chosen for a patient with a wider septum.
Once a carotid body is ablated, surgically removed, or denervated, the carotid body function (e.g., carotid body chemoreflex) does not substantially return in humans (in humans aortic chemoreceptors are considered undeveloped). To the contrary, once a carotid sinus baroreflex is removed (such as by resection of a carotid sinus nerve) it is generally compensated, after weeks or months, by the aortic or other arterial baroreceptor baroreflex. Thus, if both the carotid chemoreflex and baroreflex are removed or substantially reduced, for example by interruption of the carotid sinus nerve or intercarotid plexus nerves, baroreflex may eventually be restored while the chemoreflex may not. The consequences of temporary removal or reduction of the baroreflex can be in some cases relatively severe and require hospitalization and management with drugs, but they generally are not life threatening, terminal or permanent. Thus, it is understood that while selective removal of carotid body chemoreflex with baroreflex preservation may be desired, it may not be absolutely necessary in some cases.
The term “ablation” may refer to the act of altering tissue to suppress or inhibit its biological function or ability to respond to stimulation permanently or for an extended period of time (e.g., greater than 3 weeks, greater than 6 months, greater than a year, for several years, or for the remainder of the patient's life). For example, ablation may involve, but is not limited to, thermal necrosis or irreversible electroporation of target tissue cells.
Carotid Body Ablation (“CBA”) herein refers to ablation of a target tissue wherein the desired effect is to reduce or remove the afferent neural signaling from a chemosensor (e.g., carotid body) or reducing a chemoreflex. Chemoreflex or afferent nerve activity cannot be directly measured in a practical way, thus indexes of chemoreflex such as chemosensitivity can sometimes be used instead. Chemoreflex reduction is generally indicated by a reduction of an increase of ventilation and respiratory effort per unit of blood gas concentration, saturation or blood gas partial pressure change or by a reduction of central sympathetic nerve activity in response to stimulus (such as intermittent hypoxia or infusion of a drug) that can be measured directly. Sympathetic nerve activity can be assessed indirectly by measuring activity of peripheral nerves leading to muscles (MSNA), heart rate (HR), heart rate variability (HRV), production of hormones such as renin, epinephrine and angiotensin, and peripheral vascular resistance. All these parameters are measurable and their change can lead directly to the health improvements. In the case of CHF patients blood pH, blood PCO2, degree of hyperventilation and metabolic exercise test parameters such as peak VO2, and VE/VCO2 slope are also important. It is believed that patients with heightened chemoreflex have low VO2 and high VE/VCO2 slope measured during cardiopulmonary stress test (indexes of respiratory efficiency) as a result of, for example, tachypnea and low blood CO2. These parameters are also related to exercise limitations that further speed up patient's status deterioration towards morbidity and death. It is understood that all these indexes are indirect and imperfect and intended to direct therapy to patients that are most likely to benefit or to acquire an indication of technical success of ablation rather than to proved an exact measurement of effect or guarantee a success. It has been observed that some tachyarrhythmias in cardiac patients are sympathetically mediated. Thus, carotid body ablation may be instrumental in treating reversible atrial fibrillation and ventricular tachycardia.
In the context of this disclosure ablation includes denervation, which means destruction of nerves or their functional destruction, meaning termination of their ability to conduct signals. Selective denervation may involve, for example, interruption of afferent nerves from a carotid body while substantially preserving nerves from a carotid sinus, which conduct baroreceptor signals. Another example of selective denervation may involve interruption of nerve endings terminating in chemo sensitive cells of carotid body, a carotid sinus nerve, or intercarotid plexus which is in communication with both a carotid body and some baroreceptors wherein chemoreflex or afferent nerve stimulation from the carotid body is reduced permanently or for an extended period of time (e.g., years) and baroreflex is substantially restored in a short period of time (e.g., days or weeks). As used herein, the term “ablate” refers to interventions that suppress or inhibit natural chemoreceptor or afferent nerve functioning, which is in contrast to electrically neuromodulating or reversibly deactivating and reactivating chemoreceptor functioning (e.g., with an implantable electrical stimulator/blocker).
Carotid body ablation may include methods and systems for the thermal ablation of tissue via thermal heating mechanisms. Thermal ablation may be achieved due to a direct effect on tissues and structures that are induced by the thermal stress. Additionally or alternatively, the thermal disruption may at least in part be due to alteration of vascular or peri-vascular structures (e.g., arteries, arterioles, capillaries or veins), which perfuse the carotid body and neural fibers surrounding and innervating the carotid body (e.g., nerves that transmit afferent information from carotid body chemoreceptors to the brain). Additionally or alternatively thermal disruption may be due to a healing process, fibrosis, or scarring of tissue following thermal injury, particularly when prevention of regrowth and regeneration of active tissue is desired. As used herein, thermal mechanisms for ablation may include both thermal necrosis or thermal injury or damage (e.g., via sustained heating, convective heating or resistive heating or combination). Thermal heating mechanisms may include raising the temperature of target neural fibers above a desired threshold, for example, above a body temperature of about 37° C. e.g., to achieve thermal injury or damage, or above a temperature of about 45° C. (e.g., above about 60° C.) to achieve thermal necrosis. It is understood that both time of heating, rate of heating and sustained hot or cold temperature are factors in the resulting degree of injury.
In addition to raising temperature during thermal ablation, a length of exposure to thermal stimuli may be specified to affect an extent or degree of efficacy of the thermal ablation. For example, the length of exposure to thermal stimuli may be for example, longer than or equal to about 30 seconds, or even longer than or equal to about 2 minutes. Furthermore, the length of exposure can be less than or equal to about 10 minutes, though this should not be construed as the upper limit of the exposure period. A temperature threshold, or thermal dosage, may be determined as a function of the duration of exposure to thermal stimuli. Additionally or alternatively, the length of exposure may be determined as a function of the desired temperature threshold. These and other parameters may be specified or calculated to achieve and control desired thermal ablation.
In some embodiments, ablation of carotid body or carotid body nerves may be achieved via direct application of ablative energy to target tissue. For example, an ablation element may be applied at least proximate to the target, or an ablation element may be placed in a vicinity of a chemosensor (e.g., carotid body). In other embodiments, thermally-induced ablation may be achieved via indirect generation or application of thermal energy to the target neural fibers, such as through application of an electric field (e.g., radiofrequency, alternating current, and direct current) to the target tissue. For example, thermally induced ablation may be achieved via delivery of a pulsed or continuous thermal electric field to the target tissue such as RF and pulsed RF, the electric field being of sufficient magnitude or duration to thermally induce ablation of the target tissue (e.g., to heat or thermally ablate or cause necrosis of the targeted tissue). Additional and alternative methods and apparatuses may be utilized to achieve ablation, as described hereinafter.
An endovascular catheter for transmural ablation may be delivered into a patient's vasculature via percutaneous introduction into a blood vessel, for example a femoral, radial, brachial artery or vein, or even via a cervical or temporal artery approach into a carotid artery. For example,
Alternatively, a guide wire may be delivered through a patient's vasculature to carotid arteries and a sheath may be delivered over the guide wire. The sheath may or may not have steering or deflectable capabilities. For example, if a sheath is delivered over a wire to a common carotid artery and an ablation catheter is delivered through the sheath, deflection may facilitate positioning of the ablation catheter at a target site and reduce unnecessary contact with non-target portions of carotid vasculature, thus reducing risk of dislodging plaque. An ablation catheter may have deflection capabilities to facilitate positioning at a target site, in which case it may not be necessary for a sheath to have deflection capabilities.
Devices have been conceived for endovascular transmural carotid body ablation comprising two arms, herein referred to as Endovascular Transmural Ablation Precision-Grip (ETAP) catheters, which may also be referred to herein as Endovascular Transmural Ablation Forceps (ETAF) catheters. Embodiments of ETAP catheters disclosed herein comprise a distal end and a proximal end, wherein the distal end is inserted into a patient's vasculature and delivered proximate a target site, and the proximal end is maintained outside the patient's body. In some embodiments the distal region of an ETAP catheter comprises ablation element(s) positioned on two arms (which may also be referred to herein as splines, diverging structures, diverging arms, fingers, bifurcated structures, prongs, together as forceps arms, or individually as a forceps arm) in a configuration that positions at least one ablation element in an internal carotid artery and at least one second ablation element in an external carotid artery on an intercarotid septum at a position relative to a target carotid body or nerves associated with a carotid body that is suitable for carotid body ablation. Ablation elements may be, for example, a pair of bipolar radiofrequency electrodes; a pair of bipolar irreversible electroporation electrodes; more than two electrodes; or a single monopolar radiofrequency electrode and second electrode used as current return or to measure properties of target tissue such as electrical impedance, temperature, or blood flow. Apposition of one or both of the ablation elements with an intercarotid septum is achieved by causing a closing force of the arms, for example via resilient forces of the arms or a mechanical actuation means. Structural aspects of catheters may be described herein as bifurcated, but it is not intended that catheter be limited to only two of the structures. For example, when bifurcated is used to describe structural components, at least two are present, and there may be more than two.
The method and devices herein take advantage of natural anatomy to position ablation elements at a suitable position for carotid body ablation. For example, the diverging arms of an ETAP catheter, or another aspect of the catheter, may be configured to couple with a carotid bifurcation by advancing one finger into an internal carotid artery and the other finger into an external carotid artery until the region where the arms diverge (divergence point) and the saddle, or apex, of the bifurcation contact and further advancement the catheter into a patient's vasculature is physically impeded by the contact. The dimensions of the arms and position of ablation elements on the arms are configured so the ablation elements will be positioned relative to the saddle of the bifurcation as shown in
In some situations, common, internal and external carotid arteries may be aligned in a plane or close to a plane. However, carotid artery geometry is highly variable and in many situations the common, internal and external carotid arteries may be out of plane with one another. An ETAP catheter may comprise arms that are configured to adjust alignment with one another and with the catheter shaft in order to become aligned with carotid arteries that are out of plane. For example, the arms may pivot on a catheter shaft to accommodate out of plane vessel geometry. Alternatively, arms may comprise an elastic flexibility that allows them to bend in any radial direction to conform to vessels that are out of plane. In such an embodiment, the arms may be flexible enough to deform or deflect and adjust to vessel direction while elastic or resilient enough to apply ablation element contact force suitable for applying ablation energy. For example, the arms may comprise a structural segment that provides flexibility and elasticity. A structural segment may be, for example, a Nitinol or stainless steel spring wire with a round cross section and a diameter of about 0.004″ to 0.018″ (e.g., about 0.006″ to 0.012″). In such an embodiment, a first finger may be placed in an internal carotid artery and a second finger in an external carotid artery, closing force may be applied, and if the vessels are not in plane the arms can be configured to flex as the ablation elements contact vessel walls and slide toward two positions having approximately a shortest distance between them at a desired height from a carotid bifurcation saddle, that is to say the ablation elements are self-aligned. In these embodiments the fingers are configured to flex independently of one another with respect to the catheter shaft.
In addition to a self-aligning action, the closing force of the arms, weather passive or active, also provides contact force between ablation elements and target vessel walls of an intercarotid septum. Too little closing force may result in undesired electrode contact such as intermittent contact, contact along only part of the length of an electrode, movement of electrodes during energy delivery, unpredictable temperature measurement, excessively small ablation, or unpredictable ablation formation. Too strong a closing force may result in excessive trauma to vessel walls, plaque dislodgement, excessively large ablation, unpredictable ablation formation, or difficulty retracting the arms into a sheath. Closing force also impacts electrode contact area, as greater force within a range increases the contact area between the ablation element and the wall by pressing an electrode into distensible vessel tissue. For example, electrode contact area may be in a range of about 4 mm2 to about 7.5 mm2 per electrode. A closing force of a catheter arm may be characterized using force testing. For example, a mechanical test as shown in
Ablation element 68 may be configured as an electrode whereby inner surface 80 may be bare metal and outer surface 81 may be electrically insulated. Ablation element 68 may be configured as an electrode whereby a portion of outer surface 81 is bare metal and where inner surface 80 is may be insulated. Ablation element 68 may be configured as an electrode with a temperature sensor 82 mounted within the walls of ablation element 68 or attached to a surface of an electrode or proximate an electrode. Temperature sensor lead wire(s) 83 connect temperature sensor 82 to electrical connector 75 of proximal terminal 64 through central tube 70. Ablation element 69 may be configured as an electrode whereby inner surface 84 may be bare metal and outer surface 85 may be insulated. Ablation element 69 may be configured as an electrode whereby a portion of outer surface 85 is bare metal and where inner surface 84 is may be insulated. Ablation element 69 may be configured as an electrode with a temperature sensor 82 mounted within the walls of ablation element 69. Temperature sensor lead wire(s) 83 connect temperature sensor 82 to electrical connector 75 of proximal terminal 64 through central tube 70. Ablation element 68 may be solid metal, or a polymer/metal composite structure or a ceramic/metal composite structure. Ablation element 69 may also be solid metal, or a polymer/metal composite structure or a ceramic/metal composite structure. Arms 66 and 67 may be fabricated from a super-elastic metallic alloy such as Nitinol, but may be fabricated from another metallic alloy, or may be a composite structure. Central tube 70 may be fabricated from a super-elastic alloy, or may be constructed from another metallic alloy, or may be composite structure. Central tube 70 is configured to work in conjunction with arms actuator 74 a to apply a tensile force on the arms assembly 62 for advancement of arms sheath 63 over arms assembly 62 to close arms, and to apply a compressive force on the arms assembly 62 to withdraw arms sheath 63 from over arms assembly 62 to open arms or to apply torque to rotate arms. Central tube 70 can be configured as an electrical conduit between ablation element 68 or ablation element 69 and electrical connector 75. It may include guide wire lumens and irrigation fluid delivery lumens. Alternatively, center tube 70 may be configured with wires to connect ablation element 68 or ablation element 69 to electrical connector 75. Electrical connector 75 is configured to connect an electrode surface on ablation element 68 or an electrode surface of ablation element 69 to one pole of an electrical generator. Electrical connector 75 may be configured to connect an electrode surface of ablation element 68 to one pole of an electrical generator, and to connect an electrode surface of ablation element 69 to the opposite pole of an electrical generator. An electrical generator may be configured for connection to electrical connector 75 and to supply RF ablation current to an electrode surface on ablation element 68 or an electrode surface on ablation element 69. The electrical generator may be further configured to provide an electrode surface on ablation element 68 with neural stimulation current or neural blockade current or to provide an electrode surface on ablation element 69 with neural stimulation current or neural blockade current. The electrical generator may be further configured to provide impedance measurement. Impedance can be measured using the same frequency generator RF at a low current/voltage/power compared to ablation power. Ablation elements 68 and 69 may be constructed in a manner where their fluoroscopic appearance is distinct to provide the user with an ability to distinguish ablation element 68 from ablation element 69. Ablation elements 68 and 69 may be of same size and surface area or different. For example it can be desired to have an electrode 69 in an internal carotid artery with a larger surface area than electrode 68 placed in an external carotid artery to achieve lower current density in the internal carotid artery where risk of embolization, char and clot is more severe. Arm 66 placed in an external carotid artery may be longer than arm 67 placed in an internal carotid artery to allow for better fixation and more distal lesion while taking advantage of lower embolization risk from manipulations in an external carotid artery.
In alternative embodiments arms 66 and 67 are biased, or pre-formed, in more of a closed configuration such that they can be slid over a carotid bifurcation, as is described below with reference to alternative embodiments. In some embodiments they can be biased to a completely closed configuration in which arms 66 and 67 are engaged with each other or very nearly touching each other (e.g., 1 mm or less apart).
An alternative embodiment of an ETAP catheter 359, as shown in
Exemplary configurations of the arms 364 and 365 are shown in
In any of the embodiments herein, one or more of the ablation elements may be electrodes configured for radiofrequency ablation, bipolar radiofrequency ablation, or irreversible electroporation. For example, electrodes configured for bipolar radiofrequency ablation may be of a size that can create an effective thermal ablation contained approximately within an intercarotid septum when the electrodes are placed in an internal and external carotid artery on an intercarotid septum and a radiofrequency signal of predefined characteristics is delivered. Electrodes that are too small may create a lesion that is uncontrolled, too small, or too hot due to high electrical impedance caused by tissue coagulation or charring. Electrodes that are too large may create a lesion that is uncontrolled, too large, or too cool due to unfocused concentration of RF over a large surface area. Additionally, the size of a sheath used to deliver a catheter limits electrode diameter. In any of the embodiments herein, the ablation devices may comprise electrodes, for example, with a surface area in a range of about 8 to about 65 mm2 (e.g., about 12 to 17 mm2). For example, as shown in some of the embodiments herein (e.g.,
Electrodes may be made (e.g., machined) from an electrically conductive material such as stainless steel, copper, gold, platinum-iridium, or alloy such as 90% Au 10% Pt. For example, electrodes may be machined in a shape of a circular cylinder with hemispherical domed end with a hollow cavity, which may be used to position sensors (e.g., temperature sensor, impedance sensor), connect to structural segments of ETAP catheter arms, or for cooling irrigation. Other shapes may be used for electrodes such as elliptical cylinder, cuboids, ribbon or complex shapes.
Ablation elements may be positioned on ETAP catheter arms so they are aligned with a force vector applied by the arms. For example, a structural segment of an arm that applies a closing force toward the opposite arm may be positioned in the center of a cylindrical electrode. In this example a force vector applied by the arm is approximately equal to a force vector applied by the electrode. When these electrodes are positioned in an internal and external carotid artery and closing force is applied by the arms the electrodes may settle within the vessels approximately at two positions having the shortest distance between them (e.g., the center of the intercarotid septum). Alternatively, an ablation element may be positioned on an ETAP catheter arm so it is offset from a force vector applied by the arm. For example, an ablation element may be positioned at a distance (e.g., about 1 to 3 mm, 2 mm) perpendicular to the force vector applied by the arm so that when positioned the ablation element settles at a distance from the center of the intercarotid septum toward the medial or lateral side. A structural segment of an arm may have a preformed shape comprising a shaft that applies a force vector approximately toward the opposite arm and an extension that holds the ablation element at a distance perpendicular to the force vector. This embodiment may allow the creation of an ablation that is offset from the center of the septum toward the medial or lateral side of the septum. This may be advantageous if the position of a target (e.g., carotid body or carotid body nerves) or non-target nerves is known and an offset ablation would be more effective or safe.
Electrodes may be configured for improved consistency of alignment and surface contact with vessel walls. Consistent electrode alignment and surface contact with internal and external carotid arteries may produce more repeatable and predictable lesions contained substantially in an intercarotid septum and thus greater efficacy and safety.
In a mere example, arm 1002 is a round superelastic Nitinol wire having a diameter in second section 1003 that is about 0.012 inches, and a diameter in first section 1004 of about 0.006 inches to about 0.008 inches. In this example, first section 1004 starts about 1 to about 2 mm proximal to the electrode. First section 1004 with a thickness or diameter need not extend completely to the proximal end of electrode 1006. For example, there can be a small section of arm 1002 immediately proximal to electrode 1006 with a thickness or diameter slightly greater than the thickness or diameter of 1004.
Both electrodes in each of the embodiments in
In some embodiments the ablation catheter includes one or more coiled electrodes. For example, the electrodes can be made from a tightly wound, coiled conductive wire. Coiled electrodes can be configured with sufficient flexibility such that they may improve the electrode surface contact with vessel walls, such as by conforming to the geometry of the vessel's surface, and self-alignment. A coiled electrode may also distribute current density in proximate tissue, thus potentially avoiding hot spots in the tissue. Well distributed current density may also result in predictable lesion formation in target tissue and may reduce risk of thrombus forming on a vessel surface. In an exemplary embodiment a coiled electrode wire (e.g., round wire made from Nitinol, stainless steel, gold-platinum alloy, platinum-iridium alloy) has a diameter of about 0.008″, and the coil has a pitch of about 0.008″ to 0.012″. The coil may be wrapped around mandrel (e.g., with a diameter of about 0.030″) and held in place with epoxy. The mandrel may have a lumen along its axis and a structural arm wire may be positioned in the lumen.
The electrodes described in any of the embodiments herein (e.g., in
An ETAP catheter may be configured to slide over a carotid bifurcation to place ablation elements in position in an internal and external carotid artery. In some embodiments arms of an ETAP catheter are configured as normally, in un-stressed configurations, open, in which elastically flexible arms are pre-formed to hold ablation elements apart when unconstrained by a sheath or vessel anatomy. The embodiment shown in
In some embodiments herein in which at least one diverging arm (with or without an ablation element thereon) is configured to make passive apposition with a carotid septum wall in a desired or known location in an external or internal carotid artery, the arm is configured so that when some aspect of the catheter is coupled, or engaged with, a common carotid artery bifurcation, a portion of the arm will be in contact with the septal wall in the desired or known location. That is, the arm is configured so that the act of engaging some aspect of the catheter with the bifurcation causes a portion of the arm (e.g., an electrode thereon) to be in contact with the septal wall in the desired or known location. The arm can still be configured to be in contact with the septal wall when some aspect of the catheter has not yet engaged the bifurcation, but a portion of the arm may not yet be in the known or desired location until the engagement occurs.
Geometrical characteristics of carotid bifurcation or intercarotid septums may vary, for example, septum width, bifurcation angle, and vessel or septum shape. Regardless of whether the catheter is configured for active or passing closing forces, the geometrical characteristics of carotid bifurcation or intercarotid septums can interfere with the contact between an electrode and target tissue. For example, a U-shaped surface, convex surface or irregular surface may cause substantially straight arms to contact the surface, which may reduce or impede electrode contact with the surface. In some embodiments an ETAP catheter may therefore include a distal region comprising one or more arms having pre-formed, or unstressed, shapes or configurations that facilitate consistency of electrode contact when used on various carotid bifurcation and septum geometries.
The preformed, or unstressed, shape of the distal region may comprise a predetermined aperture between the arms that allows capture of a carotid septum and advancement over the septum in sliding apposition to walls of the septum. The predetermined aperture may also be configured to prevent the arms from opening excessively, which may cause undesirable contact with non-target regions of the carotid vessel walls. For example, arms may comprise superelastic or elastic structural members 490 having a preformed shape having an outward arch that may avoid or reduce contact between the arms and the vessel surface. The arms may be constrained to undeployed configuration when contained within a delivery sheath. The arms may elastically deform to the preformed shape when deployed from the delivery sheath.
The catheter shown in
Another embodiment of an elastic structural member 720 with a preformed, or unstressed, shape or configuration configured to facilitate consistency of electrode contact when used on various carotid bifurcation geometries is shown in
In the embodiment shown in
On the elastic structural member in
An arch or other clearance portion, in any of the embodiments herein, may provide multiple functions. For example, when the arms are advanced over an intercarotid septum the flexibility of the bend 725, arch 726 and optional bend 730 allows the arms to open; when the arms are advanced over an intercarotid septum the elasticity of the bend 725, arch 726 and optional bend 730 applies a closing force that provides a contact force between electrodes and vessel walls, and also facilitates self-alignment of electrodes within a desired target region 136 and 137 as shown in
On the elastic structural member in
The distal regions 733 of the arms may be configured to be more flexible or less elastically resilient that the proximal portion of the arms disposed proximal to regions 733. For example, the elastic structural member may be made for example from a Nitinol wire, and may have a thinner diameter in region 733 distal of the electrode than the diameter of the region proximal to the electrode. The relative thickness of the distal region provides it with more flexible or less elastically resilience than the proximal regions. In some embodiments the structural member is a round superelastic Nitinol wire with a diameter in region proximal to the electrode between about 0.010″ and about 0.014″, such as about 0.012.″ In the distal region 733 the wire can be, for example, ground down to about 0.003″ to about 0.009,″ such as about 0.006″. In alternative embodiments, separate wires are used for the regions of the structural member distal and proximal to the electrode, respectively, and connected or secured to or relative to one another in the electrode lumen.
The structural member in
An ETAP catheter may comprise a means to actively control arms configuration, that is, to open, close, adjust a degree of openness, or tighten the arms. For example, arms may be elastically predisposed to a substantially closed configuration (e.g., such that ablation elements mounted on the arms are held less than about 4 mm apart, less than about 2 mm apart, about 0 mm apart, or less than 0 mm apart) and opened by user actuation; or the arms may be elastically predisposed to an open configuration (e.g., such that ablation elements mounted on the arms are held greater than about 6 mm apart, such as between about 10 to 20 mm apart) and closed by user actuation; or the arms may be both opened and closed by user actuation. Such user control of an open or closed configuration of an ETAP catheter may allow ablation elements mounted to arms to be placed on a target site (e.g., both sides of an intercarotid septum at an appropriate height from a carotid bifurcation for effective and safe CBM) with minimal intrusion of non-target regions of the vessel wall. For example, the arms may be placed without sliding over a vessel wall. This may be particularly important to reduce a risk of dislodging atheromatous plaque, if it exists in the area, which could potentially flow up the internal carotid artery to the brain. Embodiments of ETAP catheters having open/close actuation as disclosed herein may comprise elastically flexible arms that are substantially straight (for example as shown in
An example embodiment of an ETAP catheter having a means for actively controlling an open or closed configuration is shown in
In another example embodiment shown in
As shown in
Another embodiment having arms preformed to be normally open that may be closed via application of tension in a pull wire is shown in
An embodiment of an ETAP catheter configured to open via actuation of a pull wire 807 is shown in
The catheter in
An alternative embodiment of an ETAP catheter configured to be opened and closed by a user is shown in
Controllable Deflection with Open/Close Actuation
An ETAP catheter may be configured to have controllable deflection, that is, user actuated bending of a portion of the catheter in a distal region. As described earlier, an ETAP catheter may be delivered through a sheath to a common carotid artery 102 where it may be deployed from the sheath. Carotid artery anatomy is quite variable from patient to patient or side to side and alignment of a common carotid artery with internal and external carotid arteries may involve a range of angles or planarity. Controllable deflection may allow a user to account for variable anatomy by aiming the distal end of the catheter at a carotid bifurcation prior to advancing it on to the intercarotid septum. Controllable deflection may allow a user to place ablation elements on target sites while minimizing contact with vessel walls, which may be especially important in the presence of atheromatous plaque to reduce risk of dislodging plaque. Once ablation elements are generally placed on target sites, controllable deflection may allow a user to adjust an angle of the distal section of a catheter to improve electrode wall contact. Controllable deflection may be configured to deflect in more than one plane (multi-planar) or in one plane (uni-planar), and deflection may be toward one side (unilateral) or two sides (bilateral) of a plane. Multi-planar deflection may be achieved, for example, with multiple pull wires. For example, with four pull wires, pulling any one of the wires will deflect the catheter in that direction. Pulling two adjacent wires will deflect the catheter in the 45 degree direction between the two wires.
In an example embodiment, an ETAP catheter may be configured to deflect toward both sides of a single plane and said plane may be coplanar with open and close movement of catheter arms. Such an embodiment may be delivered through a sheath to a common carotid artery, rotated so the deflection and open/close plane is approximately in plane with a plane created by internal and external carotid arteries, deflected so the distal end is aimed approximately at the carotid bifurcation, opened, advanced over the carotid septum, and closed to place ablation elements in contact with the septum one in the internal carotid artery and one in the external carotid artery. Alternatively, multi-planar deflection may reduce the need for, or amount of, rotating a catheter to align an open/close or arm plane with a bifurcation.
Referring to
The catheter shaft may be made similar to catheter fabrication methods know in the art. For example, the controllably deflectable section may comprise two pull wires positioned on opposite sided of the shaft such that tension in one wire caused by user actuation causes the shaft to deflect toward the side containing the pull wire in tension. The pull wires may be contained in lumens extruded in the catheter shaft and span approximately the full length of the catheter from the distal end to a handle. The handle may comprise a deflection actuator, such as a lever, knob, or dial that pulls one of the two pull wires at a time. The catheter shaft 849 may be made from different durometer materials to provide functionality. For example, the elongate region 851 may comprise a Pebax extrusion with a higher durometer (e.g., about 55 D to 75 D, about 63 D) than the controllably deflectable region 850, which may comprise a Pebax extrusion with a softer durometer (e.g., about 35 D to 55 D, about 40 D) so deflection is limited to the softer controllably deflectable region. In the case of a uni-directional deflection catheter embodiment, a controllably deflectable region may comprise a lumen off-axis to contain a pull wire. Tension in the pull wire would compress the controllably deflectable region causing it to deflect in the direction of the lumen from the axis. In the case of a bi-directional deflection catheter embodiment, at controllably deflectable region may comprise 2 lumens off-access on opposing sides to contain to pull wires. The pull wire lumens in the controllably deflectable region may connect to a single coaxial lumen in the elongate region. The controllable deflection described with respect to
An embodiment of an ETAP catheter, as shown in
A preformed superelastic Nitinol wire 900 is used to function as a first deflection pull wire 901, a second deflection pull wire 902, a first spline structural segment 903, a second spline structural segment 904, a first spline actuation segment 905, and a second spline actuation segment 906. The Nitinol wire 900 may have a diameter of approximately 0.006″ to 0.012″. The Nitinol wire may optionally have a varying diameter to provide desired flexibility or stiffness that varies along its length. As shown the Nitinol wire 900 is slidably positioned in the coaxial lumen 913 of the elongate section 910 then passes in to the first off axis lumen 915 of the controllably deflectable section 911 where it acts as the first deflection pull wire 901. The first deflection pull wire 901 is anchored with a first crimp 921 to a distal end piece 922 at the distal end of the controllably deflectable section. The distal end piece 922 may be made from a rigid radiopaque material such as radiopaque thermoplastic and functions as a radiopaque marker, an anchor for the first and second pull wires, an anchor for the first and second spline structural segments, and provides a protected opening to the coaxial lumen 914. The proximal ends of the deflection pull wires 901 and 902 are connected to an actuator in a handle (not shown). When tension is applied to one of the deflection pull wires the controllably deflectable section 911 compresses on the side of the tensioned wire and deflects toward said side.
The first and second structural segments 903 and 904 are made from the Nitinol wire 900 and may comprise a preformed shape as shown that elastically holds the splines in an open configuration, for example such that the electrodes 923 and 924 are approximately 10 to 20 mm apart, when unconstrained by a sheath and when tension in an open/close pull wire is released. The Nitinol wire 900 forms a 180-degree bend at the distal end of the spine where it is inserted in an electrode 923 and held in place by a friction fitted core 925. The Nitinol wire 900 returns along the spline as a first spline actuation segment 905 and enters through a central opening in the distal end piece 922 to the coaxial lumen 914. In the coaxial lumen the Nitinol wire forms another 180-degree bend to form a second spline actuation segment 906, second spline structural segment 904, and second deflection pull wire 902. In the coaxial lumen 914 the Nitinol wire 900 is connected to an open/close pull wire 927, for example with a crimp 928. The open/close pull wire is slidably contained in the coaxial lumen 914 and 913 and passes to an actuator on a handle (not shown). When tension is applied to the open/close pull wire 927 via the actuator, the first and second spline actuation segments 905 and 906 are pulled into the coaxial lumen 914 while the length of the first and second spline structural segments 903 and 904 remains consistent due to anchoring at the distal end piece 922 and the electrodes 923 and 924, thus causing the splines to move toward a closed configuration. The splines 917 and 918 may be approximately the same length or may be offset so one is longer than the other. For example, a first spline 917 may be about 6 mm long while the second spline 918 is about 11 mm long. Electrical conductors (not shown) may pass from an electrical connector on a proximal region of the catheter, through the catheter shaft and diverging arms to the electrodes.
The embodiment in
Controllable Deflection with Slide on Arms
An example embodiment of an ETAP catheter configured for controllable deflection with a slide-on arm configuration is shown in
The endovascular carotid septum ablation catheter shown in
In the embodiment shown in
In the catheter shown in
Each of the arms in the catheter shown in
The catheter shown in
One or both of the arms can have a coating layer around the arm as is disclosed herein. In some embodiments the coating layer is an insulative material.
As shown in
While not shown, the ablation elements in
In the embodiment in
The catheter in
Any other structure or feature described herein in any other embodiment of an ablation catheter can be incorporated into the catheter shown in
An illustration of an ETAP catheter configured for controllable deflection with a slide-on arm configuration is shown in
In the embodiment shown in
A wire spacer 752 having a cap 754, a column 755, wire grooves 756, and radiopaque marker grooves 757 may be placed in proximal section 721 between both sides of the elastic structural member 720 with the column 755 glued in to the distal region shaft tubing 753, the elastic structural member 720 held in wire grooves 756, and the cap 754 covering the distal opening in the tubing 753. The wire spacer 752 functions to maintain a consistent distance between the two sides of the wire 720 in the proximal section 721, hold radiopaque markers 749, and its cap may provide a rounded, atraumatic surface that may come in to contact with a carotid bifurcation 31 as shown in
Electrically insulative sleeves 750 may cover the elastic structural member 720 and function to provide dielectric strength as well as contain electrical conductors 751. Sleeves 750 may be made from a soft material (e.g., Pebax with a durometer of about 25 D). Electrical conductors 751 may comprise an ablation energy delivery (e.g., radiofrequency or irreversible electroporation) conductor and temperature sensor (e.g., T-type thermocouple) conductors. Electrical conductors 751 may pass through the catheter shaft to the proximal end terminating at an electrical connector, for example on a handle 660.
Ablation elements 743 (e.g., radiofrequency electrodes, irreversible electroporation electrodes) may be placed on the elastic structural member 720 on the electrode-mounting region 729, or on any other arm described herein. Ablation elements 743 may be, for example, electrically conductive (e.g., gold, platinum, stainless steel, or an alloy such as 90% gold 10% platinum) cylinders with a lumen passing through. Ablation elements 743 may have an exposed length 736 of about 0.157″+/−0.002″ (4 mm+/−0.5 mm) and an exposed diameter of about 0.048″+/−0.005″, and an additional mounting length 737 of about 0.030″ to which insulation 750 and 738 may be connected. Ablation elements 743 may comprise an axial lumen of about 0.032″+/−0.002″. Electrode-mounting region 729 of the elastic structural member 720 may be placed in the lumen along with electrical conductors 751. Ablation energy conductors may be electrically connected (e.g., soldered, welded) to an inner surface of the ablation elements 743. For example, a first pole of an electrical circuit connected to a first ablation energy conductor may be connected to a first electrode 737 and an opposing pole of the electrical circuit connected to a second ablation energy conductor may be connected to a second electrode such that the first and second electrodes are in a bipolar configuration. Other conductors 751 may be used for one or more temperature sensors. For example, a copper and constantan conductor may be joined to make a T-type thermocouple positioned in thermal communication with the electrode 743. Once the components are placed in the cavity of the ablation elements 743 empty space in the cavity may be filled, for example with solder, epoxy, thermally conductive epoxy, or radiopaque solder.
Any of the ablation elements can be mounted to any of the arm structures described herein even if it is not specifically stated herein.
In other embodiments the curved profile need not extend the entire length of the electrode. For example, in some embodiments the curved profile does not extend completely to the end of the electrode. In other embodiments the central region can include any length of electrode that has a linear surface in cross-section (i.e., looks like a cylinder in cross section) rather than being curved.
In a mere example, the length of electrode 1100 is about 4 mm, central width 1102 is about 0.048″+/−0.004″, and end width 1103 is about 0.008″+/−0.002″ less than center width 1102. Inner lumen 1101 can be, for example, about 0.016″. While these dimensions are not intended to be limiting, a maximum outer diameter of 0.048″+/−0.004″ may in some instances be preferred in the configuration of the embodiments described by
Electrode 1100 can be secured to any arm described or not described herein in any suitable manner. Electrode 1100 is shown with lumen 1101 along its axis, which can be, for example, about 0.016″, through which the structural members may be mounted along with conductors, electrical insulation, and adhesive (e.g., epoxy). For example, electrode can be mounted onto electrode mounting region 3002 of structural member 3000 in
Electrode 1100, or any other electrode herein, can be made from a biocompatible, electrically conductive material to conduct RF to tissue, and optionally a material of high thermal conductivity to conduct heat from the tissue or electrode to blood flow, and optionally a material that is radiopaque so it can be discerned in a fluoroscopic image. An example material is 90% gold, 10% platinum.
Additionally, electrodes with a curved surface, may facilitate electrode contact that is more consistent when the arm is configured to allow the electrode to be applied to the carotid artery wall over a range of angles, such as parallel to the carotid vessel wall +/− about 10°. In the case of a slide-on embodiment such as those shown in
As shown in
The controllably deflectable section 741, positioned distal to the elongated region, may be approximately 1 cm to 5 cm long (e.g., about 2.54 cm long) with a diameter of about 2 mm and made from extruded Pebax 554 with a durometer that is softer than the elongated region 740, (e.g., about 25 D to 55 D, about 40 D). The controllably deflectable section 741 may comprise a coaxial lumen that contains electrical conductors 751, a first off-axis lumen 555 and a second off-axis lumen 556. Pull wires 553 may be slidably contained in the first and second off-axis lumens. At a distal end of the deflectable region 741 the extrusion 554 may terminate and pull wires 553 may be anchored to the distal end of the deflectable region 741. For example, pull wires 553 may pass through holes in an anchor plate 557 and terminate in a ball 760 or bend that will not pass through the holes in the anchor plate 557. The anchor plate may be for example a relatively rigid material such as a polyimide, polycarbonate or metallic disc. The distal region 742 of the catheter may be connected to the catheter shaft for example by thermally welding distal region shaft tubing 753 to deflectable region tubing 554. When tension is applied to one of the pull wires 553 by pulling a proximal end of the pull wire, for example by manipulating an actuator 661 on a handle 660 as shown in
As shown in
The ablation catheter in
As shown in use in
As is described in more detail herein, the first and second arms are configured such that substantially all contact that occurs between the arms and the walls of the carotid arteries occurs between the ablation elements and the wall. Substantially all contact includes contact that is at least 60% between the ablation elements and the walls, at least 70% between the ablation elements and the walls, at least 80% between the ablation elements and the walls, at least 90% between the ablation elements and the wall, or more. The first and second arm in the catheter in
In the catheter in
As is described in more detail herein, the first and second arms in the embodiment in
The arms in the embodiment in
In the embodiment in
In
The first and second arms of the catheter in
In the embodiment in
The catheter in
The catheter in
In
In
The catheter in
The catheter in
The catheter in
The catheter in
The catheter in
The catheter in
The catheter in
The catheter in
The catheter in
The catheter in
The catheter in
The catheter in
The catheter in
The arm lengths of the catheter in
The ablation element(s) on the catheter in
The arms of the ablation element(s) on the catheter in
The arms in the catheter in
The catheter in
The catheter in
In any of the embodiments herein in which an ablation electrode is configured to be positioned in an external carotid artery to facilitate the ablation method, one or more electrodes can be configured to be positioned within the internal carotid artery. Placement of electrodes in an internal carotid artery can present a risk that if a thrombosis forms on the internal carotid artery wall from the ablation and the thrombus is released from the vessel wall to the blood stream, it creates a risk of brain embolism.
In some embodiments the length of electrode 1146 is about 1.25 to about 2.5 times the length of electrode 1145, although it may be any length greater. In some embodiments it is about 1.5 to about 2 times longer. In this embodiment electrodes 1145 and 1146 have the same or similar diameters, but they need not have. The two electrodes also both have a barrel configuration as described herein, but the electrodes can have any other suitable configuration and any other type of attachment with the arms (e.g., they can be flex circuits). Any other aspect of the catheters herein can be incorporated into this embodiment. For example, any arm configuration can be used for either of arms 1143 and 1144.
In some embodiments electrodes 1157 and 1156 are between about 0.005″ and 0.060″ apart. A small gap may exist between the two electrodes, which can allow them to flex relative to one another. The relative flexing may facilitate passage through a tortuous sheath, such as around tight bends.
In alternative embodiments electrodes differ in a dimension other than length to provide them with different surface areas and hence different abilities to disperse current. For example, one electrode on one arm can have the same length as a second electrode on a second arm, but can have a configuration that gives it greater surface area. For example, one electrode could have a general cylinder shape, while one has a barrel shape, perhaps with a greater central width than embodiments herein. The barrel shaped electrode would have a greater surface area, and thus would be configured to reduce current density more than the generally cylindrically shaped electrode. In another example, one electrode could have an increased surface area by being an expandable electrode mounted to an inflatable balloon. The inflatable balloon may be positioned in an internal carotid artery and occlude blood flow. The expandable electrode may be a metallic foil or flex circuit mounted to the balloon. The second electrode positioned in an external carotid artery may be a barrel electrode such as 1155 having a surface area less than the first electrode. Any aspect of the electrode(s) can be varied to impart the desired dispersion properties. Additionally, any arm described herein can be incorporated into dispersive electrode designs.
Other embodiments of ETAP catheters that may be delivered over a guide wire may comprise guide wire lumens that pass through one or both arms of a catheter. For example, as shown in
An ETAP catheter may be configured for use with two guide wires, in which a first guide wire may be placed in an external carotid artery 29 and a second guide wire is placed in an internal carotid artery 30. Two guide wires may facilitate positioning a distal region of an ETAP catheter at a carotid bifurcation by minimizing or reducing a need to manipulate the catheter thus reducing a risk of trauma to vessels or dislodging of plaque. An example of a two-guide wire ETAP catheter is shown in
Over a Guide Wire with Open/Close Actuation
The shaft comprises an elongated section 953 and a controllably deflectable section 954. The elongated section 953 may be made from extruded Pebax with a durometer of about 63 D and a wire braid 960 to enhance transmission of torque and translation from a handle (not shown) on a proximal end of the catheter. The elongated section 953 comprises a coaxial lumen 961 (shown in
A first superelastic Nitinol wire 977 is used to function as a first deflection pull wire 978 and a first arm structural segment 979. The Nitinol wire 977 may have a diameter of approximately 0.006″ to 0.012″. As shown the Nitinol wire 977 is slidably positioned in the coaxial lumen 961 then passes in to the first off axis lumen 964 of the controllably deflectable section 954 where it acts as a first deflection pull wire 978. The first deflection pull wire 978 is anchored with a crimp 980 to a distal end piece 974 at the distal end of the controllably deflectable section. The distal end piece 974 may be made from a rigid radiopaque material (e.g., radiopaque thermoplastic) and functions as a radiopaque marker, an anchor for the first and second deflection pull wires 978 and 972, an anchor for the first and second arm structural segments, and provides a protected opening to the coaxial lumen 962. When tension is applied to the first deflection pull wire 978 the controllably deflectable section may bend toward the side containing the first off-axis lumen 964.
A second preformed superelastic Nitinol wire 971 is used to function as a second deflection pull wire 972, a second arm structural segment 970, and an arm actuation pull wire 975. The Nitinol wire 971 may have a diameter of approximately 0.006″ to 0.012″. As shown the Nitinol wire 971 is slidably positioned in the coaxial lumen 961 then passes in to the second off-axis lumen 963 of the controllably deflectable section 954 where it acts as a second deflection pull wire 972. The second deflection pull wire 972 is anchored with a crimp 973 to the distal end piece 974 at the distal end of the controllably deflectable section. When tension is applied to the second deflection pull wire 972 the controllably deflectable section may bend toward the side containing the second off-axis lumen 963. The second structural segment 970 may be made from the Nitinol wire 971 and may comprise a preformed shape as shown that elastically holds the second diverging arm 956 in an open configuration, for example such that the electrodes are approximately 10 to 20 mm apart, when unconstrained by a sheath and when tension in an open/close pull wire is released. The Nitinol wire 971 forms a 180-degree bend at the distal end of the arm where it is inserted in an electrode 958 and held in place by a friction fitted core 982. The Nitinol wire 971 returns along the arm as an actuation segment 975 and enters through a central opening in the distal end piece 974 to the coaxial lumen 962 where it passes along the length of the shaft to an actuator on a handle (not shown). When tension is applied to the actuation segment 975 the second arm 956 is moved toward a closed configuration, bringing electrodes 958 and 957 closer together. The arms 955 and 956 may be approximately the same length or may be offset so one is longer than the other. For example, a first arm 955 may be about 11 mm long while the second arm 956 is about 6 mm long. Electrical conductors (not shown) may pass from an electrical connector on a proximal region of the catheter, through the catheter shaft and diverging arms to the electrodes.
Any of the embodiments disclosed herein may further comprise an irrigation lumen 480 as shown in
In some embodiments the ablation catheter may include one or more expandable or deployable structures that are configured to be positioned in the external or internal carotid artery and configured to, when in a deployed or expanded configuration, substantially stabilize the electrode with respect to the carotid artery wall and to urge or press the electrode into contact with the arterial wall. In some embodiments the deployable structures can be adapted to occlude the external or internal carotid arteries, and in some embodiments have diameters between about 4 mm and about 6 mm.
Some embodiments include a catheter configured to ablate a carotid body or its associated nerves, comprising a first diverging member comprising a first expandable structure and a first energy delivery element disposed on the first expandable structure, the first diverging member configured to be positioned in an external carotid artery; and a second diverging member comprising a second expandable structure and a second energy delivery element disposed on the second expandable structure, the second diverging member configured to be positioned in an internal carotid artery, wherein at least one of the first and second energy delivery elements is an ablation element configured to delivery ablation energy to tissue disposed between the first and second expandable structures. The first and second energy delivery elements can be disposed about the expandable structures such that they are oriented towards each other when the expandable structures are in expanded configurations, such as facing the center of the other vessel +/−about 45 degrees, such as +/−25 degrees. At least of the first and second expandable structures can be an inflatable structure with the energy delivery element mounted thereon. The first and second energy delivery elements can be RF ablation energy delivery elements configured to operate in bipolar mode to delivery RF energy to tissue disposed between the first and second ablation energy delivery elements. The catheter can further comprise a stabilizing element extending between the first and second diverging members, and configured to engage carotid bifurcation tissue provide a determination of the position of the first and second expandable structures.
Catheter 1160 includes bifurcation stabilizer 1167, extending between the diverging elongate structures 1161 and 1162 of the catheter 1160. The stabilizer is configured so that as the catheter is advanced towards bifurcation 1170, stabilizer 1167 will engage with bifurcation 1170 such that electrodes 1165 and 1166 are positioned between about 4 mm and about 15 mm cranial to bifurcation 1170. The stabilizer limits how far the catheter may be advanced by coupling with a bifurcation and positioning the electrodes at an appropriate distance cranial from the bifurcation.
Any of the embodiments of the ablation catheters herein can include a bifurcation stabilizer, which can also be referred to herein as a bifurcation pad or cushion. Tether 231 in
In alternative embodiments the device does not include stabilizer 1167, and rather the length of elongate structures between the location at which they diverge to the electrodes is between about 4 to about 15 mm so when the diverging region of the elongate structures engage the bifurcation the arms are positioned in the carotids arteries, respectively, so that the electrodes are positioned about 4 mm to about 15 mm from the bifurcation.
In use, the balloons are inflated after the electrodes are in the proper position, either when the stabilizer engages the bifurcation or when the divergence engages the bifurcation. The balloons can be in communication with a cooling fluid such as saline or chilled saline to cool the electrodes allowing them to deliver ablative energy without over heating tissue in contact with the electrodes. A cooling medium, if used, may also be used to inflate the balloons to expand the balloons. The cooling fluid may flow into the balloon through a lumen in the catheter. Optionally, the cooling medium may exit the balloon through a separate lumen in the catheter or through small holes in the balloon into the blood stream. The electrodes mounted to a balloon can be part of a flex circuit or electrically conductive film bound to the balloon material.
While an embodiment with an inflatable balloon has been provided in
A deployable structure that allows blood flow through the structure or past the electrodes during energy delivery may be beneficial since the blood flow may help to cool the electrodes. In some embodiments one or more of the inflatable balloons can be configured as perfusion balloons to allow blood to flow past the balloon when they are inflated.
Like the balloon embodiment above, an electrode is positioned on at least one spline in such as position that once the cages are expanded, the electrodes are facing one another, in the positions shown in
While four splines are shown in this embodiment, more or fewer can be used. For example, three splines about 120 degrees apart can be used.
In alternative embodiments one expandable structure is an inflatable balloon, wherein the other expandable structure is not a balloon. For example, the second expandable structure could be an expandable cage like those shown in
In alternative embodiments the catheter includes a first arm with an expandable structure and the second arm does not have an expandable structure. For example, a catheter could include a first arm with an inflatable balloon configured for expansion in the external carotid artery, and a second arm configured to apply a passive closing force form within the internal carotid artery. One use for such a catheter would be to avoid occluding the internal carotid artery during use, while there may be less concern for occluding the external carotid artery.
Any of the arm structures described herein can be a first arm of a catheter and any arm structure herein can be the second arm of the catheter. That is, any suitable combination of first and second arm structures can be combined into a single ablation catheter.
In some embodiments the first arm comprises first and second electrodes configured to be used in bipolar configuration when disposed in an external carotid artery to ablate septal tissue, wherein the catheter also supports a second arm configured to be positioned in an internal carotid artery. The second arm can be thought of as a keying element, that when deployed within the internal carotid artery, both positions the electrodes at desired axial locations within the external carotid artery as well as orients the electrodes towards the carotid septum so that the electrodes can effectively ablate septal tissue.
Optionally, the balloon may comprise more than two electrodes and when the balloon is deployed a pair from the more than two electrodes that is aligned with a carotid septum may be chosen for energy delivery.
In this embodiment electrodes 1194 are mounted on a section of the balloon facing the keying element, or oriented in the same direction as the keying element. For example, the electrodes are mounted to be in substantial alignment with the port 1199 and/or keying element 1195 when deployed. The alignment of the keying element and electrodes may facilitate alignment of the bipolar electrodes with a carotid septum, ensuring effective ablation.
In some embodiments the bipolar electrodes are made from flex circuits or a thin conductive film. Electrodes may be, for example without limitation, between about 3 mm to 5 mm long, about 0.5 mm to about 4 mm wide, and separated by a linear distance of about 3 mm to about 5 mm. In particular embodiments the electrodes are about 4 mm long and about 2 mm wide and separated by a distance of about 4 mm.
In some embodiments the balloon is configured to occlude the external carotid artery. For example, it can be a compliant balloon with an inflated diameter of about 4 mm to about 6 mm. Occluding blood flow through the external carotid artery, at least immediately around the electrodes may force RF current to flow through the tissue of the carotid septum, thus creating a lesion in the septum, instead of taking a path of least resistance through blood, which may form a shallow lesion. The balloon may also help to press the electrodes in to contact with the septum wall.
The balloon, like other balloons described herein, may be cooled to pull heat from the electrodes and vessel wall, which may allow greater power to be delivered or which may cause a lesion to be formed deeper into the septum. The balloon may be cooled by circulating a cooling fluid such as saline or chilled saline. The cooling fluid may be delivered to the balloon through a port in the catheter shaft, which also may inflate the balloon. The cooling fluid may exit through an exit lumen in the shaft of the catheter or it may weep into the blood stream. Optionally, the cooling fluid may weep from perforations in the balloon.
In alternative embodiments the balloon has a configuration that does not occlude the entire volume of the vessel between the distal and proximal ends of the balloon. For example,
In alternatives to the embodiment shown in
Catheter 2000 includes shaft 2001 to which expandable structure 2002, in the general shape of an hourglass, is secured. Expandable structure 2002 is in this embodiment an inflatable balloon, on which electrodes 2003 are mounted and which are engaging external carotid artery tissue adjacent a carotid septum. Balloon can include any of the structure or function of any other balloon described herein (e.g., irrigation).
Catheter 2000 may also have radiopaque markers to facilitate orientation of electrodes 2003 with a carotid septum. The markers may be positioned on the catheter shaft. For example, any of the radiopaque markers and their use described herein can be incorporated onto shaft 2001 and its use. For example, the catheter can be rotated to align the markers with the plane of the bifurcation, which positions the electrodes toward the septum and in position to ablate.
In the alternative embodiment shown in
As set forth herein some catheters are adapted to be advanced to a common carotid artery through a sheath, following by sheath retraction to expose the catheter, and in some instances allowing it to deploy to a pre-formed configuration or shape. The catheter can then be aligned with and advanced over a carotid septum.
In some embodiments the distance between the distal end of the sheath and the distal end of the ablation catheter may be important, for example, to expose a deflectable section of the catheter, to expose the arms fully, and/or to expose enough shaft of a catheter to allow bipolar electrodes to self-align on a carotid septum (i.e., so the stiffness of the sheath doesn't impede the arms from naturally self-aligning). In some embodiments the catheter shaft includes a radiopaque marker and the sheath includes a second radiopaque marker. The markers are positioned on the respective devices such that axial alignment of the markers following sheath retraction indicates a reasonable desired pull back distance. For example, it may be desired to pull a sheath back between about 2 cm to about 5 cm, such as about 3 cm.
System have been conceived comprising a catheter having a means for coupling with a carotid bifurcation or intercarotid septum (e.g., forceps or keyed element) for transmural carotid body ablation and an ablation energy console. The system may additionally comprise a connector cable or several cables for connecting the ablation energy console with the catheter, a delivery sheath, or a guide wire. The console may comprise a user interface that provides the user with a means to select ablation parameters, activate and deactivate an ablation, or to monitor progress of an ablation. The console may have a second user interface that allows the user to select electrical stimulation or blockade used to investigate proximity of an ablation element on the catheter to neural structures. The console may comprise a computer algorithm that controls ablation energy delivery. The algorithm may control energy delivery (e.g., controlled power delivery) based on inputs for example, user selected variables, pre-programmed variables, physiologic signals (e.g., impedance, temperature), or sensor feedback.
Other devices have been conceived for endovascular transmural carotid body ablation with a distal region of a catheter that couples with a carotid bifurcation using a keyed bifurcation structure, herein referred to as Endovascular Transmural Ablation Keyed (ETAK) catheters. An ETAK catheter may comprise an ablation element on a distal region of the catheter and, proximal to the ablation element, a keyed bifurcation structure that diverges from a central axis of the catheter. A keyed bifurcation structure may comprise, for example a guide wire passed through a side-exiting guide wire port, multiple guide wires passed through multiple guide wire ports, or a deployable side arm. Alternatively, a keyed bifurcation structure may be coaxial with a central axis of an ETAK catheter and an ablation element may be on an arm that diverges from the central axis of the catheter. A user may advance the catheter, placing the keyed bifurcation structure in an internal carotid artery and the ablation element on the distal region of the catheter in an external carotid artery, until the keyed structure is coupled with a carotid bifurcation. The keyed bifurcation structure may diverge from the central axis of the catheter proximal to an ablation element at a distance that places the ablation element at a substantially suitable position on an intercarotid septum for effective carotid body ablation. For example the ablation element may be at or between about 4 mm to 15 mm from the divergence. This distance may be fixed or may be adjustable. Apposition of an ablation element with tissue may be achieved via resilient forces of a structural member in the catheter, deployment of an expandable structure, or deflection of a deflectable section of the catheter. An ablation element may be, for example, a radiofrequency electrode, bipolar radiofrequency electrodes, a cooled radiofrequency electrode, a cryogenic applicator, an ultrasound transducer, or a microwave antenna. ETAK catheter designs may facilitate positioning and orientation, improve apposition of electrodes and protect walls of carotid arteries from injury and plaque disturbance. Contrary to some other common ablation catheters, ETAK catheter design leaves walls of internal 30 and external 29 carotid arteries, opposite to a carotid bifurcation (known as the Y sides of the carotid arteries), practically free from mechanical forces that can dislodge plaque. It is known that plaque is often found on those walls where blood flow velocity is slower.
In some embodiments the ETAK catheter includes an ablation element disposed relative to a catheter shaft such that it is configured to be positioned in an external carotid artery; and a diverging structure that diverges from a central axis of the catheter, wherein the ablation element is about 4 mm to about 15 mm distally from the divergence of the diverging structure. The ablation element can be mounted about a catheter shaft, the shaft configured to be positioned in the external carotid artery. The catheter can include a plurality of ablation elements configured to be positioned in the external carotid artery, such as mounted about a catheter shaft, the catheter shaft configured to be positioned in an external carotid artery (e.g., annular or partially annular electrodes). The ablation element can be configured to be oriented in the direction of the bifurcation structure. The catheter can include an expandable structure, such as an inflatable device or other expanding device, to which the ablation element is secured. For example the ablation element can be mounted about the inflatable structure. An inflatable balloon can include more than one ablation elements, which can be first and second RF electrodes and configured to function in bipolar mode. The ablation element can be an RF electrode configured to be operated in monopolar mode. The catheter can comprise an exit port therein configured to allow the diverging structure to be advanced therethrough. The diverging structure can be configured to rotationally orient the ablation element towards a carotid septum when the diverging structure is positioned in an internal carotid artery. The expandable structure can be configured to be expanded and create apposition between the ablation element and a carotid septal wall. The diverging structure can be configured so that when the expandable structure is in an expanded configuration the ablation element is oriented in the direction of the diverging structure. The diverging structure can diverge at an angle between 0 and about 90 degrees relative to the axis of the catheter, such as between about 30 and 70 degrees. The diverging structure can have a free end.
An embodiment shown in
Alternatively, an ETAK catheter may have an expandable structure such as balloon with multiple ablation elements mounted to the balloon. The multiple ablation elements may be rotationally oriented, as described before, by placing a side exiting guide wire in an internal carotid artery. More than one ablation element may be used to deliver ablation energy to create a larger ablation that only one element. Or, a user may choose which ablation element to activate based on a location of a target ablation site.
A carotid body ablation catheter may comprise a radially expandable structure, such as an inflatable balloon, a perfusion balloon, or a deployable wire cage, configured to position an ablation element (e.g., RF electrode, bipolar RF electrodes, ultrasound transducer, cryogenic element) at a suitable height (e.g., about 4 to 15 mm, 5 to 10 mm, 8 to 10 mm) from a carotid bifurcation for an effective and safe carotid body ablation procedure. The radially expandable structure may engage with carotid vasculature geometry such as a common carotid artery caudal to its bifurcation, a carotid bifurcation, an ostium of an external carotid artery, or an ostium of an internal carotid artery. The ablation element may be disposed on the catheter with respect to the radially expandable structure so that when the radially expandable structure is engaged with the carotid vasculature geometry the ablation element is positioned for carotid body ablation. The radially expandable structure may furthermore facilitate stabilization of the distal portion of the catheter during delivery of ablation energy. The radially expandable structure may furthermore facilitate placement of the ablation element within an external carotid artery at a suitable radial position, for example on the carotid septum or in contact with the wall of the external carotid artery facing the internal carotid artery. The ablation element may optionally be maneuvered with a means such as controllable deflection or a deployable structure such as a balloon.
An exemplary embodiment as shown in
A system has been conceived comprising a catheter, having a means for coupling with an intercarotid septum for carotid body ablation, and an ablation energy console. The system may additionally comprise a connector cable or several cables for connecting the ablation energy console with the catheter, a delivery sheath, or a guide wire. The console may be configured to deliver ablation energy to the catheter. For example, the console may be an electrical signal generator such as a radiofrequency generator or an irreversible electroporation generator. The console may further comprise a user interface that provides the user with a means to select ablation parameters, activate and deactivate an ablation, or to monitor progress of an ablation. The console may further allow a user to select electrical stimulation or blockade used to investigate proximity of an ablation element on the catheter to neural structures. The console may comprise a computer algorithm that controls ablation energy delivery. The algorithm may control energy delivery (e.g., controlled power delivery, ramp time, duration) based on inputs for example, user selected variables, pre-programmed variables, physiologic signals (e.g., impedance, temperature), anatomical features (e.g., intercarotid septum width, presence of plaque, bifurcation angle), or sensor feedback. Selectable carotid body ablation parameters may include ablation element temperature, duration of ablation element activation, ablation power, ablation element force of contact with a vessel wall, ablation element size, ablation modality, ablation element position within a vessel, or intercarotid septum width.
Pressure or force sensors may be incorporated into any of the catheter embodiments herein, for example they could be mounted to a flex circuit proximate an ablation element, and could be used to verify contact or indicate contact force. Diverging arms with open/close actuation could be actuated to a position that corresponds to a particular contact pressure range. Alternatively, a catheter could be “pushed” against the wall until contact pressure reaches a desired level. Alternatively, a baseline pressure may be chosen when a desirable contact force is visually confirmed, for example vessel distension caused by ablation element contact force may visually appear using an imaging modality such as angiography. A change of pressure or force, within an acceptable range from the baseline, measured by the sensors may indicate appropriate contact force and deviation from this range could indicate an inappropriate contact force. A computer algorithm that controls delivery of ablation energy may discontinue energy delivery if contact force deviates from the appropriate range. Furthermore, a pressure sensor may be used to indicate absolute or relative blood flow and power delivery could be augmented by feedback from the pressure sensor. Alternatively, a temperature sensor, cooled by blood flow, can be used to determine blood flow velocity. Blood flow cooling can be factored into the control algorithms as correction of energy delivery. Also sudden drop of blood flow can indicate spasm of the carotid vessel. Such an abrupt temperature rise will indicate a need to stop or reduce energy delivery instantly. For example, low flow may equal less power and/or power delivery duration, while greater flow may result in more power and/or longer duration. Power of ablation energy delivery may be decreased or duration of energy delivery may be reduced if the flow decreases. Conversely, should the flow increase power or duration may be increased. Alternatively, a pressure sensor may be used to track potential damage to nerves that are to be preserved. Heart rate may be inferred from a pressure sensor through pulsatile flow. The right vagus nerve primarily innervates the sinoatrial node while the left vagus nerve primarily innervates the atrioventricular node. Should either vagus nerve become stimulated, blocked or damaged the patient's heart rate may fluctuate or decline, which may be indicated by the pressure or flow sensor an energy delivery algorithm may stop power delivery or provide a warning accordingly. Similarly, heart function and some gauge of instantaneous heart rate variability may be measured in other ways (e.g., ECG, plethysmography, pulse oximetry) and used by an energy delivery algorithm for safety.
Contact between electrodes and tissue throughout delivery of energy, contact along a full length of an electrode, contact pressure, or stable contact may be important to create a predictable, well controlled ablation. Temperature sensors in each ablation element may be used to indicate characteristics of tissue contact. For example, as energy is applied (e.g., radiofrequency) and tissue is heated, temperature sensors in the ablation elements may be expected to increase as a function of energy delivered and tissue contact. If there is no tissue contact or contact is partial, intermittent, instable or with soft pressure, measured temperature increase may not be as expected (e.g., a lower temperature rise than expected). Temperature measured from multiple sensors may be compared to indicate characteristics of contact. For example if one sensor measures an expected temperature, increase in temperature, or temperature response to energy delivery while a different sensor does not measure an expected result then inconsistent contact may be detected. An algorithm may detect inconsistent ablation element contact and provide a warning and suggest which ablation element requires repositioning.
Tissue impedance, phase or capacitance may be measured between electrodes on each arm of an ETAP catheter in a bipolar arrangement, or between an electrode on one arm and a dispersive electrode on a second arm. Impedance measurement across an intercarotid septum may be used to indicate distance between electrodes, intercarotid septum width, carotid bifurcation angle, position on a bifurcation, tissue characteristics, ablation characteristics, electrode contact with tissue, catheter integrity, presence of plaque (e.g., calcified or atheromatous plaque). An energy delivery algorithm may incorporate impedance feedback, phase changes, or temperature to control delivery of ablation energy. For example, these feedback variables may be used to modulate energy delivery or as a safety cut-off. Ablation energy may be delivered for a predetermined duration of time (e.g., between about 20 and 90 s, or in a range of about 20-30 s) and energy delivery may be reduced or stopped if there is indication that a traumatic event or a poor ablation is about to happen, such as high temperature or temperature above set point, which may lead to events such as charring or coagulation, or significant movement or poor contact of the electrodes with respect to tissue, which may lead to unpredictable ablation or ablation at a non-target region. Calcified plaque may be detected by high impedance for a given septum width. For example, septum width may be measured using fluoroscopic visualization and if impedance is higher than a predetermined range of normal impedance for the measured septum width then calcified plaque may be present. A computer algorithm may compute presence of plaque based on input septum width and a lookup table of impedance measurements. A bipolar arrangement may be more sensitive to impedance changes and be able to prepare the generator to shut off more quickly than a monopolar arrangement. For example, a bipolar radiofrequency configuration may provide an improved signal to noise ration compared to a monopolar configuration and may provide a clear indication that electrodes are moving. However, an energy delivery control algorithm for either a bipolar or monopolar configuration may incorporate feedback variables for ablation and safety control as discussed herein. For example, prior to charring, which may be indicated by a sharp spike in impedance, several cycles of impedance fluctuation may be measured; if electrode contact with tissue is compromised or electrode position has moved an acute impedance change and simultaneous temperature change at one or both electrodes may be measured; if a catheter is compromised a feedback signal from a temperature sensor may be severed or out of a reasonable range; if a vessel is undergoing spasm impedance and temperature fluctuations as well as power phase changes may be detected simultaneously and in a sinusoidal pattern or may be determined based on hysteresis. Any of these indications may result in a reduction of energy delivery power, power shut off, or a safety warning. Variables such as impedance and temperature may be an indication of a successful ablation. For example, changes in impedance (e.g., value and phase) may be measured when carotid body perfusion is coagulated. This may be an indication that target temperature is exceeding 50-60 C, which may be an indication of technical success. Energy delivery may be stopped or continued for a short amount of time after this occurs to limit a chance that a lesion grows into that hazards medial zone. Another way an energy delivery algorithm may incorporate impedance feedback, phase changes, or temperature to control delivery of ablation energy is to adjust power delivery to meet a set point temperature, impedance, phase or capacitance.
An ETAP or ETAK catheter may be configured for monopolar radiofrequency energy delivery and may comprise only one ablation electrode on an arm and the other arm may not have an electrode but be used for positioning the arms at a carotid bifurcation and in apposition with a target ablation site such as an external carotid artery wall of an intercarotid septum. In this monopolar configuration a dispersive electrode positioned on a patient's skin may compete the radiofrequency circuit. Another embodiment of an ETAP catheter configured for monopolar radiofrequency energy delivery may be constructed the same as embodiments shown in
The inventors determined that an intercarotid septum may be an ideal ablation target for a carotid body ablation procedure. With this understanding they conducted studies to establish a safe range and technique of energy delivery to create well-controlled and consistent ablations in intercarotid septa with a goal of a high probability of CB destruction with mitigated risk to the artery walls and important adjacent non-target nerves or organs. A further goal was to assess usability (e.g., ease of delivery, positioning and targeting) of a catheter for a CBA procedure. The studies included ablation studies in animals, histological analysis, finite element modeling, and in bench testing.
A porcine model was developed having an ablation target of a bi-carotid bifurcation, which has a similar arterial bifurcation (vessel diameter of 4.2-6.2 mm, bifurcation angle of 20-45° to a human's carotid bifurcation (vessel diameter of 4-6 mm, bifurcation angle of 48.5+/−) 6.5°. The arteries also have a similar blood flow and cellular makeup.
Monopolar RF ablation was assessed in the porcine model. 14 animals were studied with a total of 63 ablations using a RF power between 10 to 40 W and energy delivery of 30 s. A monopolar RF catheter having controllable deflection and a 7 French, 4 mm long electrode was delivered to the bi-carotid septum as shown in
Bipolar RF ablation was assessed in the porcine model and compared to the monopolar results. The hypothesis was that bipolar RF energy may create an ablation that is safely contained within an intercarotid septum and also significantly large enough to ensure a high probability of effectiveness. The bipolar electrode arrangement, as shown in
Furthermore, compared to 15 W monopolar ablations (see
Finite element modeling was done to compare bipolar carotid septum ablation (shown in
A challenge of heating a large volume of tissue with conventional monopolar application of radiofrequency or other frequency alternating electric current is that current density is typically greatest in tissue nearest an active electrode. In a relatively homogeneous medium heat is generally proportional to current density. Over time, temperature will begin to increase in tissue nearest the electrode forming a lesion that grows outward by conduction of heat. Overheating tissue nearest the electrode may cause it to char which can have undesired effects such as an increase in electrical impedance of the charred tissue resulting in uncontrolled delivery of energy, unpredictable lesion formation, gas formation, or iatrogenic injury. Lesion size is a function of electrode surface area in contact with tissue, cooling conditions such as perfusion by blood, and energy delivery parameters such as power. Creating a lesion with RF in relatively non-homogeneous tissue is a function of additional factors such as the different electrical and thermal properties of the varying tissues, which may be altered by varying rates of perfusion, blood flow, or tissue composition.
Heating tissue at a distance from an electrode may be limited by overheating of tissue near an active electrode. This may be overcome by cooling the electrode, pulsing energy delivery, increasing electrode size, or adding electrodes.
Bipolar RF is another way to increase the size of a lesion by concentrating current between two active electrodes, thus maintaining a fairly high current density in the tissue between the electrodes, not only in tissue nearest an active electrode. Bipolar RF can also control the size and shape of a lesion. The ability to effectively contain concentrated current between two bipolar electrodes is a function of distance between the electrodes. In a relatively homogeneous medium, even with bipolar RF, current density will be greatest in tissue nearest the electrodes and lesions will begin to form around the electrodes and grow toward one another in the tissue between the electrodes. The greatest thermal injury may be in tissue next to the electrodes. Tissue in between the electrodes, particularly in the center, may reach an ablative deposited thermal energy dose, however the thermal exposure (temperature rise multiplied by time) will be less than that applied to tissue nearer the electrodes.
The application of trans-septal bipolar RF to a carotid septum as described herein has several beneficial mechanisms. The environment is not homogeneous so the thermal profile behaves differently that in a homogeneous medium, particularly due to the cooling action of blood flow. The distance between electrodes placed in an internal and external carotid artery on a carotid septum is variable with anatomy between about 2 to 10 mm, which is within a range sufficient to concentrate current density between electrodes enough to create a substantially trans-septal bipolar ablation. High blood flow in the internal and external carotid arteries, as well as in the common carotid artery and over the carotid bifurcation helps to remove heat from the vessel walls and tissue near the vessel walls. As bipolar RF energy is delivered across a carotid septum tissue temperature between the electrodes and along the current path will rise. Blood flow will temper the thermal increase in the vessel wall and tissue near the vessel walls, and temperature of tissue closer to and at the center will rise. The electric current has a general tendency to follow the path of least resistance. In the case of bilateral trans-septal ablation the simplified current path can be presented as two resistance elements connected in parallel: one through septum tissue and a second through a blood path around the carotid bifurcation. Blood has lower resistivity compared to septum tissue but the distance that current needs to travel is longer since the shortest path between two electrode lies through the septum path (i.e., trans-septal). This bipolar arrangement of electrodes concentrates RF resistive heating in the septum. As the tissue of the septum gets heated by the RF current its impedance drops, because ionic conduction in tissue is a function of temperature, and larger share of current is directed into the septum and lesser into the blood. The thermal dose applied to tissue across the septum will be more even, or the thermal dose of the center tissue may be greater than central tissue in an environment without blood flow. This is beneficial because the target ablation site is across the septum and it is desired to avoid iatrogenic thermal injury to the vessel walls. Additionally as described herein, bipolar RF applied to a carotid septum has been shown to contain an ablation within a thickness suitable for effective ablation of a carotid body or its associated nerves and for safe avoidance of non-target nerves or tissue near the septum.
The total impedance during bipolar carotid septum ablation is a function of resistivity (i.e. resistance per unit of volume) of the septal tissue that decreases with increasing temperature, resistivity of blood and the length of the current paths through tissue and blood. Resistance of blood that is in parallel stays constant. During ablations in animal studies that produced robust lesions total impedance was observed to drop 15-25% after a period of initial heating of septal tissue. Because of high blood flow temperature of blood in the blood path and thus resistivity of the blood does not change.
An ablation is created by resistive heating of tissue that is proportionate to the current density created by field strength in the trans-septal current path. Electric current that travels through blood may not contribute to the ablation. Current density is current that crosses through an area unit of the cross-section of the path. In septal tissue cross-section of a current path may be roughly approximated by the area of the electrode footprint.
A goal of a carotid body ablation system may be to achieve current density along the trans-septal RF current path that is high enough to achieve a robust lesion as a result of resistive heating of tissue along the septal path. Since current density in the septum cannot be measured this was achieved by FEM modeling, bench top tests in phantoms that approximated tissue properties and surrounding conditions and finally by with animal studies.
A finite element model predicted that a thermal profile formed in a carotid septum by bipolar RF energy applied to the septum from the internal carotid artery and external carotid artery would heat sufficiently across the septum while maintaining safe temperatures proximate the electrodes (
The energy delivery parameters (power, duration, ramp up slope) were studied by inventors using the embodiment described by
In the study a variety of power levels (6, 8, 10, 12 W) were applied to porcine carotid septa of different widths, but with the aim of achieving an average inter-electrode distance of 5.5 mm, which is a 3rd quartile of inter-septal distance found by a retrospective and prospective computed tomography angiography analysis. Actual inter-electrode distance was determined to range from 3.8 mm to 8.0 mm using angiography. Samples included 14 different bifurcations from 8 different animals performed at 2 different test facilities. The baseline total impedance measured between electrodes, which is a function of impedance through a blood path in carotid vasculature and impedance through septal tissue, for these samples before delivering ablative energy was 240-300 ohms. All trials in samples of varying thicknesses using power of 6, 8, or 10 W resulted in acceptable ablations with sufficient septal coverage and safe containment. Trials using 12 W resulted in electrode temperature over 60° which may be less desirable because it could indicate a high temperature of a vessel wall, which could increase risk of thrombus formation or vessel injury.
In one embodiment, power may be adjusted based on carotid septal width. To make a comparable lesion coverage for a wider septum one may need to apply more energy, for example more power for a given duration, similar power for a longer duration, or more power for longer duration. Conversely, power may be titrated down for narrower septa to ensure the produced lesion is contained in the carotid septum. A RF console may comprise a computer-controlled algorithm that adjusts energy delivery parameters such as power amplitude or duration according to septum width, which may be measured and input as a variable by a user. Septum width may be measured on an angiogram or on fluoroscopy by measuring the distance between radiopaque electrodes placed on the sides of the septum. For example, a septum measured on angiography to be between about 2 to 5 mm may correspond to a chosen power of about 6 W, a septum measured to be between 4 to 8 mm may correspond to a chosen power of about 8 W, and a septum measured to be between 7 to 10 mm may correspond to a chosen power of about 10 W.
In another embodiment power may be adjusted based on impedance measured between the two electrodes. Septum width and impedance measured across the septum between electrodes may generally be correlated. However, impedance is also a function of tissue composition. More power may need to be applied to achieve comparable lesions for a carotid septum having higher impedance, regardless of septal width. Conversely, power may be titrated down for septa measuring lower impedance to ensure the produced lesion is contained in the carotid septum. A RF console may comprise a computer-controlled algorithm that automatically adjusts energy delivery parameters such as power amplitude or duration according to measured impedance.
As set forth above, the disclosure provides devices, systems and methods for positioning a distal region of a catheter in a vessel proximate a carotid body (e.g., in a common carotid artery, internal carotid artery, external carotid artery, at a carotid bifurcation, proximate an intercarotid septum), positioning an active electrode proximate to a target ablation site (e.g., a carotid body, afferent nerves associated with a carotid body, a peripheral chemosensor, an intercarotid septum), positioning a reference electrode proximate the target ablation site, and delivering ablation energy from the active electrode through the target ablation site to the reference electrode to ablate the target site. Several methods and devices for carotid body modulation are described. As set forth above, in some embodiments a catheter includes a first electrode and a second electrode, wherein one or more aspects of the catheter is configured so that in use the first electrode is in contact with the external carotid artery proximate the carotid septum, and the second electrode is in contact with the internal carotid artery proximate the carotid septum. In use, energy is then delivered between the electrodes to ablate septal tissue to achieve a therapeutic effect.
In some embodiments, however, one or more aspects of the catheter are configured so that one or both of the electrodes are not in contact with the external and internal carotid arteries, respectively, when energy is delivered between the electrodes. These embodiments are examples of “energy-directed” carotid body ablation as used herein. Some embodiments of endovascular energy-directed ablation of a carotid body include delivering a device through a patient's vasculature to a blood vessel proximate to a target ablation site (e.g., carotid body, intercarotid plexus, carotid body nerves) of the patient, placing an active electrode associated with the device against the internal wall of the vessel adjacent to the target ablation site, placing a reference electrode in a vessel adjacent to the target ablation site but not in contact with the vessel wall, such that the target ablation site is between the active electrode and reference electrode and within a distance such that current density is concentrated or directed toward the reference electrode, and delivering ablation energy to ablate the target ablation site. These embodiments of energy-directed ablation of a carotid body differ from monopolar ablation or bipolar ablation as described below. In alternative embodiments of endovascular energy-directed carotid body ablation, neither of the electrodes are in contact with the vessels wall. In energy-directed ablation, the ablation energy may be, for example, electrical energy, irreversible electroporation, radiofrequency energy, cooled radiofrequency energy, or a pulsed electrical signal.
Monopolar radiofrequency (RF) ablation is referred to as a mode of tissue ablation wherein RF current is passed from an active electrode, typically positioned proximate a target ablation site, to a reference electrode, typically positioned on a patient's skin. The active electrode is significantly smaller than the reference electrode so that current density in tissue around the active electrode is high enough to raise tissue temperature and to thermally ablate tissue, while the current density in tissue around the reference electrode (which can also be referred to as an indifferent electrode or a return electrode) is low enough to not thermally ablate the tissue. The reference electrode is typically positioned at a distance from the active electrode such that current path in tissue proximate the active electrode is significantly diffused and a resulting tissue ablation is not directed toward the reference electrode. For example a monopolar RF ablation may comprise placing an active electrode near a nerve in a patient's back and placing a reference electrode on a surface of the patients thigh resulting in a sufficiently omnidirectional thermal ablation around the active electrode. A schematic illustration shown in
Bipolar RF ablation is referred to as a mode of tissue ablation wherein RF current is passed from a first active electrode to a second active electrode, wherein both active electrodes are typically positioned near one another (e.g., within about 30 mm, within about 15 mm, or within about 5 mm) or within a distance in which current density has a tendency to concentrate between the electrodes, which may create a continuous ablation between the electrodes, or a less omnidirectional ablation having greater concentration between the electrodes, or an ablation that is contained to a narrower path between the electrodes as compared to electrodes placed at a distance from one another that does not concentrate current density between the electrodes. Both active electrodes are similar in size, or at least similar enough that current density in tissue around both active electrodes is high enough to thermally ablate the tissue. The disclosure above includes embodiments for carotid body modulation using bipolar RF ablation with two electrodes applied across a carotid septum.
In a similar fashion to monopolar ablation, some embodiments of energy-directed ablation require only one active electrode to be in direct apposition with the wall of the vessel and associated with a high current density region in proximate tissue and resistive heating, and a reference electrode that serves to close the current return path. Unlike monopolar ablation, however, the energy-directed reference electrode is placed in a blood vessel (for example, in an internal carotid artery) and serves the additional function of directing or steering current in the desired direction, through the carotid septum. Furthermore, the energy-directed reference electrode need not have an extremely large surface area as in a skin patch to avoid a temperature increase. Heating of blood volume around an energy-directed reference electrode 1020 may be prevented or at least minimized by continuous strong blood flow that surrounds it. Compared to air, skin or bone, the impedance of blood and tissue that forms the carotid septum parenchyma is substantially similar (e.g., about 100 to about 300 ohms). This observation is important to understand the benefits on this approach. The impedance of the current path is therefore composed of a thin layer of blood and the volume of tissue in sequence. The total length of the path from an active electrode positioned in an external carotid artery to an energy-directed reference electrode placed in an internal carotid artery may be between about 3-10 mm. The presence of blood in the current path is counterintuitive and goes against tradition in the teaching of endovascular ablation.
Energy-directed RF carotid body ablation may comprise placement of an active electrode and an energy-directed reference electrode such that a target ablation tissue is between the two electrodes and that they are sufficiently close to one another such that the field and resulting ablation zone is influenced to be preferentially contained in the space between them. For example, an active electrode may be placed in an external carotid artery and a corresponding energy-directed reference electrode may be placed in an internal carotid artery. A potential benefit of this arrangement may be to reduce mechanical impact in the internal carotid artery to reduce a potential risk of dislodging plaque and causing a brain embolism. In some embodiments an active electrode is placed in an internal carotid artery and an energy-directed reference electrode is placed in an external carotid artery. Another example comprises placing an active electrode in an internal jugular vein and an energy-directed reference electrode in an external carotid artery. The arrangement may beneficially reduce embolic risk by avoiding the internal carotid artery all together. Furthermore, this arrangement may beneficially allow a catheter of a smaller diameter to be used for the reference electrode, which could be particularly important for a radial artery access catheter or temporal artery access catheter since the radial and temporal arteries are narrow (e.g., 3-5 mm diameter).
In the traditional teachings of endovascular, and especially cardiac, RF ablation, trapping a layer of blood between the electrode and the wall of the vessel is considered a safety risk. It is considered a risk because in traditional ablation delivered power is generally maximized until it is close to a safe limit for the electrode size in order to create a bigger, deeper lesion. Blood flow and velocity near the wall and the electrode is typically relatively low, and the temperature of the electrode is generally brought close to the safe limit. Thus, a thin conductive layer of blood between the electrode and wall can heat up beyond the safe level, which can lead to clot formation. In an effort to prevent heating of blood and clot formation, RF ablation with saline irrigated catheters became popular. Irrigated catheters are, however, more complex, having larger sizes and requiring an external saline pump. Additionally, irrigated catheters cannot take advantage of electrode temperature measurement to control or monitor tissue ablation.
One or more inventors have conducted animal studies to understand the extent of the risk of clotting using bipolar ablation with a custom catheter. During these studies one electrode was placed in good apposition on one side of a carotid septum, and a second electrode was placed on the other side of the carotid septum and was intentionally not contacting the wall of the vessel in which it was placed. There were some directed and consistent lesions contained in the carotid septum without clotting of blood.
The described energy-directed ablation has potential advantages over monopolar ablation in that: (a) it can direct and contain heating and ablation of a carotid septum in the desired volume and (b) it does not require an external reference electrode, and that the same or similar size and volume lesion can be achieved at lower power and electrode temperature. Furthermore, energy-directed ablation has a potential advantage over bipolar ablation in that it minimizes, and can even eliminate, contact with the surface of an internal carotid artery. Generally good apposition with the arterial wall is achieved by mechanical pressure, which can potentially lead to disruption of plaque that may be present in an internal carotid artery, and damage to the vessel. Additionally, it may be difficult to achieve good simultaneous apposition in both internal and external carotids in some individuals with complex anatomy.
Devices have been conceived for endovascular carotid body modulation comprising energy-directed ablation catheters. Embodiments of catheters disclosed herein comprise a distal end and a proximal end, wherein the distal end is inserted into a patient's vasculature and delivered proximate a target site, and the proximal end is maintained outside the patient's body.
The distal region of an energy-directed ablation catheter comprises an active electrode positioned on a first spline and an energy-directed reference electrode on a second spline in a configuration that positions the active electrode in an external carotid artery on an intercarotid septum at a position relative to a target ablation site (e.g., carotid body or nerves associated with a carotid body) that is suitable for carotid body modulation, and the energy-directed reference electrode in an internal carotid artery at a position not necessarily in contact with the carotid septum but in a position relative to the active electrode sufficient to direct and concentrate an applied current path through the septum.
In some embodiments the catheter is configured so that the reference electrode is not in contact with the internal carotid artery. In some embodiments neither electrode is in contact with a wall of the artery in which it is positioned. Splines, as used herein, can also be referred to as arms, fingers, prongs, together as forceps arms, or individually as a forceps arm.
Any of the catheters in any of the embodiments described above in which both electrodes are configured to be in contact with a carotid artery wall in use can be modified to be configured such that one or both of the electrodes are not in contact with the vessel wall when in use (i.e., is configured for energy-directed ablation).
The embodiments in
One common element in the embodiment in
An alternative embodiment of an ablation catheter 1070 shown in
Another exemplary embodiment of a catheter configured for energy-directed ablation is shown in
Another embodiment, not shown, comprises an active electrode, which may be placed in an external carotid artery, and an energy-directed reference electrode that is configured to be an embolic protection device such as a deployable net, which may be placed in an internal carotid artery and function both as a reference electrode and to catch any dislodged plaque in the blood stream flowing through the internal carotid artery, reducing embolic risk.
Ablation elements may be electrodes configured for radiofrequency ablation. Embodiments of the present disclosure may comprise an active electrode, for example, with a surface area in a range of about 8 to 65 mm2 (e.g., about 12 to 17 mm2). For example, electrodes may be cylindrical with a hemispherical domed end having a circumference of about 0.8 to 2 mm (e.g., about 1.2 mm) and a length of about 3 to 10 mm (e.g., about 4 mm). A radiofrequency signal delivered to such electrodes may have a frequency in a range of about 300 to 500 kHz and a maximum power of about 12 W (e.g., a maximum power of about 5 W, 6 W, 7 W, 8 W, 9 W, 10 W, 11 W, or 12 W) and a duration of about 30 to 120 seconds (e.g., about 30 s). Electrodes may be made (e.g., machined) from an electrically conductive material such as stainless steel, copper, gold, platinum-iridium, or alloy such as 90% Au 10% Pt. For example, electrodes may be machined in a shape of a circular cylinder with hemispherical domed end with a hollow cavity, which may be used to position sensors (e.g., temperature sensor, impedance sensor), connect to structural segments of carotid prongs, or for cooling irrigation. Other shapes may be used for electrodes such as elliptical cylinder, cuboids, ribbon or complex shapes. Alternatively, any of the ablation elements described above can be incorporated into a catheter configured for energy-directed ablation.
A method of using an ETAP catheter with having opening or closing, and deflection actuation may include the following steps:
1. Deliver a sheath (e.g., a 7 French compatible sheath) to a common carotid artery. An over the wire technique or fluoroscopic guidance may be used to deliver a sheath.
2. Deliver the ETAP catheter through the sheath to a common carotid artery. Optionally, the ETAP catheter may be connected to a console to test functionality of the catheter prior to delivering into the patient. For example, electrical current may be delivered through electrical conductors to check if all circuits are functioning properly and sensors, if any, are making reasonable measurements.
3. Deploy a distal working end of the ETAP catheter from the sheath in a closed configuration in the common carotid artery. If the ETAP catheter has a normally-open design the arms may be held in a closed configuration. For example an open/close actuator may be locked in a closed position.
4. Visualize position and rotational plane of the closed arms with respect to a carotid septum. Fluoroscopic techniques may be used to facilitate visualization. For example, contrast solution may be injected through the sheath into the common carotid artery to visualize the vasculature system and radiopaque markers may be placed on the catheter (e.g., on ablation elements and shaft).
5. Rotate/torque the ETAP catheter so arms are approximately in plane with a plane created by the axes of the internal and external carotid arteries.
6. Deflect the distal end of the ETAP catheter with a deflection actuator to aim the distal tip of the catheter at the carotid bifurcation. (note deflection plane is parallel with arms plane) An ETAP catheter configured without controllable deflection may be aimed at a carotid bifurcation using a deflectable sheath.
7. Open the arms with the open/close actuator. An ETAP catheter may be configured to open and close completely, that is, to its full range, upon actuation. Alternatively, an ETAP catheter may be configured to control variable position of the arms from fully open to fully closed. Variable position control may facilitate placement of electrodes, for example, in vasculature have a small bifurcation angle (e.g., less than about 15 degrees).
8. Advance open arms over a septum. The arms may be advanced until the bifurcation of the arms couples with the carotid bifurcation or carina. This may be indicated visually via fluoroscopy, through tactile feedback as a user feels the catheter meeting resistance, or by a contact or force sensor positioned on the distal end of the catheter. Alternatively, arms may be advanced partially, that is, before contact between the bifurcation of the arms and the carotid bifurcation made, for example as indicated visually via fluoroscopy. Partial advancement may be desired if a location of a carotid body or non-target nerves within a septum are known and a desired ablation zone is closer to the carina compared to an ablation zone created when arms are fully advanced. Furthermore, partial advancement may be desired to reduce risk of dislodging plaque that may exist at the carotid bifurcation.
9. Close the arms with the open/close actuator to bring ablation elements (e.g., RF electrodes, electroporation electrodes) into apposition with the septum. Actuation to close the arms may be fully actuated. Elasticity in elastic structural members of the arms may allow closed arms to adjust automatically to various septum thicknesses within a range (e.g., between 2 mm and 15 mm thick or between 4 mm and 10 mm thick) while applying approximately consistent electrode contact force. Alternatively, the degree of closing of the arms may variably controlled, for example, depending on septum thickness or electrode contact force, which may be indicated visually via fluoroscopy or with sensors (e.g., force or impedance sensors). An ETAP catheter may be configured to have arms that are substantially rigid, instead of elastic, so a closing force created by an open/close actuator causes the arms or ablation elements to squeeze an intercarotid septum. This may be advantageous, for example to decrease distance between ablation elements especially when a septum is thick (e.g., greater than 15 mm), which may improve the ability to create an effective ablation.
10. Run an ablation algorithm. For example, an ablation algorithm may be executed by a computerized console and may involve monitoring impedance and temperature, apply ablation energy (e.g., RF or irreversible electroporation) for a predetermined duration and at a predetermined power, shutting off ablation energy if an unwanted scenario occurs such as sudden rise in impedance, sudden large change in temperature, or physiological incidence.
11. Following ablation, open the arms with the open/close actuator to release electrode contact.
12. Retract the arms from the septum into the common carotid artery, for example by pulling the proximal end of the catheter out approximately 2 cm.
13. Close the arms with the open/close actuator. Alternatively, the arms may automatically close when the ETAP catheter is pulled into the sheath.
14. Collect the distal region of the ETAP catheter in the sheath.
15. Remove the sheath and ETAP catheter from the body. Alternatively or optionally, move the sheath and ETAP catheter to the patient's other side to perform a CBM procedure on the contralateral side. This may involve retracting the sheath into the aorta, optionally removing the ETAP catheter from the sheath, introducing a guide wire into the second common carotid artery, and repeating steps for placing the ETAP catheter and ablating.
An ablation energy source (e.g., energy field generator) may be located external to the patient. Various types of ablation energy generators or supplies, such as electrical frequency generators, ultrasonic generators, microwave generators, laser consoles, and heating or cryogenic fluid supplies, may be used to provide energy to the ablation element at the distal tip of the catheter. An electrode or other energy applicator at the distal tip of the catheter should conform to the type of energy generator coupled to the catheter. The generator may include computer controls to automatically or manually adjust frequency and strength of the energy applied to the catheter, timing and period during which energy is applied, and safety limits to the application of energy. It should be understood that embodiments of energy delivery electrodes described hereinafter may be electrically connected to the generator even though the generator is not explicitly shown or described with each embodiment.
An ablated tissue lesion at or near the carotid body may be created by the application of ablation energy from an ablation element in a vicinity of a distal end of the carotid body ablation device. The ablated tissue lesion may disable the carotid body or may suppress the activity of the carotid body or interrupt conduction of afferent nerve signals from a carotid body to sympathetic nervous system. The disabling or suppression of the carotid body reduces the responsiveness of the glomus cells to changes of blood gas composition and effectively reduces activity of afferent carotid body nerves or the chemoreflex gain of the patient.
A method in accordance with a particular embodiment includes ablating at least one of a patient's carotid bodies based at least in part on identifying the patient as having a sympathetically mediated disease such as cardiac, metabolic, or pulmonary disease such as hypertension, insulin resistance, diabetes, pulmonary hypertension, drug resistant hypertension (e.g., refractory hypertension), congestive heart failure (CHF), or dyspnea from heart failure or pulmonary disease causes.
A procedure may include diagnosis, selection based on diagnosis, further screening (e.g., baseline assessment of chemosensitivity), treating a patient based at least in part on diagnosis or further screening via a chemoreceptor (e.g., carotid body) ablation procedure such as one of the embodiments disclosed. Additionally, following ablation a method of therapy may involve conducting a post-ablation assessment to compare with the baseline assessment and making decisions based on the assessment (e.g., adjustment of drug therapy, re-treat in new position or with different parameters, or ablate a second chemoreceptor if only one was previously ablated).
A carotid body ablation procedure may comprise the following steps or a combination thereof: patient sedation, locating a target peripheral chemoreceptor, visualizing a target peripheral chemoreceptor (e.g., carotid body), confirming a target ablation site is or is proximate a peripheral chemoreceptor, confirming a target ablation site is safely distant from important non-target nerve structures that are preferably protected (e.g., hypoglossal, sympathetic and vagus nerves), providing stimulation (e.g., electrical, mechanical, chemical) to a target site or target peripheral chemoreceptor prior to, during or following an ablation step, monitoring physiological responses to said stimulation, providing temporary nerve block to a target site prior to an ablation step, monitoring physiological responses to said temporary nerve block, anesthetizing a target site, protecting the brain from potential embolism, thermally protecting an arterial or venous wall (e.g., carotid artery, jugular vein) or a medial aspect of an intercarotid septum or non-target nerve structures, ablating a target site (e.g., peripheral chemoreceptor), monitoring ablation parameters (e.g., temperature, pressure, duration, blood flow in a carotid artery), monitoring physiological responses during ablation and arresting ablation if unsafe or unwanted physiological responses occur before collateral nerve injury becomes permanent, confirming a reduction of chemoreceptor activity (e.g., chemosensitivity, HR, blood pressure, ventilation, sympathetic nerve activity) during or following an ablation step, removing a ablation device, conducting a post-ablation assessment, repeating any steps of the chemoreceptor ablation procedure on another peripheral chemoreceptor in the patient. Patient screening, as well as post-ablation assessment may include physiological tests or gathering of information, for example, chemoreflex sensitivity, central sympathetic nerve activity, heart rate, heart rate variability, blood pressure, ventilation, production of hormones, peripheral vascular resistance, blood pH, blood PCO2, degree of hyperventilation, peak VO2, VE/VCO2 slope. Directly measured maximum oxygen uptake (more correctly pVO2 in heart failure patients) and index of respiratory efficiency VE/VCO2 slope has been shown to be a reproducible marker of exercise tolerance in heart failure and provide objective and additional information regarding a patient's clinical status and prognosis.
A method of therapy may include electrical stimulation of a target region, using a stimulation electrode, to confirm proximity to a carotid body. For example, a stimulation signal having a 1-10 milliamps (mA) pulse train at about 20 to 40 Hz with a pulse duration of 50 to 500 microseconds (μs) that produces a positive carotid body stimulation effect may indicate that the stimulation electrode is within sufficient proximity to the carotid body or nerves of the carotid body to effectively ablate it. A positive carotid body stimulation effect could be increased blood pressure, heart rate, or ventilation concomitant with application of the stimulation. These variables could be monitored, recorded, or displayed to help assess confirmation of proximity to a carotid body. A catheter-based technique, for example, may have a stimulation electrode proximal to the ablation element used for ablation. Alternatively, the ablation element itself may also be used as a stimulation electrode. Alternatively, an energy delivery element that delivers a form of ablative energy that is not electrical, such as a cryogenic ablation applicator, may be configured to also deliver an electrical stimulation signal as described earlier. Yet another alternative embodiment comprises a stimulation electrode that is distinct from an ablation element. For example, during a surgical procedure a stimulation probe can be touched to a suspected carotid body that is surgically exposed. A positive carotid body stimulation effect could confirm that the suspected structure is a carotid body and ablation can commence. Physiological monitors (e.g., heart rate monitor, blood pressure monitor, blood flow monitor, MSNA monitor) may communicate with a computerized stimulation generator, which may also be an ablation generator, to provide feedback information in response to stimulation. If a physiological response correlates to a given stimulation the computerized generator may provide an indication of a positive confirmation.
Alternatively or in addition a drug known to excite the chemo sensitive cells of the carotid body can be injected directly into the carotid artery or given systemically into patients vein or artery in order to elicit hemodynamic or respiratory response. Examples of drugs that may excite a chemoreceptor include nicotine, atropine, Doxapram, Almitrine, hyperkalemia, Theophylline, adenosine, sulfides, Lobeline, Acetylcholine, ammonium chloride, methylamine, potassium chloride, anabasine, coniine, cytosine, acetaldehyde, acetyl ester and the ethyl ether of i-methylcholine, Succinylcholine, Piperidine, monophenol ester of homo-iso-muscarine and acetylsalicylamides, alkaloids of veratrum, sodium citrate, adenosinetriphosphate, dinitrophenol, caffeine, theobromine, ethyl alcohol, ether, chloroform, phenyldiguanide, sparteine, coramine(nikethamide), metrazol(pentylenetetrazol), iodomethylate of dimethylaminomethylenedioxypropane, ethyltrimethylammoniumpropane, trimethylammonium, hydroxytryptamine, papaverine, neostigmine, acidity.
A method of therapy may further comprise applying electrical or chemical stimulation to the target area or systemically following ablation to confirm a successful ablation. Heart rate, blood pressure or ventilation may be monitored for change or compared to the reaction to stimulation prior to ablation to assess if the targeted carotid body was ablated. Post-ablation stimulation may be done with the same apparatus used to conduct the pre-ablation stimulation. Physiological monitors (e.g., heart rate monitor, blood pressure monitor, blood flow monitor, MSNA monitor) may communicate with a computerized stimulation generator, which may also be an ablation generator, to provide feedback information in response to stimulation. If a physiological response correlated to a given stimulation is reduced following an ablation compared to a physiological response prior to the ablation, the computerized generator may provide an indication ablation efficacy or possible procedural suggestions such as repeating an ablation, adjusting ablation parameters, changing position, ablating another carotid body or chemosensor, or concluding the procedure.
The devices described herein may also be used to temporarily stun or block nerve conduction via electrical neural blockade. A temporary nerve block may be used to confirm position of an ablation element prior to ablation. For example, a temporary nerve block may block nerves associated with a carotid body, which may result in a physiological effect to confirm the position may be effective for ablation. Furthermore, a temporary nerve block may block important non-target nerves such as vagal, hypoglossal or sympathetic nerves that are preferably avoided, resulting in a physiological effect (e.g., physiological effects may be noted by observing the patient's eyes, tongue, throat or facial muscles or by monitoring patient's heart rate and respiration). This may alert a user that the position is not in a safe location. Likewise absence of a physiological effect indicating a temporary nerve block of such important non-target nerves in combination with a physiological effect indicating a temporary nerve block of carotid body nerves may indicate that the position is in a safe and effective location for carotid body ablation.
Important nerves may be located in proximity of the target site and may be inadvertently and unintentionally injured. Neural stimulation or blockade can help identify that these nerves are in the ablation zone before the irreversible ablation occurs. These nerves may include the following:
Vagus Nerve Bundle—The vagus is a bundle of nerves that carry separate functions, for example a) branchial motor neurons (efferent special visceral) which are responsible for swallowing and phonation and are distributed to pharyngeal branches, superior and inferior laryngeal nerves; b) visceral motor (efferent general visceral) which are responsible for involuntary muscle and gland control and are distributed to cardiac, pulmonary, esophageal, gastric, celiac plexuses, and muscles, and glands of the digestive tract; c) visceral sensory (afferent general visceral) which are responsible for visceral sensibility and are distributed to cervical, thoracic, abdominal fibers, and carotid and aortic bodies; d) visceral sensory (afferent special visceral) which are responsible for taste and are distributed to epiglottis and taste buds; e) general sensory (afferent general somatic) which are responsible for cutaneous sensibility and are distributed to auricular branch to external ear, meatus, and tympanic membrane. Dysfunction of the vagus may be detected by a) vocal changes caused by nerve damage (damage to the vagus nerve can result in trouble with moving the tongue while speaking, or hoarseness of the voice if the branch leading to the larynx is damaged); b) dysphagia due to nerve damage (the vagus nerve controls many muscles in the palate and tongue which, if damaged, can cause difficulty with swallowing); c) changes in gag reflex (the gag reflex is controlled by the vagus nerve and damage may cause this reflex to be lost, which can increase the risk of choking on saliva or food); d) hearing loss due to nerve damage (hearing loss may result from damage to the branch of the vagus nerve that innervates the concha of the ear): e) cardiovascular problems due to nerve damage (damage to the vagus nerve can cause cardiovascular side effects including irregular heartbeat and arrhythmia); or f) digestive problems due to nerve damage (damage to the vagus nerve may cause problems with contractions of the stomach and intestines, which can lead to constipation).
Superior Laryngeal Nerve—the superior laryngeal nerve is a branch of the vagus nerve bundle. Functionally, the superior laryngeal nerve function can be divided into sensory and motor components. The sensory function provides a variety of afferent signals from the supraglottic larynx. Motor function involves motor supply to the ipsilateral cricothyroid muscle. Contraction of the cricothyroid muscle tilts the cricoid lamina backward at the cricothyroid joint causing lengthening, tensing and adduction of vocal folds causing an increase in the pitch of the voice generated. Dysfunction of the superior laryngeal nerve may change the pitch of the voice and causes an inability to make explosive sounds. A bilateral palsy presents as a tiring and hoarse voice.
Cervical Sympathetic Nerve—The cervical sympathetic nerve provides efferent fibers to the internal carotid nerve, external carotid nerve, and superior cervical cardiac nerve. It provides sympathetic innervation of the head, neck and heart. Organs that are innervated by the sympathetic nerves include eyes, lacrimal gland and salivary glands. Dysfunction of the cervical sympathetic nerve includes Homer's syndrome, which is very identifiable and may include the following reactions: a) partial ptosis (drooping of the upper eyelid from loss of sympathetic innervation to the superior tarsal muscle, also known as Müller's muscle); b) upside-down ptosis (slight elevation of the lower lid); c) anhidrosis (decreased sweating on the affected side of the face); d) miosis (small pupils, for example small relative to what would be expected by the amount of light the pupil receives or constriction of the pupil to a diameter of less than two millimeters, or asymmetric, one-sided constriction of pupils); e) enophthalmos (an impression that an eye is sunken in); f) loss of ciliospinal reflex (the ciliospinal reflex, or pupillary-skin reflex, consists of dilation of the ipsilateral pupil in response to pain applied to the neck, face, and upper trunk. If the right side of the neck is subjected to a painful stimulus, the right pupil dilates about 1-2 mm from baseline. This reflex is absent in Horner's syndrome and lesions involving the cervical sympathetic fibers.)
An optional step of visualizing internal structures (e.g., carotid body or surrounding structures) may be accomplished using one or more non-invasive imaging modalities, for example fluoroscopy, radiography, arteriography, computer tomography (CT), computer tomography angiography with contrast (CTA), magnetic resonance imaging (MRI), or sonography, or minimally invasive techniques (e.g., IVUS, endoscopy, optical coherence tomography, ICE). A visualization step may be performed as part of a patient assessment, prior to an ablation procedure to assess risks and location of anatomical structures, during an ablation procedure to help guide an ablation device, or following an ablation procedure to assess outcome (e.g., efficacy of the ablation). Visualization may be used to: (a) locate a carotid body, (b) locate important non-target nerve structures that may be adversely affected, or (c) locate, identify and measure arterial plaque.
Endovascular (for example transfemoral) arteriography of the common carotid and then selective arteriography of the internal and external carotids may be used to determine a position of a catheter tip at a carotid bifurcation. Additionally, ostia of glomic arteries (these arteries may be up to 4 mm long and arise directly from the main parent artery) can be identified by dragging the dye injection catheter and releasing small amounts (“puffs”) of dye. If a glomic artery is identified it can be cannulated by a guide wire and possibly further cannulated by small caliber catheter. Direct injection of dye into glomic arteries can further assist the interventionalist in the ablation procedure. It is appreciated that the feeding glomic arteries are small and microcatheters may be needed to cannulate them.
Alternatively, ultrasound visualization may allow a physician to see the carotid arteries and even the carotid body. Another method for visualization may consist of inserting a small needle (e.g., 22 Gauge) with sonography or computer tomography (CT) guidance into or toward the carotid body. A wire or needle can be left in place as a fiducial guide, or contrast can be injected into the carotid body. Runoff of contrast to the jugular vein may confirm that the target is achieved.
Computer Tomography (CT) and computer tomography angiography (CTA) may also be used to aid in identifying a carotid body. Such imaging could be used to help guide an ablation device to a carotid body.
Ultrasound visualization (e.g., sonography) is an ultrasound-based imaging technique used for visualizing subcutaneous body structures including blood vessels and surrounding tissues. Doppler ultrasound uses reflected ultrasound waves to identify and display blood flow through a vessel. Operators typically use a hand-held transducer/transceiver placed directly on a patient's skin and aimed inward directing ultrasound waves through the patient's tissue. Ultrasound may be used to visualize a patient's carotid body to help guide an ablation device. Ultrasound can be also used to identify atherosclerotic plaque in the carotid arteries and avoid disturbing and dislodging such plaque.
Visualization and navigation steps may comprise multiple imaging modalities (e.g., CT, fluoroscopy, ultrasound) superimposed digitally to use as a map for instrument positioning. Superimposing borders of great vessels such as carotid arteries can be done to combine images.
Responses to stimulation at different coordinate points can be stored digitally as a 3-dimensional or 2-dimensional orthogonal plane map. Such an electric map of the carotid bifurcation showing points, or point coordinates that are electrically excitable such as baroreceptors, baroreceptor nerves, chemoreceptors and chemoreceptor nerves can be superimposed with an image (e.g., CT, fluoroscopy, ultrasound) of vessels. This can be used to guide the procedure, and identify target areas and areas to avoid.
In addition, as noted above, it should be understood that a device providing therapy can also be used to locate a carotid body as well as to provide various stimuli (electrical, chemical, other) to test a baseline response of the carotid body chemoreflex (CBC) or carotid sinus baroreflex (CSB) and measure changes in these responses after therapy or a need for additional therapy to achieve the desired physiological and clinical effects.
In an embodiment, a procedure may comprise assessing a patient to be a plausible candidate for carotid body ablation. Such assessment may involve diagnosing a patient with a sympathetically mediated disease (e.g., MSNA microneurography, measure of cataclomines in blood or urine, heart rate, or low/high frequency analysis of heart rate variability may be used to assess sympathetic tone). Patient assessment may further comprise other patient selection criteria, for example indices of high carotid body activity (i.e. carotid body hypersensitivity or hyperactivity) such as a combination of hyperventilation and hypocarbia at rest, high carotid body nerve activity (e.g., measured directly), incidence of periodic breathing, dyspnea, central sleep apnea elevated brain natriuretic peptide, low exercise capacity, having cardiac resynchronization therapy, atrial fibrillation, ejection fraction of the left ventricle, using beta blockers or ACE inhibitors.
Patient selection may involve non-invasive visualization such as CTA or MRI to identify location of a carotid body. For example, if the patient does not have at least one carotid body that is sufficiently within an intercarotid septum the patient may be ineligible for a CBM procedure that targets an intercarotid septum. Another example of patient selection using non-invasive visualization may involve excluding patients having large risk of dislodging plaque into an internal carotid artery.
Patient assessment may further involve selecting patients with high peripheral chemosensitivity (e.g., a respiratory response to hypoxia normalized to the desaturation of oxygen greater than or equal to about 0.7 l/min/min SpO2), which may involve characterizing a patient's chemoreceptor sensitivity, reaction to temporarily blocking carotid body chemoreflex, or a combination thereof.
Although there are many ways to measure chemosensitivity they can be divided into (a) active provoked response and (b) passive monitoring. Active tests can be done by inducing intermittent hypoxia (such as by taking breaths of nitrogen or CO2 or combination of gases) or by rebreathing air into and from a 4 to 10 liter bag. For example: a hypersensitive response to a short period of hypoxia measured by increase of respiration or heart rate may provide an indication for therapy. Ablation or significant reduction of such response could be indicative of a successful procedure. Also, electrical stimulation, drugs and chemicals (e.g., dopamine, lidocaine) exist that can block or excite a carotid body when applied locally or intravenously.
The location and baseline function of the desired area of therapy (including the carotid and aortic chemoreceptors and baroreceptors and corresponding nerves) may be determined prior to therapy by application of stimuli to the carotid body or other organs that would result in an expected change in a physiological or clinical event such as an increase or decrease in SNS activity, heart rate or blood pressure. These stimuli may also be applied after the therapy to determine the effect of the therapy or to indicate the need for repeated application of therapy to achieve the desired physiological or clinical effect(s). The stimuli can be either electrical or chemical in nature and can be delivered via the same or another catheter or can be delivered separately (such as injection of a substance through a peripheral IV to affect the CBC that would be expected to cause a predicted physiological or clinical effect).
A baseline stimulation test may be performed to select patients that may benefit from a carotid body ablation procedure. For example, patients with a high peripheral chemosensitivity gain (e.g., greater than or equal to about two standard deviations above an age matched general population chemosensitivity, or alternatively above a threshold peripheral chemosensitivity to hypoxia of 0.5 or 0.7 ml/min % O2) may be selected for a carotid body ablation procedure. A prospective patient suffering from a cardiac, metabolic, or pulmonary disease (e.g., hypertension, CHF, diabetes) may be selected. The patient may then be tested to assess a baseline peripheral chemoreceptor sensitivity (e.g., minute ventilation, tidal volume, ventilator rate, heart rate, or other response to hypoxic or hypercapnic stimulus). Baseline peripheral chemosensitivity may be assessed using tests known in the art which involve inhalation of a gas mixture having reduced O2 content (e.g., pure nitrogen, CO2, helium, or breathable gas mixture with reduced amounts of O2 and increased amounts of CO2) or rebreathing of gas into a bag. Concurrently, the patient's minute ventilation or initial sympathetically mediated physiologic parameter such as minute ventilation or HR may be measured and compared to the O2 level in the gas mixture. Tests like this may elucidate indices called chemoreceptor setpoint and gain. These indices are indicative of chemoreceptor sensitivity. If the patient's chemosensitivity is not assessed to be high (e.g., less than about two standard deviations of an age matched general population chemosensitivity, or other relevant numeric threshold) then the patient may not be a suitable candidate for a carotid body ablation procedure. Conversely, a patient with chemoreceptor hypersensitivity (e.g., greater than or equal to about two standard deviations above normal) may proceed to have a carotid body ablation procedure. Following a carotid body ablation procedure the patient's chemosensitivity may optionally be tested again and compared to the results of the baseline test. The second test or the comparison of the second test to the baseline test may provide an indication of treatment success or suggest further intervention such as possible adjustment of drug therapy, repeating the carotid body ablation procedure with adjusted parameters or location, or performing another carotid body ablation procedure on a second carotid body if the first procedure only targeted one carotid body. It may be expected that a patient having chemoreceptor hypersensitivity or hyperactivity may return to about a normal sensitivity or activity following a successful carotid body ablation procedure.
In an alternative protocol for selecting a patient for a carotid body ablation, patients with high peripheral chemosensitivity or carotid body activity (e.g., ≧about 2 standard deviations above normal) alone or in combination with other clinical and physiologic parameters may be particularly good candidates for carotid body ablation therapy if they further respond positively to temporary blocking of carotid body activity. A prospective patient suffering from a cardiac, metabolic, or pulmonary disease may be selected to be tested to assess the baseline peripheral chemoreceptor sensitivity. A patient without high chemosensitivity may not be a plausible candidate for a carotid body ablation procedure. A patient with a high chemosensitivity may be given a further assessment that temporarily blocks a carotid body chemoreflex. For example a temporary block may be done chemically, for example using a chemical such as intravascular dopamine or dopamine-like substances, intravascular alpha-2 adrenergic agonists, oxygen, in general alkalinity, or local or topical application of atropine externally to the carotid body. A patient having a negative response to the temporary carotid body block test (e.g., sympathetic activity index such as respiration, HR, heart rate variability, MSNA, vasculature resistance, etc. is not significantly altered) may be a less plausible candidate for a carotid body ablation procedure. Conversely, a patient with a positive response to the temporary carotid body block test (e.g., respiration or index of sympathetic activity is altered significantly) may be a more plausible candidate for a carotid body ablation procedure.
There are a number of potential ways to conduct a temporary carotid body block test. Hyperoxia (e.g., higher than normal levels of PO2) for example, is known to partially block (about a 50%) or reduce afferent sympathetic response of the carotid body. Thus, if a patient's sympathetic activity indexes (e.g., respiration, HR, HRV, MSNA) are reduced by hyperoxia (e.g., inhalation of higher than normal levels of O2) for 3-5 minutes, the patient may be a particularly plausible candidate for carotid body ablation therapy. A sympathetic response to hyperoxia may be achieved by monitoring minute ventilation (e.g., reduction of more than 20-30% may indicate that a patient has carotid body hyperactivity). To evoke a carotid body response, or compare it to carotid body response in normoxic conditions, CO2 above 3-4% may be mixed into the gas inspired by the patient (nitrogen content will be reduced) or another pharmacological agent can be used to invoke a carotid body response to a change of CO2, pH or glucose concentration. Alternatively, “withdrawal of hypoxic drive” to rest state respiration in response to breathing a high concentration O2 gas mix may be used for a simpler test.
An alternative temporary carotid body block test involves administering a sub-anesthetic amount of anesthetic gas halothane, which is known to temporarily suppress carotid body activity. Furthermore, there are injectable substances such as dopamine that are known to reversibly inhibit the carotid body. However, any substance, whether inhaled, injected or delivered by another manner to the carotid body that affects carotid body function in the desired fashion may be used.
Another alternative temporary carotid body block test involves application of cryogenic energy to a carotid body (i.e. removal of heat). For example, a carotid body or its nerves may be cooled to a temperature range between about −15° C. to 0° C. to temporarily reduce nerve activity or blood flow to and from a carotid body thus reducing or inhibiting carotid body activity.
An alternative method of assessing a temporary carotid body block test may involve measuring pulse pressure. Noninvasive pulse pressure devices such as Nexfin (made by BMEYE, based in Amsterdam, The Netherlands) can be used to track beat-to-beat changes in peripheral vascular resistance. Patients with hypertension or CHF may be sensitive to temporary carotid body blocking with oxygen or injection of a blocking drug. The peripheral vascular resistance of such patients may be expected to reduce substantially in response to carotid body blocking. Such patients may be good candidates for carotid body ablation therapy.
Yet another index that may be used to assess if a patient may be a good candidate for carotid body ablation therapy is increase of baroreflex, or baroreceptor sensitivity, in response to carotid body blocking. It is known that hyperactive chemosensitivity suppresses baroreflex. If carotid body activity is temporarily reduced the carotid sinus baroreflex (baroreflex sensitivity (BRS) or baroreflex gain) may be expected to increase. Baroreflex contributes a beneficial parasympathetic component to autonomic drive. Depressed BRS is often associated with an increased incidence of death and malignant ventricular arrhythmias. Baroreflex is measurable using standard non-invasive methods. One example is spectral analysis of RR interval of ECG and systolic blood pressure variability in both the high- and low-frequency bands. An increase of baroreflex gain in response to temporary blockade of carotid body can be a good indication for permanent therapy. Baroreflex sensitivity can also be measured by heart rate response to a transient rise in blood pressure induced by injection of phenylephrine.
An alternative method involves using an index of glucose tolerance to select patients and determine the results of carotid body blocking or removal in diabetic patients. There is evidence that carotid body hyperactivity contributes to progression and severity of metabolic disease.
In general, a beneficial response can be seen as an increase of parasympathetic or decrease of sympathetic tone in the overall autonomic balance. For example, Power Spectral Density (PSD) curves of respiration or HR can be calculated using nonparametric Fast Fourier Transform algorithm (FFT). FFT parameters can be set to 256-64 k buffer size, Hamming window, 50% overlap, 0 to 0.5 or 0.1 to 1.0 Hz range. HR and respiratory signals can be analyzed for the same periods of time corresponding to (1) normal unblocked carotid body breathing and (2) breathing with blocked carotid body.
Power can be calculated for three bands: the very low frequency (VLF) between 0 and 0.04 Hz, the low frequency band (LF) between 0.04-0.15 Hz and the high frequency band (HF) between 0.15-0.4 Hz. Cumulative spectral power in LF and HF bands may also be calculated; normalized to total power between 0.04 and 0.4 Hz (TF=HF+LF) and expressed as % of total. Natural breathing rate of CHF patient, for example, can be rather high, in the 0.3-0.4 Hz range.
The VLF band may be assumed to reflect periodic breathing frequency (typically 0.016 Hz) that can be present in CHF patients. It can be excluded from the HF/LF power ratio calculations.
The powers of the LF and HF oscillations characterizing heart rate variability (HRV) appear to reflect, in their reciprocal relationship, changes in the state of the sympathovagal (sympathetic to parasympathetic) balance occurring during numerous physiological and pathophysiological conditions. Thus, increase of HF contribution in particular can be considered a positive response to carotid body blocking.
Another alternative method of assessing carotid body activity comprises nuclear medicine scanning, for example with ocreotide, somatostatin analogues, or other substances produced or bound by the carotid body.
Furthermore, artificially increasing blood flow may reduce carotid body activation. Conversely artificially reducing blood flow may stimulate carotid body activation. This may be achieved with drugs know in the art to alter blood flow.
There is a considerable amount of scientific evidence to demonstrate that hypertrophy of a carotid body often accompanies disease. A hypertrophied (i.e. enlarged) carotid body may further contribute to the disease. Thus identification of patients with enlarged carotid bodies may be instrumental in determining candidates for therapy. Imaging of a carotid body may be accomplished by angiography performed with radiographic, computer tomography, or magnetic resonance imaging.
It should be understood that the available measurements are not limited to those described above. It may be possible to use any single or a combination of measurements that reflect any clinical or physiological parameter effected or changed by either increases or decreases in carotid body function to evaluate the baseline state, or change in state, of a patient's chemosensitivity.
There is a considerable amount of scientific evidence to demonstrate that hypertrophy of a carotid body often accompanies disease. A hypertrophied or enlarged carotid body may further contribute to the disease. Thus identification of patients with enlarged carotid bodies may be instrumental in determining candidates for therapy.
Further, it is possible that although patients do not meet a preselected clinical or physiological definition of high peripheral chemosensitivity (e.g., greater than or equal to about two standard deviations above normal), administration of a substance that suppresses peripheral chemosensitivity may be an alternative method of identifying a patient who is a candidate for the proposed therapy. These patients may have a different physiology or co-morbid disease state that, in concert with a higher than normal peripheral chemosensitivity (e.g., greater than or equal to normal and less than or equal to about 2 standard deviations above normal), may still allow the patient to benefit from carotid body ablation. The proposed therapy may be at least in part based on an objective that carotid body ablation will result in a clinically significant or clinically beneficial change in the patient's physiological or clinical course. It is reasonable to believe that if the desired clinical or physiological changes occur even in the absence of meeting the predefined screening criteria, then therapy could be performed.
Ablation of a target ablation site (e.g., peripheral chemoreceptor, carotid body) via an endovascular approach in patients having sympathetically mediated disease and augmented chemoreflex (e.g., high afferent nerve signaling from a carotid body to the central nervous system as in some cases indicated by high peripheral chemosensitivity) has been conceived to reduce peripheral chemosensitivity and reduce afferent signaling from peripheral chemoreceptors to the central nervous system. The expected reduction of chemoreflex activity and sensitivity to hypoxia and other stimuli such as blood flow, blood CO2, glucose concentration or blood pH can directly reduce afferent signals from chemoreceptors and produce at least one beneficial effect such as the reduction of central sympathetic activation, reduction of the sensation of breathlessness (dyspnea), vasodilation, increase of exercise capacity, reduction of blood pressure, reduction of sodium and water retention, redistribution of blood volume to skeletal muscle, reduction of insulin resistance, reduction of hyperventilation, reduction of tachypnea, reduction of hypocapnia, increase of baroreflex and barosensitivity of baroreceptors, increase of vagal tone, or improve symptoms of a sympathetically mediated disease and may ultimately slow down the disease progression and extend life. It is understood that a sympathetically mediated disease that may be treated with carotid body ablation may comprise elevated sympathetic tone, an elevated sympathetic/parasympathetic activity ratio, autonomic imbalance primarily attributable to central sympathetic tone being abnormally or undesirably high, or heightened sympathetic tone at least partially attributable to afferent excitation traceable to hypersensitivity or hyperactivity of a peripheral chemoreceptor (e.g., carotid body). In some important clinical cases where baseline hypocapnia or tachypnea is present, reduction of hyperventilation and breathing rate may be expected. It is understood that hyperventilation in the context herein means respiration in excess of metabolic needs on the individual that generally leads to slight but significant hypocapnea (blood CO2 partial pressure below normal of approximately 40 mmHg, for example in the range of 33 to 38 mmHg).
Patients having CHF or hypertension concurrent with heightened peripheral chemoreflex activity and sensitivity often react as if their system was hypercapnic even if it is not. The reaction is to hyperventilate, a maladaptive attempt to rid the system of CO2, thus overcompensating and creating a hypocapnic and alkalotic system. Some researchers attribute this hypersensitivity/hyperactivity of the carotid body to the direct effect of catecholamines, hormones circulating in excessive quantities in the blood stream of CHF patients. The procedure may be particularly useful to treat such patients who are hypocapnic and possibly alkalotic resulting from high tonic output from carotid bodies. Such patients are particularly predisposed to periodic breathing and central apnea hypopnea type events that cause arousal, disrupt sleep, cause intermittent hypoxia and are by themselves detrimental and difficult to treat.
It is appreciated that periodic breathing of Cheyne Stokes pattern occurs in patients during sleep, exercise and even at rest as a combination of central hypersensitivity to CO2, peripheral chemosensitivity to O2 and CO2 and prolonged circulatory delay. All these parameters are often present in CHF patients that are at high risk of death. Thus, patients with hypocapnea, CHF, high chemosensitivity and prolonged circulatory delay, and specifically ones that exhibit periodic breathing at rest or during exercise or induced by hypoxia are likely beneficiaries of the proposed therapy.
Hyperventilation is defined as breathing in excess of a person's metabolic need at a given time and level of activity. Hyperventilation is more specifically defined as minute ventilation in excess of that needed to remove CO2 from blood in order to maintain blood CO2 in the normal range (e.g., around 40 mmHg partial pressure). For example, patients with arterial blood PCO2 in the range of 32-37 mmHg can be considered hypocapnic and in hyperventilation.
For the purpose of this disclosure hyperventilation is equivalent to abnormally low levels of carbon dioxide in the blood (e.g., hypocapnia, hypocapnea, or hypocarbia) caused by overbreathing. Hyperventilation is the opposite of hypoventilation (e.g., underventilation) that often occurs in patients with lung disease and results in high levels of carbon dioxide in the blood (e.g., hypercapnia or hypercarbia).
A low partial pressure of carbon dioxide in the blood causes alkalosis, because CO2 is acidic in solution and reduced CO2 makes blood pH more basic, leading to lowered plasma calcium ions and nerve and muscle excitability. This condition is undesirable in cardiac patients since it can increase probability of cardiac arrhythmias.
Alkalemia may be defined as abnormal alkalinity, or increased pH of the blood. Respiratory alkalosis is a state due to excess loss of carbon dioxide from the body, usually as a result of hyperventilation. Compensated alkalosis is a form in which compensatory mechanisms have returned the pH toward normal. For example, compensation can be achieved by increased excretion of bicarbonate by the kidneys.
Compensated alkalosis at rest can become uncompensated during exercise or as a result of other changes of metabolic balance. Thus the invented method is applicable to treatment of both uncompensated and compensated respiratory alkalosis.
Tachypnea means rapid breathing. For the purpose of this disclosure a breathing rate of about 6 to 16 breaths per minute at rest is considered normal but there is a known benefit to lower rate of breathing in cardiac patients. Reduction of tachypnea can be expected to reduce respiratory dead space, increase breathing efficiency, and increase parasympathetic tone.
Therapy Example: Role of Chemoreflex and Central Sympathetic Nerve Activity in CHF
Chronic elevation in sympathetic nerve activity (SNA) is associated with the development and progression of certain types of hypertension and contributes to the progression of congestive heart failure (CHF). It is also known that sympathetic excitatory cardiac, somatic, and central/peripheral chemoreceptor reflexes are abnormally enhanced in CHF and hypertension (Ponikowski, 2011 and Giannoni, 2008 and 2009).
Arterial chemoreceptors serve an important regulatory role in the control of alveolar ventilation. They also exert a powerful influence on cardiovascular function.
Delivery of Oxygen (O2) and removal of Carbon Dioxide (CO2) in the human body is regulated by two control systems, behavioral control and metabolic control. The metabolic ventilatory control system drives our breathing at rest and ensures optimal cellular homeostasis with respect to pH, partial pressure of carbon dioxide (PCO2), and partial pressure of oxygen (PO2). Metabolic control uses two sets of chemoreceptors that provide a fine-tuning function: the central chemoreceptors located in the ventral medulla of the brain and the peripheral chemoreceptors such as the aortic chemoreceptors and the carotid body chemoreceptors. The carotid body, a small, ovoid-shaped (often described as a grain of rice), and highly vascularized organ is situated in or near the carotid bifurcation, where the common carotid artery branches in to an internal carotid artery (IC) and external carotid artery (EC). The central chemoreceptors are sensitive to hypercapnia (high PCO2), and the peripheral chemoreceptors are sensitive to hypercapnia and hypoxia (low blood PO2). Under normal conditions activation of the sensors by their respective stimuli results in quick ventilatory responses aimed at the restoration of cellular homeostasis.
As early as 1868, Pflüger recognized that hypoxia stimulated ventilation, which spurred a search for the location of oxygen-sensitive receptors both within the brain and at various sites in the peripheral circulation. When Corneille Heymans and his colleagues observed that ventilation increased when the oxygen content of the blood flowing through the bifurcation of the common carotid artery was reduced (winning him the Nobel Prize in 1938), the search for the oxygen chemosensor responsible for the ventilatory response to hypoxia was largely considered accomplished.
The persistence of stimulatory effects of hypoxia in the absence (after surgical removal) of the carotid chemoreceptors (e.g., the carotid bodies) led other investigators, among them Julius Comroe, to ascribe hypoxic chemosensitivity to other sites, including both peripheral sites (e.g., aortic bodies) and central brain sites (e.g., hypothalamus, pons and rostral ventrolateral medulla). The aortic chemoreceptor, located in the aortic body, may also be an important chemoreceptor in humans with significant influence on vascular tone and cardiac function.
Carotid Body Chemoreflex:
The carotid body is a small cluster of chemoreceptors (also known as glomus cells) and supporting cells located near, and in most cases directly at, the medial side of the bifurcation (fork) of the carotid artery, which runs along both sides of the throat.
These organs act as sensors detecting different chemical stimuli from arterial blood and triggering an action potential in the afferent fibers that communicate this information to the Central Nervous System (CNS). In response, the CNS activates reflexes that control heart rate (HR), renal function and peripheral blood circulation to maintain the desired homeostasis of blood gases, O2 and CO2, and blood pH. This closed loop control function that involves blood gas chemoreceptors is known as the carotid body chemoreflex (CBC). The carotid body chemoreflex is integrated in the CNS with the carotid sinus baroreflex (CSB) that maintains arterial blood pressure. In a healthy organism these two reflexes maintain blood pressure and blood gases within a narrow physiologic range. Chemosensors and barosensors in the aortic arch contribute redundancy and fine-tuning function to the closed loop chemoreflex and baroreflex. In addition to sensing blood gasses, the carotid body is now understood to be sensitive to blood flow and velocity, blood Ph and glucose concentration. Thus it is understood that in conditions such as hypertension, CHF, insulin resistance, diabetes and other metabolic derangements afferent signaling of carotid body nerves may be elevated. Carotid body hyperactivity may be present even in the absence of detectable hypersensitivity to hypoxia and hypercapnia that are traditionally used to index carotid body function. The purpose of the proposed therapy is therefore to remove or reduce afferent neural signals from a carotid body and reduce carotid body contribution to central sympathetic tone.
The carotid sinus baroreflex is accomplished by negative feedback systems incorporating pressure sensors (e.g., baroreceptors) that sense the arterial pressure. Baroreceptors also exist in other places, such as the aorta and coronary arteries. Important arterial baroreceptors are located in the carotid sinus, a slight dilatation of the internal carotid artery at its origin from the common carotid. The carotid sinus baroreceptors are close to but anatomically separate from the carotid body. Baroreceptors respond to stretching of the arterial wall and communicate blood pressure information to CNS. Baroreceptors are distributed in the arterial walls of the carotid sinus while the chemoreceptors (glomus cells) are clustered inside the carotid body. This makes the selective reduction of chemoreflex described in this application possible while substantially sparing the baroreflex.
The carotid body exhibits great sensitivity to hypoxia (low threshold and high gain). In chronic Congestive Heart Failure (CHF), the sympathetic nervous system activation that is directed to attenuate systemic hypoperfusion at the initial phases of CHF may ultimately exacerbate the progression of cardiac dysfunction that subsequently increases the extra-cardiac abnormalities, a positive feedback cycle of progressive deterioration, a vicious cycle with ominous consequences. It was thought that much of the increase in the sympathetic nerve activity (SNA) in CHF was based on an increase of sympathetic flow at a level of the CNS and on the depression of arterial baroreflex function. In the past several years, it has been demonstrated that an increase in the activity and sensitivity of peripheral chemoreceptors (heightened chemoreflex function) also plays an important role in the enhanced SNA that occurs in CHF.
Role of Altered Chemoreflex in CHF:
As often happens in chronic disease states, chemoreflexes that are dedicated under normal conditions to maintaining homeostasis and correcting hypoxia contribute to increase the sympathetic tone in patients with CHF, even under normoxic conditions. The understanding of how abnormally enhanced sensitivity of the peripheral chemosensors, particularly the carotid body, contributes to the tonic elevation in SNA in patients with CHF has come from several studies in animals. According to one theory, the local angiotensin receptor system plays a fundamental role in the enhanced carotid body chemoreceptor sensitivity in CHF. In addition, evidence in both CHF patients and animal models of CHF has clearly established that the carotid body chemoreflex is often hypersensitive in CHF patients and contributes to the tonic elevation in sympathetic function. This derangement derives from altered function at the level of both the afferent and central pathways of the reflex arc. The mechanisms responsible for elevated afferent activity from the carotid body in CHF are not yet fully understood.
Regardless of the exact mechanism behind the carotid body hypersensitivity, the chronic sympathetic activation driven from the carotid body and other autonomic pathways leads to further deterioration of cardiac function in a positive feedback cycle. As CHF ensues, the increasing severity of cardiac dysfunction leads to progressive escalation of these alterations in carotid body chemoreflex function to further elevate sympathetic activity and cardiac deterioration. The trigger or causative factors that occur in the development of CHF that sets this cascade of events in motion and the time course over which they occur remain obscure. Ultimately, however, causative factors are tied to the cardiac pump failure and reduced cardiac output. According to one theory, within the carotid body, a progressive and chronic reduction in blood flow may be the key to initiating the maladaptive changes that occur in carotid body chemoreflex function in CHF.
There is sufficient evidence that there is increased peripheral and central chemoreflex sensitivity in heart failure, which is likely to be correlated with the severity of the disease. There is also some evidence that the central chemoreflex is modulated by the peripheral chemoreflex. According to current theories, the carotid body is the predominant contributor to the peripheral chemoreflex in humans; the aortic body having a minor contribution.
Although the mechanisms responsible for altered central chemoreflex sensitivity remain obscure, the enhanced peripheral chemoreflex sensitivity can be linked to a depression of nitric oxide production in the carotid body affecting afferent sensitivity, and an elevation of central angiotensin II affecting central integration of chemoreceptor input. The enhanced chemoreflex may be responsible, in part, for the enhanced ventilatory response to exercise, dyspnea, Cheyne-Stokes breathing, and sympathetic activation observed in chronic heart failure patients. The enhanced chemoreflex may be also responsible for hyperventilation and tachypnea (e.g., fast breathing) at rest and exercise, periodic breathing during exercise, rest and sleep, hypocapnia, vasoconstriction, reduced peripheral organ perfusion and hypertension.
Dyspnea:
Shortness of breath, or dyspnea, is a feeling of difficult or labored breathing that is out of proportion to the patient's level of physical activity. It is a symptom of a variety of different diseases or disorders and may be either acute or chronic. Dyspnea is the most common complaint of patients with cardiopulmonary diseases.
Dyspnea is believed to result from complex interactions between neural signaling, the mechanics of breathing, and the related response of the central nervous system. A specific area has been identified in the mid-brain that may influence the perception of breathing difficulties.
The experience of dyspnea depends on its severity and underlying causes. The feeling itself results from a combination of impulses relayed to the brain from nerve endings in the lungs, rib cage, chest muscles, or diaphragm, combined with the perception and interpretation of the sensation by the patient. In some cases, the patient's sensation of breathlessness is intensified by anxiety about its cause. Patients describe dyspnea variously as unpleasant shortness of breath, a feeling of increased effort or tiredness in moving the chest muscles, a panicky feeling of being smothered, or a sense of tightness or cramping in the chest wall.
The four generally accepted categories of dyspnea are based on its causes: cardiac, pulmonary, mixed cardiac or pulmonary, and non-cardiac or non-pulmonary. The most common heart and lung diseases that produce dyspnea are asthma, pneumonia, COPD, and myocardial ischemia or heart attack (myocardial infarction). Foreign body inhalation, toxic damage to the airway, pulmonary embolism, congestive heart failure (CHF), anxiety with hyperventilation (panic disorder), anemia, and physical deconditioning because of sedentary lifestyle or obesity can produce dyspnea. In most cases, dyspnea occurs with exacerbation of the underlying disease. Dyspnea also can result from weakness or injury to the chest wall or chest muscles, decreased lung elasticity, obstruction of the airway, increased oxygen demand, or poor pumping action of the heart that results in increased pressure and fluid in the lungs, such as in CHF.
Acute dyspnea with sudden onset is a frequent cause of emergency room visits. Most cases of acute dyspnea involve pulmonary (lung and breathing) disorders, cardiovascular disease, or chest trauma. Sudden onset of dyspnea (acute dyspnea) is most typically associated with narrowing of the airways or airflow obstruction (bronchospasm), blockage of one of the arteries of the lung (pulmonary embolism), acute heart failure or myocardial infarction, pneumonia, or panic disorder.
Chronic dyspnea is different. Long-standing dyspnea (chronic dyspnea) is most often a manifestation of chronic or progressive diseases of the lung or heart, such as COPD, which includes chronic bronchitis and emphysema. The treatment of chronic dyspnea depends on the underlying disorder. Asthma can often be managed with a combination of medications to reduce airway spasms and removal of allergens from the patient's environment. COPD requires medication, lifestyle changes, and long-term physical rehabilitation. Anxiety disorders are usually treated with a combination of medication and psychotherapy.
Although the exact mechanism of dyspnea in different disease states is debated, there is no doubt that the CBC plays some role in most manifestations of this symptom. Dyspnea seems to occur most commonly when afferent input from peripheral receptors is enhanced or when cortical perception of respiratory work is excessive.
Surgical Removal of the Glomus and Resection of Carotid Body Nerves:
A surgical treatment for asthma, removal of the carotid body or glomus (glomectomy), was described by Japanese surgeon Komei Nakayama in 1940s. According to Nakayama in his study of 4,000 patients with asthma, approximately 80% were cured or improved six months after surgery and 58% allegedly maintained good results after five years. Komei Nakayama performed most of his surgeries while at the Chiba University during World War II. Later in the 1950's, a U.S. surgeon, Dr. Overholt, performed the Nakayama operation on 160 U.S. patients. He felt it necessary to remove both carotid bodies in only three cases. He reported that some patients feel relief the instant when the carotid body is removed, or even earlier, when it is inactivated by an injection of procaine (Novocain). Overholt, in his paper Glomectomy for Asthma published in Chest in 1961, described surgical glomectomy the following way: “A two-inch incision is placed in a crease line in the neck, one-third of the distance between the angle of the mandible and clavicle. The platysma muscle is divided and the sternocleidomastoid retracted laterally. The dissection is carried down to the carotid sheath exposing the bifurcation. The superior thyroid artery is ligated and divided near its take-off in order to facilitate rotation of the carotid bulb and expose the medial aspect of the bifurcation. The carotid body is about the size of a grain of rice and is hidden within the adventitia of the vessel and is of the same color. The perivascular adventitia is removed from one centimeter above to one centimeter below the bifurcation. This severs connections of the nerve plexus, which surrounds the carotid body. The dissection of the adventitia is necessary in order to locate and identify the body. It is usually located exactly at the point of bifurcation on its medial aspect. Rarely, it may be found either in the center of the crotch or on the lateral wall. The small artery entering the carotid body is clamped, divided, and ligated. The upper stalk of tissue above the carotid body is then clamped, divided, and ligated.”
In January 1965, the New England Journal of Medicine published a report of 15 cases in which there had been unilateral removal of the cervical glomus (carotid body) for the treatment of bronchial asthma, with no objective beneficial effect. This effectively stopped the practice of glomectomy to treat asthma in the U.S.
Winter developed a technique for separating nerves that contribute to the carotid sinus nerves into two bundles, carotid sinus (baroreflex) and carotid body (chemoreflex), and selectively cutting out the latter. The Winter technique is based on his discovery that carotid sinus (baroreflex) nerves are predominantly on the lateral side of the carotid bifurcation and carotid body (chemoreflex) nerves are predominantly on the medial side.
Neuromodulation of the Carotid Body Chemoreflex:
Hlavaka in U.S. Patent Application Publication 2010/0070004 filed Aug. 7, 2009, describes implanting an electrical stimulator to apply electrical signals, which block or inhibit chemoreceptor signals in a patient suffering dyspnea. Hlavaka teaches that “some patients may benefit from the ability to reactivate or modulate chemoreceptor functioning.” Hlavaka focuses on neuromodulation of the chemoreflex by selectively blocking conduction of nerves that connect the carotid body to the CNS. Hlavaka describes a traditional approach of neuromodulation with an implantable electric pulse generator that does not modify or alter tissue of the carotid body or chemoreceptors.
The central chemoreceptors are located in the brain and are difficult to access. The peripheral chemoreflex is modulated primarily by carotid bodies that are more accessible. Previous clinical practice had very limited clinical success with the surgical removal of carotid bodies to treat asthma in 1940s and 1960s.
While the invention has been described in connection with what is presently considered to be the best mode, it is to be understood that the invention is not to be limited to the disclosed embodiment(s). The invention covers various modifications and equivalent arrangements included within the spirit and scope of the appended claims.
This application claims priority to the following U.S. Provisional Applications, the disclosures of which are incorporated by reference herein in their entireties: U.S. Prov. App. No. 61/667,991, filed Jul. 4, 2012; U.S. Prov. App. No. 61/667,996, filed Jul. 4, 2012; U.S. Prov. App. No. 61/667,998, filed Jul. 4, 2012; U.S. Prov. App. No. 61/682,034, filed Aug. 10, 2012; U.S. Prov. App. No. 61/768,101, filed Feb. 22, 2013; U.S. Prov. App. No. 61/791,769, filed Mar. 15, 2013; U.S. Prov. App. No. 61/791,420, filed Mar. 15, 2013; U.S. Prov. App. No. 61/792,214, filed Mar. 15, 2013; U.S. Prov. App. No. 61/792,741, filed Mar. 15, 2013; U.S. Prov. App. No. 61/793,267, filed Mar. 15, 2013; U.S. Prov. App. No. 61/794,667, filed Mar. 15, 2013; U.S. Prov. App. No. 61/810,639, filed Apr. 10, 2013; and U.S. Prov. App. No. 61/836,100, filed Jun. 17, 2013.
| Number | Date | Country | |
|---|---|---|---|
| 61667991 | Jul 2012 | US | |
| 61667996 | Jul 2012 | US | |
| 61667998 | Jul 2012 | US | |
| 61682034 | Aug 2012 | US | |
| 61768101 | Feb 2013 | US | |
| 61791769 | Mar 2013 | US | |
| 61791420 | Mar 2013 | US | |
| 61792214 | Mar 2013 | US | |
| 61792741 | Mar 2013 | US | |
| 61793267 | Mar 2013 | US | |
| 61794667 | Mar 2013 | US | |
| 61810639 | Apr 2013 | US | |
| 61836100 | Jun 2013 | US |
